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Testosterone decline after steroid abuse revealed with new biomarker
Levels of insulinlike factor 3 (INSL3) drop noticeably in men who have abused anabolic androgenic steroids (AAS), even well after stoppage. The results suggest that the effects of AAS use on testosterone-producing Leydig cells may be long-lasting, as some clinicians have suspected. Although there is some variation of INSL3 levels among AAS users, the metric is more accurate than testosterone levels and could be a key element of future diagnostic tests.
Those are the conclusions of a new study, led by Jon Jarløv Rasmussen, MD, PhD, of the department of endocrinology at Rigshospitalet in Copenhagen*, published March 9, 2021, in the Journal of Clinical Endocrinology & Metabolism.
Results mirror clinical experience
The drop in levels, both among current and past users, is in keeping with clinical experience of endocrinologists, according to Channa Jayasena, MD, PhD, a reproductive endocrinologist at Imperial College London. He suspects lasting damage in former and current users who come to him when they discover their sperm count is low. "How long that damage lasts is another matter," Dr. Jayasena, who was not involved in the study, said in an interview.
Dr. Jayasena hopes that INSL3 could find use in tracking damage to Leydig cells from AAS use, as well as to monitor improvements in the event that treatments are found, though he noted that the scatter plots in the study showed quite a bit of variation of INSL3 levels. "So it's a great first step showing that these men, users and past users, have lower INSL3 levels, but it's going to have to be part of a broader suite of factors such as the other hormone [levels], testicular volume, duration of steroid use, etc.," said Dr. Jayasena.
In search of a reliable measure
Low testosterone levels have been shown to be associated with AAS use in some studies, but not in others. That inconsistency led the researchers in search of a more reliable measure. "Serum testosterone is not a stable marker but can fluctuate considerably within minutes to hours, whereas serum insulinlike factor 3 [levels] do not," said Dr. Rasmussen.
INSL3 appears to be involved in bone metabolism regulation as well as spermatogenesis.
Dr. Rasmussen agreed that INSL3 levels could be clinically useful for tracking Leydig cell function, especially in combination with other hormone markers like serum testosterone and gonadotropins. The group is now considering a clinical trial for treatment of hypogonadal men following illicit use of anabolic steroids, which will include INSL3 serum levels as a planned endpoint.
The researchers conducted a cross-sectional study of men aged 18-50 years who had participated in recreational strength training. Cohort 1 included 37 AAS users, 33 former users, and 30 never users. Cohort 2 included 9 current users, 9 former users, and 14 never users. They assigned participant AAS use status based on self-reporting, along with measurement of biomedical parameters including gonadotropins, sexual hormone-binding globulin (SHBG), and hematocrit.
Compared with never users' median value of 0.59 mcg/L, INSL3 serum levels were lower among current AAS (median, 0.04 mcg/L; P < .001) and former AAS (0.39 mcg/L; P = .005) users. A linear multivariate regression that adjusted for luteinizing hormone, SHBG, age, body-fat percentage, smoking status, use of other illicit drugs found lower levels among former users, compared with never users (mean difference, -0.16 mcg/L; P = .011).
An analysis of elapsed duration since AAS cessation found longer duration of AAS use was associated with reduced INSL3 levels (mean difference, -0.08; P = .022).
Although serum inhibin B levels reached the levels of never users after about 21 months, and luteinizing hormone levels recovered in about 12 months, neither serum testosterone nor INSL3 levels recovered in former users.
The study authors received funding from Anti Doping Denmark. Dr. Jayasena has no relevant financial disclosures.
*Dr. Rasmussen's affiliation has been corrected.
Levels of insulinlike factor 3 (INSL3) drop noticeably in men who have abused anabolic androgenic steroids (AAS), even well after stoppage. The results suggest that the effects of AAS use on testosterone-producing Leydig cells may be long-lasting, as some clinicians have suspected. Although there is some variation of INSL3 levels among AAS users, the metric is more accurate than testosterone levels and could be a key element of future diagnostic tests.
Those are the conclusions of a new study, led by Jon Jarløv Rasmussen, MD, PhD, of the department of endocrinology at Rigshospitalet in Copenhagen*, published March 9, 2021, in the Journal of Clinical Endocrinology & Metabolism.
Results mirror clinical experience
The drop in levels, both among current and past users, is in keeping with clinical experience of endocrinologists, according to Channa Jayasena, MD, PhD, a reproductive endocrinologist at Imperial College London. He suspects lasting damage in former and current users who come to him when they discover their sperm count is low. "How long that damage lasts is another matter," Dr. Jayasena, who was not involved in the study, said in an interview.
Dr. Jayasena hopes that INSL3 could find use in tracking damage to Leydig cells from AAS use, as well as to monitor improvements in the event that treatments are found, though he noted that the scatter plots in the study showed quite a bit of variation of INSL3 levels. "So it's a great first step showing that these men, users and past users, have lower INSL3 levels, but it's going to have to be part of a broader suite of factors such as the other hormone [levels], testicular volume, duration of steroid use, etc.," said Dr. Jayasena.
In search of a reliable measure
Low testosterone levels have been shown to be associated with AAS use in some studies, but not in others. That inconsistency led the researchers in search of a more reliable measure. "Serum testosterone is not a stable marker but can fluctuate considerably within minutes to hours, whereas serum insulinlike factor 3 [levels] do not," said Dr. Rasmussen.
INSL3 appears to be involved in bone metabolism regulation as well as spermatogenesis.
Dr. Rasmussen agreed that INSL3 levels could be clinically useful for tracking Leydig cell function, especially in combination with other hormone markers like serum testosterone and gonadotropins. The group is now considering a clinical trial for treatment of hypogonadal men following illicit use of anabolic steroids, which will include INSL3 serum levels as a planned endpoint.
The researchers conducted a cross-sectional study of men aged 18-50 years who had participated in recreational strength training. Cohort 1 included 37 AAS users, 33 former users, and 30 never users. Cohort 2 included 9 current users, 9 former users, and 14 never users. They assigned participant AAS use status based on self-reporting, along with measurement of biomedical parameters including gonadotropins, sexual hormone-binding globulin (SHBG), and hematocrit.
Compared with never users' median value of 0.59 mcg/L, INSL3 serum levels were lower among current AAS (median, 0.04 mcg/L; P < .001) and former AAS (0.39 mcg/L; P = .005) users. A linear multivariate regression that adjusted for luteinizing hormone, SHBG, age, body-fat percentage, smoking status, use of other illicit drugs found lower levels among former users, compared with never users (mean difference, -0.16 mcg/L; P = .011).
An analysis of elapsed duration since AAS cessation found longer duration of AAS use was associated with reduced INSL3 levels (mean difference, -0.08; P = .022).
Although serum inhibin B levels reached the levels of never users after about 21 months, and luteinizing hormone levels recovered in about 12 months, neither serum testosterone nor INSL3 levels recovered in former users.
The study authors received funding from Anti Doping Denmark. Dr. Jayasena has no relevant financial disclosures.
*Dr. Rasmussen's affiliation has been corrected.
Levels of insulinlike factor 3 (INSL3) drop noticeably in men who have abused anabolic androgenic steroids (AAS), even well after stoppage. The results suggest that the effects of AAS use on testosterone-producing Leydig cells may be long-lasting, as some clinicians have suspected. Although there is some variation of INSL3 levels among AAS users, the metric is more accurate than testosterone levels and could be a key element of future diagnostic tests.
Those are the conclusions of a new study, led by Jon Jarløv Rasmussen, MD, PhD, of the department of endocrinology at Rigshospitalet in Copenhagen*, published March 9, 2021, in the Journal of Clinical Endocrinology & Metabolism.
Results mirror clinical experience
The drop in levels, both among current and past users, is in keeping with clinical experience of endocrinologists, according to Channa Jayasena, MD, PhD, a reproductive endocrinologist at Imperial College London. He suspects lasting damage in former and current users who come to him when they discover their sperm count is low. "How long that damage lasts is another matter," Dr. Jayasena, who was not involved in the study, said in an interview.
Dr. Jayasena hopes that INSL3 could find use in tracking damage to Leydig cells from AAS use, as well as to monitor improvements in the event that treatments are found, though he noted that the scatter plots in the study showed quite a bit of variation of INSL3 levels. "So it's a great first step showing that these men, users and past users, have lower INSL3 levels, but it's going to have to be part of a broader suite of factors such as the other hormone [levels], testicular volume, duration of steroid use, etc.," said Dr. Jayasena.
In search of a reliable measure
Low testosterone levels have been shown to be associated with AAS use in some studies, but not in others. That inconsistency led the researchers in search of a more reliable measure. "Serum testosterone is not a stable marker but can fluctuate considerably within minutes to hours, whereas serum insulinlike factor 3 [levels] do not," said Dr. Rasmussen.
INSL3 appears to be involved in bone metabolism regulation as well as spermatogenesis.
