Reply
Authors: Veronica Miller, Patrick Harrington, Anita Howe, Tara Kieffer, Johan Lennerstrand, Oliver Lenz, Erik Lontok, Fiona McPhee, Hongmei Mo, Neil Parkin, Tami Pilot‐Matias
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Lennerstrand received grants from Medivir and Bristol‐Myers Squibb. Dr. Parkin consults for Gilead. Dr. Lenz is employed by and owns stock in Johnson & Johnson. Dr. Pilot‐Matias is employed by and owns stock in AbbVie. Dr. Kieffer is employed by and owns stock in Vertex. Dr. Mo is employed by and owns stock in Gilead. Dr. McPhee is employed by and owns stock in Bristol‐Myers Squibb. Reply: We agree with Halfon et al. that more data on rare hepatitis C virus genotype (GT) subtypes are needed. Our analysis1 was restricted to phase 2 and phase 3 trials with patients infected primarily with GT1a, GT1b, or GT2; the majority of existing cell culture phenotype data are for GT1a‐based or GT1b‐based replicons. The strategy of assessing natural resistance‐associated polymorphism prevalence in specific subtypes by searching public databases is good for hypothesis generation, but such sequence collections may not be sufficiently representative to support conclusions regarding the prevalence of polymorphisms in wild‐type GT4 subtypes, especially given the small sample size (47 sequences in the context of more than 15 GT4 subtypes). To properly define a "wild‐type" population requires a systematic and comprehensive approach. We were surprised to see 16 sequences assigned to GT4r. This result contradicts previous work in which only very few available GT4 sequences from public databases segregated to GT4r.2 The reference to "patients with treatment failure to sofosbuvir and daclatasvir" is inaccurate: the GT4 patients with treatment failure referred to in Zhou et al.2 were treated with daclatasvir, pegylated interferon, and ribavirin. To our knowledge, no GT4 treatment failures on daclatasvir and sofosbuvir have been reported to date. Information on how the data, some arguably not accurate, in figure 1 were derived is lacking. In GT3a replicons, the Y93H substitution confers >100‐fold reduced susceptibility to several NS5A inhibitors, while a lower value is reported in the figure.3 The fold‐resistance range for GT4 variants with the L30S and L30R substitutions is not consistent with published data, a discrepancy that may be related to use of a different reference replicon backbone.2 We strongly caution against generalizing across all NS5A inhibitors and concluding that a particular subtype‐specific amino acid sequence at a known resistance‐associated position impacts drug activity without further phenotypic analysis or, ideally, clinical outcome data. While there are examples of genotype‐specific or subtype‐specific amino acid differences that explain differences in direct‐acting antiviral activity, such natural amino acid differences by themselves are not consistently associated with differences in activity (e.g., NS5A amino acid position 30). Even when a polymorphism confers reduced direct‐acting antiviral activity, the clinical impact of this effect depends on other factors including patient disease characteristics, drug exposure, and treatment regimen and duration. Thus, referring to the fold‐resistance values reported in the figure as being associated with treatment is misleading. The observation that two of three subjects with GT4r failed treatment with sofosbuvir and ledipasvir is notable and warrants further characterization of these isolates, which is ongoing (H.M., personal communication). More efficacy data for this and other uncommon hepatitis C viral subtypes are needed to fully understand the impact of natural amino acid variability at resistance‐associated positions; this is particularly challenging for genotypes with many diverse subtypes, such as GT4 and GT6. The issue of monitoring treatment response according to genotype/subtype and baseline polymorphism is important and requires further study, including collaboration beyond trials sponsored as part of drug development programs.