Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

Abstract

Background and aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort.

Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively.

Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure.

Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Keywords: Direct-acting antivirals; Hepatitis C Virus; rare HCV genotypes; resistance-associated substitutions; treatment response.

Graphical abstract

Fig. 1

Flow chart of the study cohort. BOC, boceprevir; GT, genotype; IFN, interferon; P/R, pegylated interferon/ribavirin; SOF, sofosbuvir; RBV, ribavirin; TVR, telaprevir. ∗also includes patients who were treated other DAAs from clinical studies, ∗∗only in patients with GT1.

Fig. 2

Distribution of rare HCV GTs and subtypes. (A) Frequencies of rare HCV GT subtypes among DAA-naive patients and (B) rare HCV GT subtypes detected in DAA-failure patients. DAA, direct-acting antiviral; GT, genotype.

Fig. 3

Countries of origin of DAA-failure patients with rare GT subtypes. DAA, direct-acting antiviral; GT, genotype. ∗Subtype unassigned. (background picture: power point, creative commons, https://www.dahmen-quilt.com).

Fig. 4

Rare HCV GT subtypes in DAA-naive vs. -experienced patients. (A) Overall frequencies of rare GT subtypes in patients after first and second generation DAA failure compared to DAA-naive patients. (B) Distribution of rare HCV subtypes among DAA-failure patients, stratified for first and second generation DAAs. DAA, direct-acting antiviral; GT, genotype. Patients with rare GT6 subtypes and PrOD, GZR/EBR, LDV/SOF failure were partially misclassified as GT1 in commercial genotyping assays.

Fig. 5

RASs in patients with rare vs. common HCV GTs. (A) NS5A RASs detected in patients after NS5Ai failure. Pos. 28 not resistant in GT3a, Pos. 30 not resistant in GT1b. The data for GT1a, GT1b and GT3a are taken from Dietz et al. J. Hepatol., 2023. (B) NS5A RASs in DAA-naive patients. (C) Frequency of Y93H after NS5Ai failure in patients with rare GTs compared with common subtypes. (D) Prevalence of S282T after sofosbuvir treatment failure in patients with rare GT in comparison to patients with common subtypes. DAA, direct-acting antiviral; GT, genotype; NS5Ai, NS5A inhibitor; RASs, resistance-associated substitutions. ^#In patients with NS5A sequencing data available; ^§in patients with NS5B sequencing data available; ∗data from Dietz et al. J. Hepatol., 2023; ∗∗data from Dietz et al. Gastroenterology, 2018.

Fig. 6

Retreatment efficacies (mITT) in DAA-failure patients with rare GTs. DAA, direct-acting antiviral; GT, genotype. mITT (modified intention-to-treat): retreated patients with completed follow-up visits. ^#One further patient started retreatment with VOX/VEL/SOF for 12 weeks and was lost during the on-treatment visits. Thus, the overall TT SVR rate was 92% (45/49) and the VOX/VEL/SOF ITT SVR rate was 93% (27/29). Further 11 patients were not retreated, of whom 8 patients were lost and further 3 patients died due to HCC. ∗n = 4 patients with HCV GT1/GT4 subtypes unassigned.