Challenges in Treating Genotype 3 Hepatitis C Virus

In the United States, an estimated 3 to 4 million people have chronic hepatitis C virus (HCV) infection.¹ Among the 6 known genotypes of HCV, genotype 1 (GT1) is the most prevalent and accounts for three-quarters of cases.¹ Between 13% and 15% of HCV cases are genotype 2 (GT2), and approximately 10% are genotype 3 (GT3).^2,3 Globally, the distribution is different, with GT3 HCV accounting for 75% of HCV infections in South Asia, 25% in Western Europe, and 10% to 20% of all HCV infections in North America.⁴

Early clinical trials of interferon (IFN) monotherapy or IFN plus ribavirin suggested that patients with GT2 and GT3 were easier to cure than individuals with GT1.^5-7 However, these early trials of IFN-based regimens grouped patients with GT2 and GT3 together and reported pooled outcomes data.⁴ When clinical trials for the novel IFN-free direct-acting antiviral (DAA) therapies assessed outcomes by genotype, the findings upended conventional wisdom and showed GT3 was actually more difficult to cure than the other genotypes.^2,4

Sustained virological response (SVR), defined as “an HCV RNA level below the threshold of quantification,”⁴ sustained for 12 to 24 weeks after treatment ends, is considered predictive of cure. In clinical trials of the DAA agent sofosbuvir plus ribavirin, only 30% to 60% of patients with GT3 had SVR after 12 to 16 weeks of therapy compared with 95% of patients with GT2.^2,3 Data have shown patients with GT3 HCV have faster progression of fibrosis and higher rates of cirrhosis, severe steatosis, and hepatocellular carcinoma.^2,4 Steatosis is associated with higher viral loads, and cirrhosis predicts a lower likelihood of cure in treatment-naive patients, which may help explain the worse SVR rates in patients with GT3 relative to other HCV genotypes.⁴ Indeed, when SVR in patients with GT3 is stratified according to the presence of compensated cirrhosis or prior treatment failure, previously untreated patients and patients without cirrhosis are much more likely to achieve SVR with DAA therapy.⁴

Updated Guidelines for GT3 HCV

Treatment-Naive Patients Without Cirrhosis

For treatment-naive patients with GT3 who do not have cirrhosis, recently updated collaborative guidelines from the Infectious Diseases Society of America (IDSA) and the American Association for the Study of Liver Diseases (AASLD) recommend starting with an 8-week course of Mavyret (glecaprevir 300 mg/day + pibrentasvir 120 mg/day) or with a 12-week course of Epclusa (sofosbuvir 400 mg/day + velpatasvir 100 mg/day).⁸ Mavyret and Epclusa are fixed-dose combination oral tablets.

The US Food and Drug Administration approved Mavyret in August 2017 for HCV GT1 through GT6 on the basis of positive findings from ENDURANCE-3, a randomized, phase 3 trial in treatment-naive patients with GT3 HCV who were cirrhosis-free at enrollment.⁹ Patients were randomly assigned 2:1 to Mavyret (n = 233) or to sofosbuvir/daclatasvir (n = 115) for 12 weeks. The trial later added an open-label group that included 157 patients treated with Mavyret for 8 weeks.⁹ Rates of SVR12 were 95% (95% CI, 93%-98%) for the Mavyret 12-week group, 97% (95% CI, 91%-99%) for the sofosbuvir/daclatasvir group, and 95% (95% CI, 91%-99%) the Mavyret 8-week group, which were statistically equivalent.⁹ Note that the findings from ENDURANCE-3 have yet to be published in a peer-reviewed journal. Although the SVR rates in ENDURANCE-3 are much better than SVR rates observed in earlier studies of sofosbuvir/ribavirin in patients with GT3, they still lag behind SVR12 rates for patients with HCV with GT1 or GT2. In the phase 2 SURVEYOR-I and SURVEYOR-II trials of Mavyret, SVR12 ranged from 97% to 100% in patients with GT1 and 96% to 100% in patients with GT2 compared with 83% to 94% in patients with GT3.¹⁰

The US Food and Drug Administration approved Epclusa in June 2016 for patients with GT3 HCV with or without cirrhosis on the basis of results from the randomized controlled phase 3 ASTRAL-3 trial (N = 558).¹¹ Approximately 75% of patients were treatment-naive, and the remaining patients had previously received an IFN-based regimen. Patients were randomly assigned to Epclusa for 12 weeks or sofosbuvir/ribavirin for 24 weeks.¹¹ The rate of SVR12 was 95% (95% CI, 92%-98%) in the Epclusa group vs 80% (95% CI, 75%-85%) in the sofosbuvir/ribavirin group.¹¹ The ASTRAL-2 trial enrolled patients with GT2 and reported a SVR12 rate of 99% (95% CI, 96%-100%).¹¹