An 8-week triple combination of Gilead Sciences' sofosbuvir, velpatasvir and GS-9857 showed a high sustained response rate in a phase 2 study of people with difficult-to-treat hepatitis C virus (HCV), including treatment-experienced people with HCV genotype 3 and liver cirrhosis, according to results presented on Sunday at the 2015 AASLD Liver Meeting in San Francisco, USA. A 6-week regimen appeared inadequate, however, and more than 8 weeks may be needed for people who have previously used direct-acting antivirals.
Interferon-free direct-acting antiviral (DAA) therapy has revolutionised treatment for chronic hepatitis C, but there is still room to optimise therapy for difficult-to-treat patients, enabling them to take advantage of shorter-duration, ribavirin-sparing regimens like those currently available for easier-to-treat people. Ideally, such a regimen would be pan-genotypic, meaning it could be routinely prescribed without the need for genotype testing.
Edward Gane of Auckland Clinical Studies in New Zealand presented final results from a phase 2 trial (NCT02202980) evaluating a three-drug regimen consisting of the HCV NS5B polymerase inhibitor sofosbuvir, the pan-genotypic NS5A inhibitor velpatasvir (formerly GS-5816) and the pan-genotypic NS3/4A protease inhibitor GS-9857. Combining drugs that attack HCV at three different steps of its lifecycle may improve efficacy and enable shorter treatment.
This study included 157 participants divided into seven cohorts with various characteristics predicting good or poor treatment response. All were treated with the triple regimen for 4, 6 or 8 weeks. Sofosbuvir and velpatasvir were taken as a once-daily fixed-dose coformulation (400/100mg); GS-9857 (100mg) was also taken once daily.
The easiest-to-treat group – previously untreated people with HCV genotype 1 and without cirrhosis – were randomly assigned to receive the combination for 4 or 6 weeks. Treatment-naive people with genotype 1 and with cirrhosis and people with prior DAA failure (with or without cirrhosis) were all treated for 6 weeks.
Gane presented results for these first three cohorts at the EASL International Liver Congress earlier this year. Response rates ranged from 67% to 93% in the 6-week arms, but fell to a dismal 27% in the 4-week arm.
At the AASLD meeting, Gane presented findings for the final four cohorts of harder-to-treat patients:
- Genotype 1 pegylated interferon/ribavirin-experienced with cirrhosis (n = 17)
- Genotype 1 protease inhibitor-experienced with or without cirrhosis (n = 28)
- Genotype 3 treatment-naive with cirrhosis (n = 18)
- Genotype 3 pegylated interferon/ribavirin-experienced with cirrhosis (n = 19)
Both genotype 1 cohorts were treated for 8 weeks. The genotype 3 treatment-naive and treatment-experienced groups received 6 and 8 weeks of therapy, respectively.
In these four cohorts, a majority of participants were men (56% to 82%), most were white (67% to 95%) and mean ages ranged from 52 to 58 years. A third had the favourable IL28B CC gene pattern. In the protease inhibitor-experienced cohort 39% had cirrhosis.
All participants in all four cohorts completed treatment with no discontinuations.
The sustained virological response rate at 12 weeks-post-treatment (SVR12) for genotype 1 treatment-experienced patients with cirrhosis was 100%. The overall SVR12 rate in the genotype 1 protease inhibitor-experienced cohort was 89%. In this group, people with cirrhosis uncharacteristically responded better than people without cirrhosis (94% vs 82%), but the numbers were small. All three genotype 1 patients without SVR12 relapsed.
Turning to the genotype 3 cohorts, the SVR12 rate was 83% in the cohort of treatment-naïve people with cirrhosis who were treated for 6 weeks, with two relapses and one withdrawal of consent. In the treatment-experienced cohort of people with cirrhosis treated for 8 weeks, 100% achieved SVR12.
Looking more closely at the five participants who relapsed, there was no consistent pattern of drug resistance-associated variants (RAVs) at baseline or at the time of relapse. At baseline, three people had NS3 RAVs (R155K x 2, I170T, V36M, T54S and Q168K) while two had NS5A RAVs (M28V and L31M). At relapse, two had NS3 RAVs and two had NS5A RAVs. One relapser had no RAVs at either baseline or relapse. The presence of NS3 RAVs at baseline appeared to have more influence on treatment response (88% with RAVs vs 96% without) than baseline NS5A RAVs (90% vs 95%, respectively).
Treatment with the triple regimen was generally safe and well-tolerated. Only three of the 82 participants in these four cohorts experienced serious adverse events and no one discontinued treatment for this reason. The most common side-effects were headache, fatigue, nausea and diarrhoea.
Sofosbuvir/velpatasvir for 8 weeks "resulted in high SVR12 rates in difficult-to-cure, treatment-experienced populations," the researchers concluded. "Baseline RAVs reduced SVR rates among PI-experienced patients" and "treatment-emergent RAVs were uncommon."
The 8-week triple regimen was "very robust" and "looks highly efficacious" for people with previous pegylated interferon/ribavirin failure, including people with cirrhosis, Gane said. But for DAA-experienced people, "I think you have to go beyond 8 weeks," and future data will tell whether that needs to be 10 or 12 weeks.
Gane EJ et al. Sofosbuvir/GS-5816+GS-9857 for 6 or 8 weeks in genotype 1 or 3 HCV-infected patients. AASLD Liver Meeting, abstract 38, 2015.