Sara Freeman

LIVERPOOL, ENGLAND – Anti–tumor necrosis factor treatment significantly decreased fatigue in patients with rheumatoid arthritis in an analysis of data from the British Society for Rheumatology Biologics Registers Rheumatoid Arthritis Register.

Of 6,835 patients included in the analysis, 38.8% reported high levels of fatigue at baseline, which was defined as a score of 12.5 or less on the vitality domain of the Short Form (SF)-36. Of these, 66% reported clinically relevant improvements of 10 U or more on the SF-36 vitality domain 6 months after starting anti–tumor necrosis factor (TNF) treatment.

"Randomized controlled trials have shown modest improvements in fatigue with anti-TNF therapy, but fatigue has not been the primary research question in these trials, and so that led us to ask what the effect would be in patients who had clinically relevant symptoms," said Katie Druce, who performed the research as part of her postgraduate studies at the University of Aberdeen (Scotland).

Data on 13,122 patients with RA who started treatment with etanercept, adalimumab, or infliximab between 2000 and 2008 were initially considered, but only those who had data on fatigue available at baseline and at 6-month assessments were included in the analysis.

At baseline, the mean age of participants was 57 years, and most (77%) were female and white (97%). A total of 31% were not working because of illness. The patients had mean scores of 6.57 on the 28-joint Disease Activity Score, 21.1 on the bodily pain and 24.8 on the vitality domains of the SF-36, and 2.03 on the mean Health Assessment Questionnaire Disability Index.

Fatigue improved at 6 months

Ms. Druce reported at the British Society for Rheumatology (BSR) annual conference that there was an absolute improvement in fatigue at 6 months of 22.5 U in the 2,652 patients who had reported a high level of fatigue at baseline. This exceeded the value of 10 U or more that was conservatively set as the minimum clinically important difference (MCID). Furthermore, in the patients who improved – that is going from a high level to a low level of fatigue – the difference was even greater, with improvement three times the MCID, at about 32 U.

Baseline predictors of improvement included being in good mental health, no history of hypertension or depression, and not being unemployed because of ill health. Other predictors included being female, rheumatoid factor positive, having a low level of disability, and not using steroids. Patients with multiple baseline predictors of improvement appeared to have the largest absolute improvement in fatigue at 6 months.

"Importantly, we saw no association with disease activity or measures of inflammation," Ms. Druce said, and the specific anti-TNF drug used was also not influential on the findings. She noted that baseline predictors of fatigue might be able to help stratify patients who need specific fatigue management.

Pain drives fatigue in RA

The improvements in RA-related fatigue seen with biologic therapy were driven by decreases in pain and not disease activity, Ms. Druce said, reporting the finding of a separate analysis elsewhere at the conference.

"Anecdotally, from both clinicians and patients, we know that they consider fatigue to be caused by disease activity, but when we look at the evidence from the literature, we see that there is an inconsistent link between fatigue and disease activity," she said. "Yet we know that fatigue improves after anti-TNF therapy commences. So this led us to look at which variables are driving change in fatigue that we see after anti-TNF therapies are commenced," she said.

Ms. Druce and her colleagues used structural equation modeling, which evaluates the effect of one variable on an outcome and the pathway by which it has that effect, to find that for every 1–standard deviation increase in change in disease activity, there was a 0.05 increase in change in fatigue. Although this does indicate some improvement, change in pain had a greater effect, with every 1–standard deviation increase in change in pain linked to a 0.31 increase in change in fatigue.

"What we found was that 82% of the effect of change in disease activity is mediated through other variables in [our] model," Ms. Druce explained. Indeed, it was found that almost two-thirds of the change in fatigue was mediated by pain (or pain and mental health), 27% through disability (or disability and mental health), and 9% directly through mental health.

"This led us to conclude that improvements in fatigue after commencing anti-TNF therapies are driven by improvements in pain rather than directly from disease activity, but that mental health and disability are also important, and, along with pain, represent potentially modifiable factors for us to target in routine treatment," Ms. Druce said.

How can fatigue be assessed?

Fatigue is an important facet of RA that should be included in patient assessment, said Sara Hewlett, Ph.D., professor of nursing at the University of the West of England in Bristol.

Speaking during a session organized by the BSR’s Specialist Interest Group in RA, she noted that there are three reasons why fatigue is important to assess: It is important to patients, it provides information beyond disease activity, and it responds to several interventions, including physical activity, psychological strategies, and biologic medications.

Dr. Hewlett noted that there have been many instruments used to try to assess fatigue in clinical trials, but none was specifically developed to assess fatigue in patients with RA, and many were not developed using recommended methodology. That was until the development and validation of the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scales (BRAF NRS).

On the BRAF NRS, patients circle a number from 0 to 10 to indicate the average level of fatigue that they have experienced, the impact that fatigue has had on them, and how well they have subsequently coped, in the past 7 days.

Ms. Druce said she had no financial disclosures. One of her coauthors had received honoraria and research funding from Pfizer and had been a consultant for Merck Sharp & Dohme. Ms. Hewlett said she had no disclosures other than helping to develop the BRAF NRS.

LIVERPOOL, ENGLAND – Anti–tumor necrosis factor treatment significantly decreased fatigue in patients with rheumatoid arthritis in an analysis of data from the British Society for Rheumatology Biologics Registers Rheumatoid Arthritis Register.

Of 6,835 patients included in the analysis, 38.8% reported high levels of fatigue at baseline, which was defined as a score of 12.5 or less on the vitality domain of the Short Form (SF)-36. Of these, 66% reported clinically relevant improvements of 10 U or more on the SF-36 vitality domain 6 months after starting anti–tumor necrosis factor (TNF) treatment.

"Randomized controlled trials have shown modest improvements in fatigue with anti-TNF therapy, but fatigue has not been the primary research question in these trials, and so that led us to ask what the effect would be in patients who had clinically relevant symptoms," said Katie Druce, who performed the research as part of her postgraduate studies at the University of Aberdeen (Scotland).

Data on 13,122 patients with RA who started treatment with etanercept, adalimumab, or infliximab between 2000 and 2008 were initially considered, but only those who had data on fatigue available at baseline and at 6-month assessments were included in the analysis.

At baseline, the mean age of participants was 57 years, and most (77%) were female and white (97%). A total of 31% were not working because of illness. The patients had mean scores of 6.57 on the 28-joint Disease Activity Score, 21.1 on the bodily pain and 24.8 on the vitality domains of the SF-36, and 2.03 on the mean Health Assessment Questionnaire Disability Index.

Fatigue improved at 6 months

Ms. Druce reported at the British Society for Rheumatology (BSR) annual conference that there was an absolute improvement in fatigue at 6 months of 22.5 U in the 2,652 patients who had reported a high level of fatigue at baseline. This exceeded the value of 10 U or more that was conservatively set as the minimum clinically important difference (MCID). Furthermore, in the patients who improved – that is going from a high level to a low level of fatigue – the difference was even greater, with improvement three times the MCID, at about 32 U.

Baseline predictors of improvement included being in good mental health, no history of hypertension or depression, and not being unemployed because of ill health. Other predictors included being female, rheumatoid factor positive, having a low level of disability, and not using steroids. Patients with multiple baseline predictors of improvement appeared to have the largest absolute improvement in fatigue at 6 months.

"Importantly, we saw no association with disease activity or measures of inflammation," Ms. Druce said, and the specific anti-TNF drug used was also not influential on the findings. She noted that baseline predictors of fatigue might be able to help stratify patients who need specific fatigue management.

Pain drives fatigue in RA

The improvements in RA-related fatigue seen with biologic therapy were driven by decreases in pain and not disease activity, Ms. Druce said, reporting the finding of a separate analysis elsewhere at the conference.

"Anecdotally, from both clinicians and patients, we know that they consider fatigue to be caused by disease activity, but when we look at the evidence from the literature, we see that there is an inconsistent link between fatigue and disease activity," she said. "Yet we know that fatigue improves after anti-TNF therapy commences. So this led us to look at which variables are driving change in fatigue that we see after anti-TNF therapies are commenced," she said.

Ms. Druce and her colleagues used structural equation modeling, which evaluates the effect of one variable on an outcome and the pathway by which it has that effect, to find that for every 1–standard deviation increase in change in disease activity, there was a 0.05 increase in change in fatigue. Although this does indicate some improvement, change in pain had a greater effect, with every 1–standard deviation increase in change in pain linked to a 0.31 increase in change in fatigue.

"What we found was that 82% of the effect of change in disease activity is mediated through other variables in [our] model," Ms. Druce explained. Indeed, it was found that almost two-thirds of the change in fatigue was mediated by pain (or pain and mental health), 27% through disability (or disability and mental health), and 9% directly through mental health.

"This led us to conclude that improvements in fatigue after commencing anti-TNF therapies are driven by improvements in pain rather than directly from disease activity, but that mental health and disability are also important, and, along with pain, represent potentially modifiable factors for us to target in routine treatment," Ms. Druce said.

How can fatigue be assessed?

Fatigue is an important facet of RA that should be included in patient assessment, said Sara Hewlett, Ph.D., professor of nursing at the University of the West of England in Bristol.

Speaking during a session organized by the BSR’s Specialist Interest Group in RA, she noted that there are three reasons why fatigue is important to assess: It is important to patients, it provides information beyond disease activity, and it responds to several interventions, including physical activity, psychological strategies, and biologic medications.

Dr. Hewlett noted that there have been many instruments used to try to assess fatigue in clinical trials, but none was specifically developed to assess fatigue in patients with RA, and many were not developed using recommended methodology. That was until the development and validation of the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scales (BRAF NRS).

On the BRAF NRS, patients circle a number from 0 to 10 to indicate the average level of fatigue that they have experienced, the impact that fatigue has had on them, and how well they have subsequently coped, in the past 7 days.

Ms. Druce said she had no financial disclosures. One of her coauthors had received honoraria and research funding from Pfizer and had been a consultant for Merck Sharp & Dohme. Ms. Hewlett said she had no disclosures other than helping to develop the BRAF NRS.

LIVERPOOL, ENGLAND – Anti–tumor necrosis factor treatment significantly decreased fatigue in patients with rheumatoid arthritis in an analysis of data from the British Society for Rheumatology Biologics Registers Rheumatoid Arthritis Register.

Of 6,835 patients included in the analysis, 38.8% reported high levels of fatigue at baseline, which was defined as a score of 12.5 or less on the vitality domain of the Short Form (SF)-36. Of these, 66% reported clinically relevant improvements of 10 U or more on the SF-36 vitality domain 6 months after starting anti–tumor necrosis factor (TNF) treatment.

"Randomized controlled trials have shown modest improvements in fatigue with anti-TNF therapy, but fatigue has not been the primary research question in these trials, and so that led us to ask what the effect would be in patients who had clinically relevant symptoms," said Katie Druce, who performed the research as part of her postgraduate studies at the University of Aberdeen (Scotland).

Data on 13,122 patients with RA who started treatment with etanercept, adalimumab, or infliximab between 2000 and 2008 were initially considered, but only those who had data on fatigue available at baseline and at 6-month assessments were included in the analysis.

At baseline, the mean age of participants was 57 years, and most (77%) were female and white (97%). A total of 31% were not working because of illness. The patients had mean scores of 6.57 on the 28-joint Disease Activity Score, 21.1 on the bodily pain and 24.8 on the vitality domains of the SF-36, and 2.03 on the mean Health Assessment Questionnaire Disability Index.

Fatigue improved at 6 months

Ms. Druce reported at the British Society for Rheumatology (BSR) annual conference that there was an absolute improvement in fatigue at 6 months of 22.5 U in the 2,652 patients who had reported a high level of fatigue at baseline. This exceeded the value of 10 U or more that was conservatively set as the minimum clinically important difference (MCID). Furthermore, in the patients who improved – that is going from a high level to a low level of fatigue – the difference was even greater, with improvement three times the MCID, at about 32 U.

Baseline predictors of improvement included being in good mental health, no history of hypertension or depression, and not being unemployed because of ill health. Other predictors included being female, rheumatoid factor positive, having a low level of disability, and not using steroids. Patients with multiple baseline predictors of improvement appeared to have the largest absolute improvement in fatigue at 6 months.

"Importantly, we saw no association with disease activity or measures of inflammation," Ms. Druce said, and the specific anti-TNF drug used was also not influential on the findings. She noted that baseline predictors of fatigue might be able to help stratify patients who need specific fatigue management.

Pain drives fatigue in RA

The improvements in RA-related fatigue seen with biologic therapy were driven by decreases in pain and not disease activity, Ms. Druce said, reporting the finding of a separate analysis elsewhere at the conference.

"Anecdotally, from both clinicians and patients, we know that they consider fatigue to be caused by disease activity, but when we look at the evidence from the literature, we see that there is an inconsistent link between fatigue and disease activity," she said. "Yet we know that fatigue improves after anti-TNF therapy commences. So this led us to look at which variables are driving change in fatigue that we see after anti-TNF therapies are commenced," she said.

Ms. Druce and her colleagues used structural equation modeling, which evaluates the effect of one variable on an outcome and the pathway by which it has that effect, to find that for every 1–standard deviation increase in change in disease activity, there was a 0.05 increase in change in fatigue. Although this does indicate some improvement, change in pain had a greater effect, with every 1–standard deviation increase in change in pain linked to a 0.31 increase in change in fatigue.

"What we found was that 82% of the effect of change in disease activity is mediated through other variables in [our] model," Ms. Druce explained. Indeed, it was found that almost two-thirds of the change in fatigue was mediated by pain (or pain and mental health), 27% through disability (or disability and mental health), and 9% directly through mental health.

"This led us to conclude that improvements in fatigue after commencing anti-TNF therapies are driven by improvements in pain rather than directly from disease activity, but that mental health and disability are also important, and, along with pain, represent potentially modifiable factors for us to target in routine treatment," Ms. Druce said.

How can fatigue be assessed?

Fatigue is an important facet of RA that should be included in patient assessment, said Sara Hewlett, Ph.D., professor of nursing at the University of the West of England in Bristol.

