Liver Disease

Neither pentoxifylline nor prednisolone reduced 28-day mortality, 90-day mortality, or 1-year mortality among adults with alcoholic hepatitis in a multicenter clinical trial comparing the two agents, according to a report published online April 23 in the New England Journal of Medicine.

Pentoxifylline and glucocorticoids are the only drugs endorsed for this indication in treatment guidelines from the American Association for the Study of Liver Disease and the European Association for the Study of the Liver. However, the evidence in support of both has been conflicting, and their use remains controversial. The Steroids or Pentoxifylline for Alcoholic Hepatitis (SOPAH) study was a randomized, double-blind trial comparing the two drugs against each other and against placebo in 1,103 patients enrolled during a 3-year period at 65 hospitals across the United Kingdom, said Dr. Mark R. Thursz of Imperial College, London, and his associates.

The primary endpoint of the study, mortality at the conclusion of the 28-day course of treatment, was 14% in the group taking prednisolone plus placebo, 19% in those taking pentoxifylline plus placebo, 13% in those taking both prednisolone plus pentoxifylline, and 17% in those taking two placebos – all nonsignificant differences. In addition, neither active drug affected mortality or the need for liver transplantation at 90 days or at 1 year, the investigators reported (N. Engl. J. Med. 2015 April 23 [doi:10.1056/NEJMoa1412278]).

Cumulative mortality at 1 year was “alarming” but nearly identical between the groups who received the two active agents and the groups who did not: 56% with pentoxifylline and 57% without it; 57% with prednisolone and 56% without it.

Infection accounted for 24% of all deaths, but the number of infections among patients receiving prednisolone was no higher than that for the other patient groups, Dr. Thursz and his associates added.

Neither pentoxifylline nor prednisolone reduced 28-day mortality, 90-day mortality, or 1-year mortality among adults with alcoholic hepatitis in a multicenter clinical trial comparing the two agents, according to a report published online April 23 in the New England Journal of Medicine.

Pentoxifylline and glucocorticoids are the only drugs endorsed for this indication in treatment guidelines from the American Association for the Study of Liver Disease and the European Association for the Study of the Liver. However, the evidence in support of both has been conflicting, and their use remains controversial. The Steroids or Pentoxifylline for Alcoholic Hepatitis (SOPAH) study was a randomized, double-blind trial comparing the two drugs against each other and against placebo in 1,103 patients enrolled during a 3-year period at 65 hospitals across the United Kingdom, said Dr. Mark R. Thursz of Imperial College, London, and his associates.

The primary endpoint of the study, mortality at the conclusion of the 28-day course of treatment, was 14% in the group taking prednisolone plus placebo, 19% in those taking pentoxifylline plus placebo, 13% in those taking both prednisolone plus pentoxifylline, and 17% in those taking two placebos – all nonsignificant differences. In addition, neither active drug affected mortality or the need for liver transplantation at 90 days or at 1 year, the investigators reported (N. Engl. J. Med. 2015 April 23 [doi:10.1056/NEJMoa1412278]).

Cumulative mortality at 1 year was “alarming” but nearly identical between the groups who received the two active agents and the groups who did not: 56% with pentoxifylline and 57% without it; 57% with prednisolone and 56% without it.

Infection accounted for 24% of all deaths, but the number of infections among patients receiving prednisolone was no higher than that for the other patient groups, Dr. Thursz and his associates added.

Neither pentoxifylline nor prednisolone reduced 28-day mortality, 90-day mortality, or 1-year mortality among adults with alcoholic hepatitis in a multicenter clinical trial comparing the two agents, according to a report published online April 23 in the New England Journal of Medicine.

Pentoxifylline and glucocorticoids are the only drugs endorsed for this indication in treatment guidelines from the American Association for the Study of Liver Disease and the European Association for the Study of the Liver. However, the evidence in support of both has been conflicting, and their use remains controversial. The Steroids or Pentoxifylline for Alcoholic Hepatitis (SOPAH) study was a randomized, double-blind trial comparing the two drugs against each other and against placebo in 1,103 patients enrolled during a 3-year period at 65 hospitals across the United Kingdom, said Dr. Mark R. Thursz of Imperial College, London, and his associates.

The primary endpoint of the study, mortality at the conclusion of the 28-day course of treatment, was 14% in the group taking prednisolone plus placebo, 19% in those taking pentoxifylline plus placebo, 13% in those taking both prednisolone plus pentoxifylline, and 17% in those taking two placebos – all nonsignificant differences. In addition, neither active drug affected mortality or the need for liver transplantation at 90 days or at 1 year, the investigators reported (N. Engl. J. Med. 2015 April 23 [doi:10.1056/NEJMoa1412278]).

Cumulative mortality at 1 year was “alarming” but nearly identical between the groups who received the two active agents and the groups who did not: 56% with pentoxifylline and 57% without it; 57% with prednisolone and 56% without it.

Infection accounted for 24% of all deaths, but the number of infections among patients receiving prednisolone was no higher than that for the other patient groups, Dr. Thursz and his associates added.

The Food and Drug Administration has approved changes to the warnings and precautions section of the package insert for Olysio (simeprevir).

One addition to the insert is that serious symptomatic bradycardia has been reported by individuals who have taken amiodarone with sofosbuvir and another HCV direct-acting antiviral, including Olysio.

Another change is the inclusion of a statement that hepatic decompensation and hepatic failure have been reported in patients treated with Olysio in combination with peginterferon alfa and ribavirin. Related to this finding, is the other new recommendation that patients with moderate or severe hepatic impairment not take Olysio.

More details on these and other related label changes for Olysio can be found at the FDA website.

The Food and Drug Administration has approved changes to the warnings and precautions section of the package insert for Olysio (simeprevir).

One addition to the insert is that serious symptomatic bradycardia has been reported by individuals who have taken amiodarone with sofosbuvir and another HCV direct-acting antiviral, including Olysio.

Another change is the inclusion of a statement that hepatic decompensation and hepatic failure have been reported in patients treated with Olysio in combination with peginterferon alfa and ribavirin. Related to this finding, is the other new recommendation that patients with moderate or severe hepatic impairment not take Olysio.

More details on these and other related label changes for Olysio can be found at the FDA website.

The Food and Drug Administration has approved changes to the warnings and precautions section of the package insert for Olysio (simeprevir).

One addition to the insert is that serious symptomatic bradycardia has been reported by individuals who have taken amiodarone with sofosbuvir and another HCV direct-acting antiviral, including Olysio.

Another change is the inclusion of a statement that hepatic decompensation and hepatic failure have been reported in patients treated with Olysio in combination with peginterferon alfa and ribavirin. Related to this finding, is the other new recommendation that patients with moderate or severe hepatic impairment not take Olysio.

More details on these and other related label changes for Olysio can be found at the FDA website.

Insulin glargine therapy was associated with significantly greater reductions in liver fat burden in patients with type 2 diabetes than was liraglutide, judging from the findings of a prospective randomized controlled trial.

Both treatments significantly improved glycosylated hemoglobin. However, neither led to a significant change in liver fat fraction, as measured with magnetic resonance spectroscopy (MRS), according to a study published online March 26 in Diabetes Care.

Wavebreakmedia Ltd

Researchers randomized 35 patients, whose type 2 diabetes was inadequately controlled on either metformin monotherapy or combination therapy, to 12 weeks therapy starting with 10 IU of subcutaneous insulin glargine daily or a starting dose of 0.6 mg of subcutaneous liraglutide, titrated to 1.8 mg or the maximal tolerated dose.

Patients on insulin glargine showed significant reductions in MRS-based liver proton density fat fraction (13.8% to 10.6%; P = .005), and MRI-based liver volume (2,010.6 mL to 1,858.7 mL; P = .01) and total liver fat index (304.4 vs. 209.3%; P = .01).

