The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

 

 

Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^a https://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; akulshr@emory.edu

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

 

 

Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^a https://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; akulshr@emory.edu

The ongoing COVID-19 pandemic has caused more than 1 million deaths in the United States and continues to be a major public health challenge. Cases can be asymptomatic, or symptoms can range from a mild respiratory tract infection to acute respiratory distress and multiorgan failure.

Three strategies can successfully contain the pandemic and its consequences:

• Public health measures, such as masking and social distancing
• Prophylactic vaccines to reduce transmission
• Safe and effective drugs for reducing morbidity and mortality among infected patients.

Optimal treatment strategies for patients in ambulatory and hospital settings continue to evolve as new studies are reported and new strains of the virus arise. Many medical and scientific organizations, including the National Institutes of Health (NIH) COVID-19 treatment panel,¹ Infectious Diseases Society of America (IDSA),² World Health Organization (WHO),³ and Centers for Disease Control and Prevention,⁴ provide recommendations for managing patients with ­COVID-19. Their guidance is based on the strongest research available and is updated intermittently; nevertheless, a plethora of new data emerges weekly and controversies surround several treatments.

In this article, we summarize evidence for the efficacy of treatments for COVID-19. We present data based on the severity of illness, and review special considerations for some patient populations, including pregnant women and children. We focus on practical therapeutic information for primary care providers practicing in a variety of settings, including outpatient and inpatient care.

We encourage clinicians, in planning treatment, to consider:

• The availability of medications (ie, use the COVID-19 Public Therapeutic Locator^a)
• The local COVID-19 situation
• Patient factors and preferences
• Evolving evidence regarding new and existing treatments.

When planning treatment, consider the availability of medications; the local COVID-19 situation; patient factors and preferences; and evolving evidence about treatments.

Most evidence about the treatment of COVID-19 comes from studies conducted when the Omicron variant of SARS-CoV-2 was not the dominant variant, as it is today in the United States. As such, drugs authorized or approved by the US Food and Drug Administration (FDA) to treat COVID-19 or used off-label for that purpose might not be as efficacious today as they were almost a year ago. Furthermore, many trials of potential therapies against new viral variants are ongoing; if your patient is interested in enrolling in a clinical trial of an investigational COVID-19 treatment, refer them to www.clinicaltrials.gov.

General managementof COVID-19

Patients with COVID-19 experience a range of illness severity—from asymptomatic to mild symptoms, such as fever and myalgia, to critical illness requiring intensive care (TABLE 1^1,2). Patients with COVID-19 should therefore be monitored for progression, remotely or in person, until full recovery is achieved. Key concepts of general management include:

Assess and monitor patients’ oxygenation status by pulse oximetry; identify those with low or declining oxygen saturation before further clinical deterioration.

Continue to: Consider the patient's age and general health

Consider the patient’s age and general health. Patients are at higher risk of severe disease if they are > 65 years or have an underlying comorbidity.⁴

Emphasize self-isolation and supportive care, including rest, hydration, and over-the-counter medications to relieve cough, reduce fever, and alleviate other symptoms.

Drugs: Few approved, some under study

The antiviral remdesivir is the only drug fully approved for clinical use by the FDA to treat COVID-19 in patients > 12 years.^5,6

In addition, the FDA has issued an emergency use authorization (EUA) for several monoclonal antibodies as prophylaxis and treatment: tixagevimab packaged with cilgavimab (Evusheld) is the first antibody combination for pre-exposure prophylaxis (PrEP) against COVID-19; the separately packaged injectables are recommended for patients who have a history of severe allergy that prevents them from being vaccinated or those with moderate or severe immune-compromising disorders.⁷

In the pipeline. Several treatments are being tested in clinical trials to evaluate their effectiveness and safety in combating COVID-19, including:

• Antivirals, which prevent viruses from multiplying
• Immunomodulators, which reduce the body’s immune reaction to the virus
• Antibody therapies, which are manufactured antibodies against the virus
• Anti-inflammatory drugs, which reduce systemic inflammation and prevent organ dysfunction
• Cell therapies and gene therapies, which alter the expression of cells and genes.

Continue to: Outpatient treatment

 

 

Outpatient treatment

Several assessment tools that take into account patients’ age, respiratory status, and comorbidities are available for triage of patients infected with COVID-19.⁸

Most (> 80%) patients with COVID-19 have mild infection and are safely managed as outpatients or at home.^9,10 For patients at high risk of severe disease, a few options are recommended for patients who do not require hospitalization or supplemental oxygen; guidelines on treatment of COVID-19 in outpatient settings that have been developed by various organizations are summarized in TABLE 2.^7,11-25

Antiviral drugs target different stages of the SARS-CoV-2 replication cycle. They should be used early in the course of infection, particularly in patients at high risk of severe disease.

IDSA recommends antiviral therapy with molnupiravir, nirmatrelvir + ritonavir packaged together (Paxlovid), or remdesivir.^11,12,26,27 Remdesivir requires intravenous (IV) infusion on 3 consecutive days, which can be difficult in some clinic settings.^13,28 Nirmatrelvir + ritonavir should be initiated within 5 days after symptom onset. Overall, for most patients, nirmatrelvir + ritonavir is preferred because of oral dosing and higher efficacy in comparison to other antivirals. With nirmatrelvir + ritonavir, carefully consider drug–drug interactions and the need to adjust dosing in the presence of renal disease.^28,29 There are no data on the efficacy of any combination treatments with these agents (other than co-packaged Paxlovid).

Monoclonal antibodies for COVID-19 are given primarily intravenously. They bind to the viral spike protein, thus preventing SARS-CoV-2 from attaching to and entering cells. Bamlanivimab + etesevimab and bebtelovimab are available under an EUA for outpatient treatment.^14b Treatment should be initiated as early as possible in the course of infection—ideally, within 7 to 10 days after onset of symptoms.

Continue to: Bebtelovimab was recently given...

Bebtelovimab was recently given an EUA. It is a next-generation antibody that neutralizes all currently known variants and is the most potent monoclonal antibody against the Omicron variant, including its BA.2 subvariant.³¹ However, data about its activity against the BA.2 subvariant are based on laboratory testing and have not been confirmed in clinical trials. Clinical data were similar for this agent alone and for its use in combination with other monoclonal antibodies, but those trials were conducted before the emergence of Omicron.

In your decision-making about the most appropriate therapy, consider (1) the requirement that monoclonal antibodies be administered parenterally and (2) the susceptibility of the locally predominating viral variant.

Other monoclonal antibody agents are in the investigative pipeline; however, data about them have been largely presented through press releases or selectively reported in applications to the FDA for EUA. For example, preliminary reports show cilgavimab coverage against the Omicron variant¹⁴; so far, cilgavimab is not approved for treatment but is used in combination with tixagevimab for PreP—reportedly providing as long as 12 months of protection for patients who are less likely to respond to a vaccine.³²

Corticosteroids. Guidelines recommend against dexamethasone and other systemic corticosteroids in outpatient settings. For patients with moderate-to-severe symptoms but for whom hospitalization is not possible (eg, beds are unavailable), the NIH panel recommends dexamethasone, 6 mg/d, for the duration of supplemental oxygen, not to exceed 10 days of treatment.¹

Patients who were recently discharged after COVID-19 hospitalization should not continue remdesivir, dexamethasone, or baricitinib at home, even if they still require supplemental oxygen.

Continue to: Some treatments should not be in your COVID-19 toolbox

Some treatments should not be in your COVID-19 toolbox

High-quality studies are lacking for several other potential COVID-19 treatments. Some of these drugs are under investigation, with unclear benefit and with the potential risk of toxicity—and therefore should not be prescribed or used outside a clinical trial. See “Treatments not recommended for COVID-19,” page E14. ^{1-4,15-19,33-41}

Treatment during hospitalization

The NIH COVID-19 treatment panel recommends hospitalization for patients who have any of the following findings¹:

• Oxygen saturation < 94% while breathing room air
• Respiratory rate > 30 breaths/min
• A ratio of partial pressure of arterial O₂ to fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg
• Lung infiltrates > 50%.

General guidance for the care of hospitalized patients:

• Treatments that target the virus have the greatest efficacy when given early in the course of disease.
• Anti-inflammatory and immunosuppressive agents help prevent tissue damage from a dysregulated immune system. (See TABLE 3^26,42-46)
• The NIH panel,¹ IDSA,² and WHO³ recommend against dexamethasone and other corticosteroids for hospitalized patients who do not require supplemental oxygen.
• Prone positioning distributes oxygen more evenly in the lungs and improves overall oxygenation, thus reducing the need for mechanical ventilation.

Remdesivir. Once a hospitalized patient does require supplemental oxygen, the NIH panel,¹ IDSA,² and WHO³ recommend remdesivir; however, remdesivir is not recommended in many other countries because WHO has noted its limited efficacy.⁴² Dexamethasone is recommended alone, or in combination with remdesivir for patients who require increasing supplemental oxygen and those on mechanical ventilation.

Baricitinib. For patients with rapidly increasing oxygen requirements, invasive mechanical ventilation, and systemic inflammation, baricitinib, a Janus kinase inhibitor, can be administered, in addition to dexamethasone, with or without remdesivir.⁴⁷

Continue to: Tocilizumab

Tocilizumab. A monoclonal antibody and interleukin (IL)-6 inhibitor, tocilizumab is also recommended in addition to dexamethasone, with or without remdesivir.⁴⁸ Tocilizumab should be given only in combination with dexamethasone.⁴⁹ Patients should receive baricitinib or tocilizumab—not both. IDSA recommends tofacitinib, with a prophylactic dose of an anticoagulant, for patients who are hospitalized with severe COVID-19 but who are not on any form of ventilation.⁵⁰

Care of special populations

Special patient populations often seek primary care. Although many questions remain regarding the appropriate care of these populations, it is useful to summarize existing evidence and recommendations from current guidelines. 

Children. COVID-19 is generally milder in children than in adults; many infected children are asymptomatic. However, infants and children who have an underlying medical condition are at risk of severe disease, including multisystem inflammatory syndrome.⁵¹

Because patients with COVID-19 experience a range of illness severity, they should be monitored for progression, remotely or in person, until fully recovered.

The NIH panel recommends supportive care alone for most children with mild-to-moderate disease.¹ Remdesivir is recommended for hospitalized children ≥ 12 years who weigh ≥ 40 kg, have risk factors for severe disease, and have an emergent or increasing need for supplemental oxygen. Dexamethasone is recommended for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Molnupiravir is not authorized for patients < 18 years because it can impede bone and cartilage growth.

There is insufficient evidence for or against the use of monoclonal antibody products for children with COVID-19 in an ambulatory setting. For hospitalized children, there is insufficient evidence for or against use of baricitinib and tocilizumab. 

Continue to: Patients who are pregnant

Patients who are pregnant are at increased risk of severe COVID-19.^52,53 The NIH states that, in general, treatment and vaccination of pregnant patients with COVID-19 should be the same as for nonpregnant patients.¹

Pregnant subjects were excluded from several trials of COVID-19 treatments.⁵⁴ Because Janus kinase inhibitors, such as baricitinib, are associated with an increased risk of thromboembolism, they are not recommended in pregnant patients who are already at risk of thromboembolic complications. Molnupiravir is not recommended for pregnant patients because of its potential for teratogenic effects.

The Society for Maternal-Fetal Medicine states that there are no absolute contraindications to the use of monoclonal antibodies in appropriate pregnant patients with COVID-19.⁵⁵ Remdesivir has no known fetal toxicity and is recommended as a treatment that can be offered to pregnant patients. Dexamethasone can also be administered to pregnant patients who require oxygen; however, if dexamethasone is also being used to accelerate fetal lung maturity, more frequent initial dosing is needed.

Older people. COVID-19 treatments for older patients are the same as for the general adult population. However, because older people are more likely to have impaired renal function, renal function should be monitored when an older patient is being treated with COVID-19 medications that are eliminated renally (eg, remdesivir, baricitinib). Furthermore, drug–drug interactions have been reported in older patients treated with nirmatrelvir + ritonavir, primarily because of the effects of ritonavir. Review all of a patient’s medications, including over-the-counter drugs and herbal supplements, when prescribing treatment for COVID-19, and adjust the dosage by following guidance in FDA-approved prescribing information—ideally, in consultation with a pharmacist.

Immunocompromised patients. The combination product tixagevimab + cilgavimab [Evusheld] is FDA approved for COVID-19 PrEP, under an EUA, in patients who are not infected with SARS-CoV-2 who have an immune-compromising condition, who are unlikely to mount an adequate immune response to the COVID-19 vaccine, or those in whom vaccination is not recommended because of their history of a severe adverse reaction to a COVID-19 vaccine or one of its components.⁷

Continue to: Summing up

Summing up

With a growing need for effective and readily available COVID-19 treatments, there are an unprecedented number of clinical trials in process. Besides antivirals, immunomodulators, and antibody therapies, some novel mechanisms being tested include Janus kinase inhibitors, IL-6-receptor blockers, and drugs that target adult respiratory distress syndrome and cytokine release.

Guidelines recommend against using dexamethasone and other systemic corticosteroids in COVID-19 outpatient settings.

Once larger trials are completed, we can expect stronger evidence of potential treatment options and of safety and efficacy in children, pregnant women, and vulnerable populations. During the pandemic, the FDA’s EUA program has brought emerging treatments rapidly to clinicians; nevertheless, high-quality evidence, with thorough peer review, remains critical to inform COVID-19 treatment guidelines.

^a https://healthdata.gov/Health/COVID-19-PublicTherapeutic-Locator/rxn6-qnx8/data

^b Sotrovimab was effective against the Omicron variant of SARS-CoV-2—the dominant variant in early 2022— but is currently not FDA authorized in any region of the United States because of the prevalence of the Omicron BA.2 subvariant.30

CORRESPONDENCE
Ambar Kulshreshtha, MD, PhD, Department of Epidemiology, Emory Rollins School of Public Health, 4500 North Shallowford Road, Suite 134, Atlanta, GA 30338; akulshr@emory.edu

THE CASE

Louise T* is a 42-year-old woman who presented to her family medicine office for a routine annual visit. During the exam, her physician noticed bruises on Ms. T’s arms and back. Upon further inquiry, Ms. T reported that she and her husband had argued the night before the appointment. With some hesitancy, she went on to say that this was not the first time this had happened. She said that she and her husband had been arguing frequently for several years and that 6 months earlier, when he lost his job, he began hitting and pushing her.

● How would you proceed with this patient?

*The patient’s name has been changed to protect her identity.

Intimate partner violence (IPV) includes physical, sexual, or psychological aggression or stalking perpetrated by a current or former relationship partner.¹ IPV affects more than 12 million men and women living in the United States each year.² According to a national survey of IPV, approximately one-third (35.6%) of women and one-quarter (28.5%) of men living in the United States experience rape, physical violence, or stalking by an intimate partner during their lifetime.² Lifetime exposure to psychological IPV is even more prevalent, affecting nearly half of women and men (48.4% and 48.8%, respectively).²

Lifetime prevalence of any form of IPV is higher among women who identify as bisexual (59.8%) and lesbian (46.3%) compared with those who identify as heterosexual (37.2%); rates are comparable among men who identify as heterosexual (31.9%), bisexual (35.3%), and gay (35.1%).³ Preliminary data suggest that IPV may have increased in frequency and severity during the COVID-19 pandemic, particularly in the context of mandated shelter-in-place and stay-at-home orders.^4-6

IPV is associated with numerous negative health consequences. They include fear and concern for safety, mental health disorders such as posttraumatic stress disorder (PTSD), and physical health problems including physical injury, chronic pain, sleep disturbance, and frequent headaches.² IPV is also associated with a greater number of missed days from school and work and increased utilization of legal, health care, and housing services.^2,7 The overall annual cost of IPV against women is estimated at $5.8 billion, with health care costs accounting for approximately $4.1 billion.⁷ Family physicians can play an important role in curbing the devastating effects of IPV by screening patients and providing resources when needed.

Facilitate disclosure using screening tools and protocol

In Ms. T’s case, evidence of violence was clearly visible. However, not all instances of IPV leave physical marks. The US Preventive Services Task Force (USPSTF) recommends that all women of childbearing age be screened for IPV, whether or not they exhibit signs of violence.⁸ While the USPSTF has only published recommendations regarding screening women for IPV, there has been a recent push to screen all patients given that men also experience high rates of IPV.⁹

It’s helpful to ask questions such as: “Do arguments [with your partner] ever result in hitting, kicking, or pushing?” and “How often does your partner scream or curse at you?”

Utilize a brief screening tool. Directly ask patients about IPV; this can help reduce stigma, facilitate disclosure, and initiate the process of connecting patients to potentially lifesaving resources. The USPSTF lists several brief screening measures that can be used in primary care settings to assess exposure to IPV (TABLE 1^8,10-17). The brevity of these screening tools makes them well suited for busy physicians; cutoff scores facilitate the rapid identification of positive screens. While the USPSTF has not made specific recommendations regarding a screening interval, many studies examining the utility of these measures have reported on annual screenings.⁸ While there is limited evidence that brief screening alone leads to reductions in IPV,⁸ discussing IPV in a supportive and empathic manner and connecting patients to resources, such as supportive counseling, does have an important benefit: It can reduce symptoms of depression.¹⁸

Continue to: Screen patients in private; this protocol can help

Screen patients in private; this protocol can help. Given the sensitive nature of IPV and the potential danger some patients may be facing, it is important to screen patients in a safe and supportive environment.^19,20 Screening should be conducted by the primary care clinician, ideally when a trusting relationship already has been formed. Screen patients only when they are alone in a private room; avoid screening in public spaces such as clinic waiting rooms or in the vicinity of the patient’s partner or children older than age 2 years.^19,20

To provide all patients with an opportunity for private and safe IPV screening, clinics are encouraged to develop a clinic-wide policy whereby patients are routinely escorted to the exam room alone for the first portion of their visit, after which any accompanying individuals may be invited to join.²¹ Clinic staff can inform patients and accompanying individuals of this policy when they first arrive. Once in the exam room, and before the screening process begins, clearly state reporting requirements to ensure that patients can make an informed decision about whether to disclose IPV.¹⁹

Set a receptive tone. The manner in which clinicians discuss IPV with their patients is just as important as the setting. Demonstrating sensitivity and genuine concern for the patient’s safety and well-being may increase the patient’s comfort level throughout the screening process and may facilitate disclosures of IPV.^19,22 When screening patients for IPV, sit face to face rather than standing over them, maintain warm and open body language, and speak in a soft tone of voice.²²

Patients may feel more comfortable if you ask screening questions in a straightforward, nonjudgmental manner, as this helps to normalize the screening experience. We also recommend using behaviorally specific language (eg, “Do arguments [with your partner] ever result in hitting, kicking, or pushing?”¹⁶ or “How often does your partner scream or curse at you?”),¹³ as some patients who have experienced IPV will not label their experiences as “abuse” or “violence.” Not every patient who experiences IPV will be ready to disclose these events; however, maintaining a positive and supportive relationship during routine IPV screening and throughout the remainder of the medical visit may help facilitate future disclosures if, and when, a patient is ready to seek support.¹⁹

CRITICAL INTERVENTION ELEMENTS: EMPATHY AND SAFETY

A physician’s response to an IPV disclosure can have a lasting impact on the patient. We encourage family physicians to respond to IPV disclosures with empathy. Maintain eye contact and warm body language, validate the patient’s experiences (“I am sorry this happened to you,” “that must have been terrifying”), tell the patient that the violence was not their fault, and thank the patient for disclosing.²³

Continue to: Assess patient safety

Assess patient safety. Another critical component of intervention is to assess the patient’s safety and engage in safety planning. If the patient agrees to this next step, you may wish to provide a warm handoff to a trained social worker, nurse, or psychologist in the clinic who can spend more time covering this information with the patient. Some key components of a safety assessment include determining whether the violence or threat of violence is ongoing and identifying who lives in the home (eg, the partner, children, and any pets). You and the patient can also discuss red flags that would indicate elevated risk. You should discuss red flags that are unique to the patient’s relationship as well as common factors that have been found to heighten risk for IPV (eg, partner engaging in heavy alcohol use).¹

With the patient’s permission, collaboratively construct a safety plan that details how the patient can stay safe on a daily basis and how to safely leave should a dangerous situation arise (TABLE 2^9,24). The interactive safety planning tool available on the National Domestic Violence Hotline’s website can be a valuable resource (www.thehotline.org/plan-for-safety/).²⁴ Finally, if a patient is experiencing mental health concerns associated with IPV (eg, PTSD, depression, substance misuse, suicidal ideation), consider a referral to a domestic violence counseling center or mental health provider.