Dr. Rasmussen agreed that INSL3 levels could be clinically useful for tracking Leydig cell function, especially in combination with other hormone markers like serum testosterone and gonadotropins. The group is now considering a clinical trial for treatment of hypogonadal men following illicit use of anabolic steroids, which will include INSL3 serum levels as a planned endpoint.
The researchers conducted a cross-sectional study of men aged 18-50 years who had participated in recreational strength training. Cohort 1 included 37 AAS users, 33 former users, and 30 never users. Cohort 2 included 9 current users, 9 former users, and 14 never users. They assigned participant AAS use status based on self-reporting, along with measurement of biomedical parameters including gonadotropins, sexual hormone-binding globulin (SHBG), and hematocrit.
Compared with never users' median value of 0.59 mcg/L, INSL3 serum levels were lower among current AAS (median, 0.04 mcg/L; P < .001) and former AAS (0.39 mcg/L; P = .005) users. A linear multivariate regression that adjusted for luteinizing hormone, SHBG, age, body-fat percentage, smoking status, use of other illicit drugs found lower levels among former users, compared with never users (mean difference, -0.16 mcg/L; P = .011).
An analysis of elapsed duration since AAS cessation found longer duration of AAS use was associated with reduced INSL3 levels (mean difference, -0.08; P = .022).
Although serum inhibin B levels reached the levels of never users after about 21 months, and luteinizing hormone levels recovered in about 12 months, neither serum testosterone nor INSL3 levels recovered in former users.
The study authors received funding from Anti Doping Denmark. Dr. Jayasena has no relevant financial disclosures.
*Dr. Rasmussen's affiliation has been corrected.
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
FDA okays novel dual-action stimulant med for ADHD
The Food and Drug Administration has approved a new, once-daily oral stimulant medication for treatment of ADHD in people aged 6 years and older.
Azstarys (KemPharm) combines extended-release serdexmethylphenidate (SDX), KemPharm’s prodrug of dexmethylphenidate (d-MPH), coformulated with immediate-release d-MPH.
Following absorption in the gastrointestinal tract, SDX is converted to d-MPH, which is gradually released throughout the day, providing symptom control both rapidly with the d-MPH and for an extended duration with SDX.
The dual action of Azstarys addresses an unmet need for a medication that has early onset of action and long duration of therapy, with steady ADHD symptom control in one capsule, Corium, the company that will lead U.S. commercialization of the drug, stated in a news release.
“The data documenting the efficacy and safety of this new dual-action medicine, the first ever to use the novel prodrug serdexmethylphenidate together with dexmethylphenidate, is welcome news for clinicians and families to consider when choosing an appropriate ADHD therapy for children,” Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine in Las Vegas, who led the phase 3 trial of the drug, said in the release.
The study included 150 children aged 6-12 years with ADHD. Compared with placebo, treatment with Azstarys led to significant improvement in ADHD symptoms, as measured by the primary endpoint, the change from baseline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale–Combined scores averaged over 13 hours.
Adverse events seen more often with Azstarys than placebo were headache (5.4% vs. 1.3%), upper abdominal pain (4.1% vs. 1.3%), insomnia (2.7% vs. 1.3%) and pharyngitis (2.7% vs. 0%). No serious adverse events were reported.
The FDA has recommended a schedule II controlled substance classification for Azstarys and the Drug Enforcement Administration will decide on scheduling within 90 days.
Pending the DEA’s action, the launch of Azstarys is anticipated this summer. Azstarys will be available in three once-daily dosage strengths of SDX/d-MPH: 26.1/5.2 mg, 39.2/7.8 mg, and 52.3/10.4 mg.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a new, once-daily oral stimulant medication for treatment of ADHD in people aged 6 years and older.
Azstarys (KemPharm) combines extended-release serdexmethylphenidate (SDX), KemPharm’s prodrug of dexmethylphenidate (d-MPH), coformulated with immediate-release d-MPH.
Following absorption in the gastrointestinal tract, SDX is converted to d-MPH, which is gradually released throughout the day, providing symptom control both rapidly with the d-MPH and for an extended duration with SDX.
The dual action of Azstarys addresses an unmet need for a medication that has early onset of action and long duration of therapy, with steady ADHD symptom control in one capsule, Corium, the company that will lead U.S. commercialization of the drug, stated in a news release.
“The data documenting the efficacy and safety of this new dual-action medicine, the first ever to use the novel prodrug serdexmethylphenidate together with dexmethylphenidate, is welcome news for clinicians and families to consider when choosing an appropriate ADHD therapy for children,” Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine in Las Vegas, who led the phase 3 trial of the drug, said in the release.
The study included 150 children aged 6-12 years with ADHD. Compared with placebo, treatment with Azstarys led to significant improvement in ADHD symptoms, as measured by the primary endpoint, the change from baseline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale–Combined scores averaged over 13 hours.
Adverse events seen more often with Azstarys than placebo were headache (5.4% vs. 1.3%), upper abdominal pain (4.1% vs. 1.3%), insomnia (2.7% vs. 1.3%) and pharyngitis (2.7% vs. 0%). No serious adverse events were reported.
The FDA has recommended a schedule II controlled substance classification for Azstarys and the Drug Enforcement Administration will decide on scheduling within 90 days.
Pending the DEA’s action, the launch of Azstarys is anticipated this summer. Azstarys will be available in three once-daily dosage strengths of SDX/d-MPH: 26.1/5.2 mg, 39.2/7.8 mg, and 52.3/10.4 mg.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a new, once-daily oral stimulant medication for treatment of ADHD in people aged 6 years and older.
Azstarys (KemPharm) combines extended-release serdexmethylphenidate (SDX), KemPharm’s prodrug of dexmethylphenidate (d-MPH), coformulated with immediate-release d-MPH.
Following absorption in the gastrointestinal tract, SDX is converted to d-MPH, which is gradually released throughout the day, providing symptom control both rapidly with the d-MPH and for an extended duration with SDX.
The dual action of Azstarys addresses an unmet need for a medication that has early onset of action and long duration of therapy, with steady ADHD symptom control in one capsule, Corium, the company that will lead U.S. commercialization of the drug, stated in a news release.
“The data documenting the efficacy and safety of this new dual-action medicine, the first ever to use the novel prodrug serdexmethylphenidate together with dexmethylphenidate, is welcome news for clinicians and families to consider when choosing an appropriate ADHD therapy for children,” Ann Childress, MD, president of the Center for Psychiatry and Behavioral Medicine in Las Vegas, who led the phase 3 trial of the drug, said in the release.
The study included 150 children aged 6-12 years with ADHD. Compared with placebo, treatment with Azstarys led to significant improvement in ADHD symptoms, as measured by the primary endpoint, the change from baseline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale–Combined scores averaged over 13 hours.
Adverse events seen more often with Azstarys than placebo were headache (5.4% vs. 1.3%), upper abdominal pain (4.1% vs. 1.3%), insomnia (2.7% vs. 1.3%) and pharyngitis (2.7% vs. 0%). No serious adverse events were reported.
The FDA has recommended a schedule II controlled substance classification for Azstarys and the Drug Enforcement Administration will decide on scheduling within 90 days.
Pending the DEA’s action, the launch of Azstarys is anticipated this summer. Azstarys will be available in three once-daily dosage strengths of SDX/d-MPH: 26.1/5.2 mg, 39.2/7.8 mg, and 52.3/10.4 mg.
A version of this article first appeared on Medscape.com.
Semaglutide for meaningful weight loss in obesity and diabetes?
A 2.4-mg weekly injection of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide led to a clinically meaningful 5% loss in weight for roughly two-thirds of patients with both overweight/obesity and type 2 diabetes, researchers report.
These findings from the Semaglutide Treatment Effect in People With Obesity 2 (STEP 2) trial, one of four phase 3 trials of this drug, which is currently under regulatory review for weight loss, were published March 2 in The Lancet.
More than 1,000 patients (mean initial weight, 100 kg [220 pounds]) were randomly assigned to receive a lifestyle intervention plus a weekly injection of semaglutide 2.4 mg or semaglutide 1.0 mg or placebo. At 68 weeks, they had lost a mean of 9.6%, 7.0%, and 3.4%, respectively, of their starting weight.
In addition, 69% of patients who had received semaglutide 2.4 mg experienced a clinically meaningful 5% loss of weight, compared with 57% of patients who had received the lower dose and 29% of patients who had received placebo.
The higher dose of semaglutide was associated with a greater improvement in cardiometabolic risk factors. The safety profile was similar to that seen with other drugs in this class.
“By far the best results with any weight loss medicine in diabetes”
Importantly, “more than a quarter of participants lost over 15% of their body weight,” senior author Ildiko Lingvay, MD, stressed. This “is by far the best result we had with any weight loss medicine in patients with diabetes,” Dr. Lingvay, of the University of Texas, Dallas, said in a statement from the university.
“The drug works by suppressing appetite centers in the brain to reduce caloric intake,” she explained. “The medication continually tells the body that you just ate, you’re full.”
