An interferon-free regimen of sofosbuvir, daclatasvir and ribavirin for 12 weeks produced sustained response rates of 83% for people with hepatitis C virus (HCV) who had advanced liver cirrhosis and 94% for people who had received liver transplants, with similar cure rates for those with hard-to-treat HCV genotype 3, according to findings from the ALLY-1 study presented at a late-breaker session on Saturday at the European Association for the Study of the Liver (EASL) 50th International Liver Congress in Vienna, Austria. More than half of study participants with the most severe decompensated cirrhosis achieved sustained response.
The advent of direct-acting antiviral agents that can be used in interferon-free regimens has brought about a revolution in treatment for chronic hepatitis C, but there is still a need for better therapeutic options for groups with difficult-to-treat hepatitis including people with HCV genotype 3, people with advanced liver disease and liver transplant recipients.
Bristol-Myers Squibb's phase 3 ALLY trials evaluated an interferon-free regimen containing the company's HCV NS5A inhibitor daclatasvir (Daklinza) plus Gilead Sciences’ HCV NS5B polymerase inhibitor sofosbuvir (Sovaldi) in people with hepatitis C who have high unmet needs. ALLY-1 enrolled people with advanced liver cirrhosis and transplant recipients with HCV genotypes 1-6, ALLY-2 enrolled people with HIV and HCV co-infection with HCV genotypes 1-6 (recently presented at the 2015 Conference on Retroviruses and Opportunistic Infections) and ALLY-3 focused on people with HCV genotype 3 (presented at the 2014 AASLD Liver Meeting).
Sofosbuvir and daclatasvir are pangenotypic, meaning they are active against multiple HCV genotypes. Gilead’s NS5A inhibitor ledipasvir (combined with sofosbuvir in the Harvoni coformulation), in contrast, has minimal activity against genotype 3. Daclatasvir is approved in the European Union and Japan, and has been submitted for approval from the US Food and Drug Administration (FDA).
As described by Fred Poordad of the University of Texas Health Science Center, ALLY-1 enrolled 60 people with hepatitis C and advanced liver cirrhosis and 53 people who experienced HCV recurrence after liver transplantation.
Overall, about 65% of participants were men, almost all were white, about a third were Hispanic/Latino and the median age was approximately 58 years. About 60% had previously been treated for hepatitis C. A majority (about 58%) had HCV genotype 1a and about 19% had 1b. In addition, five people with cirrhosis had genotype 2, six people with cirrhosis and 11 transplant recipients had genotype 3, four people with cirrhosis had genotype 4 and one transplant recipient had genotype 6.
The people with advanced cirrhosis were divided into subgroups based on Child-Pugh class, an index of liver disease severity and prognosis based on bilirubin and albumin levels, blood clotting capacity and presence of ascites (abdominal fluid accumulation) or hepatic encephalopathy (brain impairment). Twelve were Class A, 32 were Class B and 16 were the most severe Class C. Most people in Class A or B had MELD scores less than 15 (another measure of liver disease severity), while half in Class C had a MELD score of 16-20 and a quarter had scores above 21. Sixty per cent of people in Class B and all the participants in Class C had ascites and/or encephalopathy – symptoms of liver decompensation. Six had hepatocellular carcinoma (liver cancer).
In the post-transplant cohort, 43% had absent to moderate liver fibrosis (Metavir stage F0-F2), 25% had advanced fibrosis (stage F3) and 30% had cirrhosis (stage F4). They had undergone transplantation at least three months prior, had no evidence of graft rejection at enrolment and could be taking any immunosuppressant regimen.
All participants in this open-label study received 400mg once-daily sofosbuvir, 60mg once-daily daclatasvir and ribavirin for 12 weeks. Ribavirin was started at a dose of 600mg/day, which could be adjusted based on tolerability. People in the cirrhosis cohort who interrupted therapy to undergo a liver transplant could receive 12 additional weeks of extended therapy post-transplantation.
Overall, 83% of the people with advanced cirrhosis and 94% of the post-transplant participants achieved SVR12, or HCV RNA below the lower limit of quantification (<25 IU/ml) at 12 weeks post-treatment (SVR12). Looking just at the people with genotype 1, the corresponding cure rates were 82% and 95%.
All but one of the 13 people who did not achieve SVR12 relapsed after the end of treatment. People who relapsed are now being re-treated with the same regimen for 24 weeks.
Breaking down the advanced cirrhosis cohort further by genotype, SVR12 rates were 76% for subtype 1a, 100% for 1b, 80% for genotype 2, 83% for genotype 3 and 100% for genotype 4. In the post-transplant cohort, response rates were consistently high: 97% for 1a, 90% for 1b, 91% for genotype 3 and 100% for the sole participant with genotype 6.
Looking at other factors associated with response in the cirrhosis cohort, SVR12 rates were 92% and 94% for CP Class A and B, but fell to 56% for Class C. This difference was largely driven by low albumin levels, Poordad said. SVR12 rates did not differ significantly according to demographic factors, prior treatment experience or baseline HCV RNA level.
Changes in MELD score were inconsistent, with little change in the Class A group, and more improvement than worsening in the Class B and C groups – including a few large declines among people with Class C. Four of the people with cirrhosis who had hepatocellular carcinoma received a liver transplant during treatment (including one from a donor with HCV) and all achieved SVR12.
Treatment was generally safe and well-tolerated despite advanced liver disease. The most common adverse events were headache, fatigue, anaemia, diarrhoea and nausea. Ten people with cirrhosis and five transplant recipients experienced serious adverse events, but none were deemed related to the study drugs. One person with cirrhosis and one transplant recipient stopped all treatment due to adverse events, but both nonetheless achieved SVR12. Transplant recipients did not require modification of their immunosuppressant regimen due to drug interactions and there were no cases of graft rejection or hepatic decompensation.
"The 12-week pangenotypic regimen of daclatasvir with sofosbuvir and ribavirin is generally safe, well-tolerated and efficacious in HCV patients with advanced cirrhosis and post-liver transplant recurrence," the researchers concluded. "ALLY-1 demonstrates that 12 weeks of daclatasvir + sofosbuvir + ribavirin yields high SVR rates in advanced cirrhotic and post-transplant genotype 3 patients."
Poordad raised the possibility that people with advanced cirrhosis might see enough improvement in their MELD scores with treatment to lower their eligibility for transplantation, but not enough to no longer need a new liver. "I worry we may do more harm than good," he cautioned. Further research is needed to identify which CP Class C patients are most likely to benefit from treatment.
Updated EASL hepatitis C treatment guidelines released at the Liver Congress include sofosbuvir plus daclatasvir, with or without ribavirin, as a recommended regimen for people with HCV genotype 3.
Poordad F et al. Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or post-transplant recurrence: phase 3 ALLY-1 study. EASL 50th International Liver Congress, Vienna, abstract L08, 2015.