Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of patients with chronic HCV infection: A meta-analysis.

BACKGROUND & AIMS: Glecaprevir/pibrentasvir is approved for treating adults infected with HCV genotypes 1-6. In clinical trials, glecaprevir/pibrentasvir was associated with high rates of sustained virologic response at post-treatment week 12 (SVR12) and was well tolerated. A systematic review and meta-analysis of the real-world effectiveness and safety of glecaprevir/pibrentasvir were undertaken. METHODS: Real-world studies reporting SVR12 in adults with HCV infection (n ≥20) treated with glecaprevir/pibrentasvir were identified in journal publications from January 1, 2017, to February 25, 2019, and congress presentations through April 14, 2019. Random-effects meta-analysis was used to determine SVR12 rates using data from ≥2 cohorts; intention-to-treat (ITT) analyses included patients treated with glecaprevir/pibrentasvir who had SVR12 data available, discontinued early, or were lost to follow-up; modified ITT (mITT) analyses excluded those with non-virologic failure. Naïve pooling was used to calculate adverse event (AE) rates. RESULTS: Overall, 12,531 adults were treated with glecaprevir/pibrentasvir (18 cohorts). Of patients with post-treatment week 12 data, SVR12 rates were 96.7% (95% CI 95.4-98.1) in the ITT population (n = 8,583, 15 cohorts) and 98.1% (95% CI 97.1-99.2) in the mITT population (n = 7,001, 14 cohorts). SVR12 rates were ≥95% across subgroups (HCV genotype, cirrhosis status, treatment history, treatment duration, on-label treatment, and subgroups of interest). AEs were reported in 17.7% (1,271/7,199) of patients (8 cohorts). Serious AEs were reported in 1.0% (55/5,522) of patients (6 cohorts). The most frequent AEs were pruritus, fatigue, and headache. AE-related treatment discontinuations were reported in 0.6% (33/5,595) of patients (6 cohorts). CONCLUSIONS: Consistent with clinical trials, real-world evidence indicates that glecaprevir/pibrentasvir is a well-tolerated and highly effective pangenotypic treatment for a broad range of HCV-infected patients. LAY SUMMARY: It is important to assess treatments for hepatitis C virus (HCV) in the real world, as patient populations tend to be more diverse and potentially less adherent to treatment compared to those in clinical trials. Results from 18 studies performed in real-world clinics were pooled and analyzed to investigate the effectiveness and safety of a direct-acting antiviral combination (glecaprevir/pibrentasvir) in routine clinical practice. This analysis showed that glecaprevir/pibrentasvir is highly effective and well tolerated across all HCV genotypes and patient groups studied. It also showed that results seen in the real world are similar to the results seen in clinical trials, even in patients historically considered more challenging to treat.

Global real-world evidence of sofosbuvir/velpatasvir as simple, effective HCV treatment: Analysis of 5552 patients from 12 cohorts.

BACKGROUND AND AIMS: Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real-world analysis to date, the effectiveness of pangenotypic, panfibrotic, single-tablet, sofosbuvir/velpatasvir (SOF/VEL) once-daily for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. METHODS: Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post-treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. RESULTS: Overall, 5552 patients were included: 13.3% treatment-experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non-virological reasons (67% lost to follow-up; 26.5% early treatment discontinuation). CONCLUSIONS: In this large cohort, representative of clinical practice, a simple 12-week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.

Prevalence of drug-drug interactions with pangenotypic direct-acting antivirals for hepatitis C and real-world care management in the United States: a retrospective observational study.

