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The Liver Meeting 2016
News
The Liver Meeting 2016 New treatments for NASH
Published Online November 18, 2016 http://dx.doi.org/10.1016/ S2468-1253(16)30180-7 The 2016 annual meeting of the American Association for the Study of Liver Diseases took place in Boston, MA, USA on Nov 11–15, 2016
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Arun Sanyal (Richmond, VA, USA) presented data from the ongoing CENTAUR trial of cenicriviroc, an oral drug that inhibits the cytokine receptors CCR2 and CCR5, for the treatment of patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Participants were randomised 2:1:1 to receive cenicriviroc for 2 years, placebo for 1 year followed by cenicriviroc for another year, or to receive placebo for 2 years. Results from the first year of the study were presented: 144 patients were randomly assigned to receive placebo, whilst 145 were to receive the study drug. The primary endpoint—improvement in NASH activity score by two or more points with at least a one-point reduction in either lobular inflammation or hepatocellular ballooning, and no concurrent worsening of fibrosis stage at year 1—was not significantly different between groups (19% of participants receiving placebo vs 16% of those receiving the study drug). Of the key secondary endpoints, there was no significant difference between groups for complete resolution of NASH with no worsening of fibrosis, but significantly more patients in the cenicriviroc group than in the placebo group had an improvement in fibrosis stage without a worsening of NASH. There were no major differences in treatment-emergent adverse events between groups. Rohit Loomba (San Diego, CA, USA) presented results from a randomised trial of GS-4997, an inhibitor of ASK1, alone or in combination with simtuzumab for treatment of NASH. In this five-arm study (examining two doses of GS-4997, with and without simtuzumab, and also including a group receiving simtuzumab alone), no differences were noted between the groups receiving GS-4997 alone and those receiving it in combination with simtuzumab, so data were
pooled and presented by GS-4997 treatment group only. 13 (43%) of 30 patients who received GS-4997 18 mg/kg plus simtuzumab had an improvement of fibrosis of at least one stage, compared with eight (30%) of 27 who received the drug at 6 mg/kg in combination with simtuzumab, and two (20%) of ten who received simtuzumab alone. Only one (3%) patient on the highest dose of GS-4997 progressed to cirrhosis, compared with two (7%) of those receiving the lower dose, and two (20%) of those receiving simtuzumab alone. The most common adverse events with the study drug were headache and nausea.
Paediatric primary sclerosing cholangitis To better understand the natural history of paediatric primary sclerosing cholangitis (PSC), Mark Deneau (Salt Lake City, UT, USA) and colleagues in the Pediatric PSC Consortium collated data from 36 centres worldwide, and presented data from 781 cases. Deneau noted that there was a steady increase in progression to portal hypertensive complications over time, with 38% affected by 10 years, and a similar increase in risk of stricture requiring intervention (25% at 10 years). Survival after either event was poor, with 5-year survival of 34% (95% CI 25–43) for those with portal hypertension and 36% (24–49) for those with a stricture requiring intervention. The onset of either event was a tipping point in the natural history of the disease; twothirds of these patients required a liver transplant within 5 years. In the cohort overall, 30% of patients required liver transplantation by 10 years, and despite more than 80% of the cohort having received ursodeoxycholic acid, nearly half had a liver-related event by 10 years.
Treating hepatic encephalopathy Barjesh Sharma (New Delhi, India) presented the results of a randomised trial of albumin plus lactulose versus lactulose alone for patients with overt hepatic encephalopathy. 120 patients were randomly assigned to one of the two groups; complete reversal of hepatic encephalopathy (the primary endpoint) was noted in 45 (75%) of 60 patients receiving both albumin and lactulose, compared with 32 (53%) of 60 who received lactulose alone (p=0·03). Mortality was also lower in the combination group (11 [18%] vs 19 [32%]); there were fewer deaths from sepsis in the albumin and lactulose group than in the lactulose alone group.
HCV and renal disease Patients with chronic hepatitis C virus (HCV) infection with severe renal disease currently have limited treatment options. Edward Gane presented data from the EXPEDITIONIV trial, which gave two pangenotypic direct-acting antivirals—glecaprevir and pibrentasvir, neither of which undergo significant renal excretion— to 104 patients with genotype 1–6 HCV infections for 12 weeks. Previously untreated patients as well as treatment-experienced patients could be enrolled. Those with compensated cirrhosis were also eligible. 102 (98%) of the patients achieved SVR12 (the primary endpoint), with no virological failures. 24% of patients had a serious adverse event, but none of these were deemed to be treatment related. Most treatment-related adverse events were mild to moderate in severity. These results demonstrate that a ribavirin-free regimen for patients with severe renal disease can achieve a high rate of SVR, and may be an option for these patients.