Move at the patient’s pace. Even if patients are willing to disclose IPV, they will differ in their readiness to discuss psychoeducation, safety planning, and referrals. Similarly, even if a patient is experiencing severe violence, they may not be ready to leave the relationship. Thus, it’s important to ask the patient for permission before initiating each successive step of the follow-up intervention. You and the patient may wish to schedule additional appointments to discuss this information at a pace the patient finds appropriate.

You may need to spend some time helping the patient recognize the severity of their situation and to feel empowered to take action. In addition, offer information and resources to all patients, even those who do not disclose IPV. Some patients may want to receive this information even if they do not feel comfortable sharing their experiences during the appointment.²⁰ You can also inform patients that they are welcome to bring up issues related to IPV at any future appointments in order to leave the door open to future disclosures.

THE CASE

The physician determined that Ms. T had been experiencing physical and psychological IPV in her current relationship. After responding empathically and obtaining the patient’s consent, the physician provided a warm handoff to the psychologist in the clinic. With Ms. T’s permission, the psychologist provided psychoeducation about IPV, and they discussed Ms. T’s current situation and risk level. They determined that Ms. T was at risk for subsequent episodes of IPV and they collaborated on a safety plan, making sure to discuss contact information for local and national crisis resources.

Continue to: Ms. T saved the phone number...

Ms. T saved the phone number for her local domestic violence shelter in her phone under a false name in case her husband looked through her phone. She said she planned to work on several safety plan items when her husband was away from the house and it was safe to do so. For example, she planned to identify additional ways to exit the house in an emergency and she was going to put together a bag with a change of clothes and some money and drop it off at a trusted friend’s house.

Ms. T and the psychologist agreed to follow up with an office visit in 1 week to discuss any additional safety concerns and to determine whether Ms. T could benefit from a referral to domestic violence counseling services or mental health treatment. The psychologist provided a summary of the topics she and Ms. T had discussed to the physician. The physician scheduled a follow-up appointment with Ms. T in 3 weeks to assess her current safety, troubleshoot any difficulties in implementing her safety plan, and offer additional resources, as needed.

CORRESPONDENCE
Andrea Massa, PhD, 125 Doughty Street, Suite 300, Charleston, SC 29403; massa@musc.edu

THE CASE

Louise T* is a 42-year-old woman who presented to her family medicine office for a routine annual visit. During the exam, her physician noticed bruises on Ms. T’s arms and back. Upon further inquiry, Ms. T reported that she and her husband had argued the night before the appointment. With some hesitancy, she went on to say that this was not the first time this had happened. She said that she and her husband had been arguing frequently for several years and that 6 months earlier, when he lost his job, he began hitting and pushing her.

● How would you proceed with this patient?

*The patient’s name has been changed to protect her identity.

Intimate partner violence (IPV) includes physical, sexual, or psychological aggression or stalking perpetrated by a current or former relationship partner.¹ IPV affects more than 12 million men and women living in the United States each year.² According to a national survey of IPV, approximately one-third (35.6%) of women and one-quarter (28.5%) of men living in the United States experience rape, physical violence, or stalking by an intimate partner during their lifetime.² Lifetime exposure to psychological IPV is even more prevalent, affecting nearly half of women and men (48.4% and 48.8%, respectively).²

Lifetime prevalence of any form of IPV is higher among women who identify as bisexual (59.8%) and lesbian (46.3%) compared with those who identify as heterosexual (37.2%); rates are comparable among men who identify as heterosexual (31.9%), bisexual (35.3%), and gay (35.1%).³ Preliminary data suggest that IPV may have increased in frequency and severity during the COVID-19 pandemic, particularly in the context of mandated shelter-in-place and stay-at-home orders.^4-6

IPV is associated with numerous negative health consequences. They include fear and concern for safety, mental health disorders such as posttraumatic stress disorder (PTSD), and physical health problems including physical injury, chronic pain, sleep disturbance, and frequent headaches.² IPV is also associated with a greater number of missed days from school and work and increased utilization of legal, health care, and housing services.^2,7 The overall annual cost of IPV against women is estimated at $5.8 billion, with health care costs accounting for approximately $4.1 billion.⁷ Family physicians can play an important role in curbing the devastating effects of IPV by screening patients and providing resources when needed.

Facilitate disclosure using screening tools and protocol

In Ms. T’s case, evidence of violence was clearly visible. However, not all instances of IPV leave physical marks. The US Preventive Services Task Force (USPSTF) recommends that all women of childbearing age be screened for IPV, whether or not they exhibit signs of violence.⁸ While the USPSTF has only published recommendations regarding screening women for IPV, there has been a recent push to screen all patients given that men also experience high rates of IPV.⁹

It’s helpful to ask questions such as: “Do arguments [with your partner] ever result in hitting, kicking, or pushing?” and “How often does your partner scream or curse at you?”

Utilize a brief screening tool. Directly ask patients about IPV; this can help reduce stigma, facilitate disclosure, and initiate the process of connecting patients to potentially lifesaving resources. The USPSTF lists several brief screening measures that can be used in primary care settings to assess exposure to IPV (TABLE 1^8,10-17). The brevity of these screening tools makes them well suited for busy physicians; cutoff scores facilitate the rapid identification of positive screens. While the USPSTF has not made specific recommendations regarding a screening interval, many studies examining the utility of these measures have reported on annual screenings.⁸ While there is limited evidence that brief screening alone leads to reductions in IPV,⁸ discussing IPV in a supportive and empathic manner and connecting patients to resources, such as supportive counseling, does have an important benefit: It can reduce symptoms of depression.¹⁸

Continue to: Screen patients in private; this protocol can help

Screen patients in private; this protocol can help. Given the sensitive nature of IPV and the potential danger some patients may be facing, it is important to screen patients in a safe and supportive environment.^19,20 Screening should be conducted by the primary care clinician, ideally when a trusting relationship already has been formed. Screen patients only when they are alone in a private room; avoid screening in public spaces such as clinic waiting rooms or in the vicinity of the patient’s partner or children older than age 2 years.^19,20

To provide all patients with an opportunity for private and safe IPV screening, clinics are encouraged to develop a clinic-wide policy whereby patients are routinely escorted to the exam room alone for the first portion of their visit, after which any accompanying individuals may be invited to join.²¹ Clinic staff can inform patients and accompanying individuals of this policy when they first arrive. Once in the exam room, and before the screening process begins, clearly state reporting requirements to ensure that patients can make an informed decision about whether to disclose IPV.¹⁹

Set a receptive tone. The manner in which clinicians discuss IPV with their patients is just as important as the setting. Demonstrating sensitivity and genuine concern for the patient’s safety and well-being may increase the patient’s comfort level throughout the screening process and may facilitate disclosures of IPV.^19,22 When screening patients for IPV, sit face to face rather than standing over them, maintain warm and open body language, and speak in a soft tone of voice.²²

Patients may feel more comfortable if you ask screening questions in a straightforward, nonjudgmental manner, as this helps to normalize the screening experience. We also recommend using behaviorally specific language (eg, “Do arguments [with your partner] ever result in hitting, kicking, or pushing?”¹⁶ or “How often does your partner scream or curse at you?”),¹³ as some patients who have experienced IPV will not label their experiences as “abuse” or “violence.” Not every patient who experiences IPV will be ready to disclose these events; however, maintaining a positive and supportive relationship during routine IPV screening and throughout the remainder of the medical visit may help facilitate future disclosures if, and when, a patient is ready to seek support.¹⁹

CRITICAL INTERVENTION ELEMENTS: EMPATHY AND SAFETY

A physician’s response to an IPV disclosure can have a lasting impact on the patient. We encourage family physicians to respond to IPV disclosures with empathy. Maintain eye contact and warm body language, validate the patient’s experiences (“I am sorry this happened to you,” “that must have been terrifying”), tell the patient that the violence was not their fault, and thank the patient for disclosing.²³

Continue to: Assess patient safety

Assess patient safety. Another critical component of intervention is to assess the patient’s safety and engage in safety planning. If the patient agrees to this next step, you may wish to provide a warm handoff to a trained social worker, nurse, or psychologist in the clinic who can spend more time covering this information with the patient. Some key components of a safety assessment include determining whether the violence or threat of violence is ongoing and identifying who lives in the home (eg, the partner, children, and any pets). You and the patient can also discuss red flags that would indicate elevated risk. You should discuss red flags that are unique to the patient’s relationship as well as common factors that have been found to heighten risk for IPV (eg, partner engaging in heavy alcohol use).¹

With the patient’s permission, collaboratively construct a safety plan that details how the patient can stay safe on a daily basis and how to safely leave should a dangerous situation arise (TABLE 2^9,24). The interactive safety planning tool available on the National Domestic Violence Hotline’s website can be a valuable resource (www.thehotline.org/plan-for-safety/).²⁴ Finally, if a patient is experiencing mental health concerns associated with IPV (eg, PTSD, depression, substance misuse, suicidal ideation), consider a referral to a domestic violence counseling center or mental health provider.

Move at the patient’s pace. Even if patients are willing to disclose IPV, they will differ in their readiness to discuss psychoeducation, safety planning, and referrals. Similarly, even if a patient is experiencing severe violence, they may not be ready to leave the relationship. Thus, it’s important to ask the patient for permission before initiating each successive step of the follow-up intervention. You and the patient may wish to schedule additional appointments to discuss this information at a pace the patient finds appropriate.

You may need to spend some time helping the patient recognize the severity of their situation and to feel empowered to take action. In addition, offer information and resources to all patients, even those who do not disclose IPV. Some patients may want to receive this information even if they do not feel comfortable sharing their experiences during the appointment.²⁰ You can also inform patients that they are welcome to bring up issues related to IPV at any future appointments in order to leave the door open to future disclosures.

THE CASE

The physician determined that Ms. T had been experiencing physical and psychological IPV in her current relationship. After responding empathically and obtaining the patient’s consent, the physician provided a warm handoff to the psychologist in the clinic. With Ms. T’s permission, the psychologist provided psychoeducation about IPV, and they discussed Ms. T’s current situation and risk level. They determined that Ms. T was at risk for subsequent episodes of IPV and they collaborated on a safety plan, making sure to discuss contact information for local and national crisis resources.

Continue to: Ms. T saved the phone number...

Ms. T saved the phone number for her local domestic violence shelter in her phone under a false name in case her husband looked through her phone. She said she planned to work on several safety plan items when her husband was away from the house and it was safe to do so. For example, she planned to identify additional ways to exit the house in an emergency and she was going to put together a bag with a change of clothes and some money and drop it off at a trusted friend’s house.

Ms. T and the psychologist agreed to follow up with an office visit in 1 week to discuss any additional safety concerns and to determine whether Ms. T could benefit from a referral to domestic violence counseling services or mental health treatment. The psychologist provided a summary of the topics she and Ms. T had discussed to the physician. The physician scheduled a follow-up appointment with Ms. T in 3 weeks to assess her current safety, troubleshoot any difficulties in implementing her safety plan, and offer additional resources, as needed.

CORRESPONDENCE
Andrea Massa, PhD, 125 Doughty Street, Suite 300, Charleston, SC 29403; massa@musc.edu

THE CASE

Louise T* is a 42-year-old woman who presented to her family medicine office for a routine annual visit. During the exam, her physician noticed bruises on Ms. T’s arms and back. Upon further inquiry, Ms. T reported that she and her husband had argued the night before the appointment. With some hesitancy, she went on to say that this was not the first time this had happened. She said that she and her husband had been arguing frequently for several years and that 6 months earlier, when he lost his job, he began hitting and pushing her.

● How would you proceed with this patient?

*The patient’s name has been changed to protect her identity.

Intimate partner violence (IPV) includes physical, sexual, or psychological aggression or stalking perpetrated by a current or former relationship partner.¹ IPV affects more than 12 million men and women living in the United States each year.² According to a national survey of IPV, approximately one-third (35.6%) of women and one-quarter (28.5%) of men living in the United States experience rape, physical violence, or stalking by an intimate partner during their lifetime.² Lifetime exposure to psychological IPV is even more prevalent, affecting nearly half of women and men (48.4% and 48.8%, respectively).²

Lifetime prevalence of any form of IPV is higher among women who identify as bisexual (59.8%) and lesbian (46.3%) compared with those who identify as heterosexual (37.2%); rates are comparable among men who identify as heterosexual (31.9%), bisexual (35.3%), and gay (35.1%).³ Preliminary data suggest that IPV may have increased in frequency and severity during the COVID-19 pandemic, particularly in the context of mandated shelter-in-place and stay-at-home orders.^4-6

IPV is associated with numerous negative health consequences. They include fear and concern for safety, mental health disorders such as posttraumatic stress disorder (PTSD), and physical health problems including physical injury, chronic pain, sleep disturbance, and frequent headaches.² IPV is also associated with a greater number of missed days from school and work and increased utilization of legal, health care, and housing services.^2,7 The overall annual cost of IPV against women is estimated at $5.8 billion, with health care costs accounting for approximately $4.1 billion.⁷ Family physicians can play an important role in curbing the devastating effects of IPV by screening patients and providing resources when needed.

Facilitate disclosure using screening tools and protocol

In Ms. T’s case, evidence of violence was clearly visible. However, not all instances of IPV leave physical marks. The US Preventive Services Task Force (USPSTF) recommends that all women of childbearing age be screened for IPV, whether or not they exhibit signs of violence.⁸ While the USPSTF has only published recommendations regarding screening women for IPV, there has been a recent push to screen all patients given that men also experience high rates of IPV.⁹

It’s helpful to ask questions such as: “Do arguments [with your partner] ever result in hitting, kicking, or pushing?” and “How often does your partner scream or curse at you?”

Utilize a brief screening tool. Directly ask patients about IPV; this can help reduce stigma, facilitate disclosure, and initiate the process of connecting patients to potentially lifesaving resources. The USPSTF lists several brief screening measures that can be used in primary care settings to assess exposure to IPV (TABLE 1^8,10-17). The brevity of these screening tools makes them well suited for busy physicians; cutoff scores facilitate the rapid identification of positive screens. While the USPSTF has not made specific recommendations regarding a screening interval, many studies examining the utility of these measures have reported on annual screenings.⁸ While there is limited evidence that brief screening alone leads to reductions in IPV,⁸ discussing IPV in a supportive and empathic manner and connecting patients to resources, such as supportive counseling, does have an important benefit: It can reduce symptoms of depression.¹⁸

Continue to: Screen patients in private; this protocol can help

Screen patients in private; this protocol can help. Given the sensitive nature of IPV and the potential danger some patients may be facing, it is important to screen patients in a safe and supportive environment.^19,20 Screening should be conducted by the primary care clinician, ideally when a trusting relationship already has been formed. Screen patients only when they are alone in a private room; avoid screening in public spaces such as clinic waiting rooms or in the vicinity of the patient’s partner or children older than age 2 years.^19,20

To provide all patients with an opportunity for private and safe IPV screening, clinics are encouraged to develop a clinic-wide policy whereby patients are routinely escorted to the exam room alone for the first portion of their visit, after which any accompanying individuals may be invited to join.²¹ Clinic staff can inform patients and accompanying individuals of this policy when they first arrive. Once in the exam room, and before the screening process begins, clearly state reporting requirements to ensure that patients can make an informed decision about whether to disclose IPV.¹⁹

Set a receptive tone. The manner in which clinicians discuss IPV with their patients is just as important as the setting. Demonstrating sensitivity and genuine concern for the patient’s safety and well-being may increase the patient’s comfort level throughout the screening process and may facilitate disclosures of IPV.^19,22 When screening patients for IPV, sit face to face rather than standing over them, maintain warm and open body language, and speak in a soft tone of voice.²²

Patients may feel more comfortable if you ask screening questions in a straightforward, nonjudgmental manner, as this helps to normalize the screening experience. We also recommend using behaviorally specific language (eg, “Do arguments [with your partner] ever result in hitting, kicking, or pushing?”¹⁶ or “How often does your partner scream or curse at you?”),¹³ as some patients who have experienced IPV will not label their experiences as “abuse” or “violence.” Not every patient who experiences IPV will be ready to disclose these events; however, maintaining a positive and supportive relationship during routine IPV screening and throughout the remainder of the medical visit may help facilitate future disclosures if, and when, a patient is ready to seek support.¹⁹

CRITICAL INTERVENTION ELEMENTS: EMPATHY AND SAFETY

A physician’s response to an IPV disclosure can have a lasting impact on the patient. We encourage family physicians to respond to IPV disclosures with empathy. Maintain eye contact and warm body language, validate the patient’s experiences (“I am sorry this happened to you,” “that must have been terrifying”), tell the patient that the violence was not their fault, and thank the patient for disclosing.²³

Continue to: Assess patient safety

Assess patient safety. Another critical component of intervention is to assess the patient’s safety and engage in safety planning. If the patient agrees to this next step, you may wish to provide a warm handoff to a trained social worker, nurse, or psychologist in the clinic who can spend more time covering this information with the patient. Some key components of a safety assessment include determining whether the violence or threat of violence is ongoing and identifying who lives in the home (eg, the partner, children, and any pets). You and the patient can also discuss red flags that would indicate elevated risk. You should discuss red flags that are unique to the patient’s relationship as well as common factors that have been found to heighten risk for IPV (eg, partner engaging in heavy alcohol use).¹

With the patient’s permission, collaboratively construct a safety plan that details how the patient can stay safe on a daily basis and how to safely leave should a dangerous situation arise (TABLE 2^9,24). The interactive safety planning tool available on the National Domestic Violence Hotline’s website can be a valuable resource (www.thehotline.org/plan-for-safety/).²⁴ Finally, if a patient is experiencing mental health concerns associated with IPV (eg, PTSD, depression, substance misuse, suicidal ideation), consider a referral to a domestic violence counseling center or mental health provider.

