Back HCV Treatment EASL 2015: Sofosbuvir + Daclatasvir + Ribavirin Cures Advanced Cirrhosis and Liver Transplant Patients

EASL 2015: Sofosbuvir + Daclatasvir + Ribavirin Cures Advanced Cirrhosis and Liver Transplant Patients

alt

An interferon-free regimen of sofosbuvir, daclatasvir, and ribavirin for 12 weeks produced sustained response rates of 83% for hepatitis C patients with advanced liver cirrhosis and 94% for liver transplant recipients, 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 at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last week in Vienna. More than half of patients 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 options for difficult-to-treat patient groups including people with HCV genotype 3, patients with advanced liver disease, and liver transplant recipients.

Bristol-Myers Squibb'sPhase 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 hepatitis C patients with high unmet needs. ALLY-1 enrolled people with advanced liver cirrhosis and transplant recipients with HCV genotypes 1-6, ALLY-2 enrolled HIV/HCV coinfected people with genotypes 1-6 (recently presented at the 2015 Conference on Retroviruses and Opportunistic Infections) and ALLY-3 focused on genotype 3 patients (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 U.S. Food and Drug Administration approval.

As described by Fred Poordad from the University of Texas Health Science Center, ALLY-1 enrolled 60 hepatitis C patients with advanced 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, 5 cirrhosis patients had genotype 2, 6 cirrhosis 

patients and 11 transplant recipients had genotype 3, 4 cirrhosis patients had genotype 4, and 1 transplant recipient had genotype 6.

The advanced cirrhosis patients where 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). 12 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. 60% of Class B patients and all Class C patients had ascites and/or encephalopathy -- symptoms of liver decompensation. In addition, 6 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 3 months prior, had no evidence of graft rejection at enrollment, and could be taking any immunosuppressant regimen.

All participants in this open-label study received 400 mg once-daily sofosbuvir, 60 mg once-daily daclatasvir, and ribavirin for 12 weeks. Ribavirin was started at a dose of 600 mg/day, which could be adjusted based on tolerability. Patients in the cirrhosis cohort who interrupted therapy to undergo a liver transplant could receive 12 additional weeks of extended therapy post-transplantation.

Results

  • Overall, 83% of the advanced cirrhosis patients 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 genotype 1 patients, the corresponding cure rates were 82% and 95%.
  • All but 1 of the 13 patients who did not achieve SVR12 relapsed after the end of treatment; relapsers 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 genotype 6 patient.
  • 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 Class C patients.
  • 4 of the cirrhosis patients with hepatocellular carcinoma received a liver transplant during treatment (including 1 from an HCV-infected donor) and all achieved SVR12.
  • Treatment was generally safe and well-tolerated despite advanced liver disease.
  • The most common adverse events were headache, fatigue, anemia, diarrhea, and nausea.
  • 10 cirrhosis patients and 5 transplant recipients experienced serious adverse events, but none were deemed related to the study drugs.
  • 1 cirrhosis patient and 1 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 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 now include sofosbuvir plus daclatasvir, with or without ribavirin, as a recommended regimen for people with HCV genotype 3.

4/26/15

Reference

F Poordad, ER Schiff, JM Vierling, et at. Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or post-transplant recurrence: phase 3 ALLY-1 study. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract L08.

Other Source

Bristol-Myers Squibb. ALLY-1 Trial Results Show Investigational Daclatasvir-Based Regimen Cures 94% of Post-Liver Transplant Patients with Hepatitis C and Up to 94% of Hepatitis C Patients with Cirrhosis (Child-Pugh Class A or B). Press release. April 25, 2015.