Similarly, lead author Melanie J. Davies, MD, said that the STEP 2 results “are exciting and represent a new era in weight management in people with type 2 diabetes.
“They mark a real paradigm shift in our ability to treat obesity,” with results closer to those achieved with bariatric surgery, Dr. Davies, of the University of Leicester, England, said in a statement from her institution.
“It is really encouraging,” she continued, “that along with the weight loss we saw real improvements in general health, with significant improvement in physical functioning scores, blood pressure, and blood glucose control.”
Dr. Lingvay noted that on average, patients in the four STEP clinical trials lost 10%-17% of their body weight, “which is a huge step forward compared with all other medications currently available to treat obesity.” She stressed that these results are comparable to the 20%-30% weight loss seen with bariatric surgery.
One of four trials under review
More than 90% of people with type 2 diabetes are overweight or have obesity, and more than 20% of people with obesity have diabetes, wrote Dr. Davies and colleagues.
Semaglutide (Ozempic), administered subcutaneously at a dose of 0.5 mg to 1 mg weekly, is approved by the Food and Drug Administration for the treatment of type 2 diabetes. Dosing studies indicated that it is associated with weight loss.
As previously reported, four trials of the use of semaglutide for weight loss (STEP 1, 2, 3, and 4) have been completed. The combined data were submitted to the FDA on Dec. 4, 2020 (a decision is expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
The STEP 1 and STEP 3 trials of semaglutide 2.4 mg vs. placebo were recently published. The STEP 1 trial involved 1,961 adults with obesity or overweight; the STEP 3 trial, 611 adults with obesity or overweight. In each of the trials, some patients also underwent an intensive lifestyle intervention, and some did not. In both trials, patients with type 2 diabetes were excluded.
Topline results from STEP 2 were reported in June 2020.
STEP 2 enrolled patients with type 2 diabetes
STEP 2 involved 1,210 adults in 149 outpatient clinics in 12 countries in Europe, North America, South America, the Middle East, South Africa, and Asia. All participants had type 2 diabetes.
For all patients, the body mass index was ≥27 kg/m2, and the A1c concentration was 7%-10%. The mean BMI was 35.7 kg/m2, and the mean A1c was 8.1%.
The mean age of the patients was 55 years, and 51% were women; 62% were White, 26% were Asian, 13% were Hispanic, 8% were Black, and 4% were of other ethnicity.
Participants were managed with diet and exercise alone or underwent treatment with a stable dose of up to three oral glucose-lowering agents (metformin, sulfonylureas, SGLT2 inhibitors, or thiazolidinediones) for at least 90 days. They were then randomly assigned in 1:1:1 ratio to receive semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo.
The starting dose of semaglutide was 0.25 mg/wk; the dose was escalated every 4 weeks to reach the target dose.
All patients received monthly counseling from a dietitian about calories (the goal was a 500-calorie/day deficit) and activity (the goal was 150 minutes of walking or stair climbing per week).
The mean A1c dropped by 1.6% and 1.5% in the semaglutide groups and by 0.4% in the placebo group.
Adverse events were more frequent among the patients who received semaglutide (88% and 82%) than in the placebo group (77%).
Gastrointestinal events that were mainly mild to moderate in severity were reported by 64% of patients in the 2.4-mg semaglutide group, 58% in the 1.0-mg semaglutide group, and 34% in the placebo group.
Semaglutide (Rybelsus) is approved in the United States as a once-daily oral agent for use in type 2 diabetes in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
The study was supported by Novo Nordisk. The authors’ relevant financial relationships are listed in the original article.
A version of this article first appeared on Medscape.com.
A 2.4-mg weekly injection of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide led to a clinically meaningful 5% loss in weight for roughly two-thirds of patients with both overweight/obesity and type 2 diabetes, researchers report.
These findings from the Semaglutide Treatment Effect in People With Obesity 2 (STEP 2) trial, one of four phase 3 trials of this drug, which is currently under regulatory review for weight loss, were published March 2 in The Lancet.
More than 1,000 patients (mean initial weight, 100 kg [220 pounds]) were randomly assigned to receive a lifestyle intervention plus a weekly injection of semaglutide 2.4 mg or semaglutide 1.0 mg or placebo. At 68 weeks, they had lost a mean of 9.6%, 7.0%, and 3.4%, respectively, of their starting weight.
In addition, 69% of patients who had received semaglutide 2.4 mg experienced a clinically meaningful 5% loss of weight, compared with 57% of patients who had received the lower dose and 29% of patients who had received placebo.
The higher dose of semaglutide was associated with a greater improvement in cardiometabolic risk factors. The safety profile was similar to that seen with other drugs in this class.
“By far the best results with any weight loss medicine in diabetes”
Importantly, “more than a quarter of participants lost over 15% of their body weight,” senior author Ildiko Lingvay, MD, stressed. This “is by far the best result we had with any weight loss medicine in patients with diabetes,” Dr. Lingvay, of the University of Texas, Dallas, said in a statement from the university.
“The drug works by suppressing appetite centers in the brain to reduce caloric intake,” she explained. “The medication continually tells the body that you just ate, you’re full.”
Similarly, lead author Melanie J. Davies, MD, said that the STEP 2 results “are exciting and represent a new era in weight management in people with type 2 diabetes.
“They mark a real paradigm shift in our ability to treat obesity,” with results closer to those achieved with bariatric surgery, Dr. Davies, of the University of Leicester, England, said in a statement from her institution.
“It is really encouraging,” she continued, “that along with the weight loss we saw real improvements in general health, with significant improvement in physical functioning scores, blood pressure, and blood glucose control.”
Dr. Lingvay noted that on average, patients in the four STEP clinical trials lost 10%-17% of their body weight, “which is a huge step forward compared with all other medications currently available to treat obesity.” She stressed that these results are comparable to the 20%-30% weight loss seen with bariatric surgery.
One of four trials under review
More than 90% of people with type 2 diabetes are overweight or have obesity, and more than 20% of people with obesity have diabetes, wrote Dr. Davies and colleagues.
Semaglutide (Ozempic), administered subcutaneously at a dose of 0.5 mg to 1 mg weekly, is approved by the Food and Drug Administration for the treatment of type 2 diabetes. Dosing studies indicated that it is associated with weight loss.
As previously reported, four trials of the use of semaglutide for weight loss (STEP 1, 2, 3, and 4) have been completed. The combined data were submitted to the FDA on Dec. 4, 2020 (a decision is expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
The STEP 1 and STEP 3 trials of semaglutide 2.4 mg vs. placebo were recently published. The STEP 1 trial involved 1,961 adults with obesity or overweight; the STEP 3 trial, 611 adults with obesity or overweight. In each of the trials, some patients also underwent an intensive lifestyle intervention, and some did not. In both trials, patients with type 2 diabetes were excluded.
Topline results from STEP 2 were reported in June 2020.
STEP 2 enrolled patients with type 2 diabetes
STEP 2 involved 1,210 adults in 149 outpatient clinics in 12 countries in Europe, North America, South America, the Middle East, South Africa, and Asia. All participants had type 2 diabetes.
For all patients, the body mass index was ≥27 kg/m2, and the A1c concentration was 7%-10%. The mean BMI was 35.7 kg/m2, and the mean A1c was 8.1%.
The mean age of the patients was 55 years, and 51% were women; 62% were White, 26% were Asian, 13% were Hispanic, 8% were Black, and 4% were of other ethnicity.
Participants were managed with diet and exercise alone or underwent treatment with a stable dose of up to three oral glucose-lowering agents (metformin, sulfonylureas, SGLT2 inhibitors, or thiazolidinediones) for at least 90 days. They were then randomly assigned in 1:1:1 ratio to receive semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo.
The starting dose of semaglutide was 0.25 mg/wk; the dose was escalated every 4 weeks to reach the target dose.
All patients received monthly counseling from a dietitian about calories (the goal was a 500-calorie/day deficit) and activity (the goal was 150 minutes of walking or stair climbing per week).
The mean A1c dropped by 1.6% and 1.5% in the semaglutide groups and by 0.4% in the placebo group.
Adverse events were more frequent among the patients who received semaglutide (88% and 82%) than in the placebo group (77%).
Gastrointestinal events that were mainly mild to moderate in severity were reported by 64% of patients in the 2.4-mg semaglutide group, 58% in the 1.0-mg semaglutide group, and 34% in the placebo group.
Semaglutide (Rybelsus) is approved in the United States as a once-daily oral agent for use in type 2 diabetes in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
The study was supported by Novo Nordisk. The authors’ relevant financial relationships are listed in the original article.
A version of this article first appeared on Medscape.com.
A 2.4-mg weekly injection of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide led to a clinically meaningful 5% loss in weight for roughly two-thirds of patients with both overweight/obesity and type 2 diabetes, researchers report.
These findings from the Semaglutide Treatment Effect in People With Obesity 2 (STEP 2) trial, one of four phase 3 trials of this drug, which is currently under regulatory review for weight loss, were published March 2 in The Lancet.