Speaking during a session organized by the BSR’s Specialist Interest Group in RA, she noted that there are three reasons why fatigue is important to assess: It is important to patients, it provides information beyond disease activity, and it responds to several interventions, including physical activity, psychological strategies, and biologic medications.

Dr. Hewlett noted that there have been many instruments used to try to assess fatigue in clinical trials, but none was specifically developed to assess fatigue in patients with RA, and many were not developed using recommended methodology. That was until the development and validation of the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scales (BRAF NRS).

On the BRAF NRS, patients circle a number from 0 to 10 to indicate the average level of fatigue that they have experienced, the impact that fatigue has had on them, and how well they have subsequently coped, in the past 7 days.

Ms. Druce said she had no financial disclosures. One of her coauthors had received honoraria and research funding from Pfizer and had been a consultant for Merck Sharp & Dohme. Ms. Hewlett said she had no disclosures other than helping to develop the BRAF NRS.

LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.

Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.

Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.

"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.

"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.

"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.

"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.

Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.

All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.

Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).

"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.

"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).

"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.

Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.

He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."

The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.

LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.

Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.

Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.

"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.

"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.

"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.

"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.

Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.

All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.

Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).

"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.

"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).

"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.

Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.

He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."

The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.

LIVERPOOL, ENGLAND – Reducing the once-weekly maintenance dose of etanercept from 50 mg to 25 mg was associated with worsening control of ankylosing spondylitis in an open-label, multicenter, pilot study.

Results of the ANSWER (Ankylosing Spondylitis with Etanercept Regimens) trial showed that halving the dose of the biologic almost halved the percentage of patients maintaining disease control at 6 months, from 92% to 52% of patients.

Although this was a small study, involving just 47 patients who were randomized to continue etanercept at a weekly dose of 50 mg (n = 24) or to drop down to 25 mg (n = 23) after competing 6 months’ treatment, the results suggest that other approaches are needed to see if the long-term dose of the drug can be reduced, commented study investigator Dr. Karl Gaffney of Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, England.

"A larger study is required to identify patients suitable for step-down," Dr. Gaffney said at the British Society for Rheumatology annual conference.

"We all know that anti-TNF [tumor necrosis factor] therapy is firmly established in clinical practice for patients with ankylosing spondylitis and this treatment has transformed the quality of life for many of our patients," Dr. Gaffney observed.

"The concept of dose reduction is very appealing from an economic perspective, but also in terms of the cumulative exposure and the risk of adverse effects," he added.

"In patients with rheumatoid arthritis, it’s been shown that lower doses may maintain the clinical response," Dr. Gaffney explained, citing the PRESERVE study published last year (Lancet 2013;381:918-29). However, there are limited data about whether reducing the dose of etanercept could also be successful in ankylosing spondylitis (AS) patients. This is why the ANSWER study was performed.

Patients with active AS who were not responding to conventional therapies and had not yet been treated with a biologic drug were consecutively recruited at two hospitals in England between September 2010 and September 2012. For inclusion, patients had to have sustained spinal disease and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of four or higher. The mean age of patients in the trial was 46.7 years, and the mean BASDAI at baseline was 6.8.

All recruited patients were treated with 50 mg etanercept, once weekly, for 6 months, and those with a "sufficient" clinical response were randomized to either continue this dose for a further 6 months or step down to 25 mg for continued maintenance treatment. A sufficient clinical response was defined as a 50% reduction in BASDAI or a fall of two or more units plus reduction in axial pain of 2 cm or more.

Three months into the maintenance period, patients who had been randomized to the step-down arm started to experience loss of disease control (60.9% vs. 91.7% of 50 mg–treated patients), with the gap widening by 6 months postrandomization and 39% fewer patients maintaining disease control (P = .003).

"There’s no doubt that the 50-mg group did better," Dr. Gaffney said. There were also statistically significant differences favoring the higher dose in a number of secondary outcome measures, which included other measurements of AS disease activity and quality of life. There were no significant differences in terms of adverse events between the two groups.

"However, 52% of the 25-mg arm did maintain their BASDAI response. So theoretically, there may be a subset of patients in whom we can offer this therapeutic option," Dr. Gaffney said. He noted that even in this small group of patients with short-term follow-up that the potential cost savings of being able to reduce the dose would be significant, at around £100,000 (about U.S. $170,000).

"We all have patients who do very well [on etanercept], and I think it would be very nice to be able to say, from 6 months, who we can attempt to step down," commented Dr. Nicola Goodson of University Hospital Aintree, Liverpool. Dr. Goodson chaired the session where the study findings were reported.

Although the ANSWER investigators did look for predictors of response, none were found to be significant. Patients continue to be monitored and the investigators may look at this again. Dr. Gaffney noted that all patients who had their 50-mg dose reinstated regained their clinical response.

He also highlighted during discussion: "A number of patients in the 50-mg group asked to be moved down to 25 mg at the end of the study because they wanted to explore the option. So I think this may well have some long-term consequences, especially in a disease area where we know that the treatment is more symptom modifying than radiographically modifying."

The study was funded by Pfizer. Dr. Gaffney has received research support and honoraria from Pfizer, Merck Sharp & Dohme, AbbVie, and UCB.

LIVERPOOL, ENGLAND – The risk of recurrent cancer in patients with rheumatoid arthritis did not increase with the use of biologic therapies, according to data just released from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register.

In fact, the risk of repeated cancer in patients with prior malignancies treated with biologic therapies was apparently decreased by around 50%, when compared with treatment with nonbiologic disease-modifying antirheumatic drugs (nbDMARDs).

The hazard ratios, adjusted for age and sex, for recurrent cancer were 0.55 for patients treated with drugs directed at tumor necrosis factor (TNF)-alpha and 0.47 for patients treated, off-label, with rituximab vs. nbDMARDs.

However, Dr. Luca Silva-Fernandez, who presented the findings at the British Society for Rheumatology annual conference, noted that patients treated with nbDMARDs were perhaps at higher risk of recurrent disease than were those who were treated with biologic agents at the start of their treatment, so the data do not imply that biologic agents are less likely to cause recurrent disease than do the older RA therapies.

"Our data suggest that patients with RA and prior malignancy selected to receive either an anti-TNF or rituximab therapy in the U.K. do not seem to have an increased risk of future incident malignancy," said Dr. Silva-Fernandez.

Patients treated with anti-TNFs or rituximab were more likely to have incident cancers, added Dr. Silva-Fernandez of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the BSRBR-RA Register is run.

Previous data on the use of biologic therapies in patients with prior cancer were published from the British Society for Rheumatology Biologics Registers (BSRBR) 4 years ago (Arthritis Care Res. 2010;62:755-63). These considered 293 patients with a prior malignancy identified from over 14,000 patients with RA enrolled in the register at the time. The present analysis included 425 patients who had cancer before being enrolled in the BSRBR-RA Register, which at the time of the updated analysis included around 19,000 patients.

In total, 425 new malignancies were detected in 159 of 3,787 (1.7%) patients who had been treated with an nbDMARD, 243 of 14,168 (8.9%) patients treated with an anti-TNF drug, and 23 of 257 (4.2%) patients who had received rituximab for the treatment of their RA.

There were several differences in baseline characteristics among the three groups. The mean age of patients in each treatment arm was 66.1, 62.7, and 67.3 years, respectively. A higher percentage (81%) of anti-TNF-treated patients were female when compared with the nbDMARD (74%) and rituximab (65%) arms. Biologic-treated patients tended to have a longer mean RA disease duration (anti-TNF 12 years and rituximab 14 years) than did the nbDMARD-treated patients (8 years), and higher disease severity scores at enrollment into the BSRBR-RA Register. The median time between the previous and current malignancy was 7.9 years for nbDMARDs, 11.5 years for anti-TNFs, and 5.4 years for rituximab.

The crude incident malignancy rates were 47/1,000 person-years in the nbDMARD cohort, 24/1,000 person-years in the anti-TNF-treated patients, and 25/1,000 person-years in the group treated with rituximab. Dr. Silva-Fernandez reported that the median follow-up was much shorter in rituximab-treated patients, at 3.9 years, than both the nbDMARD- (6.6 years) and anti-TNF–treated (6.9 years) groups.

After her presentation, Dr. Silva-Fernandez was asked to comment on the apparent "protective" effect of anti-TNFs on the recurrence of cancer. She replied that the nbDMARD and biologic groups were not really comparable, referring back to the differences in baseline characteristics, so such an association cannot be claimed.

With regards to a question on the use of rituximab in RA patients with a history of prior cancer, which was "off label" in this instance as it wasn’t used after anti-TNFs but "up-front," this might reflect a "channeling bias" on the part of the physicians, commented Dr. Kimmie Hyrich.

"These patients were those who had received rituximab as their first biologic for a number of reasons," said Dr. Hyrich, one of the principal investigators for the BSRBR-RA Register. "For many of them, it may have been a past cancer that made that decision," she added.

"I think, as physicians, we have a comfort in using rituximab in patients with past cancer, because it is not an absolute contraindication, so I think this is physician choice, and that’s probably why an off-license decision to treat with rituximab was made in these patients," said Dr. Hyrich, also from the University of Manchester, England.

Although patients with nonmelanoma skin cancer (NSMC) were excluded from the present analysis, Dr. Hyrich also noted in response to a question that the BSRBR RA Register team had previously reported on the rates of recurrence in patients with and without a prior history of this type of skin cancer.

Findings had shown that anti-TNFs did not appear to increase the risk of NSMC in patients without a prior history of skin cancer. In patients with a history of the disease, there was elevated risk of recurrence, regardless of whether patients received nbDMARDs or anti-TNFs, and it did not seem to occur more in the biologic-treated patients.

"I think the most striking finding, however, was regardless of treatment, all patients in the register, overall, have a marked increased risk of skin cancer, compared with general population, so I think RA itself and its treatment is probably the strongest risk factor," Dr. Hyrich said.

The BSRBR is funded by a grant from the British Society for Rheumatology (BSR), which receives funding from multiple drug companies. This income finances a separate contract between the BSR and the University of Manchester that provides and runs the BSRBR RA Register. Dr. Silva-Fernandez and Dr. Hyrich had no personal conflicts of interest.

LIVERPOOL, ENGLAND – The risk of recurrent cancer in patients with rheumatoid arthritis did not increase with the use of biologic therapies, according to data just released from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register.

In fact, the risk of repeated cancer in patients with prior malignancies treated with biologic therapies was apparently decreased by around 50%, when compared with treatment with nonbiologic disease-modifying antirheumatic drugs (nbDMARDs).

The hazard ratios, adjusted for age and sex, for recurrent cancer were 0.55 for patients treated with drugs directed at tumor necrosis factor (TNF)-alpha and 0.47 for patients treated, off-label, with rituximab vs. nbDMARDs.

However, Dr. Luca Silva-Fernandez, who presented the findings at the British Society for Rheumatology annual conference, noted that patients treated with nbDMARDs were perhaps at higher risk of recurrent disease than were those who were treated with biologic agents at the start of their treatment, so the data do not imply that biologic agents are less likely to cause recurrent disease than do the older RA therapies.

"Our data suggest that patients with RA and prior malignancy selected to receive either an anti-TNF or rituximab therapy in the U.K. do not seem to have an increased risk of future incident malignancy," said Dr. Silva-Fernandez.

Patients treated with anti-TNFs or rituximab were more likely to have incident cancers, added Dr. Silva-Fernandez of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the BSRBR-RA Register is run.

Previous data on the use of biologic therapies in patients with prior cancer were published from the British Society for Rheumatology Biologics Registers (BSRBR) 4 years ago (Arthritis Care Res. 2010;62:755-63). These considered 293 patients with a prior malignancy identified from over 14,000 patients with RA enrolled in the register at the time. The present analysis included 425 patients who had cancer before being enrolled in the BSRBR-RA Register, which at the time of the updated analysis included around 19,000 patients.

In total, 425 new malignancies were detected in 159 of 3,787 (1.7%) patients who had been treated with an nbDMARD, 243 of 14,168 (8.9%) patients treated with an anti-TNF drug, and 23 of 257 (4.2%) patients who had received rituximab for the treatment of their RA.

There were several differences in baseline characteristics among the three groups. The mean age of patients in each treatment arm was 66.1, 62.7, and 67.3 years, respectively. A higher percentage (81%) of anti-TNF-treated patients were female when compared with the nbDMARD (74%) and rituximab (65%) arms. Biologic-treated patients tended to have a longer mean RA disease duration (anti-TNF 12 years and rituximab 14 years) than did the nbDMARD-treated patients (8 years), and higher disease severity scores at enrollment into the BSRBR-RA Register. The median time between the previous and current malignancy was 7.9 years for nbDMARDs, 11.5 years for anti-TNFs, and 5.4 years for rituximab.

The crude incident malignancy rates were 47/1,000 person-years in the nbDMARD cohort, 24/1,000 person-years in the anti-TNF-treated patients, and 25/1,000 person-years in the group treated with rituximab. Dr. Silva-Fernandez reported that the median follow-up was much shorter in rituximab-treated patients, at 3.9 years, than both the nbDMARD- (6.6 years) and anti-TNF–treated (6.9 years) groups.

After her presentation, Dr. Silva-Fernandez was asked to comment on the apparent "protective" effect of anti-TNFs on the recurrence of cancer. She replied that the nbDMARD and biologic groups were not really comparable, referring back to the differences in baseline characteristics, so such an association cannot be claimed.

With regards to a question on the use of rituximab in RA patients with a history of prior cancer, which was "off label" in this instance as it wasn’t used after anti-TNFs but "up-front," this might reflect a "channeling bias" on the part of the physicians, commented Dr. Kimmie Hyrich.

"These patients were those who had received rituximab as their first biologic for a number of reasons," said Dr. Hyrich, one of the principal investigators for the BSRBR-RA Register. "For many of them, it may have been a past cancer that made that decision," she added.

"I think, as physicians, we have a comfort in using rituximab in patients with past cancer, because it is not an absolute contraindication, so I think this is physician choice, and that’s probably why an off-license decision to treat with rituximab was made in these patients," said Dr. Hyrich, also from the University of Manchester, England.

Although patients with nonmelanoma skin cancer (NSMC) were excluded from the present analysis, Dr. Hyrich also noted in response to a question that the BSRBR RA Register team had previously reported on the rates of recurrence in patients with and without a prior history of this type of skin cancer.