Move at the patient’s pace. Even if patients are willing to disclose IPV, they will differ in their readiness to discuss psychoeducation, safety planning, and referrals. Similarly, even if a patient is experiencing severe violence, they may not be ready to leave the relationship. Thus, it’s important to ask the patient for permission before initiating each successive step of the follow-up intervention. You and the patient may wish to schedule additional appointments to discuss this information at a pace the patient finds appropriate.

You may need to spend some time helping the patient recognize the severity of their situation and to feel empowered to take action. In addition, offer information and resources to all patients, even those who do not disclose IPV. Some patients may want to receive this information even if they do not feel comfortable sharing their experiences during the appointment.²⁰ You can also inform patients that they are welcome to bring up issues related to IPV at any future appointments in order to leave the door open to future disclosures.

THE CASE

The physician determined that Ms. T had been experiencing physical and psychological IPV in her current relationship. After responding empathically and obtaining the patient’s consent, the physician provided a warm handoff to the psychologist in the clinic. With Ms. T’s permission, the psychologist provided psychoeducation about IPV, and they discussed Ms. T’s current situation and risk level. They determined that Ms. T was at risk for subsequent episodes of IPV and they collaborated on a safety plan, making sure to discuss contact information for local and national crisis resources.

Continue to: Ms. T saved the phone number...

Ms. T saved the phone number for her local domestic violence shelter in her phone under a false name in case her husband looked through her phone. She said she planned to work on several safety plan items when her husband was away from the house and it was safe to do so. For example, she planned to identify additional ways to exit the house in an emergency and she was going to put together a bag with a change of clothes and some money and drop it off at a trusted friend’s house.

Ms. T and the psychologist agreed to follow up with an office visit in 1 week to discuss any additional safety concerns and to determine whether Ms. T could benefit from a referral to domestic violence counseling services or mental health treatment. The psychologist provided a summary of the topics she and Ms. T had discussed to the physician. The physician scheduled a follow-up appointment with Ms. T in 3 weeks to assess her current safety, troubleshoot any difficulties in implementing her safety plan, and offer additional resources, as needed.

CORRESPONDENCE
Andrea Massa, PhD, 125 Doughty Street, Suite 300, Charleston, SC 29403; massa@musc.edu

New COVID boosters that target the fast-spreading Omicron strains of the virus are rolling out this week, with the Centers for Disease Control and Prevention recommending these bivalent mRNA shots for Americans 12 and older.

Here are answers to frequently asked questions about the shots produced by Moderna and Pfizer/BioNTech, based on information provided by the CDC and Keri Althoff, PhD, and virologist Andrew Pekosz, PhD, Johns Hopkins Bloomberg School of Public Health epidemiologists.

Question: Who is eligible for the new bivalent boosters?

Answer: The CDC greenlighted the upgraded Pfizer/BioNTech shots for Americans 12 and older and the Moderna booster for those 18 and over, if they have received a primary vaccine series or a booster at least 2 months before.

The boosters have been redesigned to protect against the predominant BA.4 and BA.5 strains of the virus. The Biden administration is making 160 million of the booster shots available free of charge through pharmacies, doctor’s offices, clinics, and state health departments.

Q: What about children under 12?

A: The new boosters are not approved for children under 12. Additional testing and trials need to be conducted for safety and effectiveness. But officials recommend that children 5 and above receive the primary vaccine series and be boosted with one shot. Children 6 months to under 5 years are not yet eligible for boosters.

Pfizer said it hopes to ask the Food and Drug Administration for authorization in 5- to 11-year-olds in October.

Q: How do the new bivalent boosters differ from previous shots?

A: The new shots use the same mRNA technology as the prior Moderna and Pfizer/BioNTech vaccines and boosters but have been upgraded to target the newer Omicron strains. The shots use mRNA created in a lab to teach our cells to produce a specific protein that triggers an immune-system response and make antibodies that help protect us from SARS-CoV-2, the virus that causes COVID.

The recipe for the new shots incorporates the so-called “spike protein” of both the original (ancestral) strain of the virus and more highly transmissible Omicron strains (BA.4, BA.5). Once your body produces these proteins, your immune system kicks into gear to mount a response.

It’s also possible – but yet to be determined – that the new bivalent boosters will offer protection against newer but less common strains known as BA.4.6 and BA.2.75.

Q: Are there any new risks or side effects associated with these boosters?

A: Health experts don’t expect to see anything beyond what has already been noted with prior mRNA vaccines, with the vast majority of recipients experiencing only mild issues such as redness from the shot, soreness, and fatigue.

Q: Do I need one of the new shots if I’ve already had past boosters or had COVID?

A: Yes. Even if you’ve been infected with COVID in the past year and/or received the prior series of primary vaccines and boosters, you should get a bivalent Omicron shot.

Doing so will give you broader immunity against COVID and also help limit the emergence of other variants. The more Americans with high immunity, the better; it makes it less likely other variants will emerge that can escape the immunity provided by vaccines and COVID infections.

Q: How long should I wait, from the time of my last shot, before getting a new booster?

A: The bivalent boosters are most effective when given after a period of time has passed between your last shot and the new one. A 2- to 3-month waiting period is the minimum, but some evidence suggests extending it out to 4-6 months might be good timing.

To determine when you should get a new booster, check out the CDC’s Stay Up to Date with COVID-19 Vaccines Including Boosters website.

Q: What if I’ve recently had COVID?

A: There are no specific rules about a waiting period after COVID infection. But if you have been infected with the virus in the last 8 weeks, you may want to wait for 8 weeks to pass before receiving the bivalent booster to allow your immune system to get greater benefit from the shot.

Q: If I never got the original vaccines, do I need to get those shots first?

A: Yes. The bivalent vaccine has a lower dose of mRNA than the vaccines used in the primary series of vaccines, rolled out in late 2020. The bivalent vaccine is authorized for use as a booster dose and not a primary vaccine series dose.

Q: Do the Omicron-specific boosters entirely replace the other boosters?

A: Yes. The new booster shots, which target the original strain and the Omicron subvariants, are now the only available boosters for people ages 12 and older. The FDA no longer authorizes the previous booster doses for people in the approved age groups.

Q: What if I received a non-mRNA vaccine produced by Novavax or Johnson & Johnson? Should I still get an mRNA booster?

A: You can mix and match COVID vaccines, and you are eligible to get the bivalent booster 8 weeks after completing the primary COVID vaccination series – whether that was two doses of mRNA or Novavax, or one shot of J&J.

Q: How effective are the new boosters?

A: Scientists don’t have complete effectiveness data from the bivalent vaccines yet. But because the new boosters contain mRNA from the Omicron and the original strains, they are believed to offer greater protection against COVID overall.

Cellular-level data support this, with studies showing the bivalent vaccines increase neutralizing antibodies to BA.4/BA.5 strains. Scientists regard these kinds of studies as surrogate stand-ins for clinical trials. But officials will be studying the effectiveness of the new boosters, examining to what degree they reduce hospitalizations and deaths.

Q: How long will the boosters’ protection last?

A: Research shows that vaccine effectiveness eventually wanes, which is why we have the boosters. Scientists will be monitoring to see how long the protection lasts from the bivalent boosters through studies of antibody levels as well as assessments of severe COVID illnesses over time, throughout the fall and winter.

Q: Is it OK to get a flu shot and a COVID booster at the same time?

A: Yes. In fact, it’s important to get a flu shot this year because some experts believe we could see overlapping COVID-influenza surges this fall – a phenomenon some have fancifully called a “twindemic.” Getting a flu shot and COVID booster – simultaneously, if possible – is particularly important if you’re in a high-risk group.

People who are susceptible to severe complications from COVID – such as older people, people with weakened immune systems, and those with chronic health conditions – are also especially vulnerable to severe influenza complications.

Q: Will a new booster mean I can stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID?

A: No. It’s still a good idea to mask up, keep your distance from others, avoid indoor spaces with people whose vaccine status is unknown, and take other precautions against COVID.

Although the new boosters are front of mind, it’s a good idea to also use other tools in the toolbox, as well, particularly if you have contact with someone who is older, immune-suppressed, or has a chronic condition that puts them at higher risk from COVID.

Keep in mind: The community risk of infection nationwide is still high today, with about 67,400 new cases and nearly 320 deaths reported each day in the United States, according to the latest CDC reports.A version of this article first appeared on WebMD.

New COVID boosters that target the fast-spreading Omicron strains of the virus are rolling out this week, with the Centers for Disease Control and Prevention recommending these bivalent mRNA shots for Americans 12 and older.

Here are answers to frequently asked questions about the shots produced by Moderna and Pfizer/BioNTech, based on information provided by the CDC and Keri Althoff, PhD, and virologist Andrew Pekosz, PhD, Johns Hopkins Bloomberg School of Public Health epidemiologists.

Question: Who is eligible for the new bivalent boosters?

Answer: The CDC greenlighted the upgraded Pfizer/BioNTech shots for Americans 12 and older and the Moderna booster for those 18 and over, if they have received a primary vaccine series or a booster at least 2 months before.

The boosters have been redesigned to protect against the predominant BA.4 and BA.5 strains of the virus. The Biden administration is making 160 million of the booster shots available free of charge through pharmacies, doctor’s offices, clinics, and state health departments.

Q: What about children under 12?

A: The new boosters are not approved for children under 12. Additional testing and trials need to be conducted for safety and effectiveness. But officials recommend that children 5 and above receive the primary vaccine series and be boosted with one shot. Children 6 months to under 5 years are not yet eligible for boosters.

Pfizer said it hopes to ask the Food and Drug Administration for authorization in 5- to 11-year-olds in October.

Q: How do the new bivalent boosters differ from previous shots?

A: The new shots use the same mRNA technology as the prior Moderna and Pfizer/BioNTech vaccines and boosters but have been upgraded to target the newer Omicron strains. The shots use mRNA created in a lab to teach our cells to produce a specific protein that triggers an immune-system response and make antibodies that help protect us from SARS-CoV-2, the virus that causes COVID.

The recipe for the new shots incorporates the so-called “spike protein” of both the original (ancestral) strain of the virus and more highly transmissible Omicron strains (BA.4, BA.5). Once your body produces these proteins, your immune system kicks into gear to mount a response.

It’s also possible – but yet to be determined – that the new bivalent boosters will offer protection against newer but less common strains known as BA.4.6 and BA.2.75.

Q: Are there any new risks or side effects associated with these boosters?

A: Health experts don’t expect to see anything beyond what has already been noted with prior mRNA vaccines, with the vast majority of recipients experiencing only mild issues such as redness from the shot, soreness, and fatigue.

Q: Do I need one of the new shots if I’ve already had past boosters or had COVID?

A: Yes. Even if you’ve been infected with COVID in the past year and/or received the prior series of primary vaccines and boosters, you should get a bivalent Omicron shot.

Doing so will give you broader immunity against COVID and also help limit the emergence of other variants. The more Americans with high immunity, the better; it makes it less likely other variants will emerge that can escape the immunity provided by vaccines and COVID infections.

Q: How long should I wait, from the time of my last shot, before getting a new booster?

A: The bivalent boosters are most effective when given after a period of time has passed between your last shot and the new one. A 2- to 3-month waiting period is the minimum, but some evidence suggests extending it out to 4-6 months might be good timing.

To determine when you should get a new booster, check out the CDC’s Stay Up to Date with COVID-19 Vaccines Including Boosters website.

Q: What if I’ve recently had COVID?

A: There are no specific rules about a waiting period after COVID infection. But if you have been infected with the virus in the last 8 weeks, you may want to wait for 8 weeks to pass before receiving the bivalent booster to allow your immune system to get greater benefit from the shot.

Q: If I never got the original vaccines, do I need to get those shots first?

A: Yes. The bivalent vaccine has a lower dose of mRNA than the vaccines used in the primary series of vaccines, rolled out in late 2020. The bivalent vaccine is authorized for use as a booster dose and not a primary vaccine series dose.

Q: Do the Omicron-specific boosters entirely replace the other boosters?

A: Yes. The new booster shots, which target the original strain and the Omicron subvariants, are now the only available boosters for people ages 12 and older. The FDA no longer authorizes the previous booster doses for people in the approved age groups.

Q: What if I received a non-mRNA vaccine produced by Novavax or Johnson & Johnson? Should I still get an mRNA booster?

A: You can mix and match COVID vaccines, and you are eligible to get the bivalent booster 8 weeks after completing the primary COVID vaccination series – whether that was two doses of mRNA or Novavax, or one shot of J&J.

Q: How effective are the new boosters?

A: Scientists don’t have complete effectiveness data from the bivalent vaccines yet. But because the new boosters contain mRNA from the Omicron and the original strains, they are believed to offer greater protection against COVID overall.

Cellular-level data support this, with studies showing the bivalent vaccines increase neutralizing antibodies to BA.4/BA.5 strains. Scientists regard these kinds of studies as surrogate stand-ins for clinical trials. But officials will be studying the effectiveness of the new boosters, examining to what degree they reduce hospitalizations and deaths.

Q: How long will the boosters’ protection last?

A: Research shows that vaccine effectiveness eventually wanes, which is why we have the boosters. Scientists will be monitoring to see how long the protection lasts from the bivalent boosters through studies of antibody levels as well as assessments of severe COVID illnesses over time, throughout the fall and winter.

Q: Is it OK to get a flu shot and a COVID booster at the same time?

A: Yes. In fact, it’s important to get a flu shot this year because some experts believe we could see overlapping COVID-influenza surges this fall – a phenomenon some have fancifully called a “twindemic.” Getting a flu shot and COVID booster – simultaneously, if possible – is particularly important if you’re in a high-risk group.

People who are susceptible to severe complications from COVID – such as older people, people with weakened immune systems, and those with chronic health conditions – are also especially vulnerable to severe influenza complications.

Q: Will a new booster mean I can stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID?

A: No. It’s still a good idea to mask up, keep your distance from others, avoid indoor spaces with people whose vaccine status is unknown, and take other precautions against COVID.

Although the new boosters are front of mind, it’s a good idea to also use other tools in the toolbox, as well, particularly if you have contact with someone who is older, immune-suppressed, or has a chronic condition that puts them at higher risk from COVID.

Keep in mind: The community risk of infection nationwide is still high today, with about 67,400 new cases and nearly 320 deaths reported each day in the United States, according to the latest CDC reports.A version of this article first appeared on WebMD.

New COVID boosters that target the fast-spreading Omicron strains of the virus are rolling out this week, with the Centers for Disease Control and Prevention recommending these bivalent mRNA shots for Americans 12 and older.

Here are answers to frequently asked questions about the shots produced by Moderna and Pfizer/BioNTech, based on information provided by the CDC and Keri Althoff, PhD, and virologist Andrew Pekosz, PhD, Johns Hopkins Bloomberg School of Public Health epidemiologists.

Question: Who is eligible for the new bivalent boosters?

Answer: The CDC greenlighted the upgraded Pfizer/BioNTech shots for Americans 12 and older and the Moderna booster for those 18 and over, if they have received a primary vaccine series or a booster at least 2 months before.

The boosters have been redesigned to protect against the predominant BA.4 and BA.5 strains of the virus. The Biden administration is making 160 million of the booster shots available free of charge through pharmacies, doctor’s offices, clinics, and state health departments.

Q: What about children under 12?

A: The new boosters are not approved for children under 12. Additional testing and trials need to be conducted for safety and effectiveness. But officials recommend that children 5 and above receive the primary vaccine series and be boosted with one shot. Children 6 months to under 5 years are not yet eligible for boosters.

Pfizer said it hopes to ask the Food and Drug Administration for authorization in 5- to 11-year-olds in October.

Q: How do the new bivalent boosters differ from previous shots?

A: The new shots use the same mRNA technology as the prior Moderna and Pfizer/BioNTech vaccines and boosters but have been upgraded to target the newer Omicron strains. The shots use mRNA created in a lab to teach our cells to produce a specific protein that triggers an immune-system response and make antibodies that help protect us from SARS-CoV-2, the virus that causes COVID.

The recipe for the new shots incorporates the so-called “spike protein” of both the original (ancestral) strain of the virus and more highly transmissible Omicron strains (BA.4, BA.5). Once your body produces these proteins, your immune system kicks into gear to mount a response.

It’s also possible – but yet to be determined – that the new bivalent boosters will offer protection against newer but less common strains known as BA.4.6 and BA.2.75.

Q: Are there any new risks or side effects associated with these boosters?

A: Health experts don’t expect to see anything beyond what has already been noted with prior mRNA vaccines, with the vast majority of recipients experiencing only mild issues such as redness from the shot, soreness, and fatigue.

Q: Do I need one of the new shots if I’ve already had past boosters or had COVID?

A: Yes. Even if you’ve been infected with COVID in the past year and/or received the prior series of primary vaccines and boosters, you should get a bivalent Omicron shot.

Doing so will give you broader immunity against COVID and also help limit the emergence of other variants. The more Americans with high immunity, the better; it makes it less likely other variants will emerge that can escape the immunity provided by vaccines and COVID infections.

Q: How long should I wait, from the time of my last shot, before getting a new booster?

A: The bivalent boosters are most effective when given after a period of time has passed between your last shot and the new one. A 2- to 3-month waiting period is the minimum, but some evidence suggests extending it out to 4-6 months might be good timing.

To determine when you should get a new booster, check out the CDC’s Stay Up to Date with COVID-19 Vaccines Including Boosters website.