More than 1,000 patients (mean initial weight, 100 kg [220 pounds]) were randomly assigned to receive a lifestyle intervention plus a weekly injection of semaglutide 2.4 mg or semaglutide 1.0 mg or placebo. At 68 weeks, they had lost a mean of 9.6%, 7.0%, and 3.4%, respectively, of their starting weight.
In addition, 69% of patients who had received semaglutide 2.4 mg experienced a clinically meaningful 5% loss of weight, compared with 57% of patients who had received the lower dose and 29% of patients who had received placebo.
The higher dose of semaglutide was associated with a greater improvement in cardiometabolic risk factors. The safety profile was similar to that seen with other drugs in this class.
“By far the best results with any weight loss medicine in diabetes”
Importantly, “more than a quarter of participants lost over 15% of their body weight,” senior author Ildiko Lingvay, MD, stressed. This “is by far the best result we had with any weight loss medicine in patients with diabetes,” Dr. Lingvay, of the University of Texas, Dallas, said in a statement from the university.
“The drug works by suppressing appetite centers in the brain to reduce caloric intake,” she explained. “The medication continually tells the body that you just ate, you’re full.”
Similarly, lead author Melanie J. Davies, MD, said that the STEP 2 results “are exciting and represent a new era in weight management in people with type 2 diabetes.
“They mark a real paradigm shift in our ability to treat obesity,” with results closer to those achieved with bariatric surgery, Dr. Davies, of the University of Leicester, England, said in a statement from her institution.
“It is really encouraging,” she continued, “that along with the weight loss we saw real improvements in general health, with significant improvement in physical functioning scores, blood pressure, and blood glucose control.”
Dr. Lingvay noted that on average, patients in the four STEP clinical trials lost 10%-17% of their body weight, “which is a huge step forward compared with all other medications currently available to treat obesity.” She stressed that these results are comparable to the 20%-30% weight loss seen with bariatric surgery.
One of four trials under review
More than 90% of people with type 2 diabetes are overweight or have obesity, and more than 20% of people with obesity have diabetes, wrote Dr. Davies and colleagues.
Semaglutide (Ozempic), administered subcutaneously at a dose of 0.5 mg to 1 mg weekly, is approved by the Food and Drug Administration for the treatment of type 2 diabetes. Dosing studies indicated that it is associated with weight loss.
As previously reported, four trials of the use of semaglutide for weight loss (STEP 1, 2, 3, and 4) have been completed. The combined data were submitted to the FDA on Dec. 4, 2020 (a decision is expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
The STEP 1 and STEP 3 trials of semaglutide 2.4 mg vs. placebo were recently published. The STEP 1 trial involved 1,961 adults with obesity or overweight; the STEP 3 trial, 611 adults with obesity or overweight. In each of the trials, some patients also underwent an intensive lifestyle intervention, and some did not. In both trials, patients with type 2 diabetes were excluded.
Topline results from STEP 2 were reported in June 2020.
STEP 2 enrolled patients with type 2 diabetes
STEP 2 involved 1,210 adults in 149 outpatient clinics in 12 countries in Europe, North America, South America, the Middle East, South Africa, and Asia. All participants had type 2 diabetes.
For all patients, the body mass index was ≥27 kg/m2, and the A1c concentration was 7%-10%. The mean BMI was 35.7 kg/m2, and the mean A1c was 8.1%.
The mean age of the patients was 55 years, and 51% were women; 62% were White, 26% were Asian, 13% were Hispanic, 8% were Black, and 4% were of other ethnicity.
Participants were managed with diet and exercise alone or underwent treatment with a stable dose of up to three oral glucose-lowering agents (metformin, sulfonylureas, SGLT2 inhibitors, or thiazolidinediones) for at least 90 days. They were then randomly assigned in 1:1:1 ratio to receive semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo.
The starting dose of semaglutide was 0.25 mg/wk; the dose was escalated every 4 weeks to reach the target dose.
All patients received monthly counseling from a dietitian about calories (the goal was a 500-calorie/day deficit) and activity (the goal was 150 minutes of walking or stair climbing per week).
The mean A1c dropped by 1.6% and 1.5% in the semaglutide groups and by 0.4% in the placebo group.
Adverse events were more frequent among the patients who received semaglutide (88% and 82%) than in the placebo group (77%).
Gastrointestinal events that were mainly mild to moderate in severity were reported by 64% of patients in the 2.4-mg semaglutide group, 58% in the 1.0-mg semaglutide group, and 34% in the placebo group.
Semaglutide (Rybelsus) is approved in the United States as a once-daily oral agent for use in type 2 diabetes in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
The study was supported by Novo Nordisk. The authors’ relevant financial relationships are listed in the original article.
A version of this article first appeared on Medscape.com.
Decline in weekly child COVID-19 cases has almost stopped
A third COVID-19 vaccine is now in circulation and states are starting to drop mask mandates, but the latest decline in weekly child cases barely registers as a decline, according to new data from the American Academy of Pediatrics and the Children’s Hospital Association.
That’s only 702 cases – a drop of just 1.1% – the smallest by far since weekly cases peaked in mid-January, the AAP and CHA said in their weekly COVID-19 report. Since that peak, the last 7 weeks of declines have looked like this: 21.7%, 15.3%, 16.2%, 15.7%, 28.7%, 9.0%, and 1.1%.
Meanwhile, children’s share of the COVID-19 burden increased to its highest point ever: 18.0% of all new cases occurred in children during the week ending March 4, climbing from 15.7% the week before and eclipsing the previous high of 16.9%. Cumulatively, the 3.23 million cases in children represent 13.2% of all COVID-19 cases reported in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.
At the state level, the new leader in cumulative share of cases is Vermont at 19.4%, which just edged past Wyoming’s 19.3% as of the week ending March 4. The other states above 18% are Alaska (19.2%) and South Carolina (18.2%). The lowest rates can be found in Florida (8.1%), New Jersey (10.2%), Iowa (10.4%), and Utah (10.5%), the AAP and CHA said.
The overall rate of COVID-19 cases nationwide was 4,294 cases per 100,000 children as of March 4, up from 4,209 per 100,000 the week before. That measure had doubled between Dec. 3 (1,941 per 100,000) and Feb. 4 (3,899) but has only risen about 10% in the last month, the AAP/CHA data show.
Perhaps the most surprising news of the week involves the number of COVID-19 deaths in children, which went from 256 the previous week to 253 after Ohio made a downward revision of its mortality data. So far, children represent just 0.06% of all coronavirus-related deaths, a figure that has held steady since last summer in the 43 states (along with New York City and Guam) that are reporting mortality data by age, the AAP and CHA said.
A third COVID-19 vaccine is now in circulation and states are starting to drop mask mandates, but the latest decline in weekly child cases barely registers as a decline, according to new data from the American Academy of Pediatrics and the Children’s Hospital Association.
That’s only 702 cases – a drop of just 1.1% – the smallest by far since weekly cases peaked in mid-January, the AAP and CHA said in their weekly COVID-19 report. Since that peak, the last 7 weeks of declines have looked like this: 21.7%, 15.3%, 16.2%, 15.7%, 28.7%, 9.0%, and 1.1%.
Meanwhile, children’s share of the COVID-19 burden increased to its highest point ever: 18.0% of all new cases occurred in children during the week ending March 4, climbing from 15.7% the week before and eclipsing the previous high of 16.9%. Cumulatively, the 3.23 million cases in children represent 13.2% of all COVID-19 cases reported in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.
At the state level, the new leader in cumulative share of cases is Vermont at 19.4%, which just edged past Wyoming’s 19.3% as of the week ending March 4. The other states above 18% are Alaska (19.2%) and South Carolina (18.2%). The lowest rates can be found in Florida (8.1%), New Jersey (10.2%), Iowa (10.4%), and Utah (10.5%), the AAP and CHA said.
The overall rate of COVID-19 cases nationwide was 4,294 cases per 100,000 children as of March 4, up from 4,209 per 100,000 the week before. That measure had doubled between Dec. 3 (1,941 per 100,000) and Feb. 4 (3,899) but has only risen about 10% in the last month, the AAP/CHA data show.
Perhaps the most surprising news of the week involves the number of COVID-19 deaths in children, which went from 256 the previous week to 253 after Ohio made a downward revision of its mortality data. So far, children represent just 0.06% of all coronavirus-related deaths, a figure that has held steady since last summer in the 43 states (along with New York City and Guam) that are reporting mortality data by age, the AAP and CHA said.
A third COVID-19 vaccine is now in circulation and states are starting to drop mask mandates, but the latest decline in weekly child cases barely registers as a decline, according to new data from the American Academy of Pediatrics and the Children’s Hospital Association.
That’s only 702 cases – a drop of just 1.1% – the smallest by far since weekly cases peaked in mid-January, the AAP and CHA said in their weekly COVID-19 report. Since that peak, the last 7 weeks of declines have looked like this: 21.7%, 15.3%, 16.2%, 15.7%, 28.7%, 9.0%, and 1.1%.
