Safety and Tolerability of Elbasvir/Grazoprevir in Chronic Hepatitis C Virus Therapy

Integrated Analysis From Clinical Trials

Gayatri Nangia; John M. Vierling; Paul Kwo; Deborah D. Brown; Stephanie O. Klopfer; Michael N. Robertson; Barbara A. Haber; K. Rajender Reddy

Disclosures

J Viral Hepat. 2020;27(11):1222-1233. 

In This Article

Abstract and Introduction

Abstract

Direct-acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16–18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug-related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.

Introduction

Chronic hepatitis C virus (HCV) infection afflicts nearly 71 million people worldwide, and left unchecked, and can cause cirrhosis, hepatocellular carcinoma (HCC) and liver-related death.[1] Since 2011, the standard of care treatment for HCV infection has shifted from pegylated interferon (PEG-IFN)-based therapy to direct-acting antiviral (DAA)-based treatments. This change has led to significant improvements in the efficacy and tolerability of HCV therapies. However, even as DAAs have been shown to be generally safe, clinical experience also suggests that each regimen has a unique tolerability profile. For example, regimens containing simeprevir, a nonstructural protein 3/4A (NS3/4A) protease inhibitor, are associated with hyperbilirubinemia and photosensitivity reactions, and are contraindicated in individuals with Child-Pugh Class B and C cirrhosis because of increased simeprevir drug exposure in persons with hepatic impairment caused by advanced liver disease.[2] Treatment with another NS3/4A protease inhibitor, paritaprevir, is associated with elevated levels of bilirubin and alanine aminotransferase (ALT), and regimens containing asunaprevir, also a NS3/4A protease inhibitor, have been associated with mild increases in aminotransferase levels and occasional elevations in plasma bilirubin levels.[3] Sofosbuvir, a nonstructural protein 5B (NS5B) inhibitor, is contraindicated in individuals with severe renal disease.[2] The United States Food and Drug Administration has recently issued a warning about the rare occurrence of worsening liver function or liver failure in individuals with HCV infection and advanced liver disease (Child-Pugh B or C) who were receiving treatment with a regimen containing an HCV NS3/4A protease inhibitor.[4] These medicines are not indicated for use in people with moderate to severe liver impairment.

Gathering data on the safety profile of each DAA combination is essential for their continued use as the standard of care treatment for HCV infection. To that end, we have evaluated the safety and tolerability of the two-drug oral combination of elbasvir and grazoprevir (EBR/GZR). EBR/GZR is a combination of an NS5A inhibitor and an NS3/4A protease inhibitor, which has shown to be an effective treatment for people with HCV genotype (GT) 1 and GT4 infection, including those with compensated cirrhosis.[5–18] A previous integrated analysis of safety data from 1795 clinical trial participants concluded that EBR/GZR treatment regimens of 8 to 18 weeks' duration (and with concomitant ribavirin in 657 participants) were associated with a generally favourable safety profile with few serious adverse events (AEs) or discontinuations due to an AE.[19] Alanine aminotransferase elevation >5.0× the upper limit of normal (ULN) occurred in 0.8% of participants, and on-treatment decline in haemoglobin levels was restricted to participants receiving concomitant ribavirin (RBV).[19] Tolerability was similar for participants without cirrhosis and those with compensated cirrhosis. Using a large database, we have extended the observations from this preliminary report and analysed the safety profile of EBR/GZR in all clinical trial participants, including specific populations with chronic kidney disease (CKD) stage 4/5, those receiving opioid agonist therapy and those with inherited blood disorders. Safety and tolerability were assessed according to treatment duration, medical comorbidity, concomitant use of RBV, and the presence or absence of cirrhosis.

processing....