A triple regimen of grazoprevir/elbasvir (Zepatier) plus sofosbuvir (Sovaldi) without ribavirin cured 96% of previously untreated and 97% of treatment-experienced people with hepatitis C virus (HCV) genotype 3 and liver cirrhosis, matching rates seen in easier-to-treat patient groups, according to results from the C-ISLE study presented this week at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting in Boston.
The development of direct-acting antiviral (DAA) agents has made treatment of chronic hepatitis C briefer, more convenient, and much more effective than the older interferon-based therapy. But better options are still needed for the most difficult-to-treat patients, who still do not achieve the near-100% sustained response rates seen in easier-to-treat groups.
Lower response rates are associated with HCV genotype 3, presence of liver cirrhosis, prior treatment failure, and presence of DAA resistance-associated variants (RAVs). Nearly a third of people with hepatitis C worldwide have genotype 3 and it is associated with more rapid liver disease progression.
Presenter Graham Foster from Queen Mary University in London called treatment-experienced genotype 3 cirrhotic patients the “toughest of the tough.” Currently approved regimens for this group include sofosbuvir/velpatasvir (Epclusa) with ribavirin for 12 weeks or sofosbuvir plus daclatasvir (Daklinza) with ribavirin for 12 or 24 weeks, but until recently DAA combinations with pegylated interferon were still considered an option for these challenging patients.
The C-ISLE study evaluated a coformulation of Merck’s grazoprevir (an HCV protease inhibitor) and elbasvir (an NS5A inhibitor) plus Gilead Science’s sofosbuvir (an NS5B polymerase inhibitor), taken with or without ribavirin for 8 to 16 weeks, for treatment-naive and treatment-experienced genotype 3 patients with compensated cirrhosis. Grazoprevir/elbasvir is currently indicated only for genotypes 1 and 4. The earlier C-SWIFT study showed promising results for this intensified regimen, but it included few genotype 3 patients.
C-ISLE enrolled 100 participants. About two-thirds were men, 69% were white, 29% were Asian, and the average age was 53 years. Just over half (53%) had previously used pegylated interferon/ribavirin and the mean pre-treatment HCV RNA level was 6.2 log IU/mL. They had compensated cirrhosis as indicated by FibroScan transient elastometry (mean score 25.4 kPa) or liver biopsy. They had no history of hepatic decompensation, but had albumin, bilirubin, and platelet levels indicating impaired liver function.
Participants in this open-label study were randomly allocated to 5 treatment arms. Treatment-naive patients were randomized to receive grazoprevir/elbasvir plus sofosbuvir either with ribavirin for 8 weeks or without ribavirin for 12 weeks. Treatment-experienced patients were randomized to receive grazoprevir/elbasvir plus sofosbuvir with or without ribavirin for 12 weeks, or without ribavirin for 16 weeks.
The primary endpoint was sustained virological response, or continued undetectable HCV viral load at 12 weeks after completing therapy (SVR12).
- Among treatment-naive patients, SVR12 rates were 91% for 8 weeks of grazoprevir/elbasvir plus sofosbuvir with ribavirin (2 relapses) and 96% for 12 weeks of grazoprevir/elbasvir plus sofosbuvir without ribavirin (1 non-virological failure).
- Among treatment-experienced patients, SVR12 rates were 100% for 12 weeks of grazoprevir/elbasvir plus sofosbuvir without ribavirin, 94% for 12 weeks of grazoprevir/elbasvir plus sofosbuvir with ribavirin, and 94% for 16 weeks of grazoprevir/elbasvir plus sofosbuvir without ribavirin (1 non-virological failure in each of the latter 2 arms).
- However, when excluding the 3 patients who discontinued early for reasons other than virological failure (loss to follow-up, withdrawal of consent, and non-drug-related adverse event), the cure rate was 100% for all but the 8-week regimen.
- 1 of the 2 relapsers had various resistance-associated variants (including the Y93H mutation) at baseline and at the time of treatment failure, but the other had wild-type virus before and after treatment.
- The SVR12 rate was the same — 98% — for the half of patients that had pre-existing NS5A RAVs and the half that did not.
- Therapy was generally safe and well-tolerated, with no treatment discontinuations due to adverse events.
- The most frequently reported adverse events were fatigue, nausea, and skin rash or itching.
- Side effects overall and serious adverse events were more common among patients who used ribavirin and those treated for a longer duration.
“High efficacy was demonstrated in treatment-naive and treatment-experienced cirrhotic HCV genotype 3-infected patients,” the researchers concluded.
Everyone who completed treatment with grazoprevir/elbasvir plus sofosbuvir without ribavirin had a sustained response, Foster noted. Both virological failures were in the 8-week arm with ribavirin, and 1 of these patients had the Y93H mutation. However, all patients with Y93H who were treated for 12 weeks were cured.
While there has been concern about liver-related adverse events in people with cirrhosis treated with HCV protease inhibitors, no such problems were observed in this study. Foster said he would be comfortable treating people with Child-Pugh class B cirrhosis, which indicates significant compromise of liver function but not yet decompensation (class C).
By Liz Highleyman
GR Foster, K Agarwal, M Cramp, et al. C-ISLE: Grazoprevir/Elbasvir plus Sofosbuvir in Treatment-naive and Treatment-experienced HCV GT3 Cirrhotic Patients Treated for 8, 12 or 16 weeks. 67th Meeting of the American Association for the Study of Liver Diseases: Liver Meeting 2016. Boston, November 11-15, 2016. Abstract 74.