Q: What if I’ve recently had COVID?

A: There are no specific rules about a waiting period after COVID infection. But if you have been infected with the virus in the last 8 weeks, you may want to wait for 8 weeks to pass before receiving the bivalent booster to allow your immune system to get greater benefit from the shot.

Q: If I never got the original vaccines, do I need to get those shots first?

A: Yes. The bivalent vaccine has a lower dose of mRNA than the vaccines used in the primary series of vaccines, rolled out in late 2020. The bivalent vaccine is authorized for use as a booster dose and not a primary vaccine series dose.

Q: Do the Omicron-specific boosters entirely replace the other boosters?

A: Yes. The new booster shots, which target the original strain and the Omicron subvariants, are now the only available boosters for people ages 12 and older. The FDA no longer authorizes the previous booster doses for people in the approved age groups.

Q: What if I received a non-mRNA vaccine produced by Novavax or Johnson & Johnson? Should I still get an mRNA booster?

A: You can mix and match COVID vaccines, and you are eligible to get the bivalent booster 8 weeks after completing the primary COVID vaccination series – whether that was two doses of mRNA or Novavax, or one shot of J&J.

Q: How effective are the new boosters?

A: Scientists don’t have complete effectiveness data from the bivalent vaccines yet. But because the new boosters contain mRNA from the Omicron and the original strains, they are believed to offer greater protection against COVID overall.

Cellular-level data support this, with studies showing the bivalent vaccines increase neutralizing antibodies to BA.4/BA.5 strains. Scientists regard these kinds of studies as surrogate stand-ins for clinical trials. But officials will be studying the effectiveness of the new boosters, examining to what degree they reduce hospitalizations and deaths.

Q: How long will the boosters’ protection last?

A: Research shows that vaccine effectiveness eventually wanes, which is why we have the boosters. Scientists will be monitoring to see how long the protection lasts from the bivalent boosters through studies of antibody levels as well as assessments of severe COVID illnesses over time, throughout the fall and winter.

Q: Is it OK to get a flu shot and a COVID booster at the same time?

A: Yes. In fact, it’s important to get a flu shot this year because some experts believe we could see overlapping COVID-influenza surges this fall – a phenomenon some have fancifully called a “twindemic.” Getting a flu shot and COVID booster – simultaneously, if possible – is particularly important if you’re in a high-risk group.

People who are susceptible to severe complications from COVID – such as older people, people with weakened immune systems, and those with chronic health conditions – are also especially vulnerable to severe influenza complications.

Q: Will a new booster mean I can stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID?

A: No. It’s still a good idea to mask up, keep your distance from others, avoid indoor spaces with people whose vaccine status is unknown, and take other precautions against COVID.

Although the new boosters are front of mind, it’s a good idea to also use other tools in the toolbox, as well, particularly if you have contact with someone who is older, immune-suppressed, or has a chronic condition that puts them at higher risk from COVID.

Keep in mind: The community risk of infection nationwide is still high today, with about 67,400 new cases and nearly 320 deaths reported each day in the United States, according to the latest CDC reports.A version of this article first appeared on WebMD.

Treatment with the humanized monoclonal antibody litifilimab for patients with systemic lupus erythematosus (SLE) led to greater improvements in joint manifestations than did placebo in an international phase 2 trial that reflects keen interest in targeting type 1 interferon and the innate immune system.

Litifilimab was associated with an approximately three-joint reduction in the number of swollen and tender joints, compared with placebo, over 24 weeks in the study, which was published  in The New England Journal of Medicine.

The study was the first part of the LILAC trial, a two-part, phase 2 study. The second part involved cutaneous lupus erythematosus (CLE) with or without systemic manifestations. Treatment led to improvements in skin disease, as measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) scores. It was published  in the New England Journal of Medicine.

The investigational drug targets blood dendritic cell antigen 2 (BDCA2). The antigen is expressed solely on plasmacytoid dendritic cells (pDCs), which accumulate in skin lesions and organs of patients with SLE. When the antibody binds to BDCA2, “the synthesis of a variety of cytokines is shut down – type 1 interferons, type 3 interferons, TNF [tumor necrosis factor], and [other cytokines and chemokines] made by the pDCs,” Richard A. Furie, MD, lead author of the article, said in an interview.

In a phase 1 trial involving patients with SLE and CLE, the drug’s biologic activity was shown by a dampened interferon signature in blood and modulated type 1 interferon-induced proteins in the skin, he and his coinvestigators noted.

Dr. Furie is chief of rheumatology at Northwell Health and professor of medicine at the Feinstein Institutes for Medical Research at Northwell and at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York.
 

Impact on the joints

The primary analysis in the SLE trial involved 102 patients who had SLE, arthritis, and active skin disease. The patients received litifilimab 450 mg or placebo, administered subcutaneously, at weeks 0, 2, 4, 8, 12, 16, and 20. The patients were required to have at least four tender joints and at least four swollen joints, and these active joints had to be those classically involved in lupus arthritis.

The mean (± standard deviation) baseline number of active joints was 19 ± 8.4 in the litifilimab group and 21.6 ± 8.5 in placebo group. From baseline to week 24, the least-squares mean (± standard deviation) change in the total number of active joints was –15.0 ± 1.2 with litifilimab and –11.6 ± 1.3 with placebo (mean difference, –3.4; 95% confidence interval, –6.7 to -0.2; P = .04).

Most of the secondary endpoints did not support the results of the primary analysis. However, improvement was seen in the SLE Responder Index (SRI-4) – a three-component global index that Dr. Furie and others developed in 2009 using data from the phase 2 SLE trial of belimumab (Benlysta).

The composite index, used in the phase 3 trial of belimumab, captures improvement in disease activity without a worsening of the condition overall or new significant disease activity in other domains. “It’s a dichotomous measure – either you’re a responder or not,” Dr. Furie said in the interview.

Response on the SRI-4 was defined as a reduction of at least 4 points from baseline in the SLEDAI-2K score (the Systemic Lupus Erythematosus Disease Activity Index), no new disease activity as measured by one score of A (severe) or more than one score of B (moderate) on the BILAG (British Isles Lupus Assessment Group) index, and no increase of 0.3 points or more on the Physician’s Global Assessment.

A total of 56% of the patients in the litifilimab group showed responses on the SRI-4 at week 24, compared with 29% in the placebo group (least-squares mean difference, 26.4%; 95% confidence interval [CI], 9.5-43.2). This is “a robust response” that is much greater than the effect size seen in the phase 3 trial of belimumab or in research on anifrolumab (Saphnelo). Both of those drugs are approved for SLE, Dr. Furie said. “We’ll need to see if it’s reproduced in phase 3.”

There’s “little question that litifilimab works for the skin,” Dr. Furie noted. In the second part of the LILAC study, which focused on CLE, litifilimab demonstrated efficacy, and the SLE trial lends more support. Among several secondary endpoints evaluating skin-related disease activity, a reduction of at least 7 points from baseline in the CLASI-A score (a clinically relevant threshold) occurred in 56% of the litifilimab group and 34% of the placebo group.

The trial was conducted at 55 centers in Asia, Europe, Latin America, and the United States. The SLE part of the study began as a dose-ranging study aimed at evaluating cutaneous lupus activity, but owing to “slow enrollment and to allow an assessment of the effect of litifilimab on arthritis in SLE,” the protocol and primary endpoint were amended before the trial data were unblinded to evaluate only the 450-mg dose among participants with active arthritis and skin disease (at least one active skin lesion), the investigators explained.

Background therapy for SLE was allowed if the therapy was initiated at least 12 weeks before randomization and if dose levels were stable through the trial period. Glucocorticoids had to be tapered to ≤ 10 mg/day according to a specified regimen.

Making progress for lupus

Jane E. Salmon, MD, director of the Lupus and APS Center of Excellence and codirector of the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery in New York, who was not involved in the research, said in an email that she is “cautiously optimistic, because in SLE, successful phase 2 trials too often are followed by unsuccessful phase 3 trials.”

Courtesy Hospital for Special Surgery

Blocking the production of type 1 interferon by pDCs implicated in SLE pathogenesis has the theoretical advantage of preserving type 1 interferon critical to protection from viruses, she noted. Herpes infections were reported among patients who received litifilimab, but rates were not increased, compared with placebo.

Diversity is an important priority in further research, Dr. Salmon said.

Daniel J. Wallace, MD, of Cedars-Sinai Medical Center in Los Angeles, similarly pointed out in an editorial that accompanied the SLE phase 2 trial that while Black patients make up one-third of the U.S. population with lupus, only about 10% of study participants whose race and ethnicity was reported were Black). (Race was not reported by sites in Europe.)

The results of the LILAC trials “encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus,” Dr. Wallace wrote. He noted that lupus has “lagged behind its rheumatic cousins,” such as rheumatoid arthritis and vasculitis, in drug development.

Developing endpoints and study designs for SLE trials has been challenging, at least partly because it is a multisystem disease, Dr. Furie said. “But we’re making progress.”

Anifrolumab, a type 1 interferon receptor monoclonal antibody that was approved for SLE in July 2021, “may have a broader effect on type 1 interferons,” he noted, while litifilimab “may have a broader effect on proinflammatory cytokines, at least those expressed by pDCs.”

Biogen, the sponsor of the LILAC trial, is currently enrolling patients in phase 3 studies – TOPAZ-1 and TOPAZ-2 – to evaluate litifilimab in SLE over a 52-week period. The company also plans to start a pivotal study of the drug in CLE later this year, according to a press release.

Six coauthors are employees of Biogen; five, including Dr. Furie, reported serving as a consultant to the company; one served on a data and safety monitoring board for Biogen; and Dr. Salmon owns stock in the company.

A version of this article first appeared on Medscape.com.

Treatment with the humanized monoclonal antibody litifilimab for patients with systemic lupus erythematosus (SLE) led to greater improvements in joint manifestations than did placebo in an international phase 2 trial that reflects keen interest in targeting type 1 interferon and the innate immune system.

Litifilimab was associated with an approximately three-joint reduction in the number of swollen and tender joints, compared with placebo, over 24 weeks in the study, which was published  in The New England Journal of Medicine.

The study was the first part of the LILAC trial, a two-part, phase 2 study. The second part involved cutaneous lupus erythematosus (CLE) with or without systemic manifestations. Treatment led to improvements in skin disease, as measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) scores. It was published  in the New England Journal of Medicine.

The investigational drug targets blood dendritic cell antigen 2 (BDCA2). The antigen is expressed solely on plasmacytoid dendritic cells (pDCs), which accumulate in skin lesions and organs of patients with SLE. When the antibody binds to BDCA2, “the synthesis of a variety of cytokines is shut down – type 1 interferons, type 3 interferons, TNF [tumor necrosis factor], and [other cytokines and chemokines] made by the pDCs,” Richard A. Furie, MD, lead author of the article, said in an interview.

In a phase 1 trial involving patients with SLE and CLE, the drug’s biologic activity was shown by a dampened interferon signature in blood and modulated type 1 interferon-induced proteins in the skin, he and his coinvestigators noted.

Dr. Furie is chief of rheumatology at Northwell Health and professor of medicine at the Feinstein Institutes for Medical Research at Northwell and at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York.
 

Impact on the joints

The primary analysis in the SLE trial involved 102 patients who had SLE, arthritis, and active skin disease. The patients received litifilimab 450 mg or placebo, administered subcutaneously, at weeks 0, 2, 4, 8, 12, 16, and 20. The patients were required to have at least four tender joints and at least four swollen joints, and these active joints had to be those classically involved in lupus arthritis.

The mean (± standard deviation) baseline number of active joints was 19 ± 8.4 in the litifilimab group and 21.6 ± 8.5 in placebo group. From baseline to week 24, the least-squares mean (± standard deviation) change in the total number of active joints was –15.0 ± 1.2 with litifilimab and –11.6 ± 1.3 with placebo (mean difference, –3.4; 95% confidence interval, –6.7 to -0.2; P = .04).

Most of the secondary endpoints did not support the results of the primary analysis. However, improvement was seen in the SLE Responder Index (SRI-4) – a three-component global index that Dr. Furie and others developed in 2009 using data from the phase 2 SLE trial of belimumab (Benlysta).

The composite index, used in the phase 3 trial of belimumab, captures improvement in disease activity without a worsening of the condition overall or new significant disease activity in other domains. “It’s a dichotomous measure – either you’re a responder or not,” Dr. Furie said in the interview.

Response on the SRI-4 was defined as a reduction of at least 4 points from baseline in the SLEDAI-2K score (the Systemic Lupus Erythematosus Disease Activity Index), no new disease activity as measured by one score of A (severe) or more than one score of B (moderate) on the BILAG (British Isles Lupus Assessment Group) index, and no increase of 0.3 points or more on the Physician’s Global Assessment.

A total of 56% of the patients in the litifilimab group showed responses on the SRI-4 at week 24, compared with 29% in the placebo group (least-squares mean difference, 26.4%; 95% confidence interval [CI], 9.5-43.2). This is “a robust response” that is much greater than the effect size seen in the phase 3 trial of belimumab or in research on anifrolumab (Saphnelo). Both of those drugs are approved for SLE, Dr. Furie said. “We’ll need to see if it’s reproduced in phase 3.”

There’s “little question that litifilimab works for the skin,” Dr. Furie noted. In the second part of the LILAC study, which focused on CLE, litifilimab demonstrated efficacy, and the SLE trial lends more support. Among several secondary endpoints evaluating skin-related disease activity, a reduction of at least 7 points from baseline in the CLASI-A score (a clinically relevant threshold) occurred in 56% of the litifilimab group and 34% of the placebo group.

The trial was conducted at 55 centers in Asia, Europe, Latin America, and the United States. The SLE part of the study began as a dose-ranging study aimed at evaluating cutaneous lupus activity, but owing to “slow enrollment and to allow an assessment of the effect of litifilimab on arthritis in SLE,” the protocol and primary endpoint were amended before the trial data were unblinded to evaluate only the 450-mg dose among participants with active arthritis and skin disease (at least one active skin lesion), the investigators explained.

Background therapy for SLE was allowed if the therapy was initiated at least 12 weeks before randomization and if dose levels were stable through the trial period. Glucocorticoids had to be tapered to ≤ 10 mg/day according to a specified regimen.

Making progress for lupus

Jane E. Salmon, MD, director of the Lupus and APS Center of Excellence and codirector of the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery in New York, who was not involved in the research, said in an email that she is “cautiously optimistic, because in SLE, successful phase 2 trials too often are followed by unsuccessful phase 3 trials.”

Courtesy Hospital for Special Surgery

Blocking the production of type 1 interferon by pDCs implicated in SLE pathogenesis has the theoretical advantage of preserving type 1 interferon critical to protection from viruses, she noted. Herpes infections were reported among patients who received litifilimab, but rates were not increased, compared with placebo.

Diversity is an important priority in further research, Dr. Salmon said.

Daniel J. Wallace, MD, of Cedars-Sinai Medical Center in Los Angeles, similarly pointed out in an editorial that accompanied the SLE phase 2 trial that while Black patients make up one-third of the U.S. population with lupus, only about 10% of study participants whose race and ethnicity was reported were Black). (Race was not reported by sites in Europe.)

The results of the LILAC trials “encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus,” Dr. Wallace wrote. He noted that lupus has “lagged behind its rheumatic cousins,” such as rheumatoid arthritis and vasculitis, in drug development.

Developing endpoints and study designs for SLE trials has been challenging, at least partly because it is a multisystem disease, Dr. Furie said. “But we’re making progress.”

Anifrolumab, a type 1 interferon receptor monoclonal antibody that was approved for SLE in July 2021, “may have a broader effect on type 1 interferons,” he noted, while litifilimab “may have a broader effect on proinflammatory cytokines, at least those expressed by pDCs.”

Biogen, the sponsor of the LILAC trial, is currently enrolling patients in phase 3 studies – TOPAZ-1 and TOPAZ-2 – to evaluate litifilimab in SLE over a 52-week period. The company also plans to start a pivotal study of the drug in CLE later this year, according to a press release.

Six coauthors are employees of Biogen; five, including Dr. Furie, reported serving as a consultant to the company; one served on a data and safety monitoring board for Biogen; and Dr. Salmon owns stock in the company.

A version of this article first appeared on Medscape.com.

Treatment with the humanized monoclonal antibody litifilimab for patients with systemic lupus erythematosus (SLE) led to greater improvements in joint manifestations than did placebo in an international phase 2 trial that reflects keen interest in targeting type 1 interferon and the innate immune system.

Litifilimab was associated with an approximately three-joint reduction in the number of swollen and tender joints, compared with placebo, over 24 weeks in the study, which was published  in The New England Journal of Medicine.

The study was the first part of the LILAC trial, a two-part, phase 2 study. The second part involved cutaneous lupus erythematosus (CLE) with or without systemic manifestations. Treatment led to improvements in skin disease, as measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) scores. It was published  in the New England Journal of Medicine.

The investigational drug targets blood dendritic cell antigen 2 (BDCA2). The antigen is expressed solely on plasmacytoid dendritic cells (pDCs), which accumulate in skin lesions and organs of patients with SLE. When the antibody binds to BDCA2, “the synthesis of a variety of cytokines is shut down – type 1 interferons, type 3 interferons, TNF [tumor necrosis factor], and [other cytokines and chemokines] made by the pDCs,” Richard A. Furie, MD, lead author of the article, said in an interview.

In a phase 1 trial involving patients with SLE and CLE, the drug’s biologic activity was shown by a dampened interferon signature in blood and modulated type 1 interferon-induced proteins in the skin, he and his coinvestigators noted.

Dr. Furie is chief of rheumatology at Northwell Health and professor of medicine at the Feinstein Institutes for Medical Research at Northwell and at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York.
 

Impact on the joints

The primary analysis in the SLE trial involved 102 patients who had SLE, arthritis, and active skin disease. The patients received litifilimab 450 mg or placebo, administered subcutaneously, at weeks 0, 2, 4, 8, 12, 16, and 20. The patients were required to have at least four tender joints and at least four swollen joints, and these active joints had to be those classically involved in lupus arthritis.

The mean (± standard deviation) baseline number of active joints was 19 ± 8.4 in the litifilimab group and 21.6 ± 8.5 in placebo group. From baseline to week 24, the least-squares mean (± standard deviation) change in the total number of active joints was –15.0 ± 1.2 with litifilimab and –11.6 ± 1.3 with placebo (mean difference, –3.4; 95% confidence interval, –6.7 to -0.2; P = .04).

