Prevalence of Drug Resistance Associated Substitutions in Persons With Chronic Hepatitis C Infection and Virological Failure Following Initial or Re-treatment With Pan-genotypic Direct-Acting Antivirals: A Systematic Review and Meta-analysis
Inzaule S., Easterbrook P., Latona A., Ford NP., Irving W., Matthews PC., Vitoria M., Duncombe C., Giron A., McCluskey S., Lesi O., Tchamgoue S., Halford R., Adda D., Thomson E., Dusheiko G., Jordan MR.
Abstract Background The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%–12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy. Methods We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis. Results The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0–92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0–93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0–87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0–99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0–100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors. Discussion At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.