Findings had shown that anti-TNFs did not appear to increase the risk of NSMC in patients without a prior history of skin cancer. In patients with a history of the disease, there was elevated risk of recurrence, regardless of whether patients received nbDMARDs or anti-TNFs, and it did not seem to occur more in the biologic-treated patients.

"I think the most striking finding, however, was regardless of treatment, all patients in the register, overall, have a marked increased risk of skin cancer, compared with general population, so I think RA itself and its treatment is probably the strongest risk factor," Dr. Hyrich said.

The BSRBR is funded by a grant from the British Society for Rheumatology (BSR), which receives funding from multiple drug companies. This income finances a separate contract between the BSR and the University of Manchester that provides and runs the BSRBR RA Register. Dr. Silva-Fernandez and Dr. Hyrich had no personal conflicts of interest.

LIVERPOOL, ENGLAND – The risk of recurrent cancer in patients with rheumatoid arthritis did not increase with the use of biologic therapies, according to data just released from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register.

In fact, the risk of repeated cancer in patients with prior malignancies treated with biologic therapies was apparently decreased by around 50%, when compared with treatment with nonbiologic disease-modifying antirheumatic drugs (nbDMARDs).

The hazard ratios, adjusted for age and sex, for recurrent cancer were 0.55 for patients treated with drugs directed at tumor necrosis factor (TNF)-alpha and 0.47 for patients treated, off-label, with rituximab vs. nbDMARDs.

However, Dr. Luca Silva-Fernandez, who presented the findings at the British Society for Rheumatology annual conference, noted that patients treated with nbDMARDs were perhaps at higher risk of recurrent disease than were those who were treated with biologic agents at the start of their treatment, so the data do not imply that biologic agents are less likely to cause recurrent disease than do the older RA therapies.

"Our data suggest that patients with RA and prior malignancy selected to receive either an anti-TNF or rituximab therapy in the U.K. do not seem to have an increased risk of future incident malignancy," said Dr. Silva-Fernandez.

Patients treated with anti-TNFs or rituximab were more likely to have incident cancers, added Dr. Silva-Fernandez of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the BSRBR-RA Register is run.

Previous data on the use of biologic therapies in patients with prior cancer were published from the British Society for Rheumatology Biologics Registers (BSRBR) 4 years ago (Arthritis Care Res. 2010;62:755-63). These considered 293 patients with a prior malignancy identified from over 14,000 patients with RA enrolled in the register at the time. The present analysis included 425 patients who had cancer before being enrolled in the BSRBR-RA Register, which at the time of the updated analysis included around 19,000 patients.

In total, 425 new malignancies were detected in 159 of 3,787 (1.7%) patients who had been treated with an nbDMARD, 243 of 14,168 (8.9%) patients treated with an anti-TNF drug, and 23 of 257 (4.2%) patients who had received rituximab for the treatment of their RA.

There were several differences in baseline characteristics among the three groups. The mean age of patients in each treatment arm was 66.1, 62.7, and 67.3 years, respectively. A higher percentage (81%) of anti-TNF-treated patients were female when compared with the nbDMARD (74%) and rituximab (65%) arms. Biologic-treated patients tended to have a longer mean RA disease duration (anti-TNF 12 years and rituximab 14 years) than did the nbDMARD-treated patients (8 years), and higher disease severity scores at enrollment into the BSRBR-RA Register. The median time between the previous and current malignancy was 7.9 years for nbDMARDs, 11.5 years for anti-TNFs, and 5.4 years for rituximab.

The crude incident malignancy rates were 47/1,000 person-years in the nbDMARD cohort, 24/1,000 person-years in the anti-TNF-treated patients, and 25/1,000 person-years in the group treated with rituximab. Dr. Silva-Fernandez reported that the median follow-up was much shorter in rituximab-treated patients, at 3.9 years, than both the nbDMARD- (6.6 years) and anti-TNF–treated (6.9 years) groups.

After her presentation, Dr. Silva-Fernandez was asked to comment on the apparent "protective" effect of anti-TNFs on the recurrence of cancer. She replied that the nbDMARD and biologic groups were not really comparable, referring back to the differences in baseline characteristics, so such an association cannot be claimed.

With regards to a question on the use of rituximab in RA patients with a history of prior cancer, which was "off label" in this instance as it wasn’t used after anti-TNFs but "up-front," this might reflect a "channeling bias" on the part of the physicians, commented Dr. Kimmie Hyrich.

"These patients were those who had received rituximab as their first biologic for a number of reasons," said Dr. Hyrich, one of the principal investigators for the BSRBR-RA Register. "For many of them, it may have been a past cancer that made that decision," she added.

"I think, as physicians, we have a comfort in using rituximab in patients with past cancer, because it is not an absolute contraindication, so I think this is physician choice, and that’s probably why an off-license decision to treat with rituximab was made in these patients," said Dr. Hyrich, also from the University of Manchester, England.

Although patients with nonmelanoma skin cancer (NSMC) were excluded from the present analysis, Dr. Hyrich also noted in response to a question that the BSRBR RA Register team had previously reported on the rates of recurrence in patients with and without a prior history of this type of skin cancer.

Findings had shown that anti-TNFs did not appear to increase the risk of NSMC in patients without a prior history of skin cancer. In patients with a history of the disease, there was elevated risk of recurrence, regardless of whether patients received nbDMARDs or anti-TNFs, and it did not seem to occur more in the biologic-treated patients.

"I think the most striking finding, however, was regardless of treatment, all patients in the register, overall, have a marked increased risk of skin cancer, compared with general population, so I think RA itself and its treatment is probably the strongest risk factor," Dr. Hyrich said.

The BSRBR is funded by a grant from the British Society for Rheumatology (BSR), which receives funding from multiple drug companies. This income finances a separate contract between the BSR and the University of Manchester that provides and runs the BSRBR RA Register. Dr. Silva-Fernandez and Dr. Hyrich had no personal conflicts of interest.

LIVERPOOL, ENGLAND – A new analysis of data from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register confirms that anti–tumor necrosis factor treatment decreases patients’ risk for heart attack when compared with treatment with traditional, nonbiologic disease-modifying antirheumatic drugs, but a lower level of inflammation may not be the mechanism of action.

In the latest analysis, the risk of myocardial infarction was reduced by 40% if patients had been treated with an anti–tumor necrosis factor (anti-TNF) drug rather than a nonbiologic disease-modifying antirheumatic drug (nbDMARD) (adjusted hazard ratio, 0.6).

But this effect was not the result of a reduction in the severity of inflammation, said researcher Dr. Audrey Low of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis (BSRBR-RA) Register is run. Nevertheless, the effect could still relate to attributes of these drugs themselves or better overall disease control, she and her coworkers reported at the British Society for Rheumatology annual conference.

"It is now well known that our patients with rheumatoid arthritis are at increased risk of cardiovascular disease," Dr. Low observed, adding that the risk of both cardiovascular morbidity and mortality is around 50% higher than in the general population. "In particular, the risk of MI [myocardial infarction] is increased," she noted.

Inflammation is thought to play an important role in the development of both atherosclerosis and rheumatoid arthritis, and thus dampening down the inflammatory response with anti-TNF drugs could potentially modify the elevated cardiovascular risk seen in RA patients.

Previously, Dr. Low reported that the risk of MI was lowered by 30% in patients treated with anti-TNFs versus nbDMARDs. The current study looked more deeply into the possible relationship, linking BSRBR-RA Register data to those in the Myocardial Ischaemia National Audit Project (MINAP), a large MI data set derived from all hospitalizations for heart attack in England and Wales. MINAP was established in 1999, 2 years before the BSRBR-RA Register, and it collects around 90,000 records of possible MI per year. As of 2012, MINAP consisted of more than 1 million records.

The aims of the current analysis, which included 14,258 patients with active RA, were to first look at the incidence of MI in patients treated with anti-TNFs (n = 11,200) versus nbDMARDs (n = 3,058), and then to see if the severity of MI was influenced by biologic treatment. The analysis included all patients who started treatment with one of three established anti-TNFs (etanercept, infliximab, and adalimumab) and were recruited into the BSRBR-RA Register between 2001 and 2008. Patients with prior cardiovascular disease were excluded.

To verify the occurrence of MI, data from the BSRBR-RA Register were linked to data from MINAP using patients’ forenames, surnames, date of birth, National Health Service number, postal code, and gender. Events occurring in the same 30-day time window in both data sets were considered the same event. MIs were then verified using criteria set by the American Heart Association and the European Society for Cardiology, with additional criteria of thrombolysis, angioplasty, and MI listed as the underlying cause of death on death certificates, based on the World Health Organization’s International Classification of Diseases, version 10.

A total of 252 first MIs were analyzed, of which 194 occurred in anti-TNF–treated patients at a median follow-up of 5.3 years and 58 occurred in those treated with nbDMARDs at a median follow-up of 3.5 years. The corresponding crude incidence rates were 3.5 and 5.6 per 1,000 patient-years.

"Looking at the MI severity, we only analyzed those MIs that had MINAP-associated data," which was just over half of the MIs (n = 143), Dr. Low said. While the absolute levels of three cardiac enzymes measured – peak troponin I, peak troponin T, and peak creatinine kinase – were higher in the anti-TNF cohort, compared with nbDMARDs, there were not enough events in each group to achieve statistical significance.

There were also no differences between the treatment groups in terms of other cardiac measures of severity, including the phenotype of MI (ST- vs. non-ST elevated), cardiac arrest, and length of hospitalization.

"So the second conclusion is that severity and post-MI mortality do not appear to be influenced by anti-TNF therapy," Dr. Low said.

BSR president Dr. Chris Deighton, who chaired the plenary session in which the findings were presented, noted that there seemed to be a high proportion of patients in the anti-TNF arm who were also treated with steroidal or nonsteroidal anti-inflammatory drugs (NSAIDs) at enrollment. Perhaps if the anti-TNFs were working well, then any reduction in the use of these other drugs over time might have had a confounding effect on the MI risk.

Dr. Low noted that the data on the use of steroids was quite crude and often the dose was not recorded, and even less information about NSAIDs was available. "This is something that we will have to work on, and it does remain to be a potential confounding factor in the analysis," she concluded.

The BSRBR is funded by a grant from the BSR, which receives funding from multiple drug companies. This income finances a separate contract between the BSR and the University of Manchester that provides and runs the BSRBR. Dr. Low had no personal conflicts of interest.

LIVERPOOL, ENGLAND – A new analysis of data from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register confirms that anti–tumor necrosis factor treatment decreases patients’ risk for heart attack when compared with treatment with traditional, nonbiologic disease-modifying antirheumatic drugs, but a lower level of inflammation may not be the mechanism of action.

In the latest analysis, the risk of myocardial infarction was reduced by 40% if patients had been treated with an anti–tumor necrosis factor (anti-TNF) drug rather than a nonbiologic disease-modifying antirheumatic drug (nbDMARD) (adjusted hazard ratio, 0.6).

But this effect was not the result of a reduction in the severity of inflammation, said researcher Dr. Audrey Low of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis (BSRBR-RA) Register is run. Nevertheless, the effect could still relate to attributes of these drugs themselves or better overall disease control, she and her coworkers reported at the British Society for Rheumatology annual conference.

"It is now well known that our patients with rheumatoid arthritis are at increased risk of cardiovascular disease," Dr. Low observed, adding that the risk of both cardiovascular morbidity and mortality is around 50% higher than in the general population. "In particular, the risk of MI [myocardial infarction] is increased," she noted.

Inflammation is thought to play an important role in the development of both atherosclerosis and rheumatoid arthritis, and thus dampening down the inflammatory response with anti-TNF drugs could potentially modify the elevated cardiovascular risk seen in RA patients.

Previously, Dr. Low reported that the risk of MI was lowered by 30% in patients treated with anti-TNFs versus nbDMARDs. The current study looked more deeply into the possible relationship, linking BSRBR-RA Register data to those in the Myocardial Ischaemia National Audit Project (MINAP), a large MI data set derived from all hospitalizations for heart attack in England and Wales. MINAP was established in 1999, 2 years before the BSRBR-RA Register, and it collects around 90,000 records of possible MI per year. As of 2012, MINAP consisted of more than 1 million records.

The aims of the current analysis, which included 14,258 patients with active RA, were to first look at the incidence of MI in patients treated with anti-TNFs (n = 11,200) versus nbDMARDs (n = 3,058), and then to see if the severity of MI was influenced by biologic treatment. The analysis included all patients who started treatment with one of three established anti-TNFs (etanercept, infliximab, and adalimumab) and were recruited into the BSRBR-RA Register between 2001 and 2008. Patients with prior cardiovascular disease were excluded.

To verify the occurrence of MI, data from the BSRBR-RA Register were linked to data from MINAP using patients’ forenames, surnames, date of birth, National Health Service number, postal code, and gender. Events occurring in the same 30-day time window in both data sets were considered the same event. MIs were then verified using criteria set by the American Heart Association and the European Society for Cardiology, with additional criteria of thrombolysis, angioplasty, and MI listed as the underlying cause of death on death certificates, based on the World Health Organization’s International Classification of Diseases, version 10.

A total of 252 first MIs were analyzed, of which 194 occurred in anti-TNF–treated patients at a median follow-up of 5.3 years and 58 occurred in those treated with nbDMARDs at a median follow-up of 3.5 years. The corresponding crude incidence rates were 3.5 and 5.6 per 1,000 patient-years.

"Looking at the MI severity, we only analyzed those MIs that had MINAP-associated data," which was just over half of the MIs (n = 143), Dr. Low said. While the absolute levels of three cardiac enzymes measured – peak troponin I, peak troponin T, and peak creatinine kinase – were higher in the anti-TNF cohort, compared with nbDMARDs, there were not enough events in each group to achieve statistical significance.

There were also no differences between the treatment groups in terms of other cardiac measures of severity, including the phenotype of MI (ST- vs. non-ST elevated), cardiac arrest, and length of hospitalization.

"So the second conclusion is that severity and post-MI mortality do not appear to be influenced by anti-TNF therapy," Dr. Low said.

