Faculty Bibliography

The US Food and Drug Administration has now approved 10 direct-acting antivirals (DAAs) for the management of hepatitis C virus (HCV). These therapies are combined into 6 regimens that are given for varying durations, with or without ribavirin, depending on the viral genotype, the presence or absence of baseline resistance-associated variants (RAVs), and the patient type. RAVs may be present before exposure to a drug or may become detectable de novo during exposure to a drug. Emerging resistant strains are the most common cause of failure of HCV DAA regimens. Second-generation DAAs provide superior coverage of resistant variants compared with first-generation members of that class. They may also cover a broader range of viral genotypes. Numerous clinical trials have evaluated the safety and efficacy of DAAs in a variety of patient populations, including those with cirrhosis, HIV, and end-stage renal disease. This article evaluates the data from these studies, and discusses recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidance document.

GS-9190 is a NS5B non-nucleoside analogue with demonstrated effectiveness in a Phase 1 monotherapy study and in combination with other DAAs for treatment of chronic HCV infection. Here, the resistance profile of GS-9190 monotherapy in a Phase 1b study was investigated. Resistance analysis was performed by population sequencing and allele-specific PCR (AS-PCR) for Y448H with an assay cut-off of 0.5%. Phenotypic susceptibility analyses were performed on patient isolates as well as site-directed mutagenesis of mutations selected during monotherapy. No resistance-associated variants were observed in patients before or after receiving single doses of GS-9190 by population sequencing. In contrast, in patients who received GS-9190 for 8 days, mutations Y448H and Y452H in NS5B were observed by population sequencing in 21/36 (58%) and 2/36 (5.6%) patients, respectively, at Day 8 or Day 14. Among the remaining 15 patients who had no detectable Y448H at Day 8 or Day 14 by population sequencing, low frequencies of Y448H ranging from 1.3 to 9.7% were detected in 14 of 15 patients by AS-PCR. By AS-PCR, Y448H remained detectable at reduced frequency in the majority of patients analysed through 4-6 months of follow-up. Chimeric HCV replicons constructed with the NS5B sequence from patients with Y448H and Y448H + Y452H/Y demonstrated 27-fold and 78.5-fold reduced susceptibility to GS-9190. In conclusion, Y448H was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Y448H confers reduced susceptibility to GS-9190 and other NNIs and persisted in most patients for months post-treatment.

BACKGROUND & AIMS: The new pan-genotypic regimen [sofosbuvir (SOF) and velpatasvir (VEL)] for hepatitis C virus (HCV) has been associated with high efficacy. The aim of this study was to assess patient-reported outcomes (PROs) of this regimen. METHODS: The PRO data (CLDQ-HCV, SF-36, FACIT-F, WPAI) came from the ASTRAL-1 study, a multicenter multinational blinded placebo-controlled phase 3 clinical trial of a fixed dose combination of SOF 400mg and VEL 100mg for patients with genotype 1, 2, 4, 5, and 6 compared to placebo for 12weeks. RESULTS: 624 patients received active treatment [618 achieved sustained virologic response (SVR)], and 116 received placebo. The baseline PRO scores were similar. By treatment week 4, patients receiving SOF/VEL experienced improvements in general health (on average, +2.3points), emotional well-being (+3.4), FACIT-F (+1.3), and all domains of CLDQ-HCV (+2.1 to +7.3) (all p<0.005). On the other hand, the only PRO that improved in patients receiving placebo was the worry domain of CLDQ-HCV: +4.6 (p=0.002). By the end of treatment, improvement in PRO scores with SOF/VEL continued, and no improvement was noted in the placebo. Improvement in PROs were also noted 12 and 24weeks post-treatment: +3.7, on average, in patients with SVR-12 after SOF/VEL vs. -2.6, on average, in the placebo arm (p<0.005). Multivariate analysis showed that treatment-emergent changes in PROs were predicted by receiving SOF/VEL for some summary PRO score (p<0.005). CONCLUSIONS: This placebo-controlled trial shows that patients treated with SOF/VEL experience significant improvement of their PROs during treatment and after achieving SVR. LAY SUMMARY: In patients with chronic hepatitis C infection, health-related quality of life and work productivity are often impaired due to HCV-related fatigue. Treatment of hepatitis C with interferon-based regimens, which was the standard of care for all HCV patients until recently, had substantial and potentially debilitating side effects. These regimens caused additional impairment in health-related quality of life and work productivity during treatment and shortly after treatment cessation. The newly developed interferon-free combination of sofosbuvir and velpatasvir has been shown to improve health-related quality of life during treatment, and lead to an improvement in a number of indicators of patient-reported outcomes after successful clearance of HCV and achieving sustained virologic response.

BACKGROUND & AIMS: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS: In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS: The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.

BACKGROUND: Sofosbuvir (SOF) exhibits a high barrier to resistance, with no S282T NS5B substitution or phenotypic resistance detected in phase 3 registration studies. METHODS: Here, emergence of the NS5B variants L159F and V321A and possible association with resistance was evaluated in 8 studies of SOF (NEUTRINO, FISSION, POSITRON, FUSION, VALENCE, PHOTON-1, PHOTON-2, and P7977-2025) and 5 studies of combination ledipasvir (LDV) and SOF (LDV/SOF; LONESTAR, ELECTRON [LDV/SOF arms], ION1, ION2, and ION3), using deep sequencing. RESULTS: Deep sequencing detected L159F in 15% (53 of 353) and V321A in 5% (17 of 353) of patients with virologic failure in the SOF studies. Intensification of SOF treatment with LDV reduced the emergence of L159F or V321A to 2% (1 of 50 each) at virologic failure. L159F and V321A did not influence the outcome of retreatment with SOF, ribavirin, and pegylated interferon. At baseline, L159F was detected only in genotype 1-infected patients (1%) and was only associated with increased virologic failure in patients treated for short durations with SOF and ribavirin. CONCLUSIONS: Deep-sequencing analysis confirmed that NS5B variants L159F and V321A emerged in a subset of patients treated with SOF at virologic failure. These variants had no impact on retreatment outcome with SOF, ribavirin, and pegylated interferon. Baseline L159F in genotype 1 did not affect the treatment outcome with LDV/SOF.