Sofosbuvir/velpatasvir is suitable for treatment of genotype 4 variants in Africa

Sofosbuvir/velpatasvir is safe and effective for the treatment of hepatitis C genotype 4 variants that have naturally occurring resistance to some direct-acting antivirals in the NS5A inhibitor class, a study in Rwanda has shown.

Numerous subtypes of genotype 4 have been identified in sub-Saharan Africa. Some of these subtypes contain naturally occurring mutations in the NS5A region that confer resistance to the NS5A inhibitors ledipasvir and daclatasvir. Several studies have shown high rates of treatment failure when sofosbuvir/ledipasvir (Harvoni) or sofosbuvir/daclatasvir were used to treat people with genotype 4r, one of the genotype 4 variants. A study in Rwanda found a markedly lower response to sofosbuvir/ledipasvir in people with the 4r subtype compared to other subtypes of genotype 4.

Sofosbuvir/velpatasvir (Epclusa) is active against genotypes 1-6 but it has been unclear if the activity of the NS5A inhibitor velpatasvir is compromised in non-a, non-d genotype 4 subtypes, as clinical trials included few African participants with non-a, non-d genotype 4 subtypes.

EASL guidelines recommend treatment with sofosbuvir/velpatasvir/voxilaprevir (Vosevi) in settings where genotype 4 variants show resistance to NS5A inhibitors. However, this information may not be readily available and Vosevi is potentially costly owing to low demand for a generic version, emphasising the importance of testing whether the pangenotypic regimen of sofosbuvir/velpatasvir is effective in all settings.

The SHARED-3 study investigated whether sofosbuvir/velpatasvir is an effective regimen in people with hepatitis C genotype 4 in Rwanda.

The Simplifying Hepatitis C Antiviral Therapy in Rwanda for Elsewhere in the Developing World (SHARED) research programme was sponsored by Partners in Health, a Boston-based organisation that has worked extensively to develop models of care suitable for management of conditions including cancer, tuberculosis and HIV in resource-limited settings such as Malawi and Rwanda.

SHARED-3 was a single-arm study that recruited previously untreated people without decompensated cirrhosis. The study recruited 61 people all with non-a/d genotype 4 infections. Genotyping showed that 48 participants had subtype 4k, 11 had 4r, 8 had 4v, 5 had 4q and 4 had a variety of non-a, non-d subtypes. Subtype could not be sequenced in three participants. Genotyping of the NS5A gene was possible in 55 of 61 participants; all had at least two mutations associated with resistance to NS5A inhibitors. Sequencing of the NS5B gene was possible for 27 participants and showed that 15 had mutations associated with resistance to NS5B inhibitors (including sofosbuvir).

Participants received a 12-week course of treatment with sofosbuvir/velpatasvir. Twelve weeks after the completion of treatment, 59 of 61 participants had a sustained virological response.

One participant with subtype 4r and one with subtype 4k failed to have a sustained virological response. One participant with two resistance mutations and one with three resistance mutations failed to achieve a sustained virological response. No new resistance mutations emerged during treatment in either of the participants who did not have a sustained virological response. Both had greater than 95% adherence by pill count at weeks 4, 8 and 12.

Serious adverse events were uncommon, experienced by 7% of participants, and none were related to the study drugs.

The study investigators say that their findings indicate that sofosbuvir/velpatasvir is a safe and effective treatment regimen for use in regions where non-a or non-d genotype 4 subtypes are common and support the use of sofosbuvir/velptasvir as a pangenotypic first-line regimen for use in lower- and middle-income countries.

The investigators note that in many settings where genotype 4 is prevalent, treatment with sofosbuvir/daclatasvir predominates due to cost and availability. A course of treatment with sofosbuvir/daclatasvir cost an average of $86 in 2019 compared to $225 for sofosbuvir/ledipasvir. But the effectiveness of sofosbuvir/daclatasvir against non-a or non-d is uncertain and national programmes in settings where genotype 4 is prevalent will need to weigh the extra cost of sofosbuvir/velpatasvir against the potentially higher risk of treatment failure and its associated costs, the investigators note. More research is needed to develop robust investment cases for use of specific regions based on local epidemiology and prevalence of resistance, in order to ensure that countries with a higher prevalence of harder-to-treat HCV subtypes do not fall behind in their HCV elimination efforts.

A further study in the SHARED-3 research programme looked at the effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 40 people who had experienced the failure of sofosbuvir/ledipasvir or another regimen as first-line treatment in Rwanda. All but two had non-a subtypes of genotype 4, 25 had at least three NS5A mutations and 33 had at least two mutations. All but one participant had a sustained virological response. The participant who did not have a sutianed virologic response had experienced failure of two previous courses of treatment with sofosbuvir/ledipasvir and sofosbuvir/daclatasvir and had resistance-associated mutations in the NS5A and NS5B genes. This participant also developed resistance mutations in the NS3 region during treatment.

The study investigators say that as hepatitis C treatment is scaled up in sub-Saharan Africa, the need for second-line treatment will increase. Affordable generic versions of sofosbuvir/velpatasvir/voxilaprevir are needed, especially where first-line treatment consists of sofosbuvir/ledipasvir or sofosbuvir/daclatasvir.