Meanwhile, children’s share of the COVID-19 burden increased to its highest point ever: 18.0% of all new cases occurred in children during the week ending March 4, climbing from 15.7% the week before and eclipsing the previous high of 16.9%. Cumulatively, the 3.23 million cases in children represent 13.2% of all COVID-19 cases reported in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.
At the state level, the new leader in cumulative share of cases is Vermont at 19.4%, which just edged past Wyoming’s 19.3% as of the week ending March 4. The other states above 18% are Alaska (19.2%) and South Carolina (18.2%). The lowest rates can be found in Florida (8.1%), New Jersey (10.2%), Iowa (10.4%), and Utah (10.5%), the AAP and CHA said.
The overall rate of COVID-19 cases nationwide was 4,294 cases per 100,000 children as of March 4, up from 4,209 per 100,000 the week before. That measure had doubled between Dec. 3 (1,941 per 100,000) and Feb. 4 (3,899) but has only risen about 10% in the last month, the AAP/CHA data show.
Perhaps the most surprising news of the week involves the number of COVID-19 deaths in children, which went from 256 the previous week to 253 after Ohio made a downward revision of its mortality data. So far, children represent just 0.06% of all coronavirus-related deaths, a figure that has held steady since last summer in the 43 states (along with New York City and Guam) that are reporting mortality data by age, the AAP and CHA said.
Call to action on obesity amid COVID-19 pandemic
Hundreds of thousands of deaths worldwide from COVID-19 could have been avoided if obesity rates were lower, a new report says.
An analysis by the World Obesity Federation found that of the 2.5 million COVID-19 deaths reported by the end of February 2021, almost 90% (2.2 million) were in countries where more than half the population is classified as overweight.
The report, released to coincide with World Obesity Day, calls for obesity to be recognized as a disease in its own right around the world, and for people with obesity to be included in priority lists for COVID-19 testing and vaccination.
“Overweight is a highly significant predictor of developing complications from COVID-19, including the need for hospitalization, for intensive care and for mechanical ventilation,” the WOF notes in the report.
It adds that in countries where less than half the adult population is classified as overweight (body mass index > 25 mg/kg2), for example, Vietnam, the likelihood of death from COVID-19 is a small fraction – around one-tenth – of the level seen in countries where more than half the population is classified as overweight.
And while it acknowledges that figures for COVID-19 deaths are affected by the age structure of national populations and a country’s relative wealth and reporting capacity, “our findings appear to be independent of these contributory factors. Furthermore, other studies have found that overweight remains a highly significant predictor of the need for COVID-19 health care after accounting for these other influences.”
As an example, based on the U.K. experience, where an estimated 36% of COVID-19 hospitalizations have been attributed to lack of physical activity and excess body weight, it can be suggested that up to a third of the costs – between $6 trillion and $7 trillion over the longer period – might be attributable to these predisposing risks.
The report said the prevalence of obesity in the United Kingdom is expected to rise from 27.8% in 2016 to more than 35% by 2025.
Rachel Batterham, lead adviser on obesity at the Royal College of Physicians, commented: “The link between high levels of obesity and deaths from COVID-19 in the U.K. is indisputable, as is the urgent need to address the factors that lead so many people to be living with obesity.
“With 30% of COVID-19 hospitalizations in the U.K. directly attributed to overweight and obesity, and three-quarters of all critically ill patients having overweight or obesity, the human and financial costs are high.”
Window of opportunity to prioritize obesity as a disease
WOF says that evolving evidence on the close association between COVID-19 and underlying obesity “provides a new urgency … for political and collective action.”
“Obesity is a disease that does not receive prioritization commensurate with its prevalence and impact, which is rising fastest in emerging economies. It is a gateway to many other noncommunicable diseases and mental-health illness and is now a major factor in COVID-19 complications and mortality.”
The WOF also shows that COVID-19 is not a special case, noting that several other respiratory viruses lead to more severe consequences in people living with excess bodyweight, giving good reasons to expect the next pandemic to have similar effects. “For these reasons we need to recognize overweight as a major risk factor for infectious diseases including respiratory viruses.”
“To prevent pandemic health crises in future requires action now: we call on all readers to support the World Obesity Federation’s call for stronger, more resilient economies that prioritize investment in people’s health.”
There is, it stresses, “a window of opportunity to advocate for, fund and implement these actions in all countries to ensure better, more resilient and sustainable health for all, “now and in our postCOVID-19 future.”
It proposes a ROOTS approach:
- Recognize that obesity is a disease in its own right.
- Obesity monitoring and surveillance must be enhanced.
- Obesity prevention strategies must be developed.
- Treatment of obesity.
- Systems-based approaches should be applied.
A version of this article first appeared on Medscape.com.
Hundreds of thousands of deaths worldwide from COVID-19 could have been avoided if obesity rates were lower, a new report says.
An analysis by the World Obesity Federation found that of the 2.5 million COVID-19 deaths reported by the end of February 2021, almost 90% (2.2 million) were in countries where more than half the population is classified as overweight.
The report, released to coincide with World Obesity Day, calls for obesity to be recognized as a disease in its own right around the world, and for people with obesity to be included in priority lists for COVID-19 testing and vaccination.
“Overweight is a highly significant predictor of developing complications from COVID-19, including the need for hospitalization, for intensive care and for mechanical ventilation,” the WOF notes in the report.
It adds that in countries where less than half the adult population is classified as overweight (body mass index > 25 mg/kg2), for example, Vietnam, the likelihood of death from COVID-19 is a small fraction – around one-tenth – of the level seen in countries where more than half the population is classified as overweight.
And while it acknowledges that figures for COVID-19 deaths are affected by the age structure of national populations and a country’s relative wealth and reporting capacity, “our findings appear to be independent of these contributory factors. Furthermore, other studies have found that overweight remains a highly significant predictor of the need for COVID-19 health care after accounting for these other influences.”
As an example, based on the U.K. experience, where an estimated 36% of COVID-19 hospitalizations have been attributed to lack of physical activity and excess body weight, it can be suggested that up to a third of the costs – between $6 trillion and $7 trillion over the longer period – might be attributable to these predisposing risks.
The report said the prevalence of obesity in the United Kingdom is expected to rise from 27.8% in 2016 to more than 35% by 2025.
Rachel Batterham, lead adviser on obesity at the Royal College of Physicians, commented: “The link between high levels of obesity and deaths from COVID-19 in the U.K. is indisputable, as is the urgent need to address the factors that lead so many people to be living with obesity.
“With 30% of COVID-19 hospitalizations in the U.K. directly attributed to overweight and obesity, and three-quarters of all critically ill patients having overweight or obesity, the human and financial costs are high.”
Window of opportunity to prioritize obesity as a disease
WOF says that evolving evidence on the close association between COVID-19 and underlying obesity “provides a new urgency … for political and collective action.”
“Obesity is a disease that does not receive prioritization commensurate with its prevalence and impact, which is rising fastest in emerging economies. It is a gateway to many other noncommunicable diseases and mental-health illness and is now a major factor in COVID-19 complications and mortality.”
The WOF also shows that COVID-19 is not a special case, noting that several other respiratory viruses lead to more severe consequences in people living with excess bodyweight, giving good reasons to expect the next pandemic to have similar effects. “For these reasons we need to recognize overweight as a major risk factor for infectious diseases including respiratory viruses.”
“To prevent pandemic health crises in future requires action now: we call on all readers to support the World Obesity Federation’s call for stronger, more resilient economies that prioritize investment in people’s health.”
There is, it stresses, “a window of opportunity to advocate for, fund and implement these actions in all countries to ensure better, more resilient and sustainable health for all, “now and in our postCOVID-19 future.”
It proposes a ROOTS approach:
- Recognize that obesity is a disease in its own right.
- Obesity monitoring and surveillance must be enhanced.
- Obesity prevention strategies must be developed.
- Treatment of obesity.
- Systems-based approaches should be applied.
A version of this article first appeared on Medscape.com.
Hundreds of thousands of deaths worldwide from COVID-19 could have been avoided if obesity rates were lower, a new report says.
An analysis by the World Obesity Federation found that of the 2.5 million COVID-19 deaths reported by the end of February 2021, almost 90% (2.2 million) were in countries where more than half the population is classified as overweight.
The report, released to coincide with World Obesity Day, calls for obesity to be recognized as a disease in its own right around the world, and for people with obesity to be included in priority lists for COVID-19 testing and vaccination.
“Overweight is a highly significant predictor of developing complications from COVID-19, including the need for hospitalization, for intensive care and for mechanical ventilation,” the WOF notes in the report.
It adds that in countries where less than half the adult population is classified as overweight (body mass index > 25 mg/kg2), for example, Vietnam, the likelihood of death from COVID-19 is a small fraction – around one-tenth – of the level seen in countries where more than half the population is classified as overweight.
