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Authors: Behnam Saberi, Alia S. Dadabhai, Christine M. Durand, Benjamin Philosophe, Andrew M. Cameron, Mark S. Sulkowski, Ahmet Gurakar
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Durand advises for and received grants from Merck and Gilead. She received grants from ViiV HealthCare and GlaxoSmithKline. [Correction added February 9, 2018, after first online publication: The preceding sentence "Dr. Durand advises for and received grants from Merck. She advises for Gilead. She received grants from ViiV." was corrected to "Dr. Durand advises for and received grants from Merck and Gilead. She received grants from ViiV HealthCare and GlaxoSmithKline."] Dr. Gurakar advises for Gilead and Bristol‐Myers Squibb. Dr. Sulkowski advises for and received grants from Gilead, AbbVie, Merck, and Janssen. We thank Ji et al. for their response to our recent article.1 Our study retrospectively evaluated 21 hepatocellular carcinoma (HCC) patients who were treated with different direct‐acting antivirals (DAAs) for hepatitis C virus (HCV) before liver transplant.1 We demonstrated a lower than expected sustained virological response (SVR) rate of 67%.1 However, it is important to highlight that the majority of the 7 relapsers had one or more of the risk factors for treatment failure: treatment experienced, genotype 3, decompensated cirrhosis, and a sofosbuvir/ribavirin regimen (Saberi et al., Table 1A).1 These factors have been associated with lower SVR rates in the previous trials.2 Although there are limitations to our small series, we observed that 2 of our patients with genotype 1 had relapse following treatment with ledipasvir/sofosbuvir, without any identifiable risk factors for relapse. The lower SVR rates in patients with HCV/HCC has been reported by other groups as well.3 In the recent HCV‐Target study, SVR at week 12 in patients with or without HCC were 76% and 87%, respectively. When adjusted for decompensation, HCC was associated with lower odds of SVR compared to no HCC.3 We agree with Ji el al. that well‐designed, double‐blinded, clinical trials are needed to investigate the efficacy of different DAA regimens and optimal duration of therapy in patients with HCV/HCC. When designing the trials, particular attention should be given to HCV genotype, before HCV treatment status, severity of cirrhosis, type of DAA, duration of therapy, and clinically relevant resistant associated variants (RAVs). The number, size, and biology of HCC lesions, as well as information regarding the treatment of the tumors, should be assessed. Although portal venous blood has high concentrations of DAAs, the arterial blood may have lower concentrations. This may be particularly important for the nonstructural 5B inhibitor, sofosbuvir, given that it is a prodrug that undergoes intracellular phosphorylation by human enzymes to active 5′ triphosphate nucleotide.4 Following first‐pass metabolism in the liver, the systemic exposure is largely (>90%) the inactive metabolite, GS‐331007. We hypothesize that one potential explanation of lower SVR rates observed in persons with HCC is that the primary blood supply by the hepatic artery is rich in GS‐331007 rather than the sofosbuvir prodrug. Another potential explanation is inefficient conversion of sofosbuvir to its active metabolite in tumor cells. Future basic science and translational studies are needed to evaluate the possible underlying causes for the observed clinical outcomes in patients with HCC.