They also showed a trend toward a decreased MRS-based liver proton density fat fraction (12.6% to 9.9%; P = 0.06).

However patients treated with liraglutide showed no significant changes in any of these indexes (Diabetes Care 2015, March 26 [doi:10.2337/dc14-2548]).

While insulin is associated with weight gain and may be lipogenic, previous imaging studies have actually showed a reduction in liver fat with insulin therapy.

“The mechanisms by which insulin therapy may reduce liver fat include inhibition of lipolysis, which may reduce free fatty acid flux to the liver and decreased production of endogenous insulin passing through the liver to stimulate hepatic lipogenesis,” wrote Dr. An Tang, from the University of Montreal, and coauthors.

At the same time, GLP-1 agonists such as liraglutide promote weight loss and were thought to decrease liver fat by increasing fatty acid uptake and very low density–lipoprotein transport.

However, the study failed to find any significant change in biomarkers of liver fat burden among those patients randomized to liraglutide.

“It is possible that the postprandial increase in insulin secretion in the portal circulation and the decrease in glucagon secretion induced by the GLP-1 analogs could favor lipogenesis and therefore explain the lack of effect of liraglutide on hepatic steatosis observed in the current study,” the authors wrote.

The study found that patients taking liraglutide showed a significant reduction in body mass index or BMI (31.3 to 30.1 kg/m²; P = .008) while those on insulin glargine did not (31.2 to 31.3 kg/m²; P = .92).

“Interestingly, the improvement in BMI in patients randomized to liraglutide therapy was not associated with concomitant changes in the liver fat burden,” they wrote.

They noted a similar rate of adverse events in the insulin glargine and liraglutide groups.

The authors said that while the study’s short duration may have worked against liraglutide, because its impact on BMI may have had a longer term impact on liver fat fraction, they argued it was enough to address the primary end point.

“This reduction in liver fat burden on insulin therapy is reassuring and important because many patients with type 2 diabetes and NALFD [nonalcoholic fatty liver disease] have to be treated with insulin to achieve adequate glycemic control,” the authors wrote.

The study was supported by the Radiological Society of North America Research and Education Foundation, and Diabète Québec. Authors reported grants, honorarium, personal fees, and research funds from private industry.

Insulin glargine therapy was associated with significantly greater reductions in liver fat burden in patients with type 2 diabetes than was liraglutide, judging from the findings of a prospective randomized controlled trial.

Both treatments significantly improved glycosylated hemoglobin. However, neither led to a significant change in liver fat fraction, as measured with magnetic resonance spectroscopy (MRS), according to a study published online March 26 in Diabetes Care.

Wavebreakmedia Ltd

Researchers randomized 35 patients, whose type 2 diabetes was inadequately controlled on either metformin monotherapy or combination therapy, to 12 weeks therapy starting with 10 IU of subcutaneous insulin glargine daily or a starting dose of 0.6 mg of subcutaneous liraglutide, titrated to 1.8 mg or the maximal tolerated dose.

Patients on insulin glargine showed significant reductions in MRS-based liver proton density fat fraction (13.8% to 10.6%; P = .005), and MRI-based liver volume (2,010.6 mL to 1,858.7 mL; P = .01) and total liver fat index (304.4 vs. 209.3%; P = .01).

They also showed a trend toward a decreased MRS-based liver proton density fat fraction (12.6% to 9.9%; P = 0.06).

However patients treated with liraglutide showed no significant changes in any of these indexes (Diabetes Care 2015, March 26 [doi:10.2337/dc14-2548]).

While insulin is associated with weight gain and may be lipogenic, previous imaging studies have actually showed a reduction in liver fat with insulin therapy.

“The mechanisms by which insulin therapy may reduce liver fat include inhibition of lipolysis, which may reduce free fatty acid flux to the liver and decreased production of endogenous insulin passing through the liver to stimulate hepatic lipogenesis,” wrote Dr. An Tang, from the University of Montreal, and coauthors.

At the same time, GLP-1 agonists such as liraglutide promote weight loss and were thought to decrease liver fat by increasing fatty acid uptake and very low density–lipoprotein transport.

However, the study failed to find any significant change in biomarkers of liver fat burden among those patients randomized to liraglutide.

“It is possible that the postprandial increase in insulin secretion in the portal circulation and the decrease in glucagon secretion induced by the GLP-1 analogs could favor lipogenesis and therefore explain the lack of effect of liraglutide on hepatic steatosis observed in the current study,” the authors wrote.

The study found that patients taking liraglutide showed a significant reduction in body mass index or BMI (31.3 to 30.1 kg/m²; P = .008) while those on insulin glargine did not (31.2 to 31.3 kg/m²; P = .92).

“Interestingly, the improvement in BMI in patients randomized to liraglutide therapy was not associated with concomitant changes in the liver fat burden,” they wrote.

They noted a similar rate of adverse events in the insulin glargine and liraglutide groups.

The authors said that while the study’s short duration may have worked against liraglutide, because its impact on BMI may have had a longer term impact on liver fat fraction, they argued it was enough to address the primary end point.

“This reduction in liver fat burden on insulin therapy is reassuring and important because many patients with type 2 diabetes and NALFD [nonalcoholic fatty liver disease] have to be treated with insulin to achieve adequate glycemic control,” the authors wrote.

The study was supported by the Radiological Society of North America Research and Education Foundation, and Diabète Québec. Authors reported grants, honorarium, personal fees, and research funds from private industry.

Insulin glargine therapy was associated with significantly greater reductions in liver fat burden in patients with type 2 diabetes than was liraglutide, judging from the findings of a prospective randomized controlled trial.

Both treatments significantly improved glycosylated hemoglobin. However, neither led to a significant change in liver fat fraction, as measured with magnetic resonance spectroscopy (MRS), according to a study published online March 26 in Diabetes Care.

Wavebreakmedia Ltd

Researchers randomized 35 patients, whose type 2 diabetes was inadequately controlled on either metformin monotherapy or combination therapy, to 12 weeks therapy starting with 10 IU of subcutaneous insulin glargine daily or a starting dose of 0.6 mg of subcutaneous liraglutide, titrated to 1.8 mg or the maximal tolerated dose.

Patients on insulin glargine showed significant reductions in MRS-based liver proton density fat fraction (13.8% to 10.6%; P = .005), and MRI-based liver volume (2,010.6 mL to 1,858.7 mL; P = .01) and total liver fat index (304.4 vs. 209.3%; P = .01).

They also showed a trend toward a decreased MRS-based liver proton density fat fraction (12.6% to 9.9%; P = 0.06).

However patients treated with liraglutide showed no significant changes in any of these indexes (Diabetes Care 2015, March 26 [doi:10.2337/dc14-2548]).

While insulin is associated with weight gain and may be lipogenic, previous imaging studies have actually showed a reduction in liver fat with insulin therapy.

“The mechanisms by which insulin therapy may reduce liver fat include inhibition of lipolysis, which may reduce free fatty acid flux to the liver and decreased production of endogenous insulin passing through the liver to stimulate hepatic lipogenesis,” wrote Dr. An Tang, from the University of Montreal, and coauthors.

At the same time, GLP-1 agonists such as liraglutide promote weight loss and were thought to decrease liver fat by increasing fatty acid uptake and very low density–lipoprotein transport.

However, the study failed to find any significant change in biomarkers of liver fat burden among those patients randomized to liraglutide.

“It is possible that the postprandial increase in insulin secretion in the portal circulation and the decrease in glucagon secretion induced by the GLP-1 analogs could favor lipogenesis and therefore explain the lack of effect of liraglutide on hepatic steatosis observed in the current study,” the authors wrote.

The study found that patients taking liraglutide showed a significant reduction in body mass index or BMI (31.3 to 30.1 kg/m²; P = .008) while those on insulin glargine did not (31.2 to 31.3 kg/m²; P = .92).

