ReviewTherapy of chronic hepatitis C virus infection in the era of direct-acting and host-targeting antiviral agents
Introduction
Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease and an important worldwide health problem. It has been calculated that approximately 3% of the global population is chronically infected with HCV, although its prevalence is variable among different geographic areas.1, 2 Six major HCV genotypes (gts) have been identified and their geographic distