HCV genotype 4 non-a/d subtypes are common in sub-Saharan Africa.
Direct-acting antiviral treatment could be a cheaper option to slow the spread of hepatitis C virus (HCV) in developing countries.
A team, led by Neil Gupta, MD, Division of Global Health Equity, Brigham and Women's Hospital, evaluated the safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir for the treatments of adults in Rwanda with chronic HCV infections, predominately of genotype 4, and a history of direct-acting antiviral treatment failure.
In the sub-Saharan Africa region, HCV genotype 4 non-a/d subtypes, which frequently have NS5A resistance-associated substitutions, are highly prevalent.
These subtypes have been linked to higher rates of failure of treatment regiments containing NS5A inhibitors ledipasvir or daclatasvir, the most accessible direct-acting antivirals in low-income countries.
However, there remains limited clinical evidence on the efficacy of re-treatment options for these subtypes.
In the single-arm prospective trial, the investigators examined 49 adult patients with an HCV RNA titre of at least 1000 IU/mL and a documented history of direct-acting antiviral failure between September 23, 2019 and January 10, 2020. The median age of the patient population was 63 years and the median HCV viral load was 6.2 log10 IU/mL at baseline.
The investigators assessed each patient at a single study site following referral from hospitals with HCV treatment programs throughout Rwanda and patients who had sofosbuvir-ledipasvir treatment in the previous SHARED trial, while patients with decompensated liver disease or hepatitis B virus co-infections were excluded.
Each patient was treated once daily with an oral fixed-dose combination tablet containing sofosbuvir 400 mg, velpatasvir 100 mg, and voxilaprevir 100 mg for 12 weeks.
The investigators sought primary endpoints of the proportion of participants with a sustained virological response 12 weeks after the completion of treatment in the intention-to-treat population.
The team conducted viral sequencing of NS3, NS5A, and NS5B genes at baseline for all participants and at the end of follow-up at week 24 in individuals with treatment failure.
The investigators identified several genotypes, including 4r (45%; n = 18), 4k (15%; n = 6), 4b (13%; n = 5), 4q (1-%; n = 4), 4l (5%; n = 2), 4a (3%; n = 1), 4m (3%; n = 1), and 3h (3%; n = 1). In addition 1 genotype 4 isolate couldn’t be subtyped and 1 isolate was of unknown genotype.
All of the successfully sequenced isolates (83%; n = 33) had at least 2 NS5A resistance-associated substitutions and 63% (n = 25) had 3 or more.
In addition, 98% (n = 39; 95% CI, 87-100) of the participants had SVR12, while 18% (n = 7) had a total of 10 grade, 3, 4, or 5 adverse events. This included 3 cases of hypertension and 1 case of cataract, diabetes, gastrointestinal bleeding, joint pain, low back pain, vaginal cancer, and sudden death. Four of the adverse events were considered serious adverse events resulting in hospitalization.
In addition, the lone sudden death occurred at home from an unknown cause 4 weeks following the completion of treatment.
Finally, no serious adverse events were considered to be related to the study drug or resulted in treatment discontinuation.
“A 12 week course of sofosbuvir–velpatasvir–voxilaprevir is safe and efficacious for the re-treatment of individuals infected with HCV genotype 4 non-a/d subtypes with frequent baseline NS5A resistance-associated substitutions, following failure of previous direct-acting antiviral treatment,” the authors wrote. “Improved affordability and access to sofosbuvir–velpatasvir–voxilaprevir in regions with these subtypes is crucial.”
The study, “Safety and efficacy of sofosbuvir–velpatasvir–voxilaprevir for re-treatment of chronic hepatitis C virus infection in patients with previous direct-acting antiviral treatment failure in Rwanda (SHARED-3): a single-arm trial,” was published online in The Lancet Gastroenterology & Hepatology.