“Interestingly, the improvement in BMI in patients randomized to liraglutide therapy was not associated with concomitant changes in the liver fat burden,” they wrote.

They noted a similar rate of adverse events in the insulin glargine and liraglutide groups.

The authors said that while the study’s short duration may have worked against liraglutide, because its impact on BMI may have had a longer term impact on liver fat fraction, they argued it was enough to address the primary end point.

“This reduction in liver fat burden on insulin therapy is reassuring and important because many patients with type 2 diabetes and NALFD [nonalcoholic fatty liver disease] have to be treated with insulin to achieve adequate glycemic control,” the authors wrote.

The study was supported by the Radiological Society of North America Research and Education Foundation, and Diabète Québec. Authors reported grants, honorarium, personal fees, and research funds from private industry.

The high cost of the hepatitis C treatment Sovaldi has caused a steep increase in Medicaid spending, though access to the drug remains extremely limited for low-income patients, reports the Wall Street Journal’s Joseph Walker in an analysis of federal data.

The drug, manufactured by Gilead Sciences, comes at a cost of $84,000 for the course of treatment, or $1,000 per pill.

State Medicaid programs spent $1.08 billion on Sovaldi alone and $1.33 billion on all HCV treatments in the first 9 months of 2014, according to the analysis. As a result, states have started to limit access to only the most severe HCV cases, sparking tension among physicians, patients, and state officials.

Though competition between Sovaldi and AbbVie’s Viekira Pak would allow states to negotiate greater discounts and expand coverage, most states continue to deny access to all but the sickest eligible patients, according to the report.Read the full Wall Street Journal article here.

The high cost of the hepatitis C treatment Sovaldi has caused a steep increase in Medicaid spending, though access to the drug remains extremely limited for low-income patients, reports the Wall Street Journal’s Joseph Walker in an analysis of federal data.

The drug, manufactured by Gilead Sciences, comes at a cost of $84,000 for the course of treatment, or $1,000 per pill.

State Medicaid programs spent $1.08 billion on Sovaldi alone and $1.33 billion on all HCV treatments in the first 9 months of 2014, according to the analysis. As a result, states have started to limit access to only the most severe HCV cases, sparking tension among physicians, patients, and state officials.

Though competition between Sovaldi and AbbVie’s Viekira Pak would allow states to negotiate greater discounts and expand coverage, most states continue to deny access to all but the sickest eligible patients, according to the report.Read the full Wall Street Journal article here.

The high cost of the hepatitis C treatment Sovaldi has caused a steep increase in Medicaid spending, though access to the drug remains extremely limited for low-income patients, reports the Wall Street Journal’s Joseph Walker in an analysis of federal data.

The drug, manufactured by Gilead Sciences, comes at a cost of $84,000 for the course of treatment, or $1,000 per pill.

State Medicaid programs spent $1.08 billion on Sovaldi alone and $1.33 billion on all HCV treatments in the first 9 months of 2014, according to the analysis. As a result, states have started to limit access to only the most severe HCV cases, sparking tension among physicians, patients, and state officials.

Though competition between Sovaldi and AbbVie’s Viekira Pak would allow states to negotiate greater discounts and expand coverage, most states continue to deny access to all but the sickest eligible patients, according to the report.Read the full Wall Street Journal article here.

Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

Patients with compensated cirrhosis and chronic genotype 1 hepatitis C virus infections were significantly more likely to clear their infections and had fewer adverse effects when treated with simeprevir and sofosbuvir instead of peginterferon, ribavirin, and sofosbuvir, investigators reported in the April issue of Gastroenterology. “Patients given the interferon-containing regimen had a significantly greater rate of virologic relapse than patients given simeprevir and sofosbuvir ... and reported worse outcomes and more side effects,” said Dr. Brian L. Pearlman and his associates of Atlanta Medical Center and Emory University, Atlanta.

Liver disease associated with chronic hepatitis C virus (HCV) infection causes at least 350,000 deaths per year worldwide. Genotype 1 (GT-1) HCV is the most common HCV strain and the hardest to treat, especially when patients have cirrhosis. Treatments for chronic GT-1 HCV infections historically included interferon, but achieved only moderate rates of sustained virologic response (SVR) and caused adverse somatic and psychiatric effects. All-oral, interferon-free regimens are now in widespread use, but many of the pivotal trials were industry sponsored and had strict enrollment criteria, potentially limiting their generalizability in community settings, the researchers reported (Gastroenterology 2015 April [doi:10.1053/j.gastro.2014.12.027]).Their open-label trial included 82 patients with HCV GT-1a infection and Child’s grade A cirrhosis recruited from two clinical practices in Atlanta. Thirty-two of the patients were treatment naive, while 50 had previously not responded to peginterferon and ribavirin treatment. Patients were randomized to either 12 weeks of all-oral simeprevir (150 mg/day) and sofosbuvir (400 mg/day), or peginterferon alfa 2b (1.5 mcg/kg per week), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day).Fully 54 of 58 (93%) patients given the simeprevir-sofosbuvir regimen had undetectable levels of HCV RNA at 12 weeks (SVR12), compared with 18 of 24 (75%) patients who received the interferon-containing regimen (P = .02), the researchers reported. Rates of SVR12 among prior nonresponders were 92% and 64%, and were 95% and 80% for treatment-naive patients, although P-values did not reach statistical significance. The interferon group also had a higher rate of virologic relapse than did patients given simeprevir and sofosbuvir (P = .009), and had worse self-reported outcomes and more side effects, the researchers said. Patients in both groups who achieved SVR12 had higher quality-of-life scores than those who did not. Notably, almost half of patients were African American, a group that has historically had lower cure rates compared with other racial groups, said the investigators.

“Given that several new regimens for genotype 1 infection, including the sofosbuvir-ledipasvir combination pill, already have been approved, we believe that this study is very timely,” Dr. Pearlman and his associates said. “Although these are not head-to-head comparisons, the 12-week simeprevir and sofosbuvir regimen in this trial may compare favorably with the SVR rates for 12 weeks of sofosbuvir/ledipasvir and 12 weeks of the regimen, paritaprevir/ritonavir, ombitasvir and dasabuvir plus ribavirin for patients with cirrhosis, particularly for prior nonresponders to older therapies, with the caveat that many more patients were studied in the registration trials.”While industry-sponsored trials have had psychiatric exclusion criteria, several patients in the open-label trial had serious psychiatric conditions, said the researchers. A patient with stable bipolar disorder received the interferon-containing regimen, and two patients with stable schizophrenia received the all-oral regimen. None reported worsening psychiatric symptoms on treatment.

Dr. Pearlman reported having contracted research for Johnson & Johnson, Gilead, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck; and having served on speaker and advisory boards for Johnson & Johnson, Gilead, and Abbvie. He also was an investigator and author in the COSMOS trial of simeprevir and sofosbuvir in patients with HCV/HIV coinfection. The other authors reported no conflicts of interest.

For individuals infected with hepatitis C virus (HCV), new regimens are highly effective, but also very expensive, at approximately $28,000 for 4 weeks of treatment. However, the treatment is cost effective for HCV patients with cirrhosis and for those without cirrhosis who have failed other treatments, according to a new study.

©Mathier/thinkstockphotos.com

In an analysis of the cost effectiveness of sofosbuvir-based treatments for patients with HCV genotypes 2 and 3, Dr. Benjamin Linas of Boston Medical Center reported that when compared with pegylated interferon and ribavirin therapy, treatment regimens based on the new direct-acting antiviral are only cost effective for select groups (Ann. Intern Med, [doi:10.7326/M15-0674]).

Cure rates with sofosbuvir are higher than are rates with the previous standard of care, and sustained virologic response (SVR) “is associated with a greatly reduced lifetime risk for liver-related morbidity and mortality,” noted Dr. Linas and his colleagues.