BACKGROUND: Direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) have varying potentials for drug-drug interactions (DDIs). OBJECTIVES: To (1) identify prevalence of potential DDI with glecaprevir-pibrentasvir (GLE-PIB) and sofosbuvir-velpatasvir (SOF-VEL) and (2) describe health care provider actions in response to pharmacist recommendations based on potential interactions with GLE-PIB or SOF-VEL, using 2 complementary data sources. METHODS: Possible interacting drugs were identified among adult patients in a United States electronic medical record database covering 21 health care organizations and 26 million patients in 2018. DDIs were categorized as potential weak interaction (Level 1), potential interaction (Level 2), or contraindicated (Level 3). Real-world recommendations and resultant actions regarding DDIs with GLE-PIB and SOF-VEL were obtained from a specialty pharmacy database. Categorical variable comparisons were done via chi-square analysis with subsequent z-tests of column proportions. RESULTS: DDI prevalence was higher for patients prescribed GLE-PIB (317/769 [41%]) compared with those prescribed SOF-VEL (170/633 [27%]), and the prevalence of a Level 3 (contraindicated) interaction was higher with GLE-PIB than SOF-VEL (61/769 [8%] vs 2/633 [< 1%]). Across all DDI levels, analgesics (139/317 [44%]), proton-pump inhibitors (129/317 [41%]), and lipid-lowering agents (59/317 [19%]) were the top drug classes for the GLE-PIB group with potential for DDI. For SOF-VEL prescribed patients, the top drug classes were proton-pump inhibitors (83/170 [49%]), histamine-2 blockers (42/170[25%]), and lipid-lowering agents (42/170 [25%]). In real-world care management, the overall prevalence of pharmacist recommendations regarding DDIs was significantly lower for SOF-VEL (28/419 [7%]) relative to GLE-PIB (151/1,216 [12%]). Recommended guidance from pharmacists was not followed for 39% (69/179) of patients, 36% (54/151) for GLE-PIB, and 54% (15/28) for SOF-VEL. CONCLUSIONS: The potential for DDIs with pangenotypic HCV DAAs is frequent and may be more frequent with GLE-PIB than SOF-VEL. Physician responses to pharmacist alerts regarding potential interaction can be highly variable, even in cases of contraindication. DISCLOSURES: Funding for this study was provided by Gilead Sciences, Inc. Trio Health Analytics received funding from Gilead Sciences, Inc., to conduct research for this study. Tsai consults for and has received grants and honoraria from Gilead, AbbVie, Merck, and Bristol Myers Squibb; he has also received lecture fees from Gilead and AbbVie. Curry consults for Trio Health Analytics and Gilead and has also consulted for and received grants from Mallinckrodt. Flamm consults for and has received lecture fees from Gilead and AbbVie; he has also received grants from Gilead and AbbVie. Milligan and Wick are employed by Trio Health Analytics and have received research support from Gilead, Merck, and AbbVie. Younossi has received grants from Gilead, Intercept, Bristol Myers Squibb, GlaxoSmithKline, and Novo Nordisk. Afdhal is a paid consultant/advisory board member for Gilead, Echosens, Ligand, Shionogi, and Trio Health; owns stock in Spring-Bank and Allurion and has stock options in SpringBank; receives royalty income from UpToDate; and is on the board of directors for the nonprofit Liver Institute for Education and Research. Data from this study were presented at the American Association for the Study of Liver Disease (AASLD) Liver Meeting 2019; November 8-12, 2019; Boston, MA, and the European Association for Study of the Liver (EASL) International Liver Congress 2020; August 27-29, 2020; virtual.

Effectiveness of 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve, Compensated Cirrhotic Patients with Chronic Hepatitis C Infection.

INTRODUCTION: Glecaprevir/pibrentasvir (G/P) was approved on 26 September 2019 by the US Food and Drug Administration for 8-week duration in treatment-naïve (TN) hepatitis C virus (HCV)-infected patients with compensated cirrhosis (CC). Evidence from the EXPEDITION-8 study demonstrated that 8 weeks of G/P achieved a 98% intent-to-treat (ITT) sustained virologic response rate 12 weeks post treatment (SVR12) in 343 TN/CC patients. The aim of this study is to demonstrate the first US real-world effectiveness of G/P 8-week treatment in genotype 1-6 TN/CC HCV patients. METHODS: Data from 73 TN/CC patients who initiated 8 weeks of G/P treatment between August 2017 and November 2018 were collected electronically from providers and specialty pharmacies of the Trio Health network and analyzed. Cirrhosis was determined by FIB-4 > 5.2 or was physician reported. The primary outcome was Per Protocol (PP) SVR12. RESULTS: The majority (60%) of patients were male, with (mean values): age 59 years, body mass index (BMI) of 30, aspartate aminotransferase (AST) 105, and alanine aminotransferase (ALT) 101 IU/ml. HCV genotypes (GT) were: GT1 81% (59/73), GT2 10% (7/73), GT3 5% (4/73), GT4 3% (2/73), and GT6 1% (1/73). Eight percent (6/73) of patients had concurrent proton pump inhibitor (PPI) use, and 15% (11/72) had a baseline viral load > 6 MM IU/ml. Zero patients discontinued, two patients were reported as lost to follow-up, and there was one virologic failure. PP sustained virologic response at 12 weeks (SVR12) rate was 99% (70/71), and the intent-to-treat (ITT) SVR12 rate was 96% (70/73). CONCLUSIONS: Early real-world experience indicates high effectiveness of the 8-week G/P regimen in a diverse treatment-naïve, compensated cirrhotic US population.