Most of the secondary endpoints did not support the results of the primary analysis. However, improvement was seen in the SLE Responder Index (SRI-4) – a three-component global index that Dr. Furie and others developed in 2009 using data from the phase 2 SLE trial of belimumab (Benlysta).

The composite index, used in the phase 3 trial of belimumab, captures improvement in disease activity without a worsening of the condition overall or new significant disease activity in other domains. “It’s a dichotomous measure – either you’re a responder or not,” Dr. Furie said in the interview.

Response on the SRI-4 was defined as a reduction of at least 4 points from baseline in the SLEDAI-2K score (the Systemic Lupus Erythematosus Disease Activity Index), no new disease activity as measured by one score of A (severe) or more than one score of B (moderate) on the BILAG (British Isles Lupus Assessment Group) index, and no increase of 0.3 points or more on the Physician’s Global Assessment.

A total of 56% of the patients in the litifilimab group showed responses on the SRI-4 at week 24, compared with 29% in the placebo group (least-squares mean difference, 26.4%; 95% confidence interval [CI], 9.5-43.2). This is “a robust response” that is much greater than the effect size seen in the phase 3 trial of belimumab or in research on anifrolumab (Saphnelo). Both of those drugs are approved for SLE, Dr. Furie said. “We’ll need to see if it’s reproduced in phase 3.”

There’s “little question that litifilimab works for the skin,” Dr. Furie noted. In the second part of the LILAC study, which focused on CLE, litifilimab demonstrated efficacy, and the SLE trial lends more support. Among several secondary endpoints evaluating skin-related disease activity, a reduction of at least 7 points from baseline in the CLASI-A score (a clinically relevant threshold) occurred in 56% of the litifilimab group and 34% of the placebo group.

The trial was conducted at 55 centers in Asia, Europe, Latin America, and the United States. The SLE part of the study began as a dose-ranging study aimed at evaluating cutaneous lupus activity, but owing to “slow enrollment and to allow an assessment of the effect of litifilimab on arthritis in SLE,” the protocol and primary endpoint were amended before the trial data were unblinded to evaluate only the 450-mg dose among participants with active arthritis and skin disease (at least one active skin lesion), the investigators explained.

Background therapy for SLE was allowed if the therapy was initiated at least 12 weeks before randomization and if dose levels were stable through the trial period. Glucocorticoids had to be tapered to ≤ 10 mg/day according to a specified regimen.

Making progress for lupus

Jane E. Salmon, MD, director of the Lupus and APS Center of Excellence and codirector of the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery in New York, who was not involved in the research, said in an email that she is “cautiously optimistic, because in SLE, successful phase 2 trials too often are followed by unsuccessful phase 3 trials.”

Courtesy Hospital for Special Surgery

Blocking the production of type 1 interferon by pDCs implicated in SLE pathogenesis has the theoretical advantage of preserving type 1 interferon critical to protection from viruses, she noted. Herpes infections were reported among patients who received litifilimab, but rates were not increased, compared with placebo.

Diversity is an important priority in further research, Dr. Salmon said.

Daniel J. Wallace, MD, of Cedars-Sinai Medical Center in Los Angeles, similarly pointed out in an editorial that accompanied the SLE phase 2 trial that while Black patients make up one-third of the U.S. population with lupus, only about 10% of study participants whose race and ethnicity was reported were Black). (Race was not reported by sites in Europe.)

The results of the LILAC trials “encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus,” Dr. Wallace wrote. He noted that lupus has “lagged behind its rheumatic cousins,” such as rheumatoid arthritis and vasculitis, in drug development.

Developing endpoints and study designs for SLE trials has been challenging, at least partly because it is a multisystem disease, Dr. Furie said. “But we’re making progress.”

Anifrolumab, a type 1 interferon receptor monoclonal antibody that was approved for SLE in July 2021, “may have a broader effect on type 1 interferons,” he noted, while litifilimab “may have a broader effect on proinflammatory cytokines, at least those expressed by pDCs.”

Biogen, the sponsor of the LILAC trial, is currently enrolling patients in phase 3 studies – TOPAZ-1 and TOPAZ-2 – to evaluate litifilimab in SLE over a 52-week period. The company also plans to start a pivotal study of the drug in CLE later this year, according to a press release.

Six coauthors are employees of Biogen; five, including Dr. Furie, reported serving as a consultant to the company; one served on a data and safety monitoring board for Biogen; and Dr. Salmon owns stock in the company.

A version of this article first appeared on Medscape.com.

Chronic lack of exercise – dubbed “exercise deficiency” – is associated with cardiac atrophy, reduced cardiac output and chamber size, and diminished cardiorespiratory fitness (CRF) in a subgroup of patients with heart failure with preserved ejection fraction (HFpEF), researchers say.

Increasing the physical activity levels of these sedentary individuals could be an effective preventive strategy, particularly for those who are younger and middle-aged, they suggest.

Thinking of HFpEF as an exercise deficiency syndrome leading to a small heart “flies in the face of decades of cardiovascular teaching, because traditionally, we’ve thought of heart failure as the big floppy heart,” Andre La Gerche, MBBS, PhD, of the Baker Heart and Diabetes Institute, Melbourne, told this news organization.

“While it is true that some people with HFpEF have thick, stiff hearts, we propose that another subset has a normal heart, except it’s small because it’s been underexercised,” he said.

The article, published online  as part of a Focus Seminar series in the Journal of the American College of Cardiology, has “gone viral on social media,” Jason C. Kovacic, MBBS, PhD, of the Victor Chang Cardiac Research Institute, Darlinghurst, Australia, told this news organization.

Dr. Kovacic is a JACC section editor and the coordinating and senior author of the series, which covers other issues surrounding physical activity, both in athletes and the general public.
 

‘Coin-dropping moment’

To support their hypothesis that HFpEF is an exercise deficiency in certain patients, Dr. La Gerche and colleagues conducted a literature review that highlights the following points:

• There is a strong association between physical activity and both CRF and heart function.
• Exercise deficiency is a major risk factor for HFpEF in a subset of patients.
• Increasing physical activity is associated with greater cardiac mass, stroke volumes, cardiac output, and peak oxygen consumption.
• Physical inactivity leads to loss of heart muscle, reduced output and chamber size, and less ability to improve cardiac performance with exercise.
• Aging results in a smaller, stiffer heart; however, this effect is mitigated by regular exercise.
• Individuals who are sedentary throughout life cannot attenuate age-related reductions in heart size and have increasing chamber stiffness.

“When we explain it, it’s like a coin-dropping moment, because it’s actually a really simple concept,” Dr. La Gerche said. “A small heart has a small stroke volume. A patient with a small heart with a maximal stroke volume of 60 mL can generate a cardiac output of 9 L/min at a heart rate of 150 beats/min during exercise – an output that just isn’t enough. It’s like trying to drive a truck with a 50cc motorbike engine.”

“Plus,” Dr. La Gerche added, “exercise deficiency also sets the stage for comorbidities such as obesity, diabetes, and high blood pressure, all of which can ultimately lead to HFpEF.”

Considering HFpEF as an exercise deficiency syndrome has two clinical implications, Dr. La Gerche said. “First, it helps us understand the condition and diagnose more cases. For example, I think practitioners will start to recognize that breathlessness in some of their patients is associated with a small heart.”

“Second,” he said, “if it’s an exercise deficiency syndrome, the treatment is exercise. For most people, that means exercising regularly before the age of 60 to prevent HFpEF, because studies have found that after the age of 60, the heart is a bit fixed and harder to remodel. That doesn’t mean you shouldn’t try after 60 or that you won’t get benefit. But the real sweet spot is in middle age and younger.”
 

The bigger picture

The JACC Focus Seminar series starts with an article that underscores the benefits of regular physical activity. “The key is getting our patients to meet the guidelines: 150 to 300 minutes of moderate intensity exercise per week, or 75 to 250 minutes of vigorous activity per week,” Dr. Kovacic emphasized.

“Yes, we can give a statin to lower cholesterol. Yes, we can give a blood pressure medication to lower blood pressure. But when you prescribe exercise, you impact patients’ blood pressure, their cholesterol, their weight, their sense of well-being,” he said. “It cuts across so many different aspects of people’s lives that it’s important to underscore the value of exercise to everybody.”

That includes physicians, he affirmed. “It behooves all physicians to be leading by example. I would encourage those who are overweight or aren’t exercising as much as they should be to make the time to be healthy and to exercise. If you don’t, then bad health will force you to make the time to deal with bad health issues.”

Other articles in the series deal with the athlete’s heart. Christopher Semsarian, MBBS, PhD, MPH, University of Sydney, and colleagues discuss emerging data on hypertrophic cardiomyopathy and other genetic cardiovascular diseases, with the conclusion that it is probably okay for more athletes with these conditions to participate in recreational and competitive sports than was previously thought – another paradigm shift, according to Dr. Kovacic.

The final article addresses some of the challenges and controversies related to the athlete’s heart, including whether extreme exercise is associated with vulnerability to atrial fibrillation and other arrhythmias, and the impact of gender on the cardiac response to exercise, which can’t be determined now because of a paucity of data on women in sports.

Overall, Dr. Kovacic said, the series makes for “compelling” reading that should encourage readers to embark on their own studies to add to the data and support exercise prescription across the board.

No commercial funding or relevant conflicts of interest were reported.

A version of this article first appeared on Medscape.com.

Chronic lack of exercise – dubbed “exercise deficiency” – is associated with cardiac atrophy, reduced cardiac output and chamber size, and diminished cardiorespiratory fitness (CRF) in a subgroup of patients with heart failure with preserved ejection fraction (HFpEF), researchers say.

Increasing the physical activity levels of these sedentary individuals could be an effective preventive strategy, particularly for those who are younger and middle-aged, they suggest.

Thinking of HFpEF as an exercise deficiency syndrome leading to a small heart “flies in the face of decades of cardiovascular teaching, because traditionally, we’ve thought of heart failure as the big floppy heart,” Andre La Gerche, MBBS, PhD, of the Baker Heart and Diabetes Institute, Melbourne, told this news organization.

“While it is true that some people with HFpEF have thick, stiff hearts, we propose that another subset has a normal heart, except it’s small because it’s been underexercised,” he said.

The article, published online  as part of a Focus Seminar series in the Journal of the American College of Cardiology, has “gone viral on social media,” Jason C. Kovacic, MBBS, PhD, of the Victor Chang Cardiac Research Institute, Darlinghurst, Australia, told this news organization.

Dr. Kovacic is a JACC section editor and the coordinating and senior author of the series, which covers other issues surrounding physical activity, both in athletes and the general public.
 

‘Coin-dropping moment’

To support their hypothesis that HFpEF is an exercise deficiency in certain patients, Dr. La Gerche and colleagues conducted a literature review that highlights the following points:

• There is a strong association between physical activity and both CRF and heart function.
• Exercise deficiency is a major risk factor for HFpEF in a subset of patients.
• Increasing physical activity is associated with greater cardiac mass, stroke volumes, cardiac output, and peak oxygen consumption.
• Physical inactivity leads to loss of heart muscle, reduced output and chamber size, and less ability to improve cardiac performance with exercise.
• Aging results in a smaller, stiffer heart; however, this effect is mitigated by regular exercise.
• Individuals who are sedentary throughout life cannot attenuate age-related reductions in heart size and have increasing chamber stiffness.

“When we explain it, it’s like a coin-dropping moment, because it’s actually a really simple concept,” Dr. La Gerche said. “A small heart has a small stroke volume. A patient with a small heart with a maximal stroke volume of 60 mL can generate a cardiac output of 9 L/min at a heart rate of 150 beats/min during exercise – an output that just isn’t enough. It’s like trying to drive a truck with a 50cc motorbike engine.”

“Plus,” Dr. La Gerche added, “exercise deficiency also sets the stage for comorbidities such as obesity, diabetes, and high blood pressure, all of which can ultimately lead to HFpEF.”

Considering HFpEF as an exercise deficiency syndrome has two clinical implications, Dr. La Gerche said. “First, it helps us understand the condition and diagnose more cases. For example, I think practitioners will start to recognize that breathlessness in some of their patients is associated with a small heart.”

“Second,” he said, “if it’s an exercise deficiency syndrome, the treatment is exercise. For most people, that means exercising regularly before the age of 60 to prevent HFpEF, because studies have found that after the age of 60, the heart is a bit fixed and harder to remodel. That doesn’t mean you shouldn’t try after 60 or that you won’t get benefit. But the real sweet spot is in middle age and younger.”
 

The bigger picture

The JACC Focus Seminar series starts with an article that underscores the benefits of regular physical activity. “The key is getting our patients to meet the guidelines: 150 to 300 minutes of moderate intensity exercise per week, or 75 to 250 minutes of vigorous activity per week,” Dr. Kovacic emphasized.

“Yes, we can give a statin to lower cholesterol. Yes, we can give a blood pressure medication to lower blood pressure. But when you prescribe exercise, you impact patients’ blood pressure, their cholesterol, their weight, their sense of well-being,” he said. “It cuts across so many different aspects of people’s lives that it’s important to underscore the value of exercise to everybody.”

That includes physicians, he affirmed. “It behooves all physicians to be leading by example. I would encourage those who are overweight or aren’t exercising as much as they should be to make the time to be healthy and to exercise. If you don’t, then bad health will force you to make the time to deal with bad health issues.”

Other articles in the series deal with the athlete’s heart. Christopher Semsarian, MBBS, PhD, MPH, University of Sydney, and colleagues discuss emerging data on hypertrophic cardiomyopathy and other genetic cardiovascular diseases, with the conclusion that it is probably okay for more athletes with these conditions to participate in recreational and competitive sports than was previously thought – another paradigm shift, according to Dr. Kovacic.

The final article addresses some of the challenges and controversies related to the athlete’s heart, including whether extreme exercise is associated with vulnerability to atrial fibrillation and other arrhythmias, and the impact of gender on the cardiac response to exercise, which can’t be determined now because of a paucity of data on women in sports.

Overall, Dr. Kovacic said, the series makes for “compelling” reading that should encourage readers to embark on their own studies to add to the data and support exercise prescription across the board.

No commercial funding or relevant conflicts of interest were reported.

A version of this article first appeared on Medscape.com.

Chronic lack of exercise – dubbed “exercise deficiency” – is associated with cardiac atrophy, reduced cardiac output and chamber size, and diminished cardiorespiratory fitness (CRF) in a subgroup of patients with heart failure with preserved ejection fraction (HFpEF), researchers say.

Increasing the physical activity levels of these sedentary individuals could be an effective preventive strategy, particularly for those who are younger and middle-aged, they suggest.

Thinking of HFpEF as an exercise deficiency syndrome leading to a small heart “flies in the face of decades of cardiovascular teaching, because traditionally, we’ve thought of heart failure as the big floppy heart,” Andre La Gerche, MBBS, PhD, of the Baker Heart and Diabetes Institute, Melbourne, told this news organization.

“While it is true that some people with HFpEF have thick, stiff hearts, we propose that another subset has a normal heart, except it’s small because it’s been underexercised,” he said.

The article, published online  as part of a Focus Seminar series in the Journal of the American College of Cardiology, has “gone viral on social media,” Jason C. Kovacic, MBBS, PhD, of the Victor Chang Cardiac Research Institute, Darlinghurst, Australia, told this news organization.

Dr. Kovacic is a JACC section editor and the coordinating and senior author of the series, which covers other issues surrounding physical activity, both in athletes and the general public.
 

‘Coin-dropping moment’

To support their hypothesis that HFpEF is an exercise deficiency in certain patients, Dr. La Gerche and colleagues conducted a literature review that highlights the following points:

• There is a strong association between physical activity and both CRF and heart function.
• Exercise deficiency is a major risk factor for HFpEF in a subset of patients.
• Increasing physical activity is associated with greater cardiac mass, stroke volumes, cardiac output, and peak oxygen consumption.
• Physical inactivity leads to loss of heart muscle, reduced output and chamber size, and less ability to improve cardiac performance with exercise.
• Aging results in a smaller, stiffer heart; however, this effect is mitigated by regular exercise.
• Individuals who are sedentary throughout life cannot attenuate age-related reductions in heart size and have increasing chamber stiffness.

“When we explain it, it’s like a coin-dropping moment, because it’s actually a really simple concept,” Dr. La Gerche said. “A small heart has a small stroke volume. A patient with a small heart with a maximal stroke volume of 60 mL can generate a cardiac output of 9 L/min at a heart rate of 150 beats/min during exercise – an output that just isn’t enough. It’s like trying to drive a truck with a 50cc motorbike engine.”

“Plus,” Dr. La Gerche added, “exercise deficiency also sets the stage for comorbidities such as obesity, diabetes, and high blood pressure, all of which can ultimately lead to HFpEF.”

Considering HFpEF as an exercise deficiency syndrome has two clinical implications, Dr. La Gerche said. “First, it helps us understand the condition and diagnose more cases. For example, I think practitioners will start to recognize that breathlessness in some of their patients is associated with a small heart.”

“Second,” he said, “if it’s an exercise deficiency syndrome, the treatment is exercise. For most people, that means exercising regularly before the age of 60 to prevent HFpEF, because studies have found that after the age of 60, the heart is a bit fixed and harder to remodel. That doesn’t mean you shouldn’t try after 60 or that you won’t get benefit. But the real sweet spot is in middle age and younger.”
 

The bigger picture

The JACC Focus Seminar series starts with an article that underscores the benefits of regular physical activity. “The key is getting our patients to meet the guidelines: 150 to 300 minutes of moderate intensity exercise per week, or 75 to 250 minutes of vigorous activity per week,” Dr. Kovacic emphasized.

“Yes, we can give a statin to lower cholesterol. Yes, we can give a blood pressure medication to lower blood pressure. But when you prescribe exercise, you impact patients’ blood pressure, their cholesterol, their weight, their sense of well-being,” he said. “It cuts across so many different aspects of people’s lives that it’s important to underscore the value of exercise to everybody.”

That includes physicians, he affirmed. “It behooves all physicians to be leading by example. I would encourage those who are overweight or aren’t exercising as much as they should be to make the time to be healthy and to exercise. If you don’t, then bad health will force you to make the time to deal with bad health issues.”

Other articles in the series deal with the athlete’s heart. Christopher Semsarian, MBBS, PhD, MPH, University of Sydney, and colleagues discuss emerging data on hypertrophic cardiomyopathy and other genetic cardiovascular diseases, with the conclusion that it is probably okay for more athletes with these conditions to participate in recreational and competitive sports than was previously thought – another paradigm shift, according to Dr. Kovacic.

The final article addresses some of the challenges and controversies related to the athlete’s heart, including whether extreme exercise is associated with vulnerability to atrial fibrillation and other arrhythmias, and the impact of gender on the cardiac response to exercise, which can’t be determined now because of a paucity of data on women in sports.