Using sophisticated statistical modeling to compare HCV treatment with pegylated interferon and ribavirin – the previous standard of care – to the newly Food and Drug Administration–approved sofosbuvir-ribavirin regimen, Dr. Linas explored clinical outcomes and costs for several different patient groups, including treatment-naive and treatment-experienced HCV genotype 2 and 3 patients with and without cirrhosis.

Clinical outcomes, modeled from clinical trial and observational cohort data, were expressed as life expectancy in quality-adjusted life-years (QALYs) and lifetime medical costs. Investigators then calculated the incremental cost-effectiveness ratio (ICER) for each treatment strategy, dividing any additional cost for a more expensive treatment by the QALYs gained from this regimen.

Using the commonly accepted ICER threshold of $100,000 per QALY, Dr. Linas and colleagues concluded that sofosbuvir-based HCV therapy for treatment-naive patients without cirrhosis was not cost effective, with ICERs of $238,000-$266,000. Interferon-based treatments, they noted, still achieve an approximately 80% rate of cure in this population.

In the constrained resources of the real world, Dr. Linas and his associates noted that this analysis is important. “Treatment strategies that do not use limited resources where they are likely to have the greatest impact may result in unequal access to interferon-free regimens, thereby limiting the population-level benefits of new HCV treatments,” they said.

AGA Note
Review the AGA Hepatitis C Clinical Service Line to learn more about managing the disease. 

For individuals infected with hepatitis C virus (HCV), new regimens are highly effective, but also very expensive, at approximately $28,000 for 4 weeks of treatment. However, the treatment is cost effective for HCV patients with cirrhosis and for those without cirrhosis who have failed other treatments, according to a new study.

©Mathier/thinkstockphotos.com

In an analysis of the cost effectiveness of sofosbuvir-based treatments for patients with HCV genotypes 2 and 3, Dr. Benjamin Linas of Boston Medical Center reported that when compared with pegylated interferon and ribavirin therapy, treatment regimens based on the new direct-acting antiviral are only cost effective for select groups (Ann. Intern Med, [doi:10.7326/M15-0674]).

Cure rates with sofosbuvir are higher than are rates with the previous standard of care, and sustained virologic response (SVR) “is associated with a greatly reduced lifetime risk for liver-related morbidity and mortality,” noted Dr. Linas and his colleagues.

Using sophisticated statistical modeling to compare HCV treatment with pegylated interferon and ribavirin – the previous standard of care – to the newly Food and Drug Administration–approved sofosbuvir-ribavirin regimen, Dr. Linas explored clinical outcomes and costs for several different patient groups, including treatment-naive and treatment-experienced HCV genotype 2 and 3 patients with and without cirrhosis.

Clinical outcomes, modeled from clinical trial and observational cohort data, were expressed as life expectancy in quality-adjusted life-years (QALYs) and lifetime medical costs. Investigators then calculated the incremental cost-effectiveness ratio (ICER) for each treatment strategy, dividing any additional cost for a more expensive treatment by the QALYs gained from this regimen.

Using the commonly accepted ICER threshold of $100,000 per QALY, Dr. Linas and colleagues concluded that sofosbuvir-based HCV therapy for treatment-naive patients without cirrhosis was not cost effective, with ICERs of $238,000-$266,000. Interferon-based treatments, they noted, still achieve an approximately 80% rate of cure in this population.

In the constrained resources of the real world, Dr. Linas and his associates noted that this analysis is important. “Treatment strategies that do not use limited resources where they are likely to have the greatest impact may result in unequal access to interferon-free regimens, thereby limiting the population-level benefits of new HCV treatments,” they said.

AGA Note
Review the AGA Hepatitis C Clinical Service Line to learn more about managing the disease. 

For individuals infected with hepatitis C virus (HCV), new regimens are highly effective, but also very expensive, at approximately $28,000 for 4 weeks of treatment. However, the treatment is cost effective for HCV patients with cirrhosis and for those without cirrhosis who have failed other treatments, according to a new study.

©Mathier/thinkstockphotos.com

In an analysis of the cost effectiveness of sofosbuvir-based treatments for patients with HCV genotypes 2 and 3, Dr. Benjamin Linas of Boston Medical Center reported that when compared with pegylated interferon and ribavirin therapy, treatment regimens based on the new direct-acting antiviral are only cost effective for select groups (Ann. Intern Med, [doi:10.7326/M15-0674]).

Cure rates with sofosbuvir are higher than are rates with the previous standard of care, and sustained virologic response (SVR) “is associated with a greatly reduced lifetime risk for liver-related morbidity and mortality,” noted Dr. Linas and his colleagues.

Using sophisticated statistical modeling to compare HCV treatment with pegylated interferon and ribavirin – the previous standard of care – to the newly Food and Drug Administration–approved sofosbuvir-ribavirin regimen, Dr. Linas explored clinical outcomes and costs for several different patient groups, including treatment-naive and treatment-experienced HCV genotype 2 and 3 patients with and without cirrhosis.

Clinical outcomes, modeled from clinical trial and observational cohort data, were expressed as life expectancy in quality-adjusted life-years (QALYs) and lifetime medical costs. Investigators then calculated the incremental cost-effectiveness ratio (ICER) for each treatment strategy, dividing any additional cost for a more expensive treatment by the QALYs gained from this regimen.

Using the commonly accepted ICER threshold of $100,000 per QALY, Dr. Linas and colleagues concluded that sofosbuvir-based HCV therapy for treatment-naive patients without cirrhosis was not cost effective, with ICERs of $238,000-$266,000. Interferon-based treatments, they noted, still achieve an approximately 80% rate of cure in this population.

In the constrained resources of the real world, Dr. Linas and his associates noted that this analysis is important. “Treatment strategies that do not use limited resources where they are likely to have the greatest impact may result in unequal access to interferon-free regimens, thereby limiting the population-level benefits of new HCV treatments,” they said.

AGA Note
Review the AGA Hepatitis C Clinical Service Line to learn more about managing the disease. 

Taking the antiarrythmic drug amiodarone with the hepatitis C antiviral drugs ledipasvir and sofosbuvir, or with sofosbuvir plus another direct-acting antiviral drug, has been associated with cases of symptomatic bradycardia – including a fatal cardiac arrest – according to the Food and Drug Administration.

Because of the reports, the antiviral drugs’ labels now recommend against using amiodarone with those hepatitis C drugs.

An FDA statement issued March 24 described the bradycardia cases as “serious and life-threatening.” Gilead Sciences markets the ledipasvir and sofosbuvir combination as Harvoni and markets sofosbuvir as Sovaldi to treat chronic hepatitis C virus (HCV) infection.

Gilead issued a “Dear Health Care Provider” letter that provides further details of the cases. There have been nine postmarketing reports of symptomatic bradycardia in patients who were taking amiodarone with Harvoni; amiodarone with Sovaldi plus another hepatitis C antiviral drug, simeprevir (Olysio); or amiodarone with an investigational hepatitis C antiviral drug, daclatasvir.

Of those cases, six occurred with in the first 24 hours of starting treatment with the antivirals, and three cases occurred within the first 2-12 days after antiviral therapy was started. A pacemaker was needed in three cases, and one case was a fatal cardiac arrest.

In three cases, a “rechallenge with HCV treatment in the setting of continued amiodarone therapy resulted in recurrence of symptomatic bradycardia,” according to the Gilead letter.

The effect of coadministration on the blood levels of the antiviral drugs is not known, nor is the mechanism behind the cardiac effect.

The labeling of the fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) now includes a section on “serious symptomatic bradycardia” when coadministered with amiodarone, and says that coadministration is not recommended. The label adds that if a patient on amiodarone or Harvoni has no other alternative than to take that combination, patients should be counseled about the bradycardia risk.

Cardiac monitoring is recommended for inpatients during the first 48 hours the patient is taking the drugs, “after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.”