And while it acknowledges that figures for COVID-19 deaths are affected by the age structure of national populations and a country’s relative wealth and reporting capacity, “our findings appear to be independent of these contributory factors. Furthermore, other studies have found that overweight remains a highly significant predictor of the need for COVID-19 health care after accounting for these other influences.”
As an example, based on the U.K. experience, where an estimated 36% of COVID-19 hospitalizations have been attributed to lack of physical activity and excess body weight, it can be suggested that up to a third of the costs – between $6 trillion and $7 trillion over the longer period – might be attributable to these predisposing risks.
The report said the prevalence of obesity in the United Kingdom is expected to rise from 27.8% in 2016 to more than 35% by 2025.
Rachel Batterham, lead adviser on obesity at the Royal College of Physicians, commented: “The link between high levels of obesity and deaths from COVID-19 in the U.K. is indisputable, as is the urgent need to address the factors that lead so many people to be living with obesity.
“With 30% of COVID-19 hospitalizations in the U.K. directly attributed to overweight and obesity, and three-quarters of all critically ill patients having overweight or obesity, the human and financial costs are high.”
Window of opportunity to prioritize obesity as a disease
WOF says that evolving evidence on the close association between COVID-19 and underlying obesity “provides a new urgency … for political and collective action.”
“Obesity is a disease that does not receive prioritization commensurate with its prevalence and impact, which is rising fastest in emerging economies. It is a gateway to many other noncommunicable diseases and mental-health illness and is now a major factor in COVID-19 complications and mortality.”
The WOF also shows that COVID-19 is not a special case, noting that several other respiratory viruses lead to more severe consequences in people living with excess bodyweight, giving good reasons to expect the next pandemic to have similar effects. “For these reasons we need to recognize overweight as a major risk factor for infectious diseases including respiratory viruses.”
“To prevent pandemic health crises in future requires action now: we call on all readers to support the World Obesity Federation’s call for stronger, more resilient economies that prioritize investment in people’s health.”
There is, it stresses, “a window of opportunity to advocate for, fund and implement these actions in all countries to ensure better, more resilient and sustainable health for all, “now and in our postCOVID-19 future.”
It proposes a ROOTS approach:
- Recognize that obesity is a disease in its own right.
- Obesity monitoring and surveillance must be enhanced.
- Obesity prevention strategies must be developed.
- Treatment of obesity.
- Systems-based approaches should be applied.
A version of this article first appeared on Medscape.com.
Risdiplam study shows promise for spinal muscular atrophy
, according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A phase 2-3 open-label study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The first oral treatment option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
, according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A phase 2-3 open-label study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The first oral treatment option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
, according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A phase 2-3 open-label study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The first oral treatment option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Federal Government Ramps Up COVID-19 Vaccination Programs
The Biden Administration launched the first phase of the Federally Qualified Health Center (FQHC) Program for COVID-19 Vaccination. Beginning February 15, FQHCs (including centers in the Urban Indian Health Program) began directly receiving vaccines.
The announcement coincided with a boost in vaccine supply for states, Tribes, and territories. In early February, the Biden Administration announced it would expand vaccine supply to 11 million doses nationwide, a 28% increase since January 20, when President Biden took office. According to a White House fact sheet, “The Administration is committing to maintaining this as the minimum supply level for the next three weeks, and we will continue to work with manufacturers in their efforts to ramp up supply.”
In February, President Biden and Vice President Harris travelled to Arizona and toured a vaccination site at State Farm Stadium in Glendale. Arizona, one of the first states to reach out for federal help from the new administration, has 15 counties and 22 Tribes with sovereign lands in the state. Those 37 entities work collaboratively with the Federal Emergency Management Agency (FEMA), said Major General Michael McGuire, head of the Arizona National Guard.
In his remarks during the tour, President Biden addressed equity, saying, “[I]t really does matter that we have access to the people who are most in need [and are] most affected by the COVID crisis, dying at faster rates, getting sick at faster rates, …but not being able to get into the mix. …Equity is a big thing.”
To that end, one of the programs under way is to stand up four vaccination centers for the Navajo Nation. Tammy Littrell, Acting Regional Administrator for FEMA, said the centers will help increase tribal members’ access to vaccination, as well as take the burden off from having to drive in “austere winter conditions.”
In addition to more vaccines, Indian Health Services (IHS) is allocating $1 billion it received to help with COVID-19 response. Of the $1 billion, $790 million will go to testing, contact tracing, containment, and mitigation, among other things. Another $210 million will support IHS, tribal, and urban Indian health programs for vaccine-related activities to ensure broad-based distribution, access, and vaccine coverage. The money is part of the fifth round of supplemental COVID-19 funding from the Coronavirus Response and Relief Supplemental Appropriations Act. The funds transferred so far amount to nearly $3 billion.
According to IHS, the money can be used to scale up testing by public health, academic, commercial, and hospital laboratories, as well as community-based testing sites, mobile testing units, healthcare facilities, and other entities engaged in COVID-19 testing. The funds are also legally available to lease or purchase non-federally owned facilities to improve COVID-19 preparedness and response capability.
The Biden Administration launched the first phase of the Federally Qualified Health Center (FQHC) Program for COVID-19 Vaccination. Beginning February 15, FQHCs (including centers in the Urban Indian Health Program) began directly receiving vaccines.
The announcement coincided with a boost in vaccine supply for states, Tribes, and territories. In early February, the Biden Administration announced it would expand vaccine supply to 11 million doses nationwide, a 28% increase since January 20, when President Biden took office. According to a White House fact sheet, “The Administration is committing to maintaining this as the minimum supply level for the next three weeks, and we will continue to work with manufacturers in their efforts to ramp up supply.”
In February, President Biden and Vice President Harris travelled to Arizona and toured a vaccination site at State Farm Stadium in Glendale. Arizona, one of the first states to reach out for federal help from the new administration, has 15 counties and 22 Tribes with sovereign lands in the state. Those 37 entities work collaboratively with the Federal Emergency Management Agency (FEMA), said Major General Michael McGuire, head of the Arizona National Guard.
In his remarks during the tour, President Biden addressed equity, saying, “[I]t really does matter that we have access to the people who are most in need [and are] most affected by the COVID crisis, dying at faster rates, getting sick at faster rates, …but not being able to get into the mix. …Equity is a big thing.”
To that end, one of the programs under way is to stand up four vaccination centers for the Navajo Nation. Tammy Littrell, Acting Regional Administrator for FEMA, said the centers will help increase tribal members’ access to vaccination, as well as take the burden off from having to drive in “austere winter conditions.”
In addition to more vaccines, Indian Health Services (IHS) is allocating $1 billion it received to help with COVID-19 response. Of the $1 billion, $790 million will go to testing, contact tracing, containment, and mitigation, among other things. Another $210 million will support IHS, tribal, and urban Indian health programs for vaccine-related activities to ensure broad-based distribution, access, and vaccine coverage. The money is part of the fifth round of supplemental COVID-19 funding from the Coronavirus Response and Relief Supplemental Appropriations Act. The funds transferred so far amount to nearly $3 billion.
According to IHS, the money can be used to scale up testing by public health, academic, commercial, and hospital laboratories, as well as community-based testing sites, mobile testing units, healthcare facilities, and other entities engaged in COVID-19 testing. The funds are also legally available to lease or purchase non-federally owned facilities to improve COVID-19 preparedness and response capability.
The Biden Administration launched the first phase of the Federally Qualified Health Center (FQHC) Program for COVID-19 Vaccination. Beginning February 15, FQHCs (including centers in the Urban Indian Health Program) began directly receiving vaccines.
The announcement coincided with a boost in vaccine supply for states, Tribes, and territories. In early February, the Biden Administration announced it would expand vaccine supply to 11 million doses nationwide, a 28% increase since January 20, when President Biden took office. According to a White House fact sheet, “The Administration is committing to maintaining this as the minimum supply level for the next three weeks, and we will continue to work with manufacturers in their efforts to ramp up supply.”
In February, President Biden and Vice President Harris travelled to Arizona and toured a vaccination site at State Farm Stadium in Glendale. Arizona, one of the first states to reach out for federal help from the new administration, has 15 counties and 22 Tribes with sovereign lands in the state. Those 37 entities work collaboratively with the Federal Emergency Management Agency (FEMA), said Major General Michael McGuire, head of the Arizona National Guard.
In his remarks during the tour, President Biden addressed equity, saying, “[I]t really does matter that we have access to the people who are most in need [and are] most affected by the COVID crisis, dying at faster rates, getting sick at faster rates, …but not being able to get into the mix. …Equity is a big thing.”
To that end, one of the programs under way is to stand up four vaccination centers for the Navajo Nation. Tammy Littrell, Acting Regional Administrator for FEMA, said the centers will help increase tribal members’ access to vaccination, as well as take the burden off from having to drive in “austere winter conditions.”
