Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients With Chronic HCV Infection and Psychiatric Disorders

An Integrated Analysis

David Back; Pamela Belperio; Mark Bondin; Francesco Negro; Andrew H. Talal; Caroline Park; ZhenZhen Zhang; Brett Pinsky; Eric Crown; Federico J. Mensa; Fiona Marra

Disclosures

J Viral Hepat. 2019;26(8):951-960. 

In This Article

Abstract and Introduction

Abstract

Although direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection are highly efficacious and safe, treatment initiation is often limited in patients with neuropsychiatric disorders due to concerns over reduced treatment adherence and drug–drug interactions. Here, we report adherence, efficacy, safety and patient-reported outcomes (PROs) from an integrated analysis of registrational studies using the pangenotypic DAA regimen of glecaprevir and pibrentasvir (G/P). Patients with chronic HCV genotypes 1–6 infection with compensated liver disease (with or without cirrhosis) receiving G/P for 8, 12 or 16 weeks were included in this analysis. Patients were classified as having a psychiatric disorder based on medical history and/or co-medications. Primary analyses assessed treatment adherence, efficacy (sustained virologic response at post-treatment week 12; SVR12), safety and PROs. Among 2522 patients receiving G/P, 789 (31%) had a psychiatric disorder with the most common diagnoses being depression (64%; 506/789) and anxiety disorders (27%; 216/789). Treatment adherence was comparably high (>95%) in patients with and without psychiatric disorders. SVR12 rates were 97.3% (768/789; 95% CI = 96.2-98.5) and 97.5% (1689/1733; 95% CI = 96.7-98.2) in patients with and without psychiatric disorders, respectively. Among patients with psychiatric disorders, SVR12 rates remained >96% by individual psychiatric diagnoses and co-medication classes. Overall, most adverse events (AEs) were mild-to-moderate in severity with serious AEs and AEs leading to G/P discontinuation occurring at similarly low rates in both patient populations. In conclusion, G/P treatment was highly efficacious, well-tolerated and demonstrated high adherence rates in patients with chronic HCV infection and psychiatric disorders.

Introduction

Chronic hepatitis C virus infection is associated with neuropsychiatric disorders in up to 50% of cases.[1,2] Historically, patients with comorbid psychiatric disorders were less likely to receive HCV treatment since interferon (IFN)-based regimens can induce depression and other neuropsychiatric manifestations including insomnia, irritability and mood changes.[3] Treatment adherence among this patient population was also a concern due to IFN's psychiatric side effect profile and perceived risks of lower adherence in patients with psychiatric and/or substance use disorders.[3] Yet, fatigue and psychological issues contribute significantly to quality-of-life (QoL) impairments in patients with chronic HCV infection, both of which can be improved by the achievement of sustained virologic response (SVR).[4,5]

The introduction of direct-acting antivirals (DAAs) provided IFN-free treatment regimens that likely are more suitable for patients with chronic HCV infection and comorbid psychiatric disorders. Both clinical trials and real-world evidence have demonstrated that these all-oral, IFN-free regimens are highly efficacious and well tolerated with minimal treatment-emergent neuropsychiatric side effects in patients with chronic HCV infection.[6–8] Based on these data, recent HCV treatment guidelines recommend DAA regimens without any restrictions based on psychiatric comorbidities.[9,10] However, there has been more limited use of DAAs in patients with psychiatric disorders in both late phase trials and clinical practice potentially due to concerns about treatment adherence and drug–drug interactions (DDIs) with neuropsychiatric co-medications.[3,11–14] Thus, there is an unmet need to better understand the impact of psychiatric disorders on the treatment adherence, efficacy and safety of DAA regimens.

Glecaprevir (GLE; NS3/4A protease inhibitor identified by AbbVie and Enanta) and pibrentasvir (PIB; NS5A inhibitor) are potent pangenotypic inhibitors co-formulated as G/P, an all-oral, once-daily and pangenotypic DAA regimen that demonstrated high efficacy, and favourable safety and DDI profiles in patients with chronic HCV infection. In vitro, glecaprevir and pibrentasvir exhibited nanomolar and picomolar potencies, respectively, against all major HCV genotypes and both retained their activity against most resistance-associated substitutions.[15,16] Phase 1 trials investigated and thoroughly characterized the DDI profile of G/P, finding limited interactions and demonstrating that the majority of concomitant medications, including neuropsychiatric medications, can be safely taken with G/P without dose modification.[17,18] In late phase clinical trials, G/P was highly efficacious and safe in patients with chronic HCV genotypes 1–6 infection including in patients with compensated cirrhosis, end-stage renal disease and co-infection with human immunodeficiency virus (HIV).[19–26] Preliminary reports from real-world cohorts have supported these clinical trial findings with G/P showing similarly high effectiveness and a favourable safety profile in clinical practice.[27,28]

Here, we present an integrated analysis of ten Phase 2 and Phase 3 studies aimed at evaluating the impact of psychiatric disorders on the treatment adherence, efficacy, safety and patient-reported outcomes (PROs) with G/P treatment.

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