BSR president Dr. Chris Deighton, who chaired the plenary session in which the findings were presented, noted that there seemed to be a high proportion of patients in the anti-TNF arm who were also treated with steroidal or nonsteroidal anti-inflammatory drugs (NSAIDs) at enrollment. Perhaps if the anti-TNFs were working well, then any reduction in the use of these other drugs over time might have had a confounding effect on the MI risk.

Dr. Low noted that the data on the use of steroids was quite crude and often the dose was not recorded, and even less information about NSAIDs was available. "This is something that we will have to work on, and it does remain to be a potential confounding factor in the analysis," she concluded.

The BSRBR is funded by a grant from the BSR, which receives funding from multiple drug companies. This income finances a separate contract between the BSR and the University of Manchester that provides and runs the BSRBR. Dr. Low had no personal conflicts of interest.

LIVERPOOL, ENGLAND – A new analysis of data from the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis Register confirms that anti–tumor necrosis factor treatment decreases patients’ risk for heart attack when compared with treatment with traditional, nonbiologic disease-modifying antirheumatic drugs, but a lower level of inflammation may not be the mechanism of action.

In the latest analysis, the risk of myocardial infarction was reduced by 40% if patients had been treated with an anti–tumor necrosis factor (anti-TNF) drug rather than a nonbiologic disease-modifying antirheumatic drug (nbDMARD) (adjusted hazard ratio, 0.6).

But this effect was not the result of a reduction in the severity of inflammation, said researcher Dr. Audrey Low of the Arthritis Research UK Epidemiology Unit at the University of Manchester, England, where the British Society for Rheumatology Biologics Registers’ Rheumatoid Arthritis (BSRBR-RA) Register is run. Nevertheless, the effect could still relate to attributes of these drugs themselves or better overall disease control, she and her coworkers reported at the British Society for Rheumatology annual conference.

"It is now well known that our patients with rheumatoid arthritis are at increased risk of cardiovascular disease," Dr. Low observed, adding that the risk of both cardiovascular morbidity and mortality is around 50% higher than in the general population. "In particular, the risk of MI [myocardial infarction] is increased," she noted.

Inflammation is thought to play an important role in the development of both atherosclerosis and rheumatoid arthritis, and thus dampening down the inflammatory response with anti-TNF drugs could potentially modify the elevated cardiovascular risk seen in RA patients.

Previously, Dr. Low reported that the risk of MI was lowered by 30% in patients treated with anti-TNFs versus nbDMARDs. The current study looked more deeply into the possible relationship, linking BSRBR-RA Register data to those in the Myocardial Ischaemia National Audit Project (MINAP), a large MI data set derived from all hospitalizations for heart attack in England and Wales. MINAP was established in 1999, 2 years before the BSRBR-RA Register, and it collects around 90,000 records of possible MI per year. As of 2012, MINAP consisted of more than 1 million records.

The aims of the current analysis, which included 14,258 patients with active RA, were to first look at the incidence of MI in patients treated with anti-TNFs (n = 11,200) versus nbDMARDs (n = 3,058), and then to see if the severity of MI was influenced by biologic treatment. The analysis included all patients who started treatment with one of three established anti-TNFs (etanercept, infliximab, and adalimumab) and were recruited into the BSRBR-RA Register between 2001 and 2008. Patients with prior cardiovascular disease were excluded.

To verify the occurrence of MI, data from the BSRBR-RA Register were linked to data from MINAP using patients’ forenames, surnames, date of birth, National Health Service number, postal code, and gender. Events occurring in the same 30-day time window in both data sets were considered the same event. MIs were then verified using criteria set by the American Heart Association and the European Society for Cardiology, with additional criteria of thrombolysis, angioplasty, and MI listed as the underlying cause of death on death certificates, based on the World Health Organization’s International Classification of Diseases, version 10.

A total of 252 first MIs were analyzed, of which 194 occurred in anti-TNF–treated patients at a median follow-up of 5.3 years and 58 occurred in those treated with nbDMARDs at a median follow-up of 3.5 years. The corresponding crude incidence rates were 3.5 and 5.6 per 1,000 patient-years.

"Looking at the MI severity, we only analyzed those MIs that had MINAP-associated data," which was just over half of the MIs (n = 143), Dr. Low said. While the absolute levels of three cardiac enzymes measured – peak troponin I, peak troponin T, and peak creatinine kinase – were higher in the anti-TNF cohort, compared with nbDMARDs, there were not enough events in each group to achieve statistical significance.

There were also no differences between the treatment groups in terms of other cardiac measures of severity, including the phenotype of MI (ST- vs. non-ST elevated), cardiac arrest, and length of hospitalization.

"So the second conclusion is that severity and post-MI mortality do not appear to be influenced by anti-TNF therapy," Dr. Low said.

BSR president Dr. Chris Deighton, who chaired the plenary session in which the findings were presented, noted that there seemed to be a high proportion of patients in the anti-TNF arm who were also treated with steroidal or nonsteroidal anti-inflammatory drugs (NSAIDs) at enrollment. Perhaps if the anti-TNFs were working well, then any reduction in the use of these other drugs over time might have had a confounding effect on the MI risk.

Dr. Low noted that the data on the use of steroids was quite crude and often the dose was not recorded, and even less information about NSAIDs was available. "This is something that we will have to work on, and it does remain to be a potential confounding factor in the analysis," she concluded.

The BSRBR is funded by a grant from the BSR, which receives funding from multiple drug companies. This income finances a separate contract between the BSR and the University of Manchester that provides and runs the BSRBR. Dr. Low had no personal conflicts of interest.

LONDON – Cure rates of 93%-100% were achieved in patients with chronic hepatitis C virus genotype 1 treated with both simeprevir and sofosbuvir despite the presence of advanced cirrhosis in a phase IIa trial.

Sustained virologic responses with dual therapy for 12 weeks (SVR12) were 93% with and 93% without the additional use of ribavirin. SVR rates following 24 weeks of treatment were 93% for dual therapy with ribavirin and 100% with no ribavirin. The findings cast further doubt on the benefit of using ribavirin with newer antiviral agents.

"SVR12 rates were high, regardless of baseline characteristics," Dr. Eric Lawitz said when presenting these data from the COSMOS study at the International Liver Congress 2014.

Dr. Lawitz, of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio, added that the baseline characteristics included prior treatment history, METAVIR score, and the presence of known resistance factors – the Q80K polymorphism or IL28B genotype.

Simeprevir (Olysio) and sofosbuvir (Solvadi) are once-daily formulations recently approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 in several countries, including Canada and the United States.

The aim of the COSMOS study was to test the efficacy and safety of these two novel antiviral treatments in tandem in patients with chronic HCV genotype 1 infection who had not previously received any anti-HCV therapy or who had been treated with pegylated interferon plus ribavirin but had not adequately responded.

There were two cohorts of patients, Dr. Lawitz explained. The first cohort comprised 80 patients without cirrhosis (METAVIR F0-F2) who had not responded to prior treatment, while the second cohort included 87 patients with advanced cirrhosis (METAVIR F3-F4) who were either null responders or treatment naive. He presented data only on cohort 2.

Patients were randomized to receive 12 or 24 weeks of simeprevir plus sofosbuvir with or without additional ribavirin. The median age of the study population overall was 58 years, 67% was male, and 91% were white. Just less than half of randomized patients had cirrhosis, and 54% were null responders. Dr. Lawitz pointed out that genotype 1a was the most prevalent subtype of HCV, with around 40% having the Q80K polymorphism and 79% having the IL28B (non-CC) genotype.

Three patients randomized to the 24-week study arm discontinued treatment early. Reasons for discontinuation included one death unrelated to treatment, withdrawal of consent by one patient, and one adverse event unrelated to treatment (dual therapy–only arm).

"When we look at all 87 patients, the SVR12 was 82/87, with two [2.3%] patients failing for nonvirologic reasons, and three [3.4%] patients relapsing," Dr. Lawitz reported at the meeting, which was sponsored by the European Association for the Study of the Liver.

SVR12 rates were 98% and 95% in patients with METAVIR F3 and F4, respectively, and 96% and 94% in null responders and never-treated patients. SVR12 in patients with the IL28B genotype were 94%, 98%, and 95%, respectively, for the CC, CT, and TT forms.

Looking more closely at the three patients with viral relapse, no common factors were found that could help to predict the response to treatment.

On the whole, simeprevir plus sofosbuvir with or without ribavirin was generally well tolerated, Dr. Lawitz said. The most frequent adverse events were fatigue, headache, and nausea, occurring in 37.9%, 19.5%, and 17.2% of the overall study population, respectively.

"Numerically, to look at adverse events, they were more frequent in the ribavirin-containing arms compared to the ribavirin-free arms," he observed. And although bilirubin elevations were frequent, they were mostly mild and occurred primarily in the ribavirin-containing arms.

The study was sponsored by Janssen. Dr. Lawitz has received research support and speaker fees, and has acted as an advisory board member for Janssen, Gilead Sciences, and several other companies.

LONDON – Cure rates of 93%-100% were achieved in patients with chronic hepatitis C virus genotype 1 treated with both simeprevir and sofosbuvir despite the presence of advanced cirrhosis in a phase IIa trial.

Sustained virologic responses with dual therapy for 12 weeks (SVR12) were 93% with and 93% without the additional use of ribavirin. SVR rates following 24 weeks of treatment were 93% for dual therapy with ribavirin and 100% with no ribavirin. The findings cast further doubt on the benefit of using ribavirin with newer antiviral agents.

"SVR12 rates were high, regardless of baseline characteristics," Dr. Eric Lawitz said when presenting these data from the COSMOS study at the International Liver Congress 2014.

Dr. Lawitz, of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio, added that the baseline characteristics included prior treatment history, METAVIR score, and the presence of known resistance factors – the Q80K polymorphism or IL28B genotype.

Simeprevir (Olysio) and sofosbuvir (Solvadi) are once-daily formulations recently approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 in several countries, including Canada and the United States.

The aim of the COSMOS study was to test the efficacy and safety of these two novel antiviral treatments in tandem in patients with chronic HCV genotype 1 infection who had not previously received any anti-HCV therapy or who had been treated with pegylated interferon plus ribavirin but had not adequately responded.

There were two cohorts of patients, Dr. Lawitz explained. The first cohort comprised 80 patients without cirrhosis (METAVIR F0-F2) who had not responded to prior treatment, while the second cohort included 87 patients with advanced cirrhosis (METAVIR F3-F4) who were either null responders or treatment naive. He presented data only on cohort 2.

Patients were randomized to receive 12 or 24 weeks of simeprevir plus sofosbuvir with or without additional ribavirin. The median age of the study population overall was 58 years, 67% was male, and 91% were white. Just less than half of randomized patients had cirrhosis, and 54% were null responders. Dr. Lawitz pointed out that genotype 1a was the most prevalent subtype of HCV, with around 40% having the Q80K polymorphism and 79% having the IL28B (non-CC) genotype.

Three patients randomized to the 24-week study arm discontinued treatment early. Reasons for discontinuation included one death unrelated to treatment, withdrawal of consent by one patient, and one adverse event unrelated to treatment (dual therapy–only arm).

"When we look at all 87 patients, the SVR12 was 82/87, with two [2.3%] patients failing for nonvirologic reasons, and three [3.4%] patients relapsing," Dr. Lawitz reported at the meeting, which was sponsored by the European Association for the Study of the Liver.

SVR12 rates were 98% and 95% in patients with METAVIR F3 and F4, respectively, and 96% and 94% in null responders and never-treated patients. SVR12 in patients with the IL28B genotype were 94%, 98%, and 95%, respectively, for the CC, CT, and TT forms.

Looking more closely at the three patients with viral relapse, no common factors were found that could help to predict the response to treatment.

On the whole, simeprevir plus sofosbuvir with or without ribavirin was generally well tolerated, Dr. Lawitz said. The most frequent adverse events were fatigue, headache, and nausea, occurring in 37.9%, 19.5%, and 17.2% of the overall study population, respectively.

"Numerically, to look at adverse events, they were more frequent in the ribavirin-containing arms compared to the ribavirin-free arms," he observed. And although bilirubin elevations were frequent, they were mostly mild and occurred primarily in the ribavirin-containing arms.

The study was sponsored by Janssen. Dr. Lawitz has received research support and speaker fees, and has acted as an advisory board member for Janssen, Gilead Sciences, and several other companies.

LONDON – Cure rates of 93%-100% were achieved in patients with chronic hepatitis C virus genotype 1 treated with both simeprevir and sofosbuvir despite the presence of advanced cirrhosis in a phase IIa trial.

Sustained virologic responses with dual therapy for 12 weeks (SVR12) were 93% with and 93% without the additional use of ribavirin. SVR rates following 24 weeks of treatment were 93% for dual therapy with ribavirin and 100% with no ribavirin. The findings cast further doubt on the benefit of using ribavirin with newer antiviral agents.

"SVR12 rates were high, regardless of baseline characteristics," Dr. Eric Lawitz said when presenting these data from the COSMOS study at the International Liver Congress 2014.

Dr. Lawitz, of the Texas Liver Institute at the University of Texas Health Science Center in San Antonio, added that the baseline characteristics included prior treatment history, METAVIR score, and the presence of known resistance factors – the Q80K polymorphism or IL28B genotype.

Simeprevir (Olysio) and sofosbuvir (Solvadi) are once-daily formulations recently approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 in several countries, including Canada and the United States.

The aim of the COSMOS study was to test the efficacy and safety of these two novel antiviral treatments in tandem in patients with chronic HCV genotype 1 infection who had not previously received any anti-HCV therapy or who had been treated with pegylated interferon plus ribavirin but had not adequately responded.

There were two cohorts of patients, Dr. Lawitz explained. The first cohort comprised 80 patients without cirrhosis (METAVIR F0-F2) who had not responded to prior treatment, while the second cohort included 87 patients with advanced cirrhosis (METAVIR F3-F4) who were either null responders or treatment naive. He presented data only on cohort 2.