The label notes that amiodarone has a long half-life, so cardiac monitoring is still necessary if the patient discontinues amiodarone just before starting treatment with Harvoni. Similar labeling changes have been made to the Sovaldi label.

Adverse events associated with Harvoni or Sovaldi should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch/.

[email protected]

Taking the antiarrythmic drug amiodarone with the hepatitis C antiviral drugs ledipasvir and sofosbuvir, or with sofosbuvir plus another direct-acting antiviral drug, has been associated with cases of symptomatic bradycardia – including a fatal cardiac arrest – according to the Food and Drug Administration.

Because of the reports, the antiviral drugs’ labels now recommend against using amiodarone with those hepatitis C drugs.

An FDA statement issued March 24 described the bradycardia cases as “serious and life-threatening.” Gilead Sciences markets the ledipasvir and sofosbuvir combination as Harvoni and markets sofosbuvir as Sovaldi to treat chronic hepatitis C virus (HCV) infection.

Gilead issued a “Dear Health Care Provider” letter that provides further details of the cases. There have been nine postmarketing reports of symptomatic bradycardia in patients who were taking amiodarone with Harvoni; amiodarone with Sovaldi plus another hepatitis C antiviral drug, simeprevir (Olysio); or amiodarone with an investigational hepatitis C antiviral drug, daclatasvir.

Of those cases, six occurred with in the first 24 hours of starting treatment with the antivirals, and three cases occurred within the first 2-12 days after antiviral therapy was started. A pacemaker was needed in three cases, and one case was a fatal cardiac arrest.

In three cases, a “rechallenge with HCV treatment in the setting of continued amiodarone therapy resulted in recurrence of symptomatic bradycardia,” according to the Gilead letter.

The effect of coadministration on the blood levels of the antiviral drugs is not known, nor is the mechanism behind the cardiac effect.

The labeling of the fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) now includes a section on “serious symptomatic bradycardia” when coadministered with amiodarone, and says that coadministration is not recommended. The label adds that if a patient on amiodarone or Harvoni has no other alternative than to take that combination, patients should be counseled about the bradycardia risk.

Cardiac monitoring is recommended for inpatients during the first 48 hours the patient is taking the drugs, “after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.”

The label notes that amiodarone has a long half-life, so cardiac monitoring is still necessary if the patient discontinues amiodarone just before starting treatment with Harvoni. Similar labeling changes have been made to the Sovaldi label.

Adverse events associated with Harvoni or Sovaldi should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch/.

[email protected]

Taking the antiarrythmic drug amiodarone with the hepatitis C antiviral drugs ledipasvir and sofosbuvir, or with sofosbuvir plus another direct-acting antiviral drug, has been associated with cases of symptomatic bradycardia – including a fatal cardiac arrest – according to the Food and Drug Administration.

Because of the reports, the antiviral drugs’ labels now recommend against using amiodarone with those hepatitis C drugs.

An FDA statement issued March 24 described the bradycardia cases as “serious and life-threatening.” Gilead Sciences markets the ledipasvir and sofosbuvir combination as Harvoni and markets sofosbuvir as Sovaldi to treat chronic hepatitis C virus (HCV) infection.

Gilead issued a “Dear Health Care Provider” letter that provides further details of the cases. There have been nine postmarketing reports of symptomatic bradycardia in patients who were taking amiodarone with Harvoni; amiodarone with Sovaldi plus another hepatitis C antiviral drug, simeprevir (Olysio); or amiodarone with an investigational hepatitis C antiviral drug, daclatasvir.

Of those cases, six occurred with in the first 24 hours of starting treatment with the antivirals, and three cases occurred within the first 2-12 days after antiviral therapy was started. A pacemaker was needed in three cases, and one case was a fatal cardiac arrest.

In three cases, a “rechallenge with HCV treatment in the setting of continued amiodarone therapy resulted in recurrence of symptomatic bradycardia,” according to the Gilead letter.

The effect of coadministration on the blood levels of the antiviral drugs is not known, nor is the mechanism behind the cardiac effect.

The labeling of the fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) now includes a section on “serious symptomatic bradycardia” when coadministered with amiodarone, and says that coadministration is not recommended. The label adds that if a patient on amiodarone or Harvoni has no other alternative than to take that combination, patients should be counseled about the bradycardia risk.

Cardiac monitoring is recommended for inpatients during the first 48 hours the patient is taking the drugs, “after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.”

The label notes that amiodarone has a long half-life, so cardiac monitoring is still necessary if the patient discontinues amiodarone just before starting treatment with Harvoni. Similar labeling changes have been made to the Sovaldi label.

Adverse events associated with Harvoni or Sovaldi should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/Safety/MedWatch/.

[email protected]

The Food and Drug Administration approved cholic acid capsules for treatment of children aged 3 weeks and older and adults with bile acid synthesis disorders due to single enzyme defects. It is the first drug approved for this indication, the agency announced.

The bile acid also was approved as adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat soluble vitamin absorption. Cholic acid will be marketed as Cholbam by Asklepion Pharmaceuticals, the FDA said in its statement.

Approval was based on uncontrolled studies, which evaluated treatment of patients, mostly children, over a period of 18 years. In the study of 62 patients with bile acid synthesis disorders due to single enzyme defects, 64% of patients with evaluable data responded with improvements in baseline liver function tests and weight; two-thirds of patients survived longer than 3 years. In the study of cholic acid for the treatment of peroxisomal disorder in 31 children, improvements in baseline liver function tests and weight were noted in 46%; 42% of patients survived longer than 3 years.

Diarrhea was the most common adverse event associated with treatment. “The use of Cholbam should be carefully monitored by an experienced hepatologist or pediatric gastroenterologist, and treatment discontinued in patients developing worsening liver function,” according to the FDA statement.

The manufacturer is required to conduct a postapproval observational study to evaluate the long-term safety of cholic acid.

The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/205750s000lbl.pdf.

[email protected]

The Food and Drug Administration approved cholic acid capsules for treatment of children aged 3 weeks and older and adults with bile acid synthesis disorders due to single enzyme defects. It is the first drug approved for this indication, the agency announced.

The bile acid also was approved as adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat soluble vitamin absorption. Cholic acid will be marketed as Cholbam by Asklepion Pharmaceuticals, the FDA said in its statement.

Approval was based on uncontrolled studies, which evaluated treatment of patients, mostly children, over a period of 18 years. In the study of 62 patients with bile acid synthesis disorders due to single enzyme defects, 64% of patients with evaluable data responded with improvements in baseline liver function tests and weight; two-thirds of patients survived longer than 3 years. In the study of cholic acid for the treatment of peroxisomal disorder in 31 children, improvements in baseline liver function tests and weight were noted in 46%; 42% of patients survived longer than 3 years.

Diarrhea was the most common adverse event associated with treatment. “The use of Cholbam should be carefully monitored by an experienced hepatologist or pediatric gastroenterologist, and treatment discontinued in patients developing worsening liver function,” according to the FDA statement.

The manufacturer is required to conduct a postapproval observational study to evaluate the long-term safety of cholic acid.

The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/205750s000lbl.pdf.

[email protected]

The Food and Drug Administration approved cholic acid capsules for treatment of children aged 3 weeks and older and adults with bile acid synthesis disorders due to single enzyme defects. It is the first drug approved for this indication, the agency announced.

The bile acid also was approved as adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat soluble vitamin absorption. Cholic acid will be marketed as Cholbam by Asklepion Pharmaceuticals, the FDA said in its statement.

Approval was based on uncontrolled studies, which evaluated treatment of patients, mostly children, over a period of 18 years. In the study of 62 patients with bile acid synthesis disorders due to single enzyme defects, 64% of patients with evaluable data responded with improvements in baseline liver function tests and weight; two-thirds of patients survived longer than 3 years. In the study of cholic acid for the treatment of peroxisomal disorder in 31 children, improvements in baseline liver function tests and weight were noted in 46%; 42% of patients survived longer than 3 years.

