by Carolyn Chu, MD, MSc, AAHIVS, AAHIVM Chief Medical Officer

January 17, 2023

Featured Literature:

Dietz J, Müllhaupt B, Buggisch P, et al for the German HCV Resistance Study Group. Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure. J Hepatol. 2023 Jan; 78(1):57-66. doi:10.1016/j.jhep.2022.08.016. PMID 36031158. 

European collaborators evaluated the persistence of NS3, NS5A, and NS5B resistance-associated substitutions (RASs) in a real-world cohort of 678 people with HCV infection (GT1 or GT3) who experienced virologic failure to DAA treatment between 2014 and 2021. This analysis included 844 samples collected after end of treatment (EOT) at sites in Germany, Switzerland, Austria, and Belgium; basic clinical data (e.g., pretreatment status, presence of cirrhosis, DAA treatment regimen and duration, virologic response) were collected retrospectively. Mean participant age was 55 years, 45% had cirrhosis, 36% had GT1a infection, 35% GT1b, and 29% GT3; mean sampling time point was 7.5 months after EOT. NS3 RASs were identified after PI failure in 90% of participants with GT1a, 68% in participants with GT1b, and 40% in participants with GT3. Early decreases of NS3 RASs were observed within the first three months after EOT, especially in participants with GT1b and GT3 (primarily as a result of the loss of variants at position 168). By contrast, in participants with GT1a, Q80K was the only variant still detectable after follow-up month 24. NS5A RASs were commonly observed after NS5A inhibitor failure: 88% in GT1a, 95% in GT1b, and 89% in GT3. Even after follow-up month 24, observed frequency was 65% or higher. Overall, NS5A RASs remained stable in GT1b, compared to slight decreases in participants with GT1a and GT3 (primarily because of the slow decline of Y93H). Prevalence of NS5B non-nucleoside RASs after ombitasvir / paritaprevir / ritonavir plus dasabuvir failure was 56% in GT1a and 80% in GT1b: RASs decreased to 30% in GT1a but persisted in GT1b.

Author’s Commentary:

This large real-world analysis confirms that low- to medium-level RASs persisted over time among people who experienced virologic failure after DAA therapy for GT1 or GT3 infection, compared to high-level resistant RASs, which tended to disappear more quickly because of high fitness costs in the absence of DAA exposure. Additionally, high-level resistance NS5A RASs persisted longer than NS3 RASs. There did not appear to be any significant association of measured clinical parameters such as cirrhosis, age, and sex on RAS persistence. With regard to retreatment outcomes, data collection from this cohort is still ongoing and therefore this study is unable to inform whether RAS persistence impacted retreatment efficacy. Nevertheless, authors note that data on long-term persistence may be particularly helpful for consideration and selection of first-generation DAA regimens based on a class switch, since sofosbuvir / velpatasvir / voxilaprevir may not be uniformly available globally.

The author has no conflicts of interest to disclose.

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