Patients were randomized to receive 12 or 24 weeks of simeprevir plus sofosbuvir with or without additional ribavirin. The median age of the study population overall was 58 years, 67% was male, and 91% were white. Just less than half of randomized patients had cirrhosis, and 54% were null responders. Dr. Lawitz pointed out that genotype 1a was the most prevalent subtype of HCV, with around 40% having the Q80K polymorphism and 79% having the IL28B (non-CC) genotype.

Three patients randomized to the 24-week study arm discontinued treatment early. Reasons for discontinuation included one death unrelated to treatment, withdrawal of consent by one patient, and one adverse event unrelated to treatment (dual therapy–only arm).

"When we look at all 87 patients, the SVR12 was 82/87, with two [2.3%] patients failing for nonvirologic reasons, and three [3.4%] patients relapsing," Dr. Lawitz reported at the meeting, which was sponsored by the European Association for the Study of the Liver.

SVR12 rates were 98% and 95% in patients with METAVIR F3 and F4, respectively, and 96% and 94% in null responders and never-treated patients. SVR12 in patients with the IL28B genotype were 94%, 98%, and 95%, respectively, for the CC, CT, and TT forms.

Looking more closely at the three patients with viral relapse, no common factors were found that could help to predict the response to treatment.

On the whole, simeprevir plus sofosbuvir with or without ribavirin was generally well tolerated, Dr. Lawitz said. The most frequent adverse events were fatigue, headache, and nausea, occurring in 37.9%, 19.5%, and 17.2% of the overall study population, respectively.

"Numerically, to look at adverse events, they were more frequent in the ribavirin-containing arms compared to the ribavirin-free arms," he observed. And although bilirubin elevations were frequent, they were mostly mild and occurred primarily in the ribavirin-containing arms.

The study was sponsored by Janssen. Dr. Lawitz has received research support and speaker fees, and has acted as an advisory board member for Janssen, Gilead Sciences, and several other companies.

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be taking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be taking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."

LONDON – Herbal medicines and other home remedies or supplements are a significant cause of hepatotoxicity experts warned recently during a symposium at the International Liver Congress, which unintentionally coincided with World Homeopathy Awareness Week.

Although they are not at the very top of the list when it comes to drug-induced liver injury (DILI) – that accolade being reserved for antimicrobial agents used to treat tuberculosis – the use of homeopathy-based approaches are potentially on the increase in the western world and the use of such substances are often not reported to physicians.

"Herbal medicines represent a significant cause of liver injury," Dr. Dominique Larrey (Central University Hospital, Montpellier, France), said at the meeting that was sponsored by the European Association for the Study of the Liver. "Herbs can cause almost the whole spectrum of hepatic and biliary lesions, acute hepatitis being the most frequent one," he added.

The rise of herbal medicine

Dr. Larrey, who works in the liver and transplantation department of Saint Eloi Hospital, also in Montpellier, noted that the use of herbs in traditional medicine was very important in many parts of the world, notably in Asia, Africa, and Central and South America. They are used for both traditional and cultural reasons, he added, are often easy to access and are low cost in comparison to regulated medicines.

Their use is probably on the increase in western countries for a variety of reasons, Dr. Larrey suggested, such as the migration of people from cultures in which the use of traditional medicines is high, to the thinking that "what is natural can only be good" and "herbal medicines are considered completely innocuous in contrast to classical drugs." Furthermore, the lack of satisfactory treatments for some severe diseases – cancer, multiple sclerosis, AIDS, and hepatitis C virus infection to name a few – mean that people often are willing to try out complementary or alternative medicines (CAM).

In the United States, the total sale of herbal remedies in 2010 was an estimated $5.2 billion per year, having increased around 3% a year over the past decade, Dr. Larrey pointed out.

The problem is that patients do not often tell their doctors about their use of CAM. A staggering 90% of patients taking the anticoagulant drug warfarin – which is renowned for having a very narrow therapeutic window and careful monitoring is required – were taking herbal medicines in one study, he said.

Prospective studies on the use of herbal medicines in western countries are scarce but those that have been conducted specifically in patients with liver disease suggest that as many as one-fifth (Hepatology 2008;47:605-12) to one-third (Gastroenterology 2001;120[Suppl 1]:A228) might be taking herbal remedies unbeknownst to their doctor.

The problem of assessment

There are limited data on how frequently herbal medicines cause liver damage, but estimates range from 2% to 16%, Dr. Larrey observed, adding that reported cases could be just the tip of the iceberg.

"Herbal medicine hepatoxicity is clearly underestimated for many reasons," he suggested. First, their intake is hard to analyze. Second, the mechanism of liver damage is often uncertain, and third, it is hard to confirm causality. Indeed, herbal medicines do not have to undergo the rigorous testing or regulation in the same way that prescribed medicines do, and sales via the Internet make them easily available to all.

There is then the uncertainty of what is really in the preparations, if they contain the right plant at all or the wrong part of it, and then whether or not they have been stored correctly, or if they have been contaminated with other liver-damaging agents or microorganisms.

Advice for physicians

DILI from prescription and nonprescription medicines is an important but rare event in the westernized world, Dr. Robert Fontana of the University of Michigan in Ann Arbor said in an interview. However, because it can bring about very bad and unpredictable liver injury, it is of great importance for hepatologists and general family physicians alike.

"In the United States and I think worldwide, the frequency in use of [herbal treatments] is increasing and as we start to see registry data I think we will start to see more and more cases [of hepatoxicity]," Dr. Fontana said.

Dr. Fontana is part of the National Institutes of Health–funded Drug-Induced Liver Injury Network (DILIN), a multicenter, prospective registry looking at the etiologies, risk factors, and outcomes of DILI in the United States (Drug Saf. 2009;32:55-68). Data from the registry show the prevalence of herbal and dietary supplements is around 9% (n = 300) in confirmed DILI cases.

"Patients need to tell their doctors what they are taking," he advised, adding that, as physicians, "we all need to be aware and maybe ask more questions of our patients."

The LiverTox website – produced by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine – is a valuable online and freely available resource for determining if a medication, herbal, or other supplement is known to cause liver problems. This is going to have a new chapter on herbal medicines, Dr. Fontana said, and is worth using in daily practice to help advise patients on the prescription or CAM they might be taking.

Dr. Larrey and Dr. Fontana had no disclosures relevant to their comments.

New Chinese herbal medicine inhibits HCV activity

A compound named SBEL1 after the laboratory in which it was discovered has multiple effects on the hepatitis C virus (HCV) life cycle, according to data from a late-breaking poster presented at the meeting.

Researchers from the Systems Biology of Epithelia Laboratory at the National Taiwan University, Taipei, screened six herbal medicines and found that one of these – SBEL1 – inhibited HCV activity by about 90% in infected cells.

Cheng-Wei Lin and Ming-Jiun Yu pretreated liver cells with the herbal extract and then infected these cells with HCV. Compared with control cells, SBEL1-treated cells contained 23% less viral protein. This suggested that SBEL1 prevented HCV from entering the pretreated cells.

Their findings also suggested that SBEL1 reduced internal-ribosome entry site–mediated translation, a process vital for viral protein production, and might also have interfered with the RNA replication process.

"SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral life cycle," Dr. Markus Peck-Radosavljevic, the secretary-general of the European Association for the Study of the Liver, said in a press release issued by the Society.

Dr. Peck-Radosavljevic (University of Vienna, Austria), who was not involved in the research, added that this "is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately, this adds to our library of knowledge that may bring us closer to improving future treatment options."

LONDON – More than 90% of patients with chronic hepatitis C and compensated cirrhosis treated with a triple-acting, all-oral, direct-acting antiviral (DAA) regimen achieved sustained virologic responses 12 weeks after the end of therapy (SVR12) in a phase III trial.

In the TURQUOISE II study, 380 patients infected with the hepatitis C virus (HVC) genotype 1 were treated with the interferon (IFN)-free combination of ABT-450/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 or 24 weeks. Results showed that SVR12 rates were 91.8% and 95.9%.

Results were striking, compared with a historical control group using telaprevir plus pegylated IFN plus ribavirin, with the threshold for noninferiority and superiority set at 43% and 54%, respectively.

The study is the first to look at the effects of an all-oral, direct-acting antiviral regimen exclusively in patients with HVC genotype 1 infection and cirrhosis, said the lead study investigator Dr. Fred Poordad. The study findings were published online to coincide with his presentation at the International Liver Congress 2014 (N. Engl. J. Med. 2014 Apr. 12 [doi: 10.1056/NEJMoa1402869]).

TURQUOISE II was an international, multicenter, randomized, open-label trial of 380 patients with Child-Pugh class A cirrhosis caused by HCV infection, explained Dr. Poordad of the Texas Liver Institute at the University of Texas Health Science Center, San Antonio. The trial was conducted at 78 sites in Europe and North America and included both treatment-experienced (about 60%) and treatment-naive (about 40%) patients.

Results by HCV subtype showed that the regimen worked equally well in patients with genotype 1a as genotype 1b, with SVR12 rates of 88.6% and 98.5% with 12 weeks’ treatment and 94.2% and 100% with 24 weeks’ treatment, respectively.

SVR rates were also similarly high in patients according to prior treatment response and in those with portal hypertension or reduced hepatic function identified by low baseline platelet counts or low serum albumin.

Dr. Poordad noted that 8.2% and 4.1% of patients did not achieve SVR12 in the 12- and 24-week therapy groups, respectively. Premature discontinuations occurred in 1.9% and 1.7% and were with caused by an adverse event (four vs. one case) or withdrawal of consent (0 vs. two cases).

"Virologic breakthrough was an unusual event in either arm (0.5% and 1.7%, respectively)," the researcher observed. Relapse occurred in 5.9% and 0.6% of patients in the 12- and 24-week arms. "Of the 12 patients who relapsed in the 12-week arm, 7 of them were [genotype]1a null responders, largely driving the difference in relapse between these two arms," Dr. Poordad said.

He noted that 17 patients overall had a virologic failure and of these, 15 of them had at least one resistance-associated variant. The most common variants in GT1a-infected patients were D168V found in NS3 and Q30R found in NS5A. The significance and persistence of these variants is currently under investigation.

In terms of tolerability, fatigue, and shortness of breath were the most common adverse events seen, occurring in a higher percentage of patients treated with 24 (46.5% and 12.2%) vs. 12 (12.2% vs. 5.8%) weeks of treatment (P less than .05 for both comparisons). There were low rates of severe or serious adverse events and low rates of treatment discontinuation (about 2%).

"The efficacy and safety in this large cirrhotic population is similar to noncirrhotics treated with the same regimen," Dr. Poordad noted. He highlighted that the three DAA antiviral regimen – nicknamed 3D – has also been assessed in two pivotal phase III trials and has shown exceptionally high SVR12 rates. In the SAPPHIRE I trial (N. Engl. J. Med. 2014 Apr. 10 [doi:10.1056/NEJMoa1315722]), in treatment-naive patients without cirrhosis, SVR12 after 12 weeks’ therapy with the 3D regimen was 96.2% and in the SAPPHIRE II trial (N. Engl. J. Med. 2014 Apr. 10 [doi: 10.1056/NEJMoa1401561]) in treatment-experienced patients without cirrhosis it was 96.3% in treatment-experienced patients, which included those who had previously not responded to IFN-based therapy. The results of both SAPPHIRE trials were also presented at the meeting, which was sponsored by the European Association for the Study of the Liver.

Dr. Jean-Michel Pawlotsky of Hôpital Henri Mondor, Créteil, France, who chaired the late-breakers session at which the TURQUOISE II data were presented, commented that these data were "outstanding." He asked Dr. Poordad to comment on the treatment duration and when a longer treatment course might be warranted in certain patients.

"I think one has to use their clinical judgment, so if you have a patient who comes in and you cannot determine if they were a previous nonresponder or not then you can certainly consider treating a little bit longer," the investigator responded. "They certainly tolerate treatment just as well."

AbbVie sponsored the study. Dr. Poordad has received research support and acted as a consultant to the company. He also disclosed receiving grants or research support or acting as an adviser or speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, in addition to others.

LONDON – More than 90% of patients with chronic hepatitis C and compensated cirrhosis treated with a triple-acting, all-oral, direct-acting antiviral (DAA) regimen achieved sustained virologic responses 12 weeks after the end of therapy (SVR12) in a phase III trial.

In the TURQUOISE II study, 380 patients infected with the hepatitis C virus (HVC) genotype 1 were treated with the interferon (IFN)-free combination of ABT-450/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 or 24 weeks. Results showed that SVR12 rates were 91.8% and 95.9%.

Results were striking, compared with a historical control group using telaprevir plus pegylated IFN plus ribavirin, with the threshold for noninferiority and superiority set at 43% and 54%, respectively.

The study is the first to look at the effects of an all-oral, direct-acting antiviral regimen exclusively in patients with HVC genotype 1 infection and cirrhosis, said the lead study investigator Dr. Fred Poordad. The study findings were published online to coincide with his presentation at the International Liver Congress 2014 (N. Engl. J. Med. 2014 Apr. 12 [doi: 10.1056/NEJMoa1402869]).

TURQUOISE II was an international, multicenter, randomized, open-label trial of 380 patients with Child-Pugh class A cirrhosis caused by HCV infection, explained Dr. Poordad of the Texas Liver Institute at the University of Texas Health Science Center, San Antonio. The trial was conducted at 78 sites in Europe and North America and included both treatment-experienced (about 60%) and treatment-naive (about 40%) patients.

Results by HCV subtype showed that the regimen worked equally well in patients with genotype 1a as genotype 1b, with SVR12 rates of 88.6% and 98.5% with 12 weeks’ treatment and 94.2% and 100% with 24 weeks’ treatment, respectively.

SVR rates were also similarly high in patients according to prior treatment response and in those with portal hypertension or reduced hepatic function identified by low baseline platelet counts or low serum albumin.

Dr. Poordad noted that 8.2% and 4.1% of patients did not achieve SVR12 in the 12- and 24-week therapy groups, respectively. Premature discontinuations occurred in 1.9% and 1.7% and were with caused by an adverse event (four vs. one case) or withdrawal of consent (0 vs. two cases).

"Virologic breakthrough was an unusual event in either arm (0.5% and 1.7%, respectively)," the researcher observed. Relapse occurred in 5.9% and 0.6% of patients in the 12- and 24-week arms. "Of the 12 patients who relapsed in the 12-week arm, 7 of them were [genotype]1a null responders, largely driving the difference in relapse between these two arms," Dr. Poordad said.

