Faculty Bibliography

BACKGROUND:The causative relationship between clearance of infection and long-term health-related quality of life (HRQL) improvements in patients with hepatitis C virus (HCV) has been generally accepted. The aim is to assess long-term HRQL trends in HCV patients who did not achieve sustained virologic response (SVR) after treatment with direct-acting antivirals. METHODS:HCV patients who completed treatment in clinical trials and did not achieve SVR were enrolled in a long-term registry (#NCT01457768). HRQL scores were prospectively collected using Short Form-36 instrument (SF-36; 8 HRQL domains and 2 summary scores). RESULTS:242 patients were included: 54±8 years, 85% male, 38% cirrhosis. Before treatment, patients' HRQL scores were similar to the general population norms (all one-sided p>0.05) followed by significant decreases by the end of treatment (-3.4 to -6.2 points, p<0.05 for 5/8 HRQL domains and Mental Summary). By the time subjects entered the registry, all but one mean HRQL scores had returned to pre-treatment levels (p>0.05). During subsequent periods in the registry, patients experienced further HRQL decrements: up to -9.2 points, p<0.05 for all HRQL domains, at week 24; up to -8.3 points, p<0.05 for 5/8 HRQL domains, at week 48. Although these HRQL decrements were observed regardless of cirrhosis status, they were more pronounced in patients with cirrhosis (p<0.05 for 3/8 HRQL domains). CONCLUSIONS:Patients who did not achieve SVR after treatment experience worsening of HRQL scores in long-term follow-up. Re-treatment of these patients will be important not only to improve their clinical outcomes but also their quality of life.

BACKGROUND & AIMS/OBJECTIVE:Patients with hepatitis C virus (HCV) infections who achieve a sustained virologic response (SVR) to treatment have improved patient-reported outcomes (PROs). We compared post-treatment PRO scores between patients with chronic HCV infection who did and did not achieve an SVR to treatment. METHODS:Patients who completed treatment in clinical trials were enrolled in 2 registries, depending on the treatment outcome (#NCT01457755, #NCT01457768), from 2016-2017 in 17 countries in North America, Europe, and Asia-Pacific region. PRO scores (a 0-100 scale) were collected at pre-treatment (baseline); the last day of treatment; the post-treatment week 12 follow-up visit (in patients with SVR only); the registry baseline; and on registry weeks 12, 24, 36, 48, and 96 (the non-SVR registry) or every 24 weeks until week 96 (SVR registry), using the short form-36 (SF-36) instrument. RESULTS:Our analysis included 4234 patients with an SVR and 242 without an SVR from whom pre-treatment PRO data were available (mean age, 54±10 years; 63% male; 65% enrolled in the United States; 17% with cirrhosis; 12% with HIV coinfection). Upon registry enrollment, patients with an SVR had significant increases in all PRO scores compared with pre-treatment baseline levels (all P<.05). Patients without an SVR had mean reductions of ≤9.2 points in PRO scores while followed on the registry (P<.05 for 4-8 of 8 PRO domains measured by the SF-36). In contrast, patients with an SVR had sustained increases in PRO scores (mean increase of ≤7.0 points) while on the registry. In multivariate analysis, achieving an SVR was independently associated with superior scores in all SF-36 domains at all registry time points (beta from +4.8 to +15.9 points, all P≤.01). CONCLUSIONS:In a follow-up analysis of participants in clinical trials, we found that those with an SVR to treatment for HCV infection had significant increases in well-being, based on PRO scores. Patients without an SVR had decreasing PRO scores over the follow-up period.

