Faculty Bibliography

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: 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.

BACKGROUND & AIMS: HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS: Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS: The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION: Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients. METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA >/= 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

BACKGROUND & AIMS: The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. METHODS: We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET--a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment--a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. RESULTS: The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%-87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. CONCLUSIONS: In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

BACKGROUND: A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need. METHODS: We conducted a phase 3, double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group. CONCLUSIONS: Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.).