New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives

Abstract

Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon-α [corrected] plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens.

Development of a high-throughput pyrosequencing assay for monitoring temporal evolution and resistance associated variant emergence in the Hepatitis C virus protease coding-region

“…Genotype 1 viruses are the most globally prevalent and the predominant circulating strain in developed nations (Gravitz, 2011). The paucity of response rates in genotype 1 infections to pegylated interferon-α and ribavirin (PEG-IFNα/RBV) therapy (Welsch et al, 2012) has driven the development of alternative therapeutic options: small molecule inhibitors targeted at specific steps in the viral life-cycle and known as Direct Acting Antivirals (DAAs).…”

“…In combination with PEG-IFNα/RBV, the first generation of licensed protease inhibitors (PIs) have substantially increased treatment response rates in genotype 1 infected patients (Salam and Akimitsu, 2013;Welsch et al, 2012). However, RAV emergence to DAAs is well documented (Halfon and Locarnini, 2011;Sarrazin and Zeuzem, 2010).…”

Fueling fibrosis in chronic hepatitis C

“…I n the 23 y that have elapsed since the discovery of hepatitis C virus (HCV), many thousands of papers have been published dealing with chronic hepatitis C. Tremendous strides have been made, especially in the development of efficacious antiviral agents that can be administered orally (1). Nonetheless, many gaps remain in our understanding of the disease, and the burden it imposes on the health of Americans and others continues unabated.…”

Peg-interferon plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: A meta-analysis on role of response predictors

“…The recent introduction of the direct-acting antivirals (DAAs) NS3 protease inhibitors boceprevir and telaprevir has enhanced the SVR rate in patients with HCV-1 CHC to 70-80%. Indeed, the combination of one of these protease inhibitors with Peg-IFN and ribavirin, named triple therapy in the present paper, is more effective than dual therapy for HCV-1 CHC patients naïve for anti-HCV therapy and for those who relapsed after a first course of dual therapy [3][4][5][6]. Triple therapy, however, is associated with serious adverse events (AE) and entails increased costs both for drugs and for the more complex health care organization needed [3][4][5][6][7].…”

“…Second, trials on both therapy-naïve and relapser patients were included and telaprevir and boceprevir, as the DAA, were investigated together. However, therapy-naive and patients who relapsed after a first course of dual therapy had a similar probability of SVR with triple therapy [3][4][5][6]. Patients treated with boceprevir and telaprevir in triple therapy were analyzed together because of the small number of studies available and because they are both first-generation NS3 protease inhibitors that have demonstrated a similar antiviral effect.…”