The Hepatitis C Revolution Part 1

Antiviral Treatment Options

Prarthana Thiagarajan; Stephen D. Ryder

Disclosures

Curr Opin Infect Dis. 2015;28(6):563-571. 

In This Article

Abstract and Introduction

Abstract

Purpose of review The rapid evolution in the therapeutic landscape of hepatitis C presents a minefield to clinicians seeking to optimize therapy for their patients. Efficacy, evidence-base, side-effects, and drug combinations must be tailored to individual patients, taking into account comorbidities, degree of fibrosis, evidence of hepatic decompensation, and life expectancy. The review article aims to discuss novel hepatitis C virus (HCV) treatments with an overview of recent breakthrough research validating their potential. It is hoped that this systematic evaluation will clarify best available evidence for clinicians treating patients with HCV on a regular basis.

Recent findings With greater understanding of the HCV life cycle and viral genome, the last decade has seen the emergence of novel direct-acting antiviral (DAA) agents, which specifically target proteins responsible for viral replication. Landmark clinical trials have offered robust evidence supporting the use of DAA agents as pioneer treatments, alone, or in combination with standard pegylated interferon (peg-IFN) and ribavirin (RBV)-based regimens. DAAs have proved highly efficacious, with pan-genotypic activity, shortened treatment duration, and an improved side-effect profile when compared with historical peg-IFN/RBV treatment. Recent phase 3 studies have provided proof-of-concept that all-oral, IFN-free DAA regimens can yield high rates of sustained virological response across most HCV genotypes.

Summary The ability of DAAs to dramatically improve virological clearance heralds a new era in clinical therapeutics, as the unprecedented prospect of cure for a chronic viral infection becomes tangible. However, myriad clinical challenges remain before global eradication of HCV can become reality.

Introduction

Hepatitis C virus (HCV) infection represents a major global health and economic challenge. With an estimated prevalence of 185 million individuals (3% of the world's population), morbidity and mortality resulting from its sequelae of cirrhosis and hepatocellular carcinoma (HCC) remain high.[1,2] In financial terms, HCV remains a rising economic burden: the median annual cost of treating decompensated cirrhosis has been estimated at approximately 14600 US dollars per year, and HCC at 15310 US dollars per year[3] Such costs present a convincing argument for the use of effective therapy to achieve sustained virological response (SVR) in patients with HCV, thereby mitigating progression to end-stage cirrhosis and its complications.

HCV treatment has historically involved ribavirin (RBV) and pegylated interferon (peg-IFN)-based regimens. Genotypes (GT) 1, 4, 5, and 6 required 48 weeks of combination therapy, yielding SVR rates of around 40–50% for GT1 disease. For GT2 and 3, higher response rates were typically seen, with SVR of 70–80% after 24 weeks treatment.[4] Numerous side effects from treatment (peg-IFN in particular) also led to poor patient tolerability. Two first-generation DAAs, boceprevir (BOC) and telaprevir (TEL), were licensed in 2011 for triple therapy regimens in addition to peg-IFN and RBV for GT1 HCV. Their introduction led to higher SVR rates of 65–75% for GT1 patients. However, the cost of treatment was high and drug-related toxicity with BOC and TEL was significant.

Sequencing of the HCV RNA genome and understanding of the viral life cycle have been vital steps in the identification of targets for drug development. Oral direct-acting antivirals (DAAs) have a range of target receptors and inhibit viral proteins encoded by the HCV genome. The explosion of novel DAA agents into the therapeutic landscape of HCV presents an opportunity to tailor treatment according to the individual patient characteristics. Novel treatment options, their evidence-base, and current European guidelines advocating their use are summarized in this review.

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