Diarrhea was the most common adverse event associated with treatment. “The use of Cholbam should be carefully monitored by an experienced hepatologist or pediatric gastroenterologist, and treatment discontinued in patients developing worsening liver function,” according to the FDA statement.

The manufacturer is required to conduct a postapproval observational study to evaluate the long-term safety of cholic acid.

The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/205750s000lbl.pdf.

[email protected]

For patients with nonalcoholic steatohepatitis (NASH), a bile acid derivative that acts on a nuclear receptor reduced liver fat and fibrosis, but patients taking the drug also had worsening in serum lipid values and increased insulin resistance.

The lipophilic bile acid obeticholic acid showed promise in the FLINT trial (Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment) for NASH patients whose liver disease improved but did not resolve.

Dr. Brent Neuschwander-Tetri of Saint Louis University, and coinvestigators in the National Institute of Diabetes and Digestive and Kidney Diseases’ NASH Clinical Research Network, conducted the multicenter, randomized, placebo-controlled study. The findings were published in the Lancet.

Obeticholic acid, a farnesoid X nuclear receptor agonist, works at a site whose activation promotes increased insulin sensitivity and decreased serum triglycerides. Serum lipids may also be improved by increased peripheral clearance of VLDL, increased reverse cholesterol transport, and reduced lipid synthesis in the liver. Currently, the only other treatments for NASH, aside from diet and lifestyle modifications, are thiazolidinediones and vitamin E. Long-term safety and efficacy of these medications are unknown, especially in NASH patients with diabetes (Lancet 2015;385:956-65 [doi:10.1016/S0140-6736(14)61933-4]).

Study participants were adults with biopsy-confirmed NASH or borderline NASH with histologic steatosis, ballooning, and lobular inflammation, but without cirrhosis. The study excluded heavy consumers of alcohol. Baseline and final assessments included liver biopsy and demographic and anthropometric information, as well as metabolic and lipid markers and liver enzymes.

FLINT’s primary outcome measure was improved liver histology, defined as a decrease of two or more points on a nonalcoholic fatty liver disease (NAFLD) pathology scoring system, without a worsening of liver fibrosis. Resolution of NASH was a secondary outcome, as were changes in liver enzymes, body measurements, and homeostasis model of assessment of insulin resistance (HOMA-IR) levels.

The study’s Data Safety Monitoring Board recommended stopping biopsies after about half the patients had received biopsies and the primary histologic outcome measure was met, in order to avoid unnecessary patient risk.

An intention-to-treat analysis found that 50 (45%) of 110 patients receiving obeticholic acid had improved liver histology, compared to 23 (21%) of 109 patients receiving placebo (relative risk 1.9, 95% CI 1.3-2.8, P = .0002). This difference did not change with prespecified subgroup analyses. Serum AST and ALT measures decreased significantly for the treatment group. The medication was generally well tolerated, though pruritis developed in 33 (23%) of 141 patients in the intervention group and 9 (6%) of the placebo group.

Total serum cholesterol and LDL cholesterol, however, increased for the obeticholic acid group, while HDL cholesterol decreased. Insulin resistance as measured by HOMA-IR increased slightly for the treatment group, an unexpected effect. Study authors noted that this class of medication’s effect on cholesterol transport is complex. “Future studies of farnesoid X nuclear receptor agonists,” they noted, “will need to address the consequences of these changes on cardiovascular outcomes.”

Dr. Neuschwander-Tetri disclosed ties with Genentech/Roche, Nimbus Discovery, Boehringer Ingelheim, and Bristol-Myers Squibb. Several coinvestigators disclosed ties with various companies, including Intercept Pharmaceuticals, which provided partial funding for the trial under a Collaborative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases.

For patients with nonalcoholic steatohepatitis (NASH), a bile acid derivative that acts on a nuclear receptor reduced liver fat and fibrosis, but patients taking the drug also had worsening in serum lipid values and increased insulin resistance.

The lipophilic bile acid obeticholic acid showed promise in the FLINT trial (Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment) for NASH patients whose liver disease improved but did not resolve.

Dr. Brent Neuschwander-Tetri of Saint Louis University, and coinvestigators in the National Institute of Diabetes and Digestive and Kidney Diseases’ NASH Clinical Research Network, conducted the multicenter, randomized, placebo-controlled study. The findings were published in the Lancet.

Obeticholic acid, a farnesoid X nuclear receptor agonist, works at a site whose activation promotes increased insulin sensitivity and decreased serum triglycerides. Serum lipids may also be improved by increased peripheral clearance of VLDL, increased reverse cholesterol transport, and reduced lipid synthesis in the liver. Currently, the only other treatments for NASH, aside from diet and lifestyle modifications, are thiazolidinediones and vitamin E. Long-term safety and efficacy of these medications are unknown, especially in NASH patients with diabetes (Lancet 2015;385:956-65 [doi:10.1016/S0140-6736(14)61933-4]).

Study participants were adults with biopsy-confirmed NASH or borderline NASH with histologic steatosis, ballooning, and lobular inflammation, but without cirrhosis. The study excluded heavy consumers of alcohol. Baseline and final assessments included liver biopsy and demographic and anthropometric information, as well as metabolic and lipid markers and liver enzymes.

FLINT’s primary outcome measure was improved liver histology, defined as a decrease of two or more points on a nonalcoholic fatty liver disease (NAFLD) pathology scoring system, without a worsening of liver fibrosis. Resolution of NASH was a secondary outcome, as were changes in liver enzymes, body measurements, and homeostasis model of assessment of insulin resistance (HOMA-IR) levels.

The study’s Data Safety Monitoring Board recommended stopping biopsies after about half the patients had received biopsies and the primary histologic outcome measure was met, in order to avoid unnecessary patient risk.

An intention-to-treat analysis found that 50 (45%) of 110 patients receiving obeticholic acid had improved liver histology, compared to 23 (21%) of 109 patients receiving placebo (relative risk 1.9, 95% CI 1.3-2.8, P = .0002). This difference did not change with prespecified subgroup analyses. Serum AST and ALT measures decreased significantly for the treatment group. The medication was generally well tolerated, though pruritis developed in 33 (23%) of 141 patients in the intervention group and 9 (6%) of the placebo group.

Total serum cholesterol and LDL cholesterol, however, increased for the obeticholic acid group, while HDL cholesterol decreased. Insulin resistance as measured by HOMA-IR increased slightly for the treatment group, an unexpected effect. Study authors noted that this class of medication’s effect on cholesterol transport is complex. “Future studies of farnesoid X nuclear receptor agonists,” they noted, “will need to address the consequences of these changes on cardiovascular outcomes.”

Dr. Neuschwander-Tetri disclosed ties with Genentech/Roche, Nimbus Discovery, Boehringer Ingelheim, and Bristol-Myers Squibb. Several coinvestigators disclosed ties with various companies, including Intercept Pharmaceuticals, which provided partial funding for the trial under a Collaborative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases.

For patients with nonalcoholic steatohepatitis (NASH), a bile acid derivative that acts on a nuclear receptor reduced liver fat and fibrosis, but patients taking the drug also had worsening in serum lipid values and increased insulin resistance.

The lipophilic bile acid obeticholic acid showed promise in the FLINT trial (Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment) for NASH patients whose liver disease improved but did not resolve.

Dr. Brent Neuschwander-Tetri of Saint Louis University, and coinvestigators in the National Institute of Diabetes and Digestive and Kidney Diseases’ NASH Clinical Research Network, conducted the multicenter, randomized, placebo-controlled study. The findings were published in the Lancet.