He noted that 17 patients overall had a virologic failure and of these, 15 of them had at least one resistance-associated variant. The most common variants in GT1a-infected patients were D168V found in NS3 and Q30R found in NS5A. The significance and persistence of these variants is currently under investigation.

In terms of tolerability, fatigue, and shortness of breath were the most common adverse events seen, occurring in a higher percentage of patients treated with 24 (46.5% and 12.2%) vs. 12 (12.2% vs. 5.8%) weeks of treatment (P less than .05 for both comparisons). There were low rates of severe or serious adverse events and low rates of treatment discontinuation (about 2%).

"The efficacy and safety in this large cirrhotic population is similar to noncirrhotics treated with the same regimen," Dr. Poordad noted. He highlighted that the three DAA antiviral regimen – nicknamed 3D – has also been assessed in two pivotal phase III trials and has shown exceptionally high SVR12 rates. In the SAPPHIRE I trial (N. Engl. J. Med. 2014 Apr. 10 [doi:10.1056/NEJMoa1315722]), in treatment-naive patients without cirrhosis, SVR12 after 12 weeks’ therapy with the 3D regimen was 96.2% and in the SAPPHIRE II trial (N. Engl. J. Med. 2014 Apr. 10 [doi: 10.1056/NEJMoa1401561]) in treatment-experienced patients without cirrhosis it was 96.3% in treatment-experienced patients, which included those who had previously not responded to IFN-based therapy. The results of both SAPPHIRE trials were also presented at the meeting, which was sponsored by the European Association for the Study of the Liver.

Dr. Jean-Michel Pawlotsky of Hôpital Henri Mondor, Créteil, France, who chaired the late-breakers session at which the TURQUOISE II data were presented, commented that these data were "outstanding." He asked Dr. Poordad to comment on the treatment duration and when a longer treatment course might be warranted in certain patients.

"I think one has to use their clinical judgment, so if you have a patient who comes in and you cannot determine if they were a previous nonresponder or not then you can certainly consider treating a little bit longer," the investigator responded. "They certainly tolerate treatment just as well."

AbbVie sponsored the study. Dr. Poordad has received research support and acted as a consultant to the company. He also disclosed receiving grants or research support or acting as an adviser or speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, in addition to others.

LONDON – More than 90% of patients with chronic hepatitis C and compensated cirrhosis treated with a triple-acting, all-oral, direct-acting antiviral (DAA) regimen achieved sustained virologic responses 12 weeks after the end of therapy (SVR12) in a phase III trial.

In the TURQUOISE II study, 380 patients infected with the hepatitis C virus (HVC) genotype 1 were treated with the interferon (IFN)-free combination of ABT-450/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 or 24 weeks. Results showed that SVR12 rates were 91.8% and 95.9%.

Results were striking, compared with a historical control group using telaprevir plus pegylated IFN plus ribavirin, with the threshold for noninferiority and superiority set at 43% and 54%, respectively.

The study is the first to look at the effects of an all-oral, direct-acting antiviral regimen exclusively in patients with HVC genotype 1 infection and cirrhosis, said the lead study investigator Dr. Fred Poordad. The study findings were published online to coincide with his presentation at the International Liver Congress 2014 (N. Engl. J. Med. 2014 Apr. 12 [doi: 10.1056/NEJMoa1402869]).

TURQUOISE II was an international, multicenter, randomized, open-label trial of 380 patients with Child-Pugh class A cirrhosis caused by HCV infection, explained Dr. Poordad of the Texas Liver Institute at the University of Texas Health Science Center, San Antonio. The trial was conducted at 78 sites in Europe and North America and included both treatment-experienced (about 60%) and treatment-naive (about 40%) patients.

Results by HCV subtype showed that the regimen worked equally well in patients with genotype 1a as genotype 1b, with SVR12 rates of 88.6% and 98.5% with 12 weeks’ treatment and 94.2% and 100% with 24 weeks’ treatment, respectively.

SVR rates were also similarly high in patients according to prior treatment response and in those with portal hypertension or reduced hepatic function identified by low baseline platelet counts or low serum albumin.

Dr. Poordad noted that 8.2% and 4.1% of patients did not achieve SVR12 in the 12- and 24-week therapy groups, respectively. Premature discontinuations occurred in 1.9% and 1.7% and were with caused by an adverse event (four vs. one case) or withdrawal of consent (0 vs. two cases).

"Virologic breakthrough was an unusual event in either arm (0.5% and 1.7%, respectively)," the researcher observed. Relapse occurred in 5.9% and 0.6% of patients in the 12- and 24-week arms. "Of the 12 patients who relapsed in the 12-week arm, 7 of them were [genotype]1a null responders, largely driving the difference in relapse between these two arms," Dr. Poordad said.

He noted that 17 patients overall had a virologic failure and of these, 15 of them had at least one resistance-associated variant. The most common variants in GT1a-infected patients were D168V found in NS3 and Q30R found in NS5A. The significance and persistence of these variants is currently under investigation.

In terms of tolerability, fatigue, and shortness of breath were the most common adverse events seen, occurring in a higher percentage of patients treated with 24 (46.5% and 12.2%) vs. 12 (12.2% vs. 5.8%) weeks of treatment (P less than .05 for both comparisons). There were low rates of severe or serious adverse events and low rates of treatment discontinuation (about 2%).

"The efficacy and safety in this large cirrhotic population is similar to noncirrhotics treated with the same regimen," Dr. Poordad noted. He highlighted that the three DAA antiviral regimen – nicknamed 3D – has also been assessed in two pivotal phase III trials and has shown exceptionally high SVR12 rates. In the SAPPHIRE I trial (N. Engl. J. Med. 2014 Apr. 10 [doi:10.1056/NEJMoa1315722]), in treatment-naive patients without cirrhosis, SVR12 after 12 weeks’ therapy with the 3D regimen was 96.2% and in the SAPPHIRE II trial (N. Engl. J. Med. 2014 Apr. 10 [doi: 10.1056/NEJMoa1401561]) in treatment-experienced patients without cirrhosis it was 96.3% in treatment-experienced patients, which included those who had previously not responded to IFN-based therapy. The results of both SAPPHIRE trials were also presented at the meeting, which was sponsored by the European Association for the Study of the Liver.

Dr. Jean-Michel Pawlotsky of Hôpital Henri Mondor, Créteil, France, who chaired the late-breakers session at which the TURQUOISE II data were presented, commented that these data were "outstanding." He asked Dr. Poordad to comment on the treatment duration and when a longer treatment course might be warranted in certain patients.

"I think one has to use their clinical judgment, so if you have a patient who comes in and you cannot determine if they were a previous nonresponder or not then you can certainly consider treating a little bit longer," the investigator responded. "They certainly tolerate treatment just as well."

AbbVie sponsored the study. Dr. Poordad has received research support and acted as a consultant to the company. He also disclosed receiving grants or research support or acting as an adviser or speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, in addition to others.

LONDON – Simvastatin improves short-term survival after variceal bleeding in patients with cirrhosis, results of a phase III, randomized, double blind study have shown.

At 2 years’ follow-up in the randomized, double-blind, Bleeding Prevention With Simvastatin (BLEPS) study, 17 of 78 placebo-treated (22%) and 6 of 69 simvastatin-treated (9%) patients died (P = .03). This represented a 61% reduction in the risk for death (hazard ratio, 0.387).

The benefit was almost exclusively seen in patients with Child-Pugh A/B cirrhosis (n = 124) in which mortality was just 5% in statin-treated patients vs. 21% in placebo-treated patients. Mortality was 25% vs. 27%, respectively, in patients with Child-Pugh C cirrhosis (n = 23).

"Our results indicate that the administration of simvastatin should be recommended in patients on secondary prophylaxis of variceal bleeding, especially in those with Child-Pugh A/B [cirrhosis]," study investigator Dr. Juan G. Abraldes of the University of Alberta (Canada) Hospital reported at the International Liver Congress sponsored by the European Association for the Study of the Liver (EASL).

Patients with cirrhosis are at risk for a number of complications, such as portal hypertension and the subsequent development of esophageal varices and variceal bleeding. Recommended treatment consists of beta-blockers and endoscopic banding ligation to prevent rebleeding (Am. J. Gastroenterol. 2007;102:2086-102).

"[Even] with this therapy the probability of rebleeding or death is still very high," Dr. Abraldes said at the meeting. Indeed, data suggest that variceal rebleeding carries a 1-year mortality of 36% (Gut 2009;58:1144-150).

Changes in portal hypertension and liver function are major determinants for rebleeding and death, the researcher added, noting that simvastatin has been shown to not only decrease portal pressure and improve liver function but also to potentially decrease fibrosis.

Dr. Abraldes and his colleagues at 14 Spanish centers therefore set out to see if simvastatin could have any beneficial effect in addition to standard treatments for secondary prophylaxis of variceal bleeding. They recruited a total of 158 patients who had confirmed esophageal variceal bleeding in the preceding 10 days and who were due to undergo endoscopic ligation and start preventative therapy with beta-blockers.

Patients were randomized to receive simvastatin at a daily dose of 15 mg for 15 days, which could be increased to 40 mg once daily or matching doses of a placebo. The primary endpoint was a composite of rebleeding from any cause or death. The average age of recruited patients was 68 years and the majority (71%) had cirrhosis from alcoholic liver disease. Nearly half were still active alcohol users, and around one-fifth had hepatitis C viral infection.

The primary endpoint was not reduced in the simvastatin arm relative to placebo, nor was the rate of rebleeding affected when the individual components of the composite endpoint were looked at, Dr. Abraldes reported. Yet there was a "marked survival benefit with simvastatin."

The addition of simvastatin to standard treatment was not associated with any significant adverse effects as compared with placebo.

"If we have a drug which is tolerated and can influence survival in patients with cirrhosis I think it should be used," EASL commentator Dr. Mauro Bernardi of the University of Bologna, Italy, said during a press briefing. While not involved in the study, Dr. Bernardi has a keen research interest in the management of cirrhosis and related complications.

The study was conducted in patients with advance cirrhosis, who already had portal hypertension, it was noted. The benefit on survival but not rebleeding was somewhat surprising but could have occurred because the simvastatin was having a beneficial effect on liver function and perhaps also liver injury, it was proposed.

"Overall, having an effect on mortality within 2 years in patients with Child-Pugh A/B cirrhosis is a very important result," Dr. Bernardi.

During discussions following the presentation it was noted that the use of a statin is contraindicated in patients with liver disease and also that the results might not extrapolate out to all patients with cirrhosis. Further studies are clearly needed, as "there are many, many questions," that remain said the session Chairman, Dr. Peter Ferenc of the Medical University of Vienna.

The Spanish government funded the study. Dr. Abraldes and Dr. Bernardi had no disclosures.

LONDON – Simvastatin improves short-term survival after variceal bleeding in patients with cirrhosis, results of a phase III, randomized, double blind study have shown.

At 2 years’ follow-up in the randomized, double-blind, Bleeding Prevention With Simvastatin (BLEPS) study, 17 of 78 placebo-treated (22%) and 6 of 69 simvastatin-treated (9%) patients died (P = .03). This represented a 61% reduction in the risk for death (hazard ratio, 0.387).

The benefit was almost exclusively seen in patients with Child-Pugh A/B cirrhosis (n = 124) in which mortality was just 5% in statin-treated patients vs. 21% in placebo-treated patients. Mortality was 25% vs. 27%, respectively, in patients with Child-Pugh C cirrhosis (n = 23).

"Our results indicate that the administration of simvastatin should be recommended in patients on secondary prophylaxis of variceal bleeding, especially in those with Child-Pugh A/B [cirrhosis]," study investigator Dr. Juan G. Abraldes of the University of Alberta (Canada) Hospital reported at the International Liver Congress sponsored by the European Association for the Study of the Liver (EASL).

Patients with cirrhosis are at risk for a number of complications, such as portal hypertension and the subsequent development of esophageal varices and variceal bleeding. Recommended treatment consists of beta-blockers and endoscopic banding ligation to prevent rebleeding (Am. J. Gastroenterol. 2007;102:2086-102).

"[Even] with this therapy the probability of rebleeding or death is still very high," Dr. Abraldes said at the meeting. Indeed, data suggest that variceal rebleeding carries a 1-year mortality of 36% (Gut 2009;58:1144-150).

Changes in portal hypertension and liver function are major determinants for rebleeding and death, the researcher added, noting that simvastatin has been shown to not only decrease portal pressure and improve liver function but also to potentially decrease fibrosis.

Dr. Abraldes and his colleagues at 14 Spanish centers therefore set out to see if simvastatin could have any beneficial effect in addition to standard treatments for secondary prophylaxis of variceal bleeding. They recruited a total of 158 patients who had confirmed esophageal variceal bleeding in the preceding 10 days and who were due to undergo endoscopic ligation and start preventative therapy with beta-blockers.

Patients were randomized to receive simvastatin at a daily dose of 15 mg for 15 days, which could be increased to 40 mg once daily or matching doses of a placebo. The primary endpoint was a composite of rebleeding from any cause or death. The average age of recruited patients was 68 years and the majority (71%) had cirrhosis from alcoholic liver disease. Nearly half were still active alcohol users, and around one-fifth had hepatitis C viral infection.

The primary endpoint was not reduced in the simvastatin arm relative to placebo, nor was the rate of rebleeding affected when the individual components of the composite endpoint were looked at, Dr. Abraldes reported. Yet there was a "marked survival benefit with simvastatin."

The addition of simvastatin to standard treatment was not associated with any significant adverse effects as compared with placebo.

"If we have a drug which is tolerated and can influence survival in patients with cirrhosis I think it should be used," EASL commentator Dr. Mauro Bernardi of the University of Bologna, Italy, said during a press briefing. While not involved in the study, Dr. Bernardi has a keen research interest in the management of cirrhosis and related complications.

The study was conducted in patients with advance cirrhosis, who already had portal hypertension, it was noted. The benefit on survival but not rebleeding was somewhat surprising but could have occurred because the simvastatin was having a beneficial effect on liver function and perhaps also liver injury, it was proposed.