Rob Brierley www.thelancet.com/gastrohep Vol 2 January 2017
The Liver Meeting 2016 New treatments for NASH
Published Online November 18, 2016 http://dx.doi.org/10.1016/ S2468-1253(16)30180-7 The 2016 annual meeting of the American Association for the Study of Liver Diseases took place in Boston, MA, USA on Nov 11–15, 2016
8
Arun Sanyal (Richmond, VA, USA) presented data from the ongoing CENTAUR trial of cenicriviroc, an oral drug that inhibits the cytokine receptors CCR2 and CCR5, for the treatment of patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Participants were randomised 2:1:1 to receive cenicriviroc for 2 years, placebo for 1 year followed by cenicriviroc for another year, or to receive placebo for 2 years. Results from the first year of the study were presented: 144 patients were randomly assigned to receive placebo, whilst 145 were to receive the study drug. The primary endpoint—improvement in NASH activity score by two or more points with at least a one-point reduction in either lobular inflammation or hepatocellular ballooning, and no concurrent worsening of fibrosis stage at year 1—was not significantly different between groups (19% of participants receiving placebo vs 16% of those receiving the study drug). Of the key secondary endpoints, there was no significant difference between groups for complete resolution of NASH with no worsening of fibrosis, but significantly more patients in the cenicriviroc group than in the placebo group had an improvement in fibrosis stage without a worsening of NASH. There were no major differences in treatment-emergent adverse events between groups. Rohit Loomba (San Diego, CA, USA) presented results from a randomised trial of GS-4997, an inhibitor of ASK1, alone or in combination with simtuzumab for treatment of NASH. In this five-arm study (examining two doses of GS-4997, with and without simtuzumab, and also including a group receiving simtuzumab alone), no differences were noted between the groups receiving GS-4997 alone and those receiving it in combination with simtuzumab, so data were
pooled and presented by GS-4997 treatment group only. 13 (43%) of 30 patients who received GS-4997 18 mg/kg plus simtuzumab had an improvement of fibrosis of at least one stage, compared with eight (30%) of 27 who received the drug at 6 mg/kg in combination with simtuzumab, and two (20%) of ten who received simtuzumab alone. Only one (3%) patient on the highest dose of GS-4997 progressed to cirrhosis, compared with two (7%) of those receiving the lower dose, and two (20%) of those receiving simtuzumab alone. The most common adverse events with the study drug were headache and nausea.
Paediatric primary sclerosing cholangitis To better understand the natural history of paediatric primary sclerosing cholangitis (PSC), Mark Deneau (Salt Lake City, UT, USA) and colleagues in the Pediatric PSC Consortium collated data from 36 centres worldwide, and presented data from 781 cases. Deneau noted that there was a steady increase in progression to portal hypertensive complications over time, with 38% affected by 10 years, and a similar increase in risk of stricture requiring intervention (25% at 10 years). Survival after either event was poor, with 5-year survival of 34% (95% CI 25–43) for those with portal hypertension and 36% (24–49) for those with a stricture requiring intervention. The onset of either event was a tipping point in the natural history of the disease; twothirds of these patients required a liver transplant within 5 years. In the cohort overall, 30% of patients required liver transplantation by 10 years, and despite more than 80% of the cohort having received ursodeoxycholic acid, nearly half had a liver-related event by 10 years.
Treating hepatic encephalopathy Barjesh Sharma (New Delhi, India) presented the results of a randomised trial of albumin plus lactulose versus lactulose alone for patients with overt hepatic encephalopathy. 120 patients were randomly assigned to one of the two groups; complete reversal of hepatic encephalopathy (the primary endpoint) was noted in 45 (75%) of 60 patients receiving both albumin and lactulose, compared with 32 (53%) of 60 who received lactulose alone (p=0·03). Mortality was also lower in the combination group (11 [18%] vs 19 [32%]); there were fewer deaths from sepsis in the albumin and lactulose group than in the lactulose alone group.
HCV and renal disease Patients with chronic hepatitis C virus (HCV) infection with severe renal disease currently have limited treatment options. Edward Gane presented data from the EXPEDITIONIV trial, which gave two pangenotypic direct-acting antivirals—glecaprevir and pibrentasvir, neither of which undergo significant renal excretion— to 104 patients with genotype 1–6 HCV infections for 12 weeks. Previously untreated patients as well as treatment-experienced patients could be enrolled. Those with compensated cirrhosis were also eligible. 102 (98%) of the patients achieved SVR12 (the primary endpoint), with no virological failures. 24% of patients had a serious adverse event, but none of these were deemed to be treatment related. Most treatment-related adverse events were mild to moderate in severity. These results demonstrate that a ribavirin-free regimen for patients with severe renal disease can achieve a high rate of SVR, and may be an option for these patients.
Rob Brierley www.thelancet.com/gastrohep Vol 2 January 2017