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Meta-Analysis
. 2024 Dec 17;79(6):1437-1446.
doi: 10.1093/cid/ciae431.

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

Seth Inzaule  1 , Philippa Easterbrook  2 , Ashley Latona  3 , Nathan P Ford  2 , William Irving  4 , Philippa C Matthews  5 , Marco Vitoria  2 , Chris Duncombe  6 , Amalia Giron  7 , Suzanne McCluskey  8 , Olufunmilayo Lesi  2 , Serge Tchamgoue  9 , Rachel Halford  10 , Danjuma Adda  10 , Emma Thomson  11 , Geoff Dusheiko  12 , Michael R Jordan  3
Affiliations
Meta-Analysis

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

Seth Inzaule et al. Clin Infect Dis. .

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.

Keywords: chronic hepatitis C virus; initial treatment and retreatment; pan-genotypic direct acting agents; resistance-associated substitutions; treatment failure.

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Conflict of interest statement

Potential conflicts of interest. W. I. reports personal fees from Roche diagnostics, Gilead Sciences, and Source Bioscience Limited outside of the submitted work and stock or stock options in GlaxoSmithKline. P. C. M. reports funding from Francis Crick Institute and University College London Biomedical Research Centre (BRC) and Wellcome Trust during the submitted work, as well as royalties from Oxford University Press and funding from GlaxoSmithKline outside of the submitted work. S. T. reports funding or personal fees ViiV Healthcare and Gilead Sciences outside of the submitted work. D. A. reports funding from Gilead Sciences and Pfizer outside of the submitted work. R. H. serves as the president of World Hepatitis Alliance. All other authors declare no competing interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study selection among patients with viral non-suppression after WHO recommended first-line direct acting antiviral treatment of hepatitis C. Abbreviation: WHO, World Health Organization.
Figure 2.
Figure 2.
Prevalence of post-treatment RAS among patients treated with SOF/DAC, SOF/VEL, or GLE/PIB as initial regimen. Abbreviations: CI, confidence interval; DAC, daclatasvir; ES, effect size (odds ratio); GLE, glecaprevir; I2, heterogeneity quantified using the I2 statistic; PIB, pibrentasvir; RAS, resistance associated substitution; SOF, sofosbuvir; VEL, velpatasvir.
Figure 3.
Figure 3.
Study selection among patients with viral non-suppression after retreatment with WHO recommended second-line direct acting antiviral treatment of hepatitis C. Abbreviation: WHO, World Health Organization.
Figure 4.
Figure 4.
Prevalence of post-treatment RAS among patients re-treated with SOF/VEL/VOX or GLE/PIB. CI, confidence interval; DAC, daclatasvir; ES, effect size (odds ratio); GLE, glecaprevir; I2, heterogeneity quantified using the I2 statistic; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
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