Overall, Dr. Kovacic said, the series makes for “compelling” reading that should encourage readers to embark on their own studies to add to the data and support exercise prescription across the board.

No commercial funding or relevant conflicts of interest were reported.

A version of this article first appeared on Medscape.com.

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

SAN DIEGO–A cardiologist/vascular medicine specialist urged hematologist and oncologists within the US Department of Veterans Affairs system to think beyond the guidelines–at least until they’re updated–when they consider how to treat peripheral artery disease (PAD).

The 2016 American College of Cardiology/American Heart Association guidelines for PAD care are due for an update and don’t reflect recent positive research into the role that the blood thinner rivaroxaban can play in certain patients, said Geoffrey Barnes, MD, MSc, of the University of Michigan Health System, in a presentation here at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

Recent research has “really got us excited about the potential for this drug in this particular patient population,” Barnes said, although he cautioned that it’s most appropriate for patients at highest risk of PAD.

Research has found that patients with PAD are more likely to develop cancer, apparently because of common risk factors, and there’s discussion about whether they should undergo special screening. Cancer treatment may also boost the risk of PAD, according to a 2021 US study that tracked 248 patients with both breast cancer and PAD. “Of all patients, 48% were on statins and 54% were on antiplatelet therapies,” the study found, although the 2016 guidelines recommend both (statins for all patients with PAD, antiplatelets for those with symptoms).

In his presentation, Barnes noted that the 2016 guidelines specifically recommend aspirin (75-325 mg daily) or clopidogrel (75 mg) in patients with symptomatic PAD. Treatment is especially important, he said, because the risk of cardiovascular mortality in PAD is high. A 2020 study found that 9.1% of 13,885 patients died over a median 30-month follow-up.

The good news about treatment Brand said, came in a 2020 industry-funded study of patients with PAD who had undergone revascularization. Various outcomes such as amputation, heart attack, and death from cardiovascular causes—the primary efficacy outcome—were less common in subjects who took 2.5 mg twice daily of rivaroxaban plus aspirin or placebo plus aspirin (hazard ratio, 0.85, 95% CI, 0.76-0.96; P = .009). 

So who should go on rivaroxaban? As Brand noted, a 2019 study found that patients with no high-risk features didn’t benefit much in terms of risk of vascular events, but those with high-risk features did. In higher-risk patients, the study found, “rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.”

Per the study, patients at higher risk are those with heart failure, at least 2 vascular beds affected, renal insufficiency, or diabetes.

Brand supports the use of rivaroxaban in these patients. However, he cautioned colleagues not to switch out the drug with apixaban, another blood thinner. “These are not interchangeable,” he said. “You do need to stick with rivaroxaban. And you do need to remember that you’re going to use 2.5 milligrams twice a day—very different than many of the other ways we are using rivaroxaban.”

Brand discloses consulting fees (Pfizer/Bristol-Myers Squib, Janssen, Acelis Connected Health, Boston Scientific, Abbott Vascular), grant funding (Boston Scientific) and board of directors service (Anticoagulation Forum).

A new study provides yet more evidence that a significant subset of people who experience persistent fatigue and exercise intolerance following COVID-19 will meet diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Data from the prospective observational study of 42 patients with “post-COVID-19 syndrome (PCS),” including persistent fatigue and exercise intolerance, suggest that a large proportion will meet strict diagnostic criteria for ME/CFS, including the hallmark postexertional malaise (PEM). Still others may experience similar disability but lack duration and/or severity requirements for the diagnosis.

Moreover, disease severity and symptom burden were found similar in those with ME/CFS following COVID-19 and in a group of 19 age- and sex-matched individuals with ME/CFS that wasn’t associated with COVID-19.

“The major finding is that ME/CFS is indeed part of the spectrum of the post-COVID syndrome and very similar to the ME/CFS we know after other infectious triggers,” senior author Carmen Scheibenbogen, MD, acting director of the Institute for Medical Immunology at the Charité University Medicine Campus Virchow-Klinikum, Berlin, told this news organization.

Importantly, from a clinical standpoint, both diminished hand-grip strength (HGS) and orthostatic intolerance were common across all patient groups, as were several laboratory values, Claudia Kedor, MD, and colleagues at Charité report in the paper, published online in Nature Communications.

Of the 42 with PCS, including persistent fatigue and exercise intolerance lasting at least 6 months, 19 met the rigorous Canadian Consensus Criteria (CCC) for ME/CFS, established in 2003, which require PEM, along with sleep dysfunction, significant persistent fatigue, pain, and several other symptoms from neurological/cognitive, autonomic, neuroendocrine, and immune categories that persist for at least 6 months.

Of the 23 who did not meet the CCC criteria, 18 still experienced PEM but for less than the required 14 hours set by the authors based on recent data. The original CCC had suggested 24 hours as the PEM duration. Eight subjects met all the Canadian criteria except for the neurological/cognitive symptoms. None of the 42 had evidence of severe depression.

The previously widely used 1994 “Fukuda” criteria for ME/CFS are no longer recommended because they don’t require PEM, which is now considered a key symptom. The more recent 2015 Institute (now Academy) of Medicine criteria don’t define the length of PEM, the authors note in the paper.

Dr. Scheibenbogen said, “Post-COVID has a spectrum of syndromes and conditions. We see that a subset of patients have similar symptoms of ME/CFS but don’t fulfill the CCC, although they may meet less stringent criteria. We think this is of relevance for both diagnostic markers and development of therapy, because there may be different pathomechanisms between the subsets of post-COVID patients.”

She pointed to other studies from her group suggesting that inflammation is present early in post-COVID (not yet published), while in the subset that goes on to ME/CFS, autoantibodies or endothelial dysfunction play a more important role. «At the moment, it’s quite complex, and I don’t think in the end we will have just one pathomechanism. So I think we’ll need to develop various treatment strategies.”

Asked to comment on the new data, Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital, both in Boston, and editor in chief of the Harvard Health Letter, told this news organization, “This paper adds to the evidence that an illness with symptoms that meet criteria for ME/CFS can follow COVID-19 in nearly half of those patients who have lingering symptoms. This can occur even in people who initially have only mild symptoms from COVID-19, although it is more likely to happen in the people who are sickest when they first get COVID-19. And those who meet criteria for ME/CFS were seriously impaired in their ability to function, [both] at work and at home.”

But, Dr. Komaroff also cautioned, “the study does not help in determining what fraction of all people who are infected with SARS-CoV-2 go on to develop a condition like ME/CFS, nor how long that condition will last. It is crucial that we get answers to these questions, as the impact on the economy, the health care system, and the disability system could be substantial.”

He pointed to a recent report from the Brookings Institution (2022 Aug 24. “New data shows long Covid is keeping as many as 4 million people out of work” Katie Bach) “finding that “long COVID may be a major contributor to the shortage of job applicants plaguing many businesses.”
 

Biomarkers include hand-grip strength, orthostatic intolerance, lab measures

Hand-grip strength, as assessed by 10 repeat grips at maximum force and repeated after 60 minutes, were lower for all those meeting ME/CFS criteria, compared with the healthy controls. Hand-grip strength parameters were also positively correlated with laboratory hemoglobin measures in both PCS groups who did and didn’t meet the Canadian ME/CFS criteria.

A total of three patients with PCS who didn’t meet ME/CFS criteria and seven with PCS who met ME/CFS criteria had sitting blood pressures of greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic. Five patients with PCS – four who met ME/CFS criteria and one who didn’t – fulfilled criteria for postural orthostatic tachycardia syndrome. Orthostatic hypotension was diagnosed in a total of seven with PCS, including one who did not meet ME/CFS criteria and the rest who did.

Among significant laboratory findings, mannose-binding lectin deficiency, which is associated with increased infection susceptibility and found in only about 6% of historical controls, was found more frequently in both of the PCS cohorts (17% of those with ME/CFS and 23% of those without) than it has been in the past among those with ME/CFS, compared with historical controls (15%).

There was only slight elevation in C-reactive protein, the most commonly measured marker of inflammation. However, another marker indicating inflammation within the last 3-4 months, interleukin 8 assessed in erythrocytes, was above normal in 37% with PCS and ME/CFS and in 48% with PCS who did not meet the ME/CFS criteria.

Elevated antinuclear antibodies, anti–thyroid peroxidase antibodies, vitamin D deficiencies, and folic acid deficiencies were all seen in small numbers of the PCS patients. Angiotensin-converting enzyme 1 levels were below the normal range in 31% of all patients.

“We must anticipate that this pandemic has the potential to dramatically increase the number of ME/CFS patients,” Dr. Kedor and colleagues write. “At the same time, it offers the unique chance to identify ME/CFS patients in a very early stage of disease and apply interventions such as pacing and coping early with a better therapeutic prognosis. Further, it is an unprecedented opportunity to understand the underlying pathomechanism and characterize targets for specific treatment approaches.”

Dr. Scheibenbogen and Dr. Komaroff reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study provides yet more evidence that a significant subset of people who experience persistent fatigue and exercise intolerance following COVID-19 will meet diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Data from the prospective observational study of 42 patients with “post-COVID-19 syndrome (PCS),” including persistent fatigue and exercise intolerance, suggest that a large proportion will meet strict diagnostic criteria for ME/CFS, including the hallmark postexertional malaise (PEM). Still others may experience similar disability but lack duration and/or severity requirements for the diagnosis.

Moreover, disease severity and symptom burden were found similar in those with ME/CFS following COVID-19 and in a group of 19 age- and sex-matched individuals with ME/CFS that wasn’t associated with COVID-19.

“The major finding is that ME/CFS is indeed part of the spectrum of the post-COVID syndrome and very similar to the ME/CFS we know after other infectious triggers,” senior author Carmen Scheibenbogen, MD, acting director of the Institute for Medical Immunology at the Charité University Medicine Campus Virchow-Klinikum, Berlin, told this news organization.

Importantly, from a clinical standpoint, both diminished hand-grip strength (HGS) and orthostatic intolerance were common across all patient groups, as were several laboratory values, Claudia Kedor, MD, and colleagues at Charité report in the paper, published online in Nature Communications.

Of the 42 with PCS, including persistent fatigue and exercise intolerance lasting at least 6 months, 19 met the rigorous Canadian Consensus Criteria (CCC) for ME/CFS, established in 2003, which require PEM, along with sleep dysfunction, significant persistent fatigue, pain, and several other symptoms from neurological/cognitive, autonomic, neuroendocrine, and immune categories that persist for at least 6 months.

Of the 23 who did not meet the CCC criteria, 18 still experienced PEM but for less than the required 14 hours set by the authors based on recent data. The original CCC had suggested 24 hours as the PEM duration. Eight subjects met all the Canadian criteria except for the neurological/cognitive symptoms. None of the 42 had evidence of severe depression.

The previously widely used 1994 “Fukuda” criteria for ME/CFS are no longer recommended because they don’t require PEM, which is now considered a key symptom. The more recent 2015 Institute (now Academy) of Medicine criteria don’t define the length of PEM, the authors note in the paper.

Dr. Scheibenbogen said, “Post-COVID has a spectrum of syndromes and conditions. We see that a subset of patients have similar symptoms of ME/CFS but don’t fulfill the CCC, although they may meet less stringent criteria. We think this is of relevance for both diagnostic markers and development of therapy, because there may be different pathomechanisms between the subsets of post-COVID patients.”

She pointed to other studies from her group suggesting that inflammation is present early in post-COVID (not yet published), while in the subset that goes on to ME/CFS, autoantibodies or endothelial dysfunction play a more important role. «At the moment, it’s quite complex, and I don’t think in the end we will have just one pathomechanism. So I think we’ll need to develop various treatment strategies.”

Asked to comment on the new data, Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital, both in Boston, and editor in chief of the Harvard Health Letter, told this news organization, “This paper adds to the evidence that an illness with symptoms that meet criteria for ME/CFS can follow COVID-19 in nearly half of those patients who have lingering symptoms. This can occur even in people who initially have only mild symptoms from COVID-19, although it is more likely to happen in the people who are sickest when they first get COVID-19. And those who meet criteria for ME/CFS were seriously impaired in their ability to function, [both] at work and at home.”

But, Dr. Komaroff also cautioned, “the study does not help in determining what fraction of all people who are infected with SARS-CoV-2 go on to develop a condition like ME/CFS, nor how long that condition will last. It is crucial that we get answers to these questions, as the impact on the economy, the health care system, and the disability system could be substantial.”

He pointed to a recent report from the Brookings Institution (2022 Aug 24. “New data shows long Covid is keeping as many as 4 million people out of work” Katie Bach) “finding that “long COVID may be a major contributor to the shortage of job applicants plaguing many businesses.”
 

Biomarkers include hand-grip strength, orthostatic intolerance, lab measures

Hand-grip strength, as assessed by 10 repeat grips at maximum force and repeated after 60 minutes, were lower for all those meeting ME/CFS criteria, compared with the healthy controls. Hand-grip strength parameters were also positively correlated with laboratory hemoglobin measures in both PCS groups who did and didn’t meet the Canadian ME/CFS criteria.

A total of three patients with PCS who didn’t meet ME/CFS criteria and seven with PCS who met ME/CFS criteria had sitting blood pressures of greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic. Five patients with PCS – four who met ME/CFS criteria and one who didn’t – fulfilled criteria for postural orthostatic tachycardia syndrome. Orthostatic hypotension was diagnosed in a total of seven with PCS, including one who did not meet ME/CFS criteria and the rest who did.

Among significant laboratory findings, mannose-binding lectin deficiency, which is associated with increased infection susceptibility and found in only about 6% of historical controls, was found more frequently in both of the PCS cohorts (17% of those with ME/CFS and 23% of those without) than it has been in the past among those with ME/CFS, compared with historical controls (15%).

There was only slight elevation in C-reactive protein, the most commonly measured marker of inflammation. However, another marker indicating inflammation within the last 3-4 months, interleukin 8 assessed in erythrocytes, was above normal in 37% with PCS and ME/CFS and in 48% with PCS who did not meet the ME/CFS criteria.

Elevated antinuclear antibodies, anti–thyroid peroxidase antibodies, vitamin D deficiencies, and folic acid deficiencies were all seen in small numbers of the PCS patients. Angiotensin-converting enzyme 1 levels were below the normal range in 31% of all patients.

“We must anticipate that this pandemic has the potential to dramatically increase the number of ME/CFS patients,” Dr. Kedor and colleagues write. “At the same time, it offers the unique chance to identify ME/CFS patients in a very early stage of disease and apply interventions such as pacing and coping early with a better therapeutic prognosis. Further, it is an unprecedented opportunity to understand the underlying pathomechanism and characterize targets for specific treatment approaches.”

Dr. Scheibenbogen and Dr. Komaroff reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new study provides yet more evidence that a significant subset of people who experience persistent fatigue and exercise intolerance following COVID-19 will meet diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Data from the prospective observational study of 42 patients with “post-COVID-19 syndrome (PCS),” including persistent fatigue and exercise intolerance, suggest that a large proportion will meet strict diagnostic criteria for ME/CFS, including the hallmark postexertional malaise (PEM). Still others may experience similar disability but lack duration and/or severity requirements for the diagnosis.

Moreover, disease severity and symptom burden were found similar in those with ME/CFS following COVID-19 and in a group of 19 age- and sex-matched individuals with ME/CFS that wasn’t associated with COVID-19.

“The major finding is that ME/CFS is indeed part of the spectrum of the post-COVID syndrome and very similar to the ME/CFS we know after other infectious triggers,” senior author Carmen Scheibenbogen, MD, acting director of the Institute for Medical Immunology at the Charité University Medicine Campus Virchow-Klinikum, Berlin, told this news organization.

Importantly, from a clinical standpoint, both diminished hand-grip strength (HGS) and orthostatic intolerance were common across all patient groups, as were several laboratory values, Claudia Kedor, MD, and colleagues at Charité report in the paper, published online in Nature Communications.

Of the 42 with PCS, including persistent fatigue and exercise intolerance lasting at least 6 months, 19 met the rigorous Canadian Consensus Criteria (CCC) for ME/CFS, established in 2003, which require PEM, along with sleep dysfunction, significant persistent fatigue, pain, and several other symptoms from neurological/cognitive, autonomic, neuroendocrine, and immune categories that persist for at least 6 months.

Of the 23 who did not meet the CCC criteria, 18 still experienced PEM but for less than the required 14 hours set by the authors based on recent data. The original CCC had suggested 24 hours as the PEM duration. Eight subjects met all the Canadian criteria except for the neurological/cognitive symptoms. None of the 42 had evidence of severe depression.

The previously widely used 1994 “Fukuda” criteria for ME/CFS are no longer recommended because they don’t require PEM, which is now considered a key symptom. The more recent 2015 Institute (now Academy) of Medicine criteria don’t define the length of PEM, the authors note in the paper.

Dr. Scheibenbogen said, “Post-COVID has a spectrum of syndromes and conditions. We see that a subset of patients have similar symptoms of ME/CFS but don’t fulfill the CCC, although they may meet less stringent criteria. We think this is of relevance for both diagnostic markers and development of therapy, because there may be different pathomechanisms between the subsets of post-COVID patients.”

She pointed to other studies from her group suggesting that inflammation is present early in post-COVID (not yet published), while in the subset that goes on to ME/CFS, autoantibodies or endothelial dysfunction play a more important role. «At the moment, it’s quite complex, and I don’t think in the end we will have just one pathomechanism. So I think we’ll need to develop various treatment strategies.”

Asked to comment on the new data, Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital, both in Boston, and editor in chief of the Harvard Health Letter, told this news organization, “This paper adds to the evidence that an illness with symptoms that meet criteria for ME/CFS can follow COVID-19 in nearly half of those patients who have lingering symptoms. This can occur even in people who initially have only mild symptoms from COVID-19, although it is more likely to happen in the people who are sickest when they first get COVID-19. And those who meet criteria for ME/CFS were seriously impaired in their ability to function, [both] at work and at home.”

But, Dr. Komaroff also cautioned, “the study does not help in determining what fraction of all people who are infected with SARS-CoV-2 go on to develop a condition like ME/CFS, nor how long that condition will last. It is crucial that we get answers to these questions, as the impact on the economy, the health care system, and the disability system could be substantial.”

He pointed to a recent report from the Brookings Institution (2022 Aug 24. “New data shows long Covid is keeping as many as 4 million people out of work” Katie Bach) “finding that “long COVID may be a major contributor to the shortage of job applicants plaguing many businesses.”
 