Obeticholic acid, a farnesoid X nuclear receptor agonist, works at a site whose activation promotes increased insulin sensitivity and decreased serum triglycerides. Serum lipids may also be improved by increased peripheral clearance of VLDL, increased reverse cholesterol transport, and reduced lipid synthesis in the liver. Currently, the only other treatments for NASH, aside from diet and lifestyle modifications, are thiazolidinediones and vitamin E. Long-term safety and efficacy of these medications are unknown, especially in NASH patients with diabetes (Lancet 2015;385:956-65 [doi:10.1016/S0140-6736(14)61933-4]).

Study participants were adults with biopsy-confirmed NASH or borderline NASH with histologic steatosis, ballooning, and lobular inflammation, but without cirrhosis. The study excluded heavy consumers of alcohol. Baseline and final assessments included liver biopsy and demographic and anthropometric information, as well as metabolic and lipid markers and liver enzymes.

FLINT’s primary outcome measure was improved liver histology, defined as a decrease of two or more points on a nonalcoholic fatty liver disease (NAFLD) pathology scoring system, without a worsening of liver fibrosis. Resolution of NASH was a secondary outcome, as were changes in liver enzymes, body measurements, and homeostasis model of assessment of insulin resistance (HOMA-IR) levels.

The study’s Data Safety Monitoring Board recommended stopping biopsies after about half the patients had received biopsies and the primary histologic outcome measure was met, in order to avoid unnecessary patient risk.

An intention-to-treat analysis found that 50 (45%) of 110 patients receiving obeticholic acid had improved liver histology, compared to 23 (21%) of 109 patients receiving placebo (relative risk 1.9, 95% CI 1.3-2.8, P = .0002). This difference did not change with prespecified subgroup analyses. Serum AST and ALT measures decreased significantly for the treatment group. The medication was generally well tolerated, though pruritis developed in 33 (23%) of 141 patients in the intervention group and 9 (6%) of the placebo group.

Total serum cholesterol and LDL cholesterol, however, increased for the obeticholic acid group, while HDL cholesterol decreased. Insulin resistance as measured by HOMA-IR increased slightly for the treatment group, an unexpected effect. Study authors noted that this class of medication’s effect on cholesterol transport is complex. “Future studies of farnesoid X nuclear receptor agonists,” they noted, “will need to address the consequences of these changes on cardiovascular outcomes.”

Dr. Neuschwander-Tetri disclosed ties with Genentech/Roche, Nimbus Discovery, Boehringer Ingelheim, and Bristol-Myers Squibb. Several coinvestigators disclosed ties with various companies, including Intercept Pharmaceuticals, which provided partial funding for the trial under a Collaborative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases.

Two different statistical models found that novel therapies for chronic HCV infection, particularly the combination of sofosbuvir and ledipasvir, are cost effective in most patients, according to separate reports published online March 17 in Annals of Internal Medicine.

However, both groups of researchers cautioned that if these expensive agents are made available to the millions of eligible patients across the country, it would have an immense impact on health care costs for both public and private payers.

Courtesy NIH

The novel therapies, which typically contain sofosbuvir in combination with ledipasvir, simeprevir, or daclatasvir, substantially reduce the length of treatment, achieve much higher rates of sustained viral response (SVR), and offer interferon-free alternatives for patients who can’t tolerate or don’t respond to standard interferon-based treatments. But it is unclear whether these benefits justify their profound expense, compared with current care. Both statistical models were developed to examine this issue, but from different perspectives.

In one study, funded primarily by the National Institutes of Health, investigators constructed a model that simulated 120 possible clinical courses of HCV-infected adults based on different ages and sexes, treatment histories, HCV genotypes, fibrosis scores, and interferon tolerances. For each of these patient profiles, they ran simulations in which patients received either “the old standard of care” (peginterferon and ribavirin, either with or without boceprevir and telaprevir) or sofosbuvir plus ledipasvir.

The average per-patient cost of standard care ranged from $15,000 to $71,000, depending on the patient profile, while that of sofosbuvir-ledipasvir ranged from $66,000 to $154,000, said Jagpreet Chhatwal, Ph.D., of the University of Texas MD Anderson Cancer Center, Houston, and his associates.

Compared with standard care, treating 10,000 patients with sofosbuvir-ledipasvir was projected to prevent 600 cases of decompensated cirrhosis, 310 cases of hepatocellular carcinoma (HCC), 60 liver transplantations, and 550 liver-related deaths, which would result in substantial cost savings. Also, compared with standard care, the incremental cost-effectiveness ratio of sofosbuvir-ledipasvir was $55,400 per additional quality-of-life-year (QALY) gained, which falls well within the accepted range for therapies for other medical conditions. Thus, the new therapy proved to be cost-effective for most HCV patients (Ann. Intern. Med. 2015 March 17 [doi:10.7326/M14-1336]). But there was an important caveat: Many more patients would be eligible for the novel therapies than for the standard care, because the novel therapies are much more easily tolerated. With the addition of so many eligible patients, the resources needed to treat them “could be immense and unsustainable.” Compared with standard care, giving these novel HCV therapies to all eligible patients “would cost an additional $65 billion in the next 5 years,” which would not be counterbalanced by the estimated $16 billion saved by preventing cirrhosis, HCC, and transplantations.

Therefore, “despite the cost-effectiveness of [novel] HCV treatments, our analysis shows that it is unaffordable at the current price,” Dr. Chhatwal and his associates said.

In the other study, funded primarily by CVS Health, researchers developed a discrete-event simulation model of the natural history and progression of liver disease in treatment-naive patients, categorized by whether they were infected with HCV genotype 1, 2, or 3. Several possible treatment regimens were considered for each genotype, and the SVR rates they were projected to attain were derived from those reported in clinical trials, said Mehdi Najafzadeh, Ph.D., of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

“From a societal perspective, the newly approved PEG-free regimen of sofosbuvir-ledipasvir for 12 weeks could be very cost-effective relative to usual care (costing $12,825/QALY gained) for patients with HCV genotype 1.” This treatment proved to be the optimal strategy in the greatest number of simulations involving genotype 1.

Similarly, for genotype 3 the combination of sofosbuvir plus ledipasvir plus ribavirin for 12 weeks cost $73,000/QALY gained, compared with usual care. This also represents “relatively good value.” However, for genotype 2 the most cost-effective novel therapy, sofosbuvir-ribavirin, was $110,168/QALY gained, which is not considered cost-effective, Dr. Najafzadeh and his associates said (Ann. Intern. Med. 2015 March 17 [doi:10.7326;M14-1152]). Again, an important caveat to these findings was that, at their current prices, the cost of these drugs were not outweighed by the savings that accrued from preventing the complications of HCV. And “regardless of the cost-effectiveness of novel HCV treatments, there is considerable concern that their very high prices could substantially increase short-term overall drug spending for many public and private payers,” the investigators noted.

However, the fact that these regimens don’t reduce health care costs “is an exceptionally high bar” to hold them to – one that “is generally not expected when evaluating whether a new strategy represents good value for the money,” they added.

[email protected]

Two different statistical models found that novel therapies for chronic HCV infection, particularly the combination of sofosbuvir and ledipasvir, are cost effective in most patients, according to separate reports published online March 17 in Annals of Internal Medicine.

However, both groups of researchers cautioned that if these expensive agents are made available to the millions of eligible patients across the country, it would have an immense impact on health care costs for both public and private payers.

Courtesy NIH

The novel therapies, which typically contain sofosbuvir in combination with ledipasvir, simeprevir, or daclatasvir, substantially reduce the length of treatment, achieve much higher rates of sustained viral response (SVR), and offer interferon-free alternatives for patients who can’t tolerate or don’t respond to standard interferon-based treatments. But it is unclear whether these benefits justify their profound expense, compared with current care. Both statistical models were developed to examine this issue, but from different perspectives.