"Overall, having an effect on mortality within 2 years in patients with Child-Pugh A/B cirrhosis is a very important result," Dr. Bernardi.

During discussions following the presentation it was noted that the use of a statin is contraindicated in patients with liver disease and also that the results might not extrapolate out to all patients with cirrhosis. Further studies are clearly needed, as "there are many, many questions," that remain said the session Chairman, Dr. Peter Ferenc of the Medical University of Vienna.

The Spanish government funded the study. Dr. Abraldes and Dr. Bernardi had no disclosures.

LONDON – Simvastatin improves short-term survival after variceal bleeding in patients with cirrhosis, results of a phase III, randomized, double blind study have shown.

At 2 years’ follow-up in the randomized, double-blind, Bleeding Prevention With Simvastatin (BLEPS) study, 17 of 78 placebo-treated (22%) and 6 of 69 simvastatin-treated (9%) patients died (P = .03). This represented a 61% reduction in the risk for death (hazard ratio, 0.387).

The benefit was almost exclusively seen in patients with Child-Pugh A/B cirrhosis (n = 124) in which mortality was just 5% in statin-treated patients vs. 21% in placebo-treated patients. Mortality was 25% vs. 27%, respectively, in patients with Child-Pugh C cirrhosis (n = 23).

"Our results indicate that the administration of simvastatin should be recommended in patients on secondary prophylaxis of variceal bleeding, especially in those with Child-Pugh A/B [cirrhosis]," study investigator Dr. Juan G. Abraldes of the University of Alberta (Canada) Hospital reported at the International Liver Congress sponsored by the European Association for the Study of the Liver (EASL).

Patients with cirrhosis are at risk for a number of complications, such as portal hypertension and the subsequent development of esophageal varices and variceal bleeding. Recommended treatment consists of beta-blockers and endoscopic banding ligation to prevent rebleeding (Am. J. Gastroenterol. 2007;102:2086-102).

"[Even] with this therapy the probability of rebleeding or death is still very high," Dr. Abraldes said at the meeting. Indeed, data suggest that variceal rebleeding carries a 1-year mortality of 36% (Gut 2009;58:1144-150).

Changes in portal hypertension and liver function are major determinants for rebleeding and death, the researcher added, noting that simvastatin has been shown to not only decrease portal pressure and improve liver function but also to potentially decrease fibrosis.

Dr. Abraldes and his colleagues at 14 Spanish centers therefore set out to see if simvastatin could have any beneficial effect in addition to standard treatments for secondary prophylaxis of variceal bleeding. They recruited a total of 158 patients who had confirmed esophageal variceal bleeding in the preceding 10 days and who were due to undergo endoscopic ligation and start preventative therapy with beta-blockers.

Patients were randomized to receive simvastatin at a daily dose of 15 mg for 15 days, which could be increased to 40 mg once daily or matching doses of a placebo. The primary endpoint was a composite of rebleeding from any cause or death. The average age of recruited patients was 68 years and the majority (71%) had cirrhosis from alcoholic liver disease. Nearly half were still active alcohol users, and around one-fifth had hepatitis C viral infection.

The primary endpoint was not reduced in the simvastatin arm relative to placebo, nor was the rate of rebleeding affected when the individual components of the composite endpoint were looked at, Dr. Abraldes reported. Yet there was a "marked survival benefit with simvastatin."

The addition of simvastatin to standard treatment was not associated with any significant adverse effects as compared with placebo.

"If we have a drug which is tolerated and can influence survival in patients with cirrhosis I think it should be used," EASL commentator Dr. Mauro Bernardi of the University of Bologna, Italy, said during a press briefing. While not involved in the study, Dr. Bernardi has a keen research interest in the management of cirrhosis and related complications.

The study was conducted in patients with advance cirrhosis, who already had portal hypertension, it was noted. The benefit on survival but not rebleeding was somewhat surprising but could have occurred because the simvastatin was having a beneficial effect on liver function and perhaps also liver injury, it was proposed.

"Overall, having an effect on mortality within 2 years in patients with Child-Pugh A/B cirrhosis is a very important result," Dr. Bernardi.

During discussions following the presentation it was noted that the use of a statin is contraindicated in patients with liver disease and also that the results might not extrapolate out to all patients with cirrhosis. Further studies are clearly needed, as "there are many, many questions," that remain said the session Chairman, Dr. Peter Ferenc of the Medical University of Vienna.

The Spanish government funded the study. Dr. Abraldes and Dr. Bernardi had no disclosures.

LONDON – A single daily pill containing two novel antiviral agents produced sustained virologic response rates of more than 90% in as little as 8-12 weeks in three multicenter, open-label phase III studies involving 1,952 patients with chronic hepatitis C virus infection.

The combination pill, containing fixed doses of 400 mg sofosbuvir and 90 mg ledipasvir, was given alone or together with ribavirin but without pegylated interferon (peg-IFN) for 8, 12, or 24 weeks in the ION-1, ION-2, and ION-3 trials. Results of the first two trials showed that a 12-week course of sofosbuvir/ledipasvir was enough to clear the virus in the majority of patients, but results of the latter showed that an 8-week regimen of the daily pill was sufficient.

The findings of all three studies were published online in the New England Journal of Medicine to coincide with their presentation at the International Liver Congress sponsored by the European Association for the Study of the Liver.

"The real advance seen in the ION trials is that the sofosbuvir-ledipasvir combination tablet enables us to treat almost all genotype 1 patients with a short duration of 8-12 weeks of treatment," Dr. Nezam Afdhal* of Beth Israel Deaconess Medical Center, Boston, said in a press statement issued by his institution, which was one of the key centers involved in the studies.

Since patients who were unable to be treated with peg-IFN were included in the studies, these data could potentially expand the population of patients who could now be treated, as well as increase the overall cure rate, Dr. Afdhal added. Patients with compensated cirrhosis also were included in the ION-1 (n = 136) and ION-2 trials (n = 88).

ION-1 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1402454]) and ION-2 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1316366]) were designed to investigate the efficacy and safety of the sofosbuvir/ledipasvir fixed-dose combination given with or without ribavirin for 12 and 24 weeks in patients with chronic genotype 1 hepatitis C virus (HCV) infection who were treatment experienced and treatment naive, respectively. Results showed that similar cure rates could be achieved in patients regardless of the duration of the regimen.

Indeed, sustained virologic response at 12 weeks after the end of treatment (SVR12) in ION-1 in treatment-naive patients (n = 865) was 99% with the daily pill alone and 97% if ribavirin also was given. There was little benefit of continuing therapy for up to 24 weeks, with SVR12 of 98% for the daily pill given alone and 99% with additional ribavirin.

SVR12 in previously treated patients in the ION-2 trial (n = 440) was 94% with the daily pill alone and 96% if ribavirin also was given for 12 weeks. There was little benefit of continuing therapy for 24 weeks, with SVR12 of 99% for the daily pill used alone and together with ribavirin.

ION-3 (N. Engl. J. Med. 2014 Apr. 11 [doi:10.1056/NEJMoa1402355]) looked at whether 8 weeks of treatment was as effective as 12 weeks of treatment. The open-label study included 647 patients with HCV genotype 1 infection without cirrhosis who had not been previously treated. SVR at 8 weeks was 94%, versus 95% for the 12-week regimen. The addition of ribavirin did not increase the SVR, which was 93% at 8 weeks, showing that a shorter regimen was just as effective as the 12-week course.

Adverse events were more common in the ribavirin-treated patients than in those who received only the combined sofosbuvir/ledipasvir pill. The most common adverse events seen in the trials – fatigue, headache, insomnia, and nausea – were linked to ribavirin therapy.

"With cure rates well in excess of 90% with as little as 8 weeks of treatment for some patients, these data represent a significant advance in the race to develop a new, all-oral treatment for hepatitis C," said Dr. Markus Peck-Radosavljevic, the Secretary General of EASL. He noted, in a press statement issued by the association, that avoiding the use of both peg-IFN and ribavirin had the potential to bring forward more patients for treatment as it is likely to be much more tolerable.

Gilead Sciences funded the trials. Dr. Afdhal has received research support, honoraria, or other fees in the past 12 months from Gilead Sciences, Abbott, BMS, Boehringer Ingelheim, Echosens, Janssen, GSK, Idenix, Ligan, Merck, Medgenics, Novartis, Quest, Springbank, TRIO Healthcare, and Vertex. Dr. Peck-Radosavljevic made no disclosures.

*Correction 5/8/2014: In a previous version of the story Dr. Afdhal's name was misspelled. This version has been updated.

LONDON – A single daily pill containing two novel antiviral agents produced sustained virologic response rates of more than 90% in as little as 8-12 weeks in three multicenter, open-label phase III studies involving 1,952 patients with chronic hepatitis C virus infection.

The combination pill, containing fixed doses of 400 mg sofosbuvir and 90 mg ledipasvir, was given alone or together with ribavirin but without pegylated interferon (peg-IFN) for 8, 12, or 24 weeks in the ION-1, ION-2, and ION-3 trials. Results of the first two trials showed that a 12-week course of sofosbuvir/ledipasvir was enough to clear the virus in the majority of patients, but results of the latter showed that an 8-week regimen of the daily pill was sufficient.

The findings of all three studies were published online in the New England Journal of Medicine to coincide with their presentation at the International Liver Congress sponsored by the European Association for the Study of the Liver.

"The real advance seen in the ION trials is that the sofosbuvir-ledipasvir combination tablet enables us to treat almost all genotype 1 patients with a short duration of 8-12 weeks of treatment," Dr. Nezam Afdhal* of Beth Israel Deaconess Medical Center, Boston, said in a press statement issued by his institution, which was one of the key centers involved in the studies.

Since patients who were unable to be treated with peg-IFN were included in the studies, these data could potentially expand the population of patients who could now be treated, as well as increase the overall cure rate, Dr. Afdhal added. Patients with compensated cirrhosis also were included in the ION-1 (n = 136) and ION-2 trials (n = 88).

ION-1 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1402454]) and ION-2 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1316366]) were designed to investigate the efficacy and safety of the sofosbuvir/ledipasvir fixed-dose combination given with or without ribavirin for 12 and 24 weeks in patients with chronic genotype 1 hepatitis C virus (HCV) infection who were treatment experienced and treatment naive, respectively. Results showed that similar cure rates could be achieved in patients regardless of the duration of the regimen.

Indeed, sustained virologic response at 12 weeks after the end of treatment (SVR12) in ION-1 in treatment-naive patients (n = 865) was 99% with the daily pill alone and 97% if ribavirin also was given. There was little benefit of continuing therapy for up to 24 weeks, with SVR12 of 98% for the daily pill given alone and 99% with additional ribavirin.

SVR12 in previously treated patients in the ION-2 trial (n = 440) was 94% with the daily pill alone and 96% if ribavirin also was given for 12 weeks. There was little benefit of continuing therapy for 24 weeks, with SVR12 of 99% for the daily pill used alone and together with ribavirin.

ION-3 (N. Engl. J. Med. 2014 Apr. 11 [doi:10.1056/NEJMoa1402355]) looked at whether 8 weeks of treatment was as effective as 12 weeks of treatment. The open-label study included 647 patients with HCV genotype 1 infection without cirrhosis who had not been previously treated. SVR at 8 weeks was 94%, versus 95% for the 12-week regimen. The addition of ribavirin did not increase the SVR, which was 93% at 8 weeks, showing that a shorter regimen was just as effective as the 12-week course.

Adverse events were more common in the ribavirin-treated patients than in those who received only the combined sofosbuvir/ledipasvir pill. The most common adverse events seen in the trials – fatigue, headache, insomnia, and nausea – were linked to ribavirin therapy.

"With cure rates well in excess of 90% with as little as 8 weeks of treatment for some patients, these data represent a significant advance in the race to develop a new, all-oral treatment for hepatitis C," said Dr. Markus Peck-Radosavljevic, the Secretary General of EASL. He noted, in a press statement issued by the association, that avoiding the use of both peg-IFN and ribavirin had the potential to bring forward more patients for treatment as it is likely to be much more tolerable.

Gilead Sciences funded the trials. Dr. Afdhal has received research support, honoraria, or other fees in the past 12 months from Gilead Sciences, Abbott, BMS, Boehringer Ingelheim, Echosens, Janssen, GSK, Idenix, Ligan, Merck, Medgenics, Novartis, Quest, Springbank, TRIO Healthcare, and Vertex. Dr. Peck-Radosavljevic made no disclosures.

*Correction 5/8/2014: In a previous version of the story Dr. Afdhal's name was misspelled. This version has been updated.

LONDON – A single daily pill containing two novel antiviral agents produced sustained virologic response rates of more than 90% in as little as 8-12 weeks in three multicenter, open-label phase III studies involving 1,952 patients with chronic hepatitis C virus infection.

The combination pill, containing fixed doses of 400 mg sofosbuvir and 90 mg ledipasvir, was given alone or together with ribavirin but without pegylated interferon (peg-IFN) for 8, 12, or 24 weeks in the ION-1, ION-2, and ION-3 trials. Results of the first two trials showed that a 12-week course of sofosbuvir/ledipasvir was enough to clear the virus in the majority of patients, but results of the latter showed that an 8-week regimen of the daily pill was sufficient.

The findings of all three studies were published online in the New England Journal of Medicine to coincide with their presentation at the International Liver Congress sponsored by the European Association for the Study of the Liver.

"The real advance seen in the ION trials is that the sofosbuvir-ledipasvir combination tablet enables us to treat almost all genotype 1 patients with a short duration of 8-12 weeks of treatment," Dr. Nezam Afdhal* of Beth Israel Deaconess Medical Center, Boston, said in a press statement issued by his institution, which was one of the key centers involved in the studies.

Since patients who were unable to be treated with peg-IFN were included in the studies, these data could potentially expand the population of patients who could now be treated, as well as increase the overall cure rate, Dr. Afdhal added. Patients with compensated cirrhosis also were included in the ION-1 (n = 136) and ION-2 trials (n = 88).