Biomarkers include hand-grip strength, orthostatic intolerance, lab measures

Hand-grip strength, as assessed by 10 repeat grips at maximum force and repeated after 60 minutes, were lower for all those meeting ME/CFS criteria, compared with the healthy controls. Hand-grip strength parameters were also positively correlated with laboratory hemoglobin measures in both PCS groups who did and didn’t meet the Canadian ME/CFS criteria.

A total of three patients with PCS who didn’t meet ME/CFS criteria and seven with PCS who met ME/CFS criteria had sitting blood pressures of greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic. Five patients with PCS – four who met ME/CFS criteria and one who didn’t – fulfilled criteria for postural orthostatic tachycardia syndrome. Orthostatic hypotension was diagnosed in a total of seven with PCS, including one who did not meet ME/CFS criteria and the rest who did.

Among significant laboratory findings, mannose-binding lectin deficiency, which is associated with increased infection susceptibility and found in only about 6% of historical controls, was found more frequently in both of the PCS cohorts (17% of those with ME/CFS and 23% of those without) than it has been in the past among those with ME/CFS, compared with historical controls (15%).

There was only slight elevation in C-reactive protein, the most commonly measured marker of inflammation. However, another marker indicating inflammation within the last 3-4 months, interleukin 8 assessed in erythrocytes, was above normal in 37% with PCS and ME/CFS and in 48% with PCS who did not meet the ME/CFS criteria.

Elevated antinuclear antibodies, anti–thyroid peroxidase antibodies, vitamin D deficiencies, and folic acid deficiencies were all seen in small numbers of the PCS patients. Angiotensin-converting enzyme 1 levels were below the normal range in 31% of all patients.

“We must anticipate that this pandemic has the potential to dramatically increase the number of ME/CFS patients,” Dr. Kedor and colleagues write. “At the same time, it offers the unique chance to identify ME/CFS patients in a very early stage of disease and apply interventions such as pacing and coping early with a better therapeutic prognosis. Further, it is an unprecedented opportunity to understand the underlying pathomechanism and characterize targets for specific treatment approaches.”

Dr. Scheibenbogen and Dr. Komaroff reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

COVID-19 infection is significantly associated with chronically impaired cerebral vasoreactivity (CVR), results of a small study show.

In a small prospective study, participants who previously had COVID-19, even those with mild illness, had significantly decreased CVR, compared with never-infected individuals.

Results also showed cerebral blood flow (CBF) was greater in never-infected versus previously infected participants, and whole-brain CVR was lower in previously infected versus never-infected participants. Although CVR was also smaller in those with versus those without post-COVID neurologic conditions, the difference was not considered significant.

“It is important to remember that while our findings were statistically significant, we had a relatively small sample size – 25 total participants – and so we encourage future larger studies in this domain to see if these results are reproducible at a larger scale,” lead author Andrew Callen, MD, assistant professor of radiology, Neuroradiology Section, University of Colorado at Denver, Aurora, said in an interview.

“In a practical sense, it may encourage treating clinicians to be more aggressive with preventative neurovascular and cardiovascular health measures and/or screening in this patient population,” Dr. Callen said.

The findings were published online  in the American Journal of Roentgenology.
 

Endothelial dysfunction

The acute phase SARS-CoV-2 infection “is associated with strokes that have features of both vascular inflammation and thromboembolism,” the investigators note.

Moreover, following the acute phase of infection, up to three-quarters of patients “experience persistent neurologic symptoms not attributable to another diagnosis, including headache, difficulty concentrating, vision changes, disequilibrium, and fatigue,” they write.

Preliminary studies “suggest a potential role for endothelial and circulatory dysfunction” in these symptoms, they add.

The researchers note that vessel wall imaging is an MRI technique that can detect and characterize arterial vascular inflammation and may differentiate vasculitic arterial pathology from atherosclerotic pathology.

Dr. Callen conducted previous research assessing cerebral vasoreactivity in women living with HIV. He noted that this is a population at a much higher risk of stroke, compared with uninfected individuals with otherwise similar cardiovascular risk factors, even when their viral load is controlled with antiretroviral therapies.

Evidence has pointed to chronic endothelial dysfunction in these individuals, and endothelial function and dysfunction can be measured through vasoreactivity testing, Dr. Callen said.

“As the COVID pandemic progressed, not only did we observe an increased rate of stroke in individuals acutely infected with COVID, but histopathological evidence began to emerge which suggested that the COVID-19 virus had tropism to and often damaged the vascular endothelium,” he noted.

This emerging evidence prompted Dr. Callen to wonder whether “individuals previously infected with COVID might also demonstrate long-term impairment in cerebral vasoreactivity or if we might see abnormalities using high resolution vessel wall imaging.”

In the current study, 15 individuals with prior SARS-CoV-2 infection (11 women, 4 men; mean age, 43 years) were compared with 10 never-infected individuals (8 women, 2 men; mean age, 43 years) who functioned as the control group.

The previously infected individuals, of whom three had prior critical infection and 12 had prior mild infection, were assessed, on average, about 8 months after infection. Of this group, seven had various post-COVID neurologic conditions, including headache, memory impairment, insomnia, depression, disequilibrium, fatigue, personality change, phantosmias (detecting smells that aren’t present), dysgeusia (taste disorder), and tinnitus.

All participants underwent MRI and vessel wall imaging. The MRI included arterial spin labeling perfusion imaging with acetazolamide stimulus to measure CBF and calculate CVR. The vessel wall imaging examinations used a contrast-enhanced black-blood 3D T1-weighted sequence.
 

Imaging data

Prior to acetazolamide administration, the mean whole-cortex CBF did not differ significantly between never-infected and previously infected participants. However, following the acetazolamide administration, the mean whole-cortex CBF was greater in never-infected participants (73.8 mL/100 g/min vs. 60.5 mL/100 g/min, respectively; P = .04).

Moreover, the mean whole-brain CVR was greater in never-infected participants, compared with previously infected participants (27.8 mL/100 g/min vs. 19.1 mL/100 g/min; P < .001).

After adjusting for age and sex, researchers found that prior infection was associated with a lower whole-brain CVR (–8.9 mL/100 g/min; 95% confidence interval, 4.6-13.3 ml/100g/min; P < .001).

Previously infected individuals also showed significantly lower CVR, even after the researchers excluded those with prior critical illness.

A nonsignificant difference was found in previously infected participants, with smaller CVR in participants with versus without post-COVID neurologic symptoms (16.9 vs. 21.0 mL/100 g/min; P = .22).

In addition, 40% of the previously infected participants versus 10% of the never-infected participants had at least one vessel wall imaging abnormality – but the difference was not deemed significant (P = .18). Notably, “all detected vessel wall imaging abnormalities were morphologically consistent with atherosclerosis rather than vasculitis,” the investigators said.

Dr. Callen said it is “unknown whether the lack of statistical significance in the differences in vasoreactivity impairment with those living with long COVID symptoms is due to a lack of a biomechanistic correlation or due to statistical underpowering.”

If it is the latter, “it may emphasize the role of vascular health in those living with long COVID symptoms and potentially all individuals living with COVID,” he added.
 

Independent risk factor?

Commenting on the study for this article, Jared Narvid, MD, associate professor of neuroradiology, University of California, San Francisco, said it “adds to the literature suggesting a correlation between COVID-19 infection and measures of cerebrovascular abnormality.”

Dr. Narvid, who was not involved with the research, added that “although it is a small case-control study, it is well executed and should encourage scientists to further study whether COVID-19 infection represents an independent risk factor for cerebrovascular disease.”

The investigators agree. “Future studies are needed to determine the clinical implications arising from SARS-CoV-2–associated CVR impairment,” they write.

The study was funded by a University of Colorado department of radiology Faculty Development Seed Grant. The investigators and Dr. Narvid report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

COVID-19 infection is significantly associated with chronically impaired cerebral vasoreactivity (CVR), results of a small study show.

In a small prospective study, participants who previously had COVID-19, even those with mild illness, had significantly decreased CVR, compared with never-infected individuals.

Results also showed cerebral blood flow (CBF) was greater in never-infected versus previously infected participants, and whole-brain CVR was lower in previously infected versus never-infected participants. Although CVR was also smaller in those with versus those without post-COVID neurologic conditions, the difference was not considered significant.

“It is important to remember that while our findings were statistically significant, we had a relatively small sample size – 25 total participants – and so we encourage future larger studies in this domain to see if these results are reproducible at a larger scale,” lead author Andrew Callen, MD, assistant professor of radiology, Neuroradiology Section, University of Colorado at Denver, Aurora, said in an interview.

“In a practical sense, it may encourage treating clinicians to be more aggressive with preventative neurovascular and cardiovascular health measures and/or screening in this patient population,” Dr. Callen said.

The findings were published online  in the American Journal of Roentgenology.
 

Endothelial dysfunction

The acute phase SARS-CoV-2 infection “is associated with strokes that have features of both vascular inflammation and thromboembolism,” the investigators note.

Moreover, following the acute phase of infection, up to three-quarters of patients “experience persistent neurologic symptoms not attributable to another diagnosis, including headache, difficulty concentrating, vision changes, disequilibrium, and fatigue,” they write.

Preliminary studies “suggest a potential role for endothelial and circulatory dysfunction” in these symptoms, they add.

The researchers note that vessel wall imaging is an MRI technique that can detect and characterize arterial vascular inflammation and may differentiate vasculitic arterial pathology from atherosclerotic pathology.

Dr. Callen conducted previous research assessing cerebral vasoreactivity in women living with HIV. He noted that this is a population at a much higher risk of stroke, compared with uninfected individuals with otherwise similar cardiovascular risk factors, even when their viral load is controlled with antiretroviral therapies.

Evidence has pointed to chronic endothelial dysfunction in these individuals, and endothelial function and dysfunction can be measured through vasoreactivity testing, Dr. Callen said.

“As the COVID pandemic progressed, not only did we observe an increased rate of stroke in individuals acutely infected with COVID, but histopathological evidence began to emerge which suggested that the COVID-19 virus had tropism to and often damaged the vascular endothelium,” he noted.

This emerging evidence prompted Dr. Callen to wonder whether “individuals previously infected with COVID might also demonstrate long-term impairment in cerebral vasoreactivity or if we might see abnormalities using high resolution vessel wall imaging.”

In the current study, 15 individuals with prior SARS-CoV-2 infection (11 women, 4 men; mean age, 43 years) were compared with 10 never-infected individuals (8 women, 2 men; mean age, 43 years) who functioned as the control group.

The previously infected individuals, of whom three had prior critical infection and 12 had prior mild infection, were assessed, on average, about 8 months after infection. Of this group, seven had various post-COVID neurologic conditions, including headache, memory impairment, insomnia, depression, disequilibrium, fatigue, personality change, phantosmias (detecting smells that aren’t present), dysgeusia (taste disorder), and tinnitus.

All participants underwent MRI and vessel wall imaging. The MRI included arterial spin labeling perfusion imaging with acetazolamide stimulus to measure CBF and calculate CVR. The vessel wall imaging examinations used a contrast-enhanced black-blood 3D T1-weighted sequence.
 

Imaging data

Prior to acetazolamide administration, the mean whole-cortex CBF did not differ significantly between never-infected and previously infected participants. However, following the acetazolamide administration, the mean whole-cortex CBF was greater in never-infected participants (73.8 mL/100 g/min vs. 60.5 mL/100 g/min, respectively; P = .04).

Moreover, the mean whole-brain CVR was greater in never-infected participants, compared with previously infected participants (27.8 mL/100 g/min vs. 19.1 mL/100 g/min; P < .001).

After adjusting for age and sex, researchers found that prior infection was associated with a lower whole-brain CVR (–8.9 mL/100 g/min; 95% confidence interval, 4.6-13.3 ml/100g/min; P < .001).

Previously infected individuals also showed significantly lower CVR, even after the researchers excluded those with prior critical illness.

A nonsignificant difference was found in previously infected participants, with smaller CVR in participants with versus without post-COVID neurologic symptoms (16.9 vs. 21.0 mL/100 g/min; P = .22).

In addition, 40% of the previously infected participants versus 10% of the never-infected participants had at least one vessel wall imaging abnormality – but the difference was not deemed significant (P = .18). Notably, “all detected vessel wall imaging abnormalities were morphologically consistent with atherosclerosis rather than vasculitis,” the investigators said.

Dr. Callen said it is “unknown whether the lack of statistical significance in the differences in vasoreactivity impairment with those living with long COVID symptoms is due to a lack of a biomechanistic correlation or due to statistical underpowering.”

If it is the latter, “it may emphasize the role of vascular health in those living with long COVID symptoms and potentially all individuals living with COVID,” he added.
 

Independent risk factor?

Commenting on the study for this article, Jared Narvid, MD, associate professor of neuroradiology, University of California, San Francisco, said it “adds to the literature suggesting a correlation between COVID-19 infection and measures of cerebrovascular abnormality.”

Dr. Narvid, who was not involved with the research, added that “although it is a small case-control study, it is well executed and should encourage scientists to further study whether COVID-19 infection represents an independent risk factor for cerebrovascular disease.”

The investigators agree. “Future studies are needed to determine the clinical implications arising from SARS-CoV-2–associated CVR impairment,” they write.

The study was funded by a University of Colorado department of radiology Faculty Development Seed Grant. The investigators and Dr. Narvid report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

COVID-19 infection is significantly associated with chronically impaired cerebral vasoreactivity (CVR), results of a small study show.

In a small prospective study, participants who previously had COVID-19, even those with mild illness, had significantly decreased CVR, compared with never-infected individuals.

Results also showed cerebral blood flow (CBF) was greater in never-infected versus previously infected participants, and whole-brain CVR was lower in previously infected versus never-infected participants. Although CVR was also smaller in those with versus those without post-COVID neurologic conditions, the difference was not considered significant.

“It is important to remember that while our findings were statistically significant, we had a relatively small sample size – 25 total participants – and so we encourage future larger studies in this domain to see if these results are reproducible at a larger scale,” lead author Andrew Callen, MD, assistant professor of radiology, Neuroradiology Section, University of Colorado at Denver, Aurora, said in an interview.

“In a practical sense, it may encourage treating clinicians to be more aggressive with preventative neurovascular and cardiovascular health measures and/or screening in this patient population,” Dr. Callen said.

The findings were published online  in the American Journal of Roentgenology.
 

Endothelial dysfunction

The acute phase SARS-CoV-2 infection “is associated with strokes that have features of both vascular inflammation and thromboembolism,” the investigators note.

Moreover, following the acute phase of infection, up to three-quarters of patients “experience persistent neurologic symptoms not attributable to another diagnosis, including headache, difficulty concentrating, vision changes, disequilibrium, and fatigue,” they write.

Preliminary studies “suggest a potential role for endothelial and circulatory dysfunction” in these symptoms, they add.

The researchers note that vessel wall imaging is an MRI technique that can detect and characterize arterial vascular inflammation and may differentiate vasculitic arterial pathology from atherosclerotic pathology.

Dr. Callen conducted previous research assessing cerebral vasoreactivity in women living with HIV. He noted that this is a population at a much higher risk of stroke, compared with uninfected individuals with otherwise similar cardiovascular risk factors, even when their viral load is controlled with antiretroviral therapies.

Evidence has pointed to chronic endothelial dysfunction in these individuals, and endothelial function and dysfunction can be measured through vasoreactivity testing, Dr. Callen said.

“As the COVID pandemic progressed, not only did we observe an increased rate of stroke in individuals acutely infected with COVID, but histopathological evidence began to emerge which suggested that the COVID-19 virus had tropism to and often damaged the vascular endothelium,” he noted.

This emerging evidence prompted Dr. Callen to wonder whether “individuals previously infected with COVID might also demonstrate long-term impairment in cerebral vasoreactivity or if we might see abnormalities using high resolution vessel wall imaging.”

In the current study, 15 individuals with prior SARS-CoV-2 infection (11 women, 4 men; mean age, 43 years) were compared with 10 never-infected individuals (8 women, 2 men; mean age, 43 years) who functioned as the control group.

The previously infected individuals, of whom three had prior critical infection and 12 had prior mild infection, were assessed, on average, about 8 months after infection. Of this group, seven had various post-COVID neurologic conditions, including headache, memory impairment, insomnia, depression, disequilibrium, fatigue, personality change, phantosmias (detecting smells that aren’t present), dysgeusia (taste disorder), and tinnitus.

All participants underwent MRI and vessel wall imaging. The MRI included arterial spin labeling perfusion imaging with acetazolamide stimulus to measure CBF and calculate CVR. The vessel wall imaging examinations used a contrast-enhanced black-blood 3D T1-weighted sequence.
 

Imaging data

Prior to acetazolamide administration, the mean whole-cortex CBF did not differ significantly between never-infected and previously infected participants. However, following the acetazolamide administration, the mean whole-cortex CBF was greater in never-infected participants (73.8 mL/100 g/min vs. 60.5 mL/100 g/min, respectively; P = .04).

Moreover, the mean whole-brain CVR was greater in never-infected participants, compared with previously infected participants (27.8 mL/100 g/min vs. 19.1 mL/100 g/min; P < .001).

After adjusting for age and sex, researchers found that prior infection was associated with a lower whole-brain CVR (–8.9 mL/100 g/min; 95% confidence interval, 4.6-13.3 ml/100g/min; P < .001).

Previously infected individuals also showed significantly lower CVR, even after the researchers excluded those with prior critical illness.

A nonsignificant difference was found in previously infected participants, with smaller CVR in participants with versus without post-COVID neurologic symptoms (16.9 vs. 21.0 mL/100 g/min; P = .22).

In addition, 40% of the previously infected participants versus 10% of the never-infected participants had at least one vessel wall imaging abnormality – but the difference was not deemed significant (P = .18). Notably, “all detected vessel wall imaging abnormalities were morphologically consistent with atherosclerosis rather than vasculitis,” the investigators said.

Dr. Callen said it is “unknown whether the lack of statistical significance in the differences in vasoreactivity impairment with those living with long COVID symptoms is due to a lack of a biomechanistic correlation or due to statistical underpowering.”

If it is the latter, “it may emphasize the role of vascular health in those living with long COVID symptoms and potentially all individuals living with COVID,” he added.
 

Independent risk factor?

Commenting on the study for this article, Jared Narvid, MD, associate professor of neuroradiology, University of California, San Francisco, said it “adds to the literature suggesting a correlation between COVID-19 infection and measures of cerebrovascular abnormality.”

Dr. Narvid, who was not involved with the research, added that “although it is a small case-control study, it is well executed and should encourage scientists to further study whether COVID-19 infection represents an independent risk factor for cerebrovascular disease.”

