Elsevier

Journal of Hepatology

Volume 62, Issue 2, February 2015, Pages 286-293
Journal of Hepatology

Research Article
Safety profile of boceprevir and telaprevir in chronic hepatitis C: Real world experience from HCV-TARGET

https://doi.org/10.1016/j.jhep.2014.08.052Get rights and content

Background & Aims

The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated.

Methods

In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up.

Results

A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response.

Conclusions

In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.

Introduction

Following a decade of only modest advances in the treatment of chronic hepatitis C virus (HCV), telaprevir and boceprevir, both HCV protease inhibitors, were approved by the FDA in 2011 as the first direct-acting antiviral agents (DAAs) to be used in combination with pegylated interferon-alfa (PegIFNα) and ribavirin for genotype 1 HCV infection. For treatment-naïve patients, the protease inhibitors improved the likelihood of a sustained virologic response relative to PegIFNα and ribavirin alone from 40–50% to 67–75% [1], [2], [3], [4]. The triple therapy regimens involved frequent on-treatment monitoring for response, and the addition of the third agent created a new set of adverse events, such as rash and incremental anaemia, requiring additional resources for management [5].

The patient population in the real world may differ from that which was reflected in the phase 3 registration trials. Whereas the current patient population seen in clinic settings may include a large proportion of older patients with cirrhosis, relatively few patients with cirrhosis (all compensated) were included in the registration trials of both boceprevir and telaprevir [2], [3]. Recently, a large European cohort enrolled a broad clinical patient population including those with compromised liver function and reported that the addition of a protease inhibitor to PegIFNα and ribavirin increased the likelihood of adverse events, many of which were serious and led to premature discontinuation of therapy [6]. Other studies reported that the presence of cirrhosis further increased the potential for anaemia [3], [4], [5], [7] and hepatic decompensation [2], [3], [4], [6]. A recent study of patients at tertiary European referral centres reported a higher proportion of patients who stopped HCV triple therapy than in registration trials [8]. The difference in discontinuation rates was attributed to the more frequent occurrences of both virological treatment failure and adverse events. In order to provide a more accurate safety profile of the clinical HCV population, we designed and executed a cohort study of the safety of triple therapy with boceprevir or telaprevir in predominantly genotype 1-infected patients, treated at a consortium of academic and community medical centres.

Section snippets

Study population and design

HCV-TARGET is a longitudinal, observational study in chronic hepatitis C patients from a consortium of academic (n = 38) and community (n = 52) medical centres. Patients ⩾18 years old were included if they were being treated or had been treated with antiviral regimens containing PegIFNα and ribavirin, in combination with telaprevir or boceprevir. Treatment was chosen and administered per local standards at the study site. The study protocol did not define specific treatment populations, regimens,

Patient characteristics

Between May 2011 and June 2013, 2757 patients consented to participate in HCV-TARGET and 2122 started therapy prior to September 1, 2012. Of these, 2084 received at least one dose of telaprevir or boceprevir and were included in the current safety analysis (Fig. 1). Baseline characteristics for all treated patients are shown in Table 1. Seventy nine percent of patients were white and 16% were black. Median age was 56 years and 61% of patients were male. HCV genotype 1a was reported in 56% and

Discussion

This report describes the safety profiles of boceprevir and telaprevir in the largest and most diverse population treated for hepatitis C with these agents in the United States. We analysed the experiences of more than 2000 patients who were among the first U.S. patients to receive triple therapy at more than 100 medical centres. Our results demonstrate that patients treated in clinical practice with these agents were older and had more advanced disease than the registration trial participants,

Financial support

HCV-TARGET is an investigator-initiated study, jointly sponsored by The University of Florida, Gainesville, FL (PI: D.R. Nelson), and The University of North Carolina at Chapel Hill, Chapel Hill, NC (PI: M.W. Fried). It was funded in part by Vertex Pharmaceuticals, Inc., Merck & Co., Kadmon Corporation, and Genentech and in part by CTSA UF UL1TR000064 and UNC1UL1TR001111. M.W. Fried is funded in part by the NIH Mid-Career Mentoring Award K24 DK066144.

Conflict of interest

S.C. Gordon has received grant/research support from Abbott Pharmaceuticals, Bristol-Myers Squibb, Exalenz BioScience, Gilead Pharmaceuticals, Intercept Pharmaceuticals, Merck, and Vertex Pharmaceuticals; has received financial compensation for consultancy from AbbVie, Amgen, CVS Caremark, Gilead Pharmaceuticals, and Merck and received royalties from Up-To-Date. A.J. Muir has received grant/research support from AbbVie, Achillion, Bristol Myers-Squibb, Gilead, Vertex and Merck and has received

Acknowledgments

We thank the staff of the data coordinating center at UNC Chapel Hill: Lucy Akushevich, Kenneth Bergquist, John Baron, Paul Stewart, Dianne Mattingly, and Wendy Robertson; the staff of clinical coordinating center at UF Gainesville: Lauren Morelli, Anthe Hoffman, Dona-Marie Mintz, Lasheaka McClellan, Angela Bauer, Patrick Horne, Rennie Mills; the nurses and patients who were involved in this study; and Valérie Philippon, Ph.D. for her assistance in the preparation of the manuscript, with

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