In addition to more vaccines, Indian Health Services (IHS) is allocating $1 billion it received to help with COVID-19 response. Of the $1 billion, $790 million will go to testing, contact tracing, containment, and mitigation, among other things. Another $210 million will support IHS, tribal, and urban Indian health programs for vaccine-related activities to ensure broad-based distribution, access, and vaccine coverage. The money is part of the fifth round of supplemental COVID-19 funding from the Coronavirus Response and Relief Supplemental Appropriations Act. The funds transferred so far amount to nearly $3 billion.
According to IHS, the money can be used to scale up testing by public health, academic, commercial, and hospital laboratories, as well as community-based testing sites, mobile testing units, healthcare facilities, and other entities engaged in COVID-19 testing. The funds are also legally available to lease or purchase non-federally owned facilities to improve COVID-19 preparedness and response capability.
Pediatric TB – more work needed, especially with HIV-coinfection
Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.
“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.
Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
TB and CLHIV
Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.
Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
Pediatric TB diagnosis
Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.
However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.
In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.
“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
Pediatric TB treatment
Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.
Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.
In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.
Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.
“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.
Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.
Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.
Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.
“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.
Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.
Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.
“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.
Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
TB and CLHIV
Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.
Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
Pediatric TB diagnosis
Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.
However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.
In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.
“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
Pediatric TB treatment
Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.
Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.
In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.
Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.
“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.
Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.
Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.
Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.
“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.
Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.
Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.
“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.
Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
TB and CLHIV
Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.
Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
Pediatric TB diagnosis
Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.
However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.
In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.
“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
Pediatric TB treatment
Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.
Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.
In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.
Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.
“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.
Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.
Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.
Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.
“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.
Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.
FROM CROI 2021
Are long-acting injectables the future of TB treatment?
Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.
“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.
He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
Current TB preventive therapies
Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.
While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
LAI drugs
LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.
The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.
Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.
“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.
Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.
Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.
Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
Considerations for development and implementation
“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.
Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.
Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.
“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).
“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.
“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.
While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.
Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.
Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.
“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.
He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
Current TB preventive therapies
Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.
While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
LAI drugs
LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.
The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.
Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.
“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.
Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.
Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.
Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
Considerations for development and implementation
“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.
Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.
Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.
“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).
“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.
“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.
While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.
Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.
Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.
“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.
He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
Current TB preventive therapies
Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.
While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
LAI drugs
LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.
The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.
Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.
“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.
Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.
Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.
Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
Considerations for development and implementation
“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.
Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.
Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.
“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).
“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.
“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.
While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.
Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.
FROM CROI 2021
Who do you call in those late, quiet hours, when all seems lost?
I swear by Apollo Physician and Asclepius and Hygeia and Panacea and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant.
On my desk sits a bust of Hygeia, a mask from Venice, next to a small sculpture and a figurine of the plague doctor. Nearby, there is a Klimt closeup of Hygeia, a postcard portraying Asclepius, St. Sebastian paintings, and quotes from Maimonides. They whisper secrets and nod to the challenges of the past. These medical specters, ancient voices of the past, keep me grounded. They speak, listen, and elevate me, too. They bring life into my otherwise quiet room.
We all began our careers swearing to Apollo, Asclepius, Hygeia, and Panacea when we recited the Hippocratic Oath. I call upon them, and other gods and totems, and saints and ancient healers, now more than ever. As an atheist, I don’t appeal to them as prayers, but as Hippocrates intended. I look to their supernatural healing powers as a source of strength and as revealers of the natural and observable phenomena.
Apollo was one of the Twelve Olympians, a God of medicine, father of Asclepius. He was a healer, though his arrows also bore the plagues of the Gods.
For centuries, Apollo was found floating above the marble dissection table in the Bologna anatomical theater, guiding students who dove into the secrets of the human body.
Asclepius, son of Apollo, was hailed as a god of medicine. He healed many from plagues at his temples throughout the Ancient Greek and Roman empires. He was mentored in the healing arts by the centaur, Chiron. His many daughters and sons represent various aspects of medicine including cures, healing, recovery, sanitation, and beauty. To Asclepius, temples were places of healing, an ancient ancestor to modern hospitals.
Two of his daughters, Panacea and Hygeia, gave us the healing words of panacea and hygiene. Today, these acts of hygiene, handwashing, mask-wearing, and sanitation are discussed across the world louder than ever. While we’re all wishing for a panacea, we know it will take all the attributes of medicine to get us through this pandemic.
Hospitalists are part of the frontline teams facing this pandemic head-on. Gowning up for MRSA isolation seems quaint nowadays.
My attendings spoke of their fears, up against the unknown while on service in the 1980s, when HIV appeared. 2014 brought the Ebola biocontainment units. Now, this generation works daily against a modern plague, where every day is a risk of exposure. When every patient is in isolation, the garb begins to reflect the PPE that emerged during a 17th-century plague epidemics, the plague doctor outfit.
Godfather II fans recall the famous portrayal of the August 16th festival to San Rocco play out in the streets of New York. For those stricken with COVID-19 and recovered, you emulate San Rocco, in your continued return to service.
The Scuola Grande di San Rocco, in Venice, is the epitome of healing and greatness in one building. Tintoretto, the great Venetian painter, assembled the story of healing through art and portraits of San Rocco. The scuola, a confraternity, was a community of healers, gathered in one place to look after the less fortunate.
Hospitalists march into the hospital risking their lives. We always wear PPE for MRSA, ESBL, or C. diff. And enter reverse isolation rooms wearing N95s for possible TB cases. But those don’t elevate to the volume, to the same fear, as gowning up for COVID-19.
Hospitalists, frontline health care workers, embody the story of San Sebastian, another plague saint who absorbed the arrows, the symbolic plagues, onto his own shoulders so no one else had to bear them. San Sebastian was a Christian persecuted by a Roman emperor once his beliefs were discovered. He is often laden with arrows in spots where buboes would have appeared: the armpits and the groin. His sacrifice for others’ recovery became a symbol of absorbing the plague, the wounds, and the impact of the arrows.
This sacrifice epitomizes the daily work the frontline nurses, ER docs, intensivists, hospitalists, and the entire hospital staff perform daily, bearing the slung arrows of coronavirus.
One of the images I think of frequently during this time lies atop Castel San Angelo in Rome. Built in 161 AD, it has served as a mausoleum, prison, papal residence, and is currently a museum. Atop San’Angelo stands St. Michael, the destroyer of the dragon. He is sheathing his sword in representation of the end of the plague in 590.
The arrows flow, yet the sword will be sheathed. Evil will be halted. The stories of these ancient totems and strength can give us strength as they remind us of the work that was done for centuries: pestilence, famine, war. The great killers never go away completely.
Fast forward to today
These medical specters serve as reminders of what makes the field of medicine so inspiring: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories, we spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day. These specters encourage us to defeat any and all of the scourges that come our way.
I hear and read stories about the frontline heroes, the vaccine makers, the PPE creators, the health care workers, grocery store clerks, and teachers. I’m honored to hear of these stories and your sacrifices. I’m inspired to continue upholding your essence, your fight, and your stories. In keeping with ancient empire metaphors, you are taking the slings of the diseased arrows flying to our brethren as you try to keep yourself and others safe.
The sheathing of this sword will come. These arrows will be silenced. But until then, I lean on these pictures, these stories, and these saints, to give us all the strength to wake up each morning and continue healing.
They serve as reminders of what makes the field of medicine so great: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day and defeat any and all scourges that come our way.
So, who do you call in those late, quiet hours, when all seems lost?
Dr. Messler is the executive director, quality initiatives at Glytec and works as a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. This essay appeared initially on The Hospital Leader, the official blog of SHM.
I swear by Apollo Physician and Asclepius and Hygeia and Panacea and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant.
On my desk sits a bust of Hygeia, a mask from Venice, next to a small sculpture and a figurine of the plague doctor. Nearby, there is a Klimt closeup of Hygeia, a postcard portraying Asclepius, St. Sebastian paintings, and quotes from Maimonides. They whisper secrets and nod to the challenges of the past. These medical specters, ancient voices of the past, keep me grounded. They speak, listen, and elevate me, too. They bring life into my otherwise quiet room.
We all began our careers swearing to Apollo, Asclepius, Hygeia, and Panacea when we recited the Hippocratic Oath. I call upon them, and other gods and totems, and saints and ancient healers, now more than ever. As an atheist, I don’t appeal to them as prayers, but as Hippocrates intended. I look to their supernatural healing powers as a source of strength and as revealers of the natural and observable phenomena.
Apollo was one of the Twelve Olympians, a God of medicine, father of Asclepius. He was a healer, though his arrows also bore the plagues of the Gods.
For centuries, Apollo was found floating above the marble dissection table in the Bologna anatomical theater, guiding students who dove into the secrets of the human body.
Asclepius, son of Apollo, was hailed as a god of medicine. He healed many from plagues at his temples throughout the Ancient Greek and Roman empires. He was mentored in the healing arts by the centaur, Chiron. His many daughters and sons represent various aspects of medicine including cures, healing, recovery, sanitation, and beauty. To Asclepius, temples were places of healing, an ancient ancestor to modern hospitals.