The aim of this study was to evaluate changes in noninvasive tests of fibrosis (NITs) to understand the natural history of cirrhosis regression following removal of the causative exposure. In this ongoing, prospective cirrhosis registry study, 1574 subjects with HCV cirrhosis who achieved SVR via sofosbuvir (SOF)-based regimens were enrolled. Routine assessments included semi-annual Child-Pugh- Turcotte (CPT) scoring and measurement of the Enhanced Liver Fibrosis (ELF) test, as well as annual liver stiffness measurement by transient elastography (LS by TE). Logistic regression was used to identify predictors of fibrosis improvement as defined by NITs. As of May 2019, median duration of follow-up was 123 weeks (IQR 96, 168). At week 144, 49% of those with baseline CPT class B/C had improved CPT class, while 98% of those with baseline CPT class A remained in CPT class A. During follow-up, changes in ELF and LS by TE suggested fibrosis improvement in an increasing proportion of patients with both F3 and F4 fibrosis at enrollment (Figure). ELF score improved by >=0.5 units at week 144 in 27% and 47% of patients with baseline F3 (ELF 9.8-11.3) and F4 (ELF > 11.3) fibrosis, respectively. Predictors of ELF improvement included higher ELF (p<0.001) and AST (p = 0.049), and lower platelets (p = 0.02) and BMI (p = 0.10) at registry baseline. In patients with cirrhosis in whom HCV has been eradicated by SOF-based therapy, NITs suggest significant fibrosis improvement in 25-50% of patients within 3 years. Associations between reductions in these NITs and improvements in clinical outcomes require evaluation during longerterm follow-up

BACKGROUND/AIMS/OBJECTIVE:Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS:We performed a phase 3b, open label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n=78, group A) or 16 weeks (n=49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n=21, group C) or G/P for 16 weeks (n=29, group D). The primary endpoint was a sustained virologic response 12 weeks after treatment (SVR12). Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions (RASs) in NS3 and NS5A. RESULTS:Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with an SVR12 in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 patients with HCV genotype 1a infection (7.3%), 6 in group A (7.9%), 3 in group B (6.1%), 3 in group C (14.3%), and 1 in group D (3.4%). Most patients had baseline RASs in NS5A. Treatment-emergent RASs in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS:In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced an SVR12 in more than 90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov no: NCT03092375.

Background: Standard of care nucleos(t)ide analogs (Nrtl) are effective in chronic HBV (CHB) infection, but achieve low rates of sustained responses off therapy. The combination of the HBV Core Inhibitor ABI-H0731 (731) with a Nrtl has demonstrated potent antiviral activity in prior clinical studies and is being evaluated in a long-term treatment study.
Method(s): Studies ABI-H0731-201 and ABI-H0731-202 were 24-wk double-blind, placebo (Pbo)-controlled studies in CHB patients (pts). After 24 wks of treatment, pts could enter the open-label extension study ABI-H0731-211 and receive 731+Nrtl for up to an additional 52 wks. The study diagram summarizes study design, patient flow and monitored parameters. This interim report summarizes data for HBeAg+ pts only.
Result(s): Final Wk 24 results confirmed greater mean Iog10 declines in HBV DNA (5.27 vs 3.99; p=0.017) and RNA (2.34 vs 0.61; p<0.001) are achieved with 731+ETV vs ETV in Study 202. By Wk 24 in Study 201, the proportion of pts on 731+Nrtl vs Nrtl achieving DNA "TND" was 69% vs 0% (p<0.001), and the proportion of pts achieving RNA <35 U/mL whose baseline RNA > 35 U/mL was 52% vs 0% (p=0.0013) respectively. There are 64 HBeAg+ pts currently on treatment in Study 211, having received an overall treatment duration of >32 wks. Among the 27 HBeAg+ pts receiving 731+Nrtl in Study 201, 41% (11/27) have now achieved DNA TND along with RNA <35 U/mL and HBeAg <1 lU/mL At their last timepoint, Study 202 (Rx naive) pts now in Study 211 (n=22) have demonstrated mean DNA and RNA declines of 6.1 and 3.0 logs, respectively, with observed mean log changes of >0.6 for HBeAg (11 pts >0.5, 4 pts >1.0), >0.8 log for HBcrAg (7 pts >1.0, 3 pts >2.0) and >0.4 log for HBsAg (7 pts >0.5, 3 pts >1.0). When, administered in combination with Nrtl for up to 1 year, 731 has been well-tolerated, with only mild/moderate adverse events and lab abnormalities, and only a single discontinuation due to a Grade 1 rash.
Conclusion(s): ABI-H0731 continues to exhibit a favorable safety and tolerability profile in pts treated for up to 1 yr. The combination of 731+Nrtl results in faster, deeper declines in HBV DNA and RNA than Nrtl alone, as well as subsequent declines in the surrogate markers of cccDNA (pgRNA, HBeAg and HBcrAg) predictive of cccDNA pool depletion, and HBsAg. The emergent data supports the continued development of ABI-H0731. Updated safety and efficacy data will be presented