The investigators agree. “Future studies are needed to determine the clinical implications arising from SARS-CoV-2–associated CVR impairment,” they write.

The study was funded by a University of Colorado department of radiology Faculty Development Seed Grant. The investigators and Dr. Narvid report no relevant financial relationships.

A version of this article first appeared on Medscape.com .

“BMI is trash. Full stop.” This controversial tweet received 26,500 likes and almost 3,000 retweets. The 400 comments from medical and non–health care personnel ranged from agreeable to contrary to offensive.

Regardless of your opinion on BMI (body mass index), this conversation highlighted that the medical community needs to discuss the limitations of BMI and decide its future.

As a Black woman who is an obesity expert living with the impact of obesity in my own life, I know the emotion that a BMI conversation can evoke. Before emotions hijack the conversation, let’s discuss BMI’s past, present, and future.
 

BMI: From observational measurement to clinical use

Imagine walking into your favorite clothing store where an eager clerk greets you with a shirt to try on. The fit is off, but the clerk insists that the shirt must fit because everyone who’s your height should be able to wear it. This scenario seems ridiculous. But this is how we’ve come to use the BMI. Instead of thinking that people of the same height may be the same size, we declare that they must be the same size.

The idea behind the BMI was conceived in 1832 by Belgian anthropologist and mathematician Adolphe Quetelet, but he didn’t intend for it to be a health measure. Instead, it was simply an observation of how people’s weight changed in proportion to height over their lifetime.

Fast-forward to the 20th century, when insurance companies began using weight as an indicator of health status. Weights were recorded in a “Life Table.” Individual health status was determined on the basis of arbitrary cut-offs for weight on the Life Tables. Furthermore, White men set the “normal” weight standards because they were the primary insurance holders.

In 1972, Dr. Ancel Keys, a physician and leading expert in body composition at the time, cried foul on this practice and sought to standardize the use of weight as a health indicator. Dr. Keys used Quetelet’s calculation and termed it the Body Mass Index.

By 1985, the U.S. National Institutes of Health and the World Health Organization adopted the BMI. By the 21st century, BMI had become widely used in clinical settings. For example, the Centers for Medicare & Medicaid Services adopted BMI as a quality-of-care measure, placing even more pressure on clinicians to use BMI as a health screening tool.
 

BMI as a tool to diagnose obesity

We can’t discuss BMI without discussing the disease of obesity. BMI is the most widely used tool to diagnose obesity. In the United States, one-third of Americans meet the criteria for obesity. Another one-third are at risk for obesity.

Compared with BMI’s relatively quick acceptance into clinical practice, however, obesity was only recently recognized as a disease.

Historically, obesity has been viewed as a lifestyle choice, fueled by misinformation and multiple forms of bias. The historical bias associated with BMI and discrimination has led some public health officials and scholars to dismiss the use of BMI or fail to recognize obesity as disease.

This is a dangerous conclusion, because it comes to the detriment of the very people disproportionately impacted by obesity-related health disparities.

Furthermore, weight bias continues to prevent people living with obesity from receiving insurance coverage for life-enhancing obesity medications and interventions.
 

Is it time to phase out BMI?

The BMI is intertwined with many forms of bias: age, gender, racial, ethnic, and even weight. Therefore, it is time to phase out BMI. However, phasing out BMI is complex and will take time, given that:

• Obesity is still a relatively “young” disease. 2023 marks the 10th anniversary of obesity’s recognition as a disease by the American Medical Association. Currently, BMI is the most widely used tool to diagnose obesity. Tools such as waist circumference, body composition, and metabolic health assessment will need to replace the BMI. Shifting from BMI emphasizes that obesity is more than a number on the scale. Obesity, as defined by the Obesity Medicine Association, is indeed a “chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.”
• Much of our health research is tied to BMI. There have been some shifts in looking at non–weight-related health indicators. However, we need more robust studies evaluating other health indicators beyond weight and BMI. The availability of this data will help eliminate the need for BMI and promote individualized health assessment.
• Current treatment guidelines for obesity medications are based on BMI. (Note: Medications to treat obesity are called “anti-obesity” medications or AOMs. However, given the stigma associated with obesity, I prefer not to use the term “anti-obesity.”) Presently this interferes with long-term obesity treatment. Once BMI is “normal,” many patients lose insurance coverage for their obesity medication, despite needing long-term metabolic support to overcome the compensatory mechanism of weight regain. Obesity is a chronic disease that exists independent of weight status. Therefore, using non-BMI measures will help ensure appropriate lifetime support for obesity.

The preceding are barriers, not impossibilities. In the interim, if BMI is still used in any capacity, the BMI reference chart should be an adjusted BMI chart based on age, race, ethnicity, biological sex, and obesity-related conditions. Furthermore, BMI isn’t the sole determining factor of health status.

Instead, an “abnormal” BMI should initiate conversation and further testing, if needed, to determine an individual’s health. For example, compare two people of the same height with different BMIs and lifestyles. Current studies support that a person flagged as having a high adjusted BMI but practicing a healthy lifestyle and having no metabolic diseases is less at risk than a person with a “normal” BMI but high waist circumference and an unhealthy lifestyle.

Regardless of your personal feelings, the facts are clear. Technology empowers us with better tools than BMI to determine health status. Therefore, it’s not a matter of if we will stop using BMI but when.

Sylvia Gonsahn-Bollie, MD, DipABOM, is an integrative obesity specialist who specializes in individualized solutions for emotional and biological overeating. Connect with her at www.embraceyouweightloss.com or on Instagram @embraceyoumd. Her bestselling book, “Embrace You: Your Guide to Transforming Weight Loss Misconceptions Into Lifelong Wellness,” is Healthline.com’s Best Overall Weight Loss Book 2022 and one of Livestrong.com’s picks for the 8 Best Weight-Loss Books to Read in 2022.

A version of this article first appeared on Medscape.com.

“BMI is trash. Full stop.” This controversial tweet received 26,500 likes and almost 3,000 retweets. The 400 comments from medical and non–health care personnel ranged from agreeable to contrary to offensive.

Regardless of your opinion on BMI (body mass index), this conversation highlighted that the medical community needs to discuss the limitations of BMI and decide its future.

As a Black woman who is an obesity expert living with the impact of obesity in my own life, I know the emotion that a BMI conversation can evoke. Before emotions hijack the conversation, let’s discuss BMI’s past, present, and future.
 

BMI: From observational measurement to clinical use

Imagine walking into your favorite clothing store where an eager clerk greets you with a shirt to try on. The fit is off, but the clerk insists that the shirt must fit because everyone who’s your height should be able to wear it. This scenario seems ridiculous. But this is how we’ve come to use the BMI. Instead of thinking that people of the same height may be the same size, we declare that they must be the same size.

The idea behind the BMI was conceived in 1832 by Belgian anthropologist and mathematician Adolphe Quetelet, but he didn’t intend for it to be a health measure. Instead, it was simply an observation of how people’s weight changed in proportion to height over their lifetime.

Fast-forward to the 20th century, when insurance companies began using weight as an indicator of health status. Weights were recorded in a “Life Table.” Individual health status was determined on the basis of arbitrary cut-offs for weight on the Life Tables. Furthermore, White men set the “normal” weight standards because they were the primary insurance holders.

In 1972, Dr. Ancel Keys, a physician and leading expert in body composition at the time, cried foul on this practice and sought to standardize the use of weight as a health indicator. Dr. Keys used Quetelet’s calculation and termed it the Body Mass Index.

By 1985, the U.S. National Institutes of Health and the World Health Organization adopted the BMI. By the 21st century, BMI had become widely used in clinical settings. For example, the Centers for Medicare & Medicaid Services adopted BMI as a quality-of-care measure, placing even more pressure on clinicians to use BMI as a health screening tool.
 

BMI as a tool to diagnose obesity

We can’t discuss BMI without discussing the disease of obesity. BMI is the most widely used tool to diagnose obesity. In the United States, one-third of Americans meet the criteria for obesity. Another one-third are at risk for obesity.

Compared with BMI’s relatively quick acceptance into clinical practice, however, obesity was only recently recognized as a disease.

Historically, obesity has been viewed as a lifestyle choice, fueled by misinformation and multiple forms of bias. The historical bias associated with BMI and discrimination has led some public health officials and scholars to dismiss the use of BMI or fail to recognize obesity as disease.

This is a dangerous conclusion, because it comes to the detriment of the very people disproportionately impacted by obesity-related health disparities.

Furthermore, weight bias continues to prevent people living with obesity from receiving insurance coverage for life-enhancing obesity medications and interventions.
 

Is it time to phase out BMI?

The BMI is intertwined with many forms of bias: age, gender, racial, ethnic, and even weight. Therefore, it is time to phase out BMI. However, phasing out BMI is complex and will take time, given that:

• Obesity is still a relatively “young” disease. 2023 marks the 10th anniversary of obesity’s recognition as a disease by the American Medical Association. Currently, BMI is the most widely used tool to diagnose obesity. Tools such as waist circumference, body composition, and metabolic health assessment will need to replace the BMI. Shifting from BMI emphasizes that obesity is more than a number on the scale. Obesity, as defined by the Obesity Medicine Association, is indeed a “chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.”
• Much of our health research is tied to BMI. There have been some shifts in looking at non–weight-related health indicators. However, we need more robust studies evaluating other health indicators beyond weight and BMI. The availability of this data will help eliminate the need for BMI and promote individualized health assessment.
• Current treatment guidelines for obesity medications are based on BMI. (Note: Medications to treat obesity are called “anti-obesity” medications or AOMs. However, given the stigma associated with obesity, I prefer not to use the term “anti-obesity.”) Presently this interferes with long-term obesity treatment. Once BMI is “normal,” many patients lose insurance coverage for their obesity medication, despite needing long-term metabolic support to overcome the compensatory mechanism of weight regain. Obesity is a chronic disease that exists independent of weight status. Therefore, using non-BMI measures will help ensure appropriate lifetime support for obesity.

The preceding are barriers, not impossibilities. In the interim, if BMI is still used in any capacity, the BMI reference chart should be an adjusted BMI chart based on age, race, ethnicity, biological sex, and obesity-related conditions. Furthermore, BMI isn’t the sole determining factor of health status.

Instead, an “abnormal” BMI should initiate conversation and further testing, if needed, to determine an individual’s health. For example, compare two people of the same height with different BMIs and lifestyles. Current studies support that a person flagged as having a high adjusted BMI but practicing a healthy lifestyle and having no metabolic diseases is less at risk than a person with a “normal” BMI but high waist circumference and an unhealthy lifestyle.

Regardless of your personal feelings, the facts are clear. Technology empowers us with better tools than BMI to determine health status. Therefore, it’s not a matter of if we will stop using BMI but when.

Sylvia Gonsahn-Bollie, MD, DipABOM, is an integrative obesity specialist who specializes in individualized solutions for emotional and biological overeating. Connect with her at www.embraceyouweightloss.com or on Instagram @embraceyoumd. Her bestselling book, “Embrace You: Your Guide to Transforming Weight Loss Misconceptions Into Lifelong Wellness,” is Healthline.com’s Best Overall Weight Loss Book 2022 and one of Livestrong.com’s picks for the 8 Best Weight-Loss Books to Read in 2022.

A version of this article first appeared on Medscape.com.

“BMI is trash. Full stop.” This controversial tweet received 26,500 likes and almost 3,000 retweets. The 400 comments from medical and non–health care personnel ranged from agreeable to contrary to offensive.

Regardless of your opinion on BMI (body mass index), this conversation highlighted that the medical community needs to discuss the limitations of BMI and decide its future.

As a Black woman who is an obesity expert living with the impact of obesity in my own life, I know the emotion that a BMI conversation can evoke. Before emotions hijack the conversation, let’s discuss BMI’s past, present, and future.
 

BMI: From observational measurement to clinical use

Imagine walking into your favorite clothing store where an eager clerk greets you with a shirt to try on. The fit is off, but the clerk insists that the shirt must fit because everyone who’s your height should be able to wear it. This scenario seems ridiculous. But this is how we’ve come to use the BMI. Instead of thinking that people of the same height may be the same size, we declare that they must be the same size.

The idea behind the BMI was conceived in 1832 by Belgian anthropologist and mathematician Adolphe Quetelet, but he didn’t intend for it to be a health measure. Instead, it was simply an observation of how people’s weight changed in proportion to height over their lifetime.

Fast-forward to the 20th century, when insurance companies began using weight as an indicator of health status. Weights were recorded in a “Life Table.” Individual health status was determined on the basis of arbitrary cut-offs for weight on the Life Tables. Furthermore, White men set the “normal” weight standards because they were the primary insurance holders.

In 1972, Dr. Ancel Keys, a physician and leading expert in body composition at the time, cried foul on this practice and sought to standardize the use of weight as a health indicator. Dr. Keys used Quetelet’s calculation and termed it the Body Mass Index.

By 1985, the U.S. National Institutes of Health and the World Health Organization adopted the BMI. By the 21st century, BMI had become widely used in clinical settings. For example, the Centers for Medicare & Medicaid Services adopted BMI as a quality-of-care measure, placing even more pressure on clinicians to use BMI as a health screening tool.
 

BMI as a tool to diagnose obesity

We can’t discuss BMI without discussing the disease of obesity. BMI is the most widely used tool to diagnose obesity. In the United States, one-third of Americans meet the criteria for obesity. Another one-third are at risk for obesity.

Compared with BMI’s relatively quick acceptance into clinical practice, however, obesity was only recently recognized as a disease.

Historically, obesity has been viewed as a lifestyle choice, fueled by misinformation and multiple forms of bias. The historical bias associated with BMI and discrimination has led some public health officials and scholars to dismiss the use of BMI or fail to recognize obesity as disease.

This is a dangerous conclusion, because it comes to the detriment of the very people disproportionately impacted by obesity-related health disparities.

Furthermore, weight bias continues to prevent people living with obesity from receiving insurance coverage for life-enhancing obesity medications and interventions.
 

Is it time to phase out BMI?

The BMI is intertwined with many forms of bias: age, gender, racial, ethnic, and even weight. Therefore, it is time to phase out BMI. However, phasing out BMI is complex and will take time, given that:

• Obesity is still a relatively “young” disease. 2023 marks the 10th anniversary of obesity’s recognition as a disease by the American Medical Association. Currently, BMI is the most widely used tool to diagnose obesity. Tools such as waist circumference, body composition, and metabolic health assessment will need to replace the BMI. Shifting from BMI emphasizes that obesity is more than a number on the scale. Obesity, as defined by the Obesity Medicine Association, is indeed a “chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.”
• Much of our health research is tied to BMI. There have been some shifts in looking at non–weight-related health indicators. However, we need more robust studies evaluating other health indicators beyond weight and BMI. The availability of this data will help eliminate the need for BMI and promote individualized health assessment.
• Current treatment guidelines for obesity medications are based on BMI. (Note: Medications to treat obesity are called “anti-obesity” medications or AOMs. However, given the stigma associated with obesity, I prefer not to use the term “anti-obesity.”) Presently this interferes with long-term obesity treatment. Once BMI is “normal,” many patients lose insurance coverage for their obesity medication, despite needing long-term metabolic support to overcome the compensatory mechanism of weight regain. Obesity is a chronic disease that exists independent of weight status. Therefore, using non-BMI measures will help ensure appropriate lifetime support for obesity.

The preceding are barriers, not impossibilities. In the interim, if BMI is still used in any capacity, the BMI reference chart should be an adjusted BMI chart based on age, race, ethnicity, biological sex, and obesity-related conditions. Furthermore, BMI isn’t the sole determining factor of health status.

Instead, an “abnormal” BMI should initiate conversation and further testing, if needed, to determine an individual’s health. For example, compare two people of the same height with different BMIs and lifestyles. Current studies support that a person flagged as having a high adjusted BMI but practicing a healthy lifestyle and having no metabolic diseases is less at risk than a person with a “normal” BMI but high waist circumference and an unhealthy lifestyle.

Regardless of your personal feelings, the facts are clear. Technology empowers us with better tools than BMI to determine health status. Therefore, it’s not a matter of if we will stop using BMI but when.

Sylvia Gonsahn-Bollie, MD, DipABOM, is an integrative obesity specialist who specializes in individualized solutions for emotional and biological overeating. Connect with her at www.embraceyouweightloss.com or on Instagram @embraceyoumd. Her bestselling book, “Embrace You: Your Guide to Transforming Weight Loss Misconceptions Into Lifelong Wellness,” is Healthline.com’s Best Overall Weight Loss Book 2022 and one of Livestrong.com’s picks for the 8 Best Weight-Loss Books to Read in 2022.

A version of this article first appeared on Medscape.com.

PARIS – Adding cabozantinib (Cabometyx, Exelixis) to standard-of-care immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy) markedly improved progression-free survival (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.

At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.

The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.

The research was presented at the European Society for Medical Oncology Congress in Paris.

The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.

Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.

The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.

However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.

In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.

The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.

He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”

“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.

He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”

Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”

“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.

“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”

Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.

He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.

Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”

So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”

Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”

However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.

Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.

“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.

“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
 

Details of the new results

The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.

They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.

Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.

The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).

At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.

Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.

Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.

However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.

But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.

Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.

Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.

Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.

However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.

Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.

He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”

In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.

He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.

The study was funded by Exelixis.

Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.

A version of this article first appeared on Medscape.com.

PARIS – Adding cabozantinib (Cabometyx, Exelixis) to standard-of-care immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy) markedly improved progression-free survival (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.

At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.

The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.

The research was presented at the European Society for Medical Oncology Congress in Paris.

The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.

Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.

The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.

However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.

In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.

The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.

He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”

“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.

He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”

Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”

“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.

“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”

Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.

He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.

Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”

So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”

Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”

However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.

Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.

“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.

“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
 

Details of the new results

The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.

They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.

Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.

The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).

At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.

Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.

Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.

However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.

But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.

Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.

Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.

Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.

However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.

Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.

He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”

In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.

He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.

The study was funded by Exelixis.

Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.

A version of this article first appeared on Medscape.com.

PARIS – Adding cabozantinib (Cabometyx, Exelixis) to standard-of-care immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy) markedly improved progression-free survival (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.

At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.

The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.

The research was presented at the European Society for Medical Oncology Congress in Paris.

The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.

Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.

The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.

However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.

In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.

The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.

He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”

“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.

He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”

Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”

“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.

“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”

Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.

He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.

Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”

So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”

Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”

However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.

Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.

“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.

“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
 

Details of the new results

The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.

They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.

Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.

The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).

At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.

Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.

Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.

However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.

But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.

Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.

Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.

Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.

However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.

Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.

He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”

In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.

He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.

The study was funded by Exelixis.

Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.

A version of this article first appeared on Medscape.com.