Two of his daughters, Panacea and Hygeia, gave us the healing words of panacea and hygiene. Today, these acts of hygiene, handwashing, mask-wearing, and sanitation are discussed across the world louder than ever. While we’re all wishing for a panacea, we know it will take all the attributes of medicine to get us through this pandemic.
Hospitalists are part of the frontline teams facing this pandemic head-on. Gowning up for MRSA isolation seems quaint nowadays.
My attendings spoke of their fears, up against the unknown while on service in the 1980s, when HIV appeared. 2014 brought the Ebola biocontainment units. Now, this generation works daily against a modern plague, where every day is a risk of exposure. When every patient is in isolation, the garb begins to reflect the PPE that emerged during a 17th-century plague epidemics, the plague doctor outfit.
Godfather II fans recall the famous portrayal of the August 16th festival to San Rocco play out in the streets of New York. For those stricken with COVID-19 and recovered, you emulate San Rocco, in your continued return to service.
The Scuola Grande di San Rocco, in Venice, is the epitome of healing and greatness in one building. Tintoretto, the great Venetian painter, assembled the story of healing through art and portraits of San Rocco. The scuola, a confraternity, was a community of healers, gathered in one place to look after the less fortunate.
Hospitalists march into the hospital risking their lives. We always wear PPE for MRSA, ESBL, or C. diff. And enter reverse isolation rooms wearing N95s for possible TB cases. But those don’t elevate to the volume, to the same fear, as gowning up for COVID-19.
Hospitalists, frontline health care workers, embody the story of San Sebastian, another plague saint who absorbed the arrows, the symbolic plagues, onto his own shoulders so no one else had to bear them. San Sebastian was a Christian persecuted by a Roman emperor once his beliefs were discovered. He is often laden with arrows in spots where buboes would have appeared: the armpits and the groin. His sacrifice for others’ recovery became a symbol of absorbing the plague, the wounds, and the impact of the arrows.
This sacrifice epitomizes the daily work the frontline nurses, ER docs, intensivists, hospitalists, and the entire hospital staff perform daily, bearing the slung arrows of coronavirus.
One of the images I think of frequently during this time lies atop Castel San Angelo in Rome. Built in 161 AD, it has served as a mausoleum, prison, papal residence, and is currently a museum. Atop San’Angelo stands St. Michael, the destroyer of the dragon. He is sheathing his sword in representation of the end of the plague in 590.
The arrows flow, yet the sword will be sheathed. Evil will be halted. The stories of these ancient totems and strength can give us strength as they remind us of the work that was done for centuries: pestilence, famine, war. The great killers never go away completely.
Fast forward to today
These medical specters serve as reminders of what makes the field of medicine so inspiring: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories, we spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day. These specters encourage us to defeat any and all of the scourges that come our way.
I hear and read stories about the frontline heroes, the vaccine makers, the PPE creators, the health care workers, grocery store clerks, and teachers. I’m honored to hear of these stories and your sacrifices. I’m inspired to continue upholding your essence, your fight, and your stories. In keeping with ancient empire metaphors, you are taking the slings of the diseased arrows flying to our brethren as you try to keep yourself and others safe.
The sheathing of this sword will come. These arrows will be silenced. But until then, I lean on these pictures, these stories, and these saints, to give us all the strength to wake up each morning and continue healing.
They serve as reminders of what makes the field of medicine so great: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day and defeat any and all scourges that come our way.
So, who do you call in those late, quiet hours, when all seems lost?
Dr. Messler is the executive director, quality initiatives at Glytec and works as a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. This essay appeared initially on The Hospital Leader, the official blog of SHM.
I swear by Apollo Physician and Asclepius and Hygeia and Panacea and all the gods and goddesses, making them my witnesses, that I will fulfill according to my ability and judgment this oath and this covenant.
On my desk sits a bust of Hygeia, a mask from Venice, next to a small sculpture and a figurine of the plague doctor. Nearby, there is a Klimt closeup of Hygeia, a postcard portraying Asclepius, St. Sebastian paintings, and quotes from Maimonides. They whisper secrets and nod to the challenges of the past. These medical specters, ancient voices of the past, keep me grounded. They speak, listen, and elevate me, too. They bring life into my otherwise quiet room.
We all began our careers swearing to Apollo, Asclepius, Hygeia, and Panacea when we recited the Hippocratic Oath. I call upon them, and other gods and totems, and saints and ancient healers, now more than ever. As an atheist, I don’t appeal to them as prayers, but as Hippocrates intended. I look to their supernatural healing powers as a source of strength and as revealers of the natural and observable phenomena.
Apollo was one of the Twelve Olympians, a God of medicine, father of Asclepius. He was a healer, though his arrows also bore the plagues of the Gods.
For centuries, Apollo was found floating above the marble dissection table in the Bologna anatomical theater, guiding students who dove into the secrets of the human body.
Asclepius, son of Apollo, was hailed as a god of medicine. He healed many from plagues at his temples throughout the Ancient Greek and Roman empires. He was mentored in the healing arts by the centaur, Chiron. His many daughters and sons represent various aspects of medicine including cures, healing, recovery, sanitation, and beauty. To Asclepius, temples were places of healing, an ancient ancestor to modern hospitals.
Two of his daughters, Panacea and Hygeia, gave us the healing words of panacea and hygiene. Today, these acts of hygiene, handwashing, mask-wearing, and sanitation are discussed across the world louder than ever. While we’re all wishing for a panacea, we know it will take all the attributes of medicine to get us through this pandemic.
Hospitalists are part of the frontline teams facing this pandemic head-on. Gowning up for MRSA isolation seems quaint nowadays.
My attendings spoke of their fears, up against the unknown while on service in the 1980s, when HIV appeared. 2014 brought the Ebola biocontainment units. Now, this generation works daily against a modern plague, where every day is a risk of exposure. When every patient is in isolation, the garb begins to reflect the PPE that emerged during a 17th-century plague epidemics, the plague doctor outfit.
Godfather II fans recall the famous portrayal of the August 16th festival to San Rocco play out in the streets of New York. For those stricken with COVID-19 and recovered, you emulate San Rocco, in your continued return to service.
The Scuola Grande di San Rocco, in Venice, is the epitome of healing and greatness in one building. Tintoretto, the great Venetian painter, assembled the story of healing through art and portraits of San Rocco. The scuola, a confraternity, was a community of healers, gathered in one place to look after the less fortunate.
Hospitalists march into the hospital risking their lives. We always wear PPE for MRSA, ESBL, or C. diff. And enter reverse isolation rooms wearing N95s for possible TB cases. But those don’t elevate to the volume, to the same fear, as gowning up for COVID-19.
Hospitalists, frontline health care workers, embody the story of San Sebastian, another plague saint who absorbed the arrows, the symbolic plagues, onto his own shoulders so no one else had to bear them. San Sebastian was a Christian persecuted by a Roman emperor once his beliefs were discovered. He is often laden with arrows in spots where buboes would have appeared: the armpits and the groin. His sacrifice for others’ recovery became a symbol of absorbing the plague, the wounds, and the impact of the arrows.
This sacrifice epitomizes the daily work the frontline nurses, ER docs, intensivists, hospitalists, and the entire hospital staff perform daily, bearing the slung arrows of coronavirus.
One of the images I think of frequently during this time lies atop Castel San Angelo in Rome. Built in 161 AD, it has served as a mausoleum, prison, papal residence, and is currently a museum. Atop San’Angelo stands St. Michael, the destroyer of the dragon. He is sheathing his sword in representation of the end of the plague in 590.
The arrows flow, yet the sword will be sheathed. Evil will be halted. The stories of these ancient totems and strength can give us strength as they remind us of the work that was done for centuries: pestilence, famine, war. The great killers never go away completely.
Fast forward to today
These medical specters serve as reminders of what makes the field of medicine so inspiring: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories, we spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day. These specters encourage us to defeat any and all of the scourges that come our way.
I hear and read stories about the frontline heroes, the vaccine makers, the PPE creators, the health care workers, grocery store clerks, and teachers. I’m honored to hear of these stories and your sacrifices. I’m inspired to continue upholding your essence, your fight, and your stories. In keeping with ancient empire metaphors, you are taking the slings of the diseased arrows flying to our brethren as you try to keep yourself and others safe.
The sheathing of this sword will come. These arrows will be silenced. But until then, I lean on these pictures, these stories, and these saints, to give us all the strength to wake up each morning and continue healing.
They serve as reminders of what makes the field of medicine so great: the selfless acts, the fortitude of spirit, the healers, the long history, and the shoulders of giants we stand upon. From these stories spring the healing waters we bathe in to give us the courage to wake up and care for our patients each day and defeat any and all scourges that come our way.
So, who do you call in those late, quiet hours, when all seems lost?
Dr. Messler is the executive director, quality initiatives at Glytec and works as a hospitalist at Morton Plant Hospitalist group in Clearwater, Fla. This essay appeared initially on The Hospital Leader, the official blog of SHM.