ION-1 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1402454]) and ION-2 (N. Engl. J. Med. 2014 Apr. 12 [doi:10.1056/NEJMoa1316366]) were designed to investigate the efficacy and safety of the sofosbuvir/ledipasvir fixed-dose combination given with or without ribavirin for 12 and 24 weeks in patients with chronic genotype 1 hepatitis C virus (HCV) infection who were treatment experienced and treatment naive, respectively. Results showed that similar cure rates could be achieved in patients regardless of the duration of the regimen.

Indeed, sustained virologic response at 12 weeks after the end of treatment (SVR12) in ION-1 in treatment-naive patients (n = 865) was 99% with the daily pill alone and 97% if ribavirin also was given. There was little benefit of continuing therapy for up to 24 weeks, with SVR12 of 98% for the daily pill given alone and 99% with additional ribavirin.

SVR12 in previously treated patients in the ION-2 trial (n = 440) was 94% with the daily pill alone and 96% if ribavirin also was given for 12 weeks. There was little benefit of continuing therapy for 24 weeks, with SVR12 of 99% for the daily pill used alone and together with ribavirin.

ION-3 (N. Engl. J. Med. 2014 Apr. 11 [doi:10.1056/NEJMoa1402355]) looked at whether 8 weeks of treatment was as effective as 12 weeks of treatment. The open-label study included 647 patients with HCV genotype 1 infection without cirrhosis who had not been previously treated. SVR at 8 weeks was 94%, versus 95% for the 12-week regimen. The addition of ribavirin did not increase the SVR, which was 93% at 8 weeks, showing that a shorter regimen was just as effective as the 12-week course.

Adverse events were more common in the ribavirin-treated patients than in those who received only the combined sofosbuvir/ledipasvir pill. The most common adverse events seen in the trials – fatigue, headache, insomnia, and nausea – were linked to ribavirin therapy.

"With cure rates well in excess of 90% with as little as 8 weeks of treatment for some patients, these data represent a significant advance in the race to develop a new, all-oral treatment for hepatitis C," said Dr. Markus Peck-Radosavljevic, the Secretary General of EASL. He noted, in a press statement issued by the association, that avoiding the use of both peg-IFN and ribavirin had the potential to bring forward more patients for treatment as it is likely to be much more tolerable.

Gilead Sciences funded the trials. Dr. Afdhal has received research support, honoraria, or other fees in the past 12 months from Gilead Sciences, Abbott, BMS, Boehringer Ingelheim, Echosens, Janssen, GSK, Idenix, Ligan, Merck, Medgenics, Novartis, Quest, Springbank, TRIO Healthcare, and Vertex. Dr. Peck-Radosavljevic made no disclosures.

*Correction 5/8/2014: In a previous version of the story Dr. Afdhal's name was misspelled. This version has been updated.

LONDON – Obeticholic acid significantly reduced key liver enzyme and bilirubin levels in patients with primary biliary cirrhosis in a phase III trial.

Results of POISE [PBC OCA International Study of Efficacy] showed that at the final 1-year assessment, 46% of patients treated with an initial 5-mg daily dose of OCA, and 47% of those treated with a 10-mg daily dose, achieved the primary endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal (ULN) with bilirubin levels less than the ULN and a 15% or greater reduction ALP. In comparison, just 10% of placebo-treated patients achieved this endpoint, which has been linked to a reduction in the need for liver transplantation and death.

Significant reductions (P less than .001) in levels of other key liver enzymes – gamma glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase – were also seen with active versus placebo treatment.

Study investigator Frederik Nevens said in an interview that OCA represents the first new treatment for PBC in 2 decades and it could even be "aspirin for hepatologists" if data from translational research are borne out in clinical trials.

Indeed, Dr. Nevens, of University Hospital Gasthuisberg in Leuven, Belgium, said that because OCA targets the farnesoid-X receptor, which is a nuclear receptor involved in multiple metabolic and other pathways, it could have widespread clinical applications.

"It has an effect on fibrosis, probably, it has an effect on portal hypertension, and it has an effect on cholestasis," he said. Furthermore, it reduces bacterial translocation from the gut, which has implications for the prevention of liver infections, and there is also the suggestion that it might be of benefit in patients with diabetes, Crohn’s disease, and malignancies.

"Certainly it also has a beneficial effect on NASH [nonalcoholic steatohepatitis], and NASH is one of the most common [liver] problems these days," Dr. Nevens observed. Recently, the phase II FLINT trial conducted with OCA in patients with NASH was halted because of positive interim results.

PBC affects mostly women, at rate of about 1 in 1,000 women over 40 years of age in the United States, and is the fifth most common reason for liver transplantation in the country, Dr. Nevens said. Currently, ursodeoxycholic acid is the only approved treatment, although fewer than 50% of patients respond adequately to the drug.

The POISE data clearly have shown a potential benefit for OCA in patients with PBC, the researcher said at the meeting, sponsored by the European Association for the Study of the Liver. Data from a phase II trial had already shown that OCA with or without the standard treatment (ursodeoxycholic acid) at a dose of 10-50 mg produced significant improvement in cholestasis but the main side effect was pruritus. While itching is a characteristic of PBC itself, a key aim of the phase III trial was to reduce the prevalence of this side effect.

Significantly lowering and titrating the dose reduced the occurrence and impact of pruritus, Dr. Nevens reported during a late-breaking trials session. Nevertheless, the side effect was seen in more than two-thirds of patients given the 10-mg dose and 56% of those given the 5-mg dose, which was titrated up to 10 mg over a 6-month period, compared with 38% of placebo-treated patients. The bile acid sequestrant cholestyramine was permitted as a means to alleviate itching and was used in 26%, 19%, and 11% of patients, respectively.

"Titration from 5 to 10 mg based on clinical response improved tolerance, minimized dropouts due to pruritus, and showed comparable efficacy to 10 mg OCA," Dr. Nevens said. "The long-term safety and efficacy is currently being evaluated in an open-label extension study," he added, noting almost all patients (95%) completing the phase III trial had opted to continue therapy in the extension study.

Further confirmation of OCA’s benefits are needed, but the problem with doing a trial to prove that mortality is reduced as a result of long-term treatment is that it would not be ethical to treat patients with placebo for 10 years, Dr. Nevens pointed out. Reduction in ALP and bilirubin levels, as used in POISE, was a good surrogate marker for outcome, he said. The Global PBC Study Group found that ALP less than 1.67 times the ULN and normal predicted the likelihood of transplant-free survival with a hazard ratio of 3.53.

Intercept Pharmaceuticals sponsored the study. Dr. Nevens was an investigator for the POISE trial but did not receive any grants or speaker fees from the company.

LONDON – Obeticholic acid significantly reduced key liver enzyme and bilirubin levels in patients with primary biliary cirrhosis in a phase III trial.

Results of POISE [PBC OCA International Study of Efficacy] showed that at the final 1-year assessment, 46% of patients treated with an initial 5-mg daily dose of OCA, and 47% of those treated with a 10-mg daily dose, achieved the primary endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal (ULN) with bilirubin levels less than the ULN and a 15% or greater reduction ALP. In comparison, just 10% of placebo-treated patients achieved this endpoint, which has been linked to a reduction in the need for liver transplantation and death.

Significant reductions (P less than .001) in levels of other key liver enzymes – gamma glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase – were also seen with active versus placebo treatment.

Study investigator Frederik Nevens said in an interview that OCA represents the first new treatment for PBC in 2 decades and it could even be "aspirin for hepatologists" if data from translational research are borne out in clinical trials.

Indeed, Dr. Nevens, of University Hospital Gasthuisberg in Leuven, Belgium, said that because OCA targets the farnesoid-X receptor, which is a nuclear receptor involved in multiple metabolic and other pathways, it could have widespread clinical applications.

"It has an effect on fibrosis, probably, it has an effect on portal hypertension, and it has an effect on cholestasis," he said. Furthermore, it reduces bacterial translocation from the gut, which has implications for the prevention of liver infections, and there is also the suggestion that it might be of benefit in patients with diabetes, Crohn’s disease, and malignancies.

"Certainly it also has a beneficial effect on NASH [nonalcoholic steatohepatitis], and NASH is one of the most common [liver] problems these days," Dr. Nevens observed. Recently, the phase II FLINT trial conducted with OCA in patients with NASH was halted because of positive interim results.

PBC affects mostly women, at rate of about 1 in 1,000 women over 40 years of age in the United States, and is the fifth most common reason for liver transplantation in the country, Dr. Nevens said. Currently, ursodeoxycholic acid is the only approved treatment, although fewer than 50% of patients respond adequately to the drug.

The POISE data clearly have shown a potential benefit for OCA in patients with PBC, the researcher said at the meeting, sponsored by the European Association for the Study of the Liver. Data from a phase II trial had already shown that OCA with or without the standard treatment (ursodeoxycholic acid) at a dose of 10-50 mg produced significant improvement in cholestasis but the main side effect was pruritus. While itching is a characteristic of PBC itself, a key aim of the phase III trial was to reduce the prevalence of this side effect.

Significantly lowering and titrating the dose reduced the occurrence and impact of pruritus, Dr. Nevens reported during a late-breaking trials session. Nevertheless, the side effect was seen in more than two-thirds of patients given the 10-mg dose and 56% of those given the 5-mg dose, which was titrated up to 10 mg over a 6-month period, compared with 38% of placebo-treated patients. The bile acid sequestrant cholestyramine was permitted as a means to alleviate itching and was used in 26%, 19%, and 11% of patients, respectively.

"Titration from 5 to 10 mg based on clinical response improved tolerance, minimized dropouts due to pruritus, and showed comparable efficacy to 10 mg OCA," Dr. Nevens said. "The long-term safety and efficacy is currently being evaluated in an open-label extension study," he added, noting almost all patients (95%) completing the phase III trial had opted to continue therapy in the extension study.

Further confirmation of OCA’s benefits are needed, but the problem with doing a trial to prove that mortality is reduced as a result of long-term treatment is that it would not be ethical to treat patients with placebo for 10 years, Dr. Nevens pointed out. Reduction in ALP and bilirubin levels, as used in POISE, was a good surrogate marker for outcome, he said. The Global PBC Study Group found that ALP less than 1.67 times the ULN and normal predicted the likelihood of transplant-free survival with a hazard ratio of 3.53.

Intercept Pharmaceuticals sponsored the study. Dr. Nevens was an investigator for the POISE trial but did not receive any grants or speaker fees from the company.

LONDON – Obeticholic acid significantly reduced key liver enzyme and bilirubin levels in patients with primary biliary cirrhosis in a phase III trial.

Results of POISE [PBC OCA International Study of Efficacy] showed that at the final 1-year assessment, 46% of patients treated with an initial 5-mg daily dose of OCA, and 47% of those treated with a 10-mg daily dose, achieved the primary endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal (ULN) with bilirubin levels less than the ULN and a 15% or greater reduction ALP. In comparison, just 10% of placebo-treated patients achieved this endpoint, which has been linked to a reduction in the need for liver transplantation and death.

Significant reductions (P less than .001) in levels of other key liver enzymes – gamma glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase – were also seen with active versus placebo treatment.

Study investigator Frederik Nevens said in an interview that OCA represents the first new treatment for PBC in 2 decades and it could even be "aspirin for hepatologists" if data from translational research are borne out in clinical trials.

Indeed, Dr. Nevens, of University Hospital Gasthuisberg in Leuven, Belgium, said that because OCA targets the farnesoid-X receptor, which is a nuclear receptor involved in multiple metabolic and other pathways, it could have widespread clinical applications.

"It has an effect on fibrosis, probably, it has an effect on portal hypertension, and it has an effect on cholestasis," he said. Furthermore, it reduces bacterial translocation from the gut, which has implications for the prevention of liver infections, and there is also the suggestion that it might be of benefit in patients with diabetes, Crohn’s disease, and malignancies.

"Certainly it also has a beneficial effect on NASH [nonalcoholic steatohepatitis], and NASH is one of the most common [liver] problems these days," Dr. Nevens observed. Recently, the phase II FLINT trial conducted with OCA in patients with NASH was halted because of positive interim results.

PBC affects mostly women, at rate of about 1 in 1,000 women over 40 years of age in the United States, and is the fifth most common reason for liver transplantation in the country, Dr. Nevens said. Currently, ursodeoxycholic acid is the only approved treatment, although fewer than 50% of patients respond adequately to the drug.

The POISE data clearly have shown a potential benefit for OCA in patients with PBC, the researcher said at the meeting, sponsored by the European Association for the Study of the Liver. Data from a phase II trial had already shown that OCA with or without the standard treatment (ursodeoxycholic acid) at a dose of 10-50 mg produced significant improvement in cholestasis but the main side effect was pruritus. While itching is a characteristic of PBC itself, a key aim of the phase III trial was to reduce the prevalence of this side effect.

Significantly lowering and titrating the dose reduced the occurrence and impact of pruritus, Dr. Nevens reported during a late-breaking trials session. Nevertheless, the side effect was seen in more than two-thirds of patients given the 10-mg dose and 56% of those given the 5-mg dose, which was titrated up to 10 mg over a 6-month period, compared with 38% of placebo-treated patients. The bile acid sequestrant cholestyramine was permitted as a means to alleviate itching and was used in 26%, 19%, and 11% of patients, respectively.

"Titration from 5 to 10 mg based on clinical response improved tolerance, minimized dropouts due to pruritus, and showed comparable efficacy to 10 mg OCA," Dr. Nevens said. "The long-term safety and efficacy is currently being evaluated in an open-label extension study," he added, noting almost all patients (95%) completing the phase III trial had opted to continue therapy in the extension study.

Further confirmation of OCA’s benefits are needed, but the problem with doing a trial to prove that mortality is reduced as a result of long-term treatment is that it would not be ethical to treat patients with placebo for 10 years, Dr. Nevens pointed out. Reduction in ALP and bilirubin levels, as used in POISE, was a good surrogate marker for outcome, he said. The Global PBC Study Group found that ALP less than 1.67 times the ULN and normal predicted the likelihood of transplant-free survival with a hazard ratio of 3.53.

Intercept Pharmaceuticals sponsored the study. Dr. Nevens was an investigator for the POISE trial but did not receive any grants or speaker fees from the company.