Changing demographics among populations prescribed HCV treatment, 2013-2017.

OBJECTIVES: We analyzed the demographics and disease characteristics of patients prescribed treatment for chronic hepatitis C virus (HCV) infection from 2013 through 2017, a time frame that encompasses the expansion of available direct-acting antiviral inhibitors. STUDY DESIGN: Retrospective analysis. METHODS: Using a proprietary disease-management program, data for 19,944 patients receiving HCV treatment were collected from providers and specialty pharmacies. Six-month time periods accounting for introductions of novel treatments were established as follows: December 2013 to May 2014 (n = 1438), simeprevir and sofosbuvir; October 2014 to March 2015 (n = 2242), ledipasvir/sofosbuvir and ombitasvir/paritaprevir/ritonavir plus dasabuvir; October 2015 to March 2016 (n = 5514), daclatasvir; July 2016 to December 2016 (n = 5562), elbasvir/grazoprevir and sofosbuvir/velpatasvir; and July 2017 to December 2017 (n = 5188), sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Changes over time were evaluated for statistical significance. RESULTS: In the 2013-2014 time period, 44% of patients receiving prescriptions for HCV treatment were treatment-experienced and 45% had cirrhosis. By 2017, only 14% were treatment-experienced (P <.001) and 21% had cirrhosis (P <.001). The percentage of patients with HCV genotype 1 increased from 69% to 87% from 2013-2014 to 2014-2015 (P <.001) but subsequently decreased to 74% in 2017 (P <.001). The percentage of patients receiving HCV prescriptions in an academic setting declined from 61% in 2013-2014 to 13% in 2017 (P <.001). CONCLUSIONS: In the United States, since the introduction of interferon-free HCV regimens, the patient population prescribed treatment has changed, becoming predominantly treatment-naïve, without cirrhosis, and treated in nonacademic centers.

Mutational analysis of the stator subunit E of the yeast V-ATPase.

Subunit E is a component of the peripheral stalk(s) that couples membrane and peripheral subunits of the V-ATPase complex. In order to elucidate the function of subunit E, site-directed mutations were performed at the amino terminus and carboxyl terminus. Except for S78A and D233A/T202A, which exhibited V(1)V(o) assembly defects, the function of subunit E was resistant to mutations. Most mutations complemented the growth phenotype of vma4Delta mutants, including T6A and D233A, which only had 25% of the wild-type ATPase activity. Residues Ser-78 and Thr-202 were essential for V(1)V(o) assembly and function. The mutation S78A destabilized subunit E and prevented assembly of V(1) subunits at the membranes. Mutant T202A membranes exhibited 2-fold increased V(max) and about 2-fold less of V(1)V(o) assembly; the mutation increased the specific activity of V(1)V(o) by enhancing the k(cat) of the enzyme 4-fold. Reduced levels of V(1)V(o) and V(o) complexes at T202A membranes suggest that the balance between V(1)V(o) and V(o) was not perturbed; instead, cells adjusted the amount of assembled V-ATPase complexes in order to compensate for the enhanced activity. These results indicated communication between subunit E and the catalytic sites at the A(3)B(3) hexamer and suggest potential regulatory roles for the carboxyl end of subunit E. At the carboxyl end, alanine substitution of Asp-233 significantly reduced ATP hydrolysis, although the truncation 229-233Delta and the point mutation K230A did not affect assembly and activity. The implication of these results for the topology and functions of subunit E within the V-ATPase complex are discussed.