In one study, funded primarily by the National Institutes of Health, investigators constructed a model that simulated 120 possible clinical courses of HCV-infected adults based on different ages and sexes, treatment histories, HCV genotypes, fibrosis scores, and interferon tolerances. For each of these patient profiles, they ran simulations in which patients received either “the old standard of care” (peginterferon and ribavirin, either with or without boceprevir and telaprevir) or sofosbuvir plus ledipasvir.

The average per-patient cost of standard care ranged from $15,000 to $71,000, depending on the patient profile, while that of sofosbuvir-ledipasvir ranged from $66,000 to $154,000, said Jagpreet Chhatwal, Ph.D., of the University of Texas MD Anderson Cancer Center, Houston, and his associates.

Compared with standard care, treating 10,000 patients with sofosbuvir-ledipasvir was projected to prevent 600 cases of decompensated cirrhosis, 310 cases of hepatocellular carcinoma (HCC), 60 liver transplantations, and 550 liver-related deaths, which would result in substantial cost savings. Also, compared with standard care, the incremental cost-effectiveness ratio of sofosbuvir-ledipasvir was $55,400 per additional quality-of-life-year (QALY) gained, which falls well within the accepted range for therapies for other medical conditions. Thus, the new therapy proved to be cost-effective for most HCV patients (Ann. Intern. Med. 2015 March 17 [doi:10.7326/M14-1336]). But there was an important caveat: Many more patients would be eligible for the novel therapies than for the standard care, because the novel therapies are much more easily tolerated. With the addition of so many eligible patients, the resources needed to treat them “could be immense and unsustainable.” Compared with standard care, giving these novel HCV therapies to all eligible patients “would cost an additional $65 billion in the next 5 years,” which would not be counterbalanced by the estimated $16 billion saved by preventing cirrhosis, HCC, and transplantations.

Therefore, “despite the cost-effectiveness of [novel] HCV treatments, our analysis shows that it is unaffordable at the current price,” Dr. Chhatwal and his associates said.

In the other study, funded primarily by CVS Health, researchers developed a discrete-event simulation model of the natural history and progression of liver disease in treatment-naive patients, categorized by whether they were infected with HCV genotype 1, 2, or 3. Several possible treatment regimens were considered for each genotype, and the SVR rates they were projected to attain were derived from those reported in clinical trials, said Mehdi Najafzadeh, Ph.D., of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

“From a societal perspective, the newly approved PEG-free regimen of sofosbuvir-ledipasvir for 12 weeks could be very cost-effective relative to usual care (costing $12,825/QALY gained) for patients with HCV genotype 1.” This treatment proved to be the optimal strategy in the greatest number of simulations involving genotype 1.

Similarly, for genotype 3 the combination of sofosbuvir plus ledipasvir plus ribavirin for 12 weeks cost $73,000/QALY gained, compared with usual care. This also represents “relatively good value.” However, for genotype 2 the most cost-effective novel therapy, sofosbuvir-ribavirin, was $110,168/QALY gained, which is not considered cost-effective, Dr. Najafzadeh and his associates said (Ann. Intern. Med. 2015 March 17 [doi:10.7326;M14-1152]). Again, an important caveat to these findings was that, at their current prices, the cost of these drugs were not outweighed by the savings that accrued from preventing the complications of HCV. And “regardless of the cost-effectiveness of novel HCV treatments, there is considerable concern that their very high prices could substantially increase short-term overall drug spending for many public and private payers,” the investigators noted.

However, the fact that these regimens don’t reduce health care costs “is an exceptionally high bar” to hold them to – one that “is generally not expected when evaluating whether a new strategy represents good value for the money,” they added.

[email protected]

Two different statistical models found that novel therapies for chronic HCV infection, particularly the combination of sofosbuvir and ledipasvir, are cost effective in most patients, according to separate reports published online March 17 in Annals of Internal Medicine.

However, both groups of researchers cautioned that if these expensive agents are made available to the millions of eligible patients across the country, it would have an immense impact on health care costs for both public and private payers.

Courtesy NIH

The novel therapies, which typically contain sofosbuvir in combination with ledipasvir, simeprevir, or daclatasvir, substantially reduce the length of treatment, achieve much higher rates of sustained viral response (SVR), and offer interferon-free alternatives for patients who can’t tolerate or don’t respond to standard interferon-based treatments. But it is unclear whether these benefits justify their profound expense, compared with current care. Both statistical models were developed to examine this issue, but from different perspectives.

In one study, funded primarily by the National Institutes of Health, investigators constructed a model that simulated 120 possible clinical courses of HCV-infected adults based on different ages and sexes, treatment histories, HCV genotypes, fibrosis scores, and interferon tolerances. For each of these patient profiles, they ran simulations in which patients received either “the old standard of care” (peginterferon and ribavirin, either with or without boceprevir and telaprevir) or sofosbuvir plus ledipasvir.

The average per-patient cost of standard care ranged from $15,000 to $71,000, depending on the patient profile, while that of sofosbuvir-ledipasvir ranged from $66,000 to $154,000, said Jagpreet Chhatwal, Ph.D., of the University of Texas MD Anderson Cancer Center, Houston, and his associates.

Compared with standard care, treating 10,000 patients with sofosbuvir-ledipasvir was projected to prevent 600 cases of decompensated cirrhosis, 310 cases of hepatocellular carcinoma (HCC), 60 liver transplantations, and 550 liver-related deaths, which would result in substantial cost savings. Also, compared with standard care, the incremental cost-effectiveness ratio of sofosbuvir-ledipasvir was $55,400 per additional quality-of-life-year (QALY) gained, which falls well within the accepted range for therapies for other medical conditions. Thus, the new therapy proved to be cost-effective for most HCV patients (Ann. Intern. Med. 2015 March 17 [doi:10.7326/M14-1336]). But there was an important caveat: Many more patients would be eligible for the novel therapies than for the standard care, because the novel therapies are much more easily tolerated. With the addition of so many eligible patients, the resources needed to treat them “could be immense and unsustainable.” Compared with standard care, giving these novel HCV therapies to all eligible patients “would cost an additional $65 billion in the next 5 years,” which would not be counterbalanced by the estimated $16 billion saved by preventing cirrhosis, HCC, and transplantations.

Therefore, “despite the cost-effectiveness of [novel] HCV treatments, our analysis shows that it is unaffordable at the current price,” Dr. Chhatwal and his associates said.

In the other study, funded primarily by CVS Health, researchers developed a discrete-event simulation model of the natural history and progression of liver disease in treatment-naive patients, categorized by whether they were infected with HCV genotype 1, 2, or 3. Several possible treatment regimens were considered for each genotype, and the SVR rates they were projected to attain were derived from those reported in clinical trials, said Mehdi Najafzadeh, Ph.D., of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

“From a societal perspective, the newly approved PEG-free regimen of sofosbuvir-ledipasvir for 12 weeks could be very cost-effective relative to usual care (costing $12,825/QALY gained) for patients with HCV genotype 1.” This treatment proved to be the optimal strategy in the greatest number of simulations involving genotype 1.

Similarly, for genotype 3 the combination of sofosbuvir plus ledipasvir plus ribavirin for 12 weeks cost $73,000/QALY gained, compared with usual care. This also represents “relatively good value.” However, for genotype 2 the most cost-effective novel therapy, sofosbuvir-ribavirin, was $110,168/QALY gained, which is not considered cost-effective, Dr. Najafzadeh and his associates said (Ann. Intern. Med. 2015 March 17 [doi:10.7326;M14-1152]). Again, an important caveat to these findings was that, at their current prices, the cost of these drugs were not outweighed by the savings that accrued from preventing the complications of HCV. And “regardless of the cost-effectiveness of novel HCV treatments, there is considerable concern that their very high prices could substantially increase short-term overall drug spending for many public and private payers,” the investigators noted.

However, the fact that these regimens don’t reduce health care costs “is an exceptionally high bar” to hold them to – one that “is generally not expected when evaluating whether a new strategy represents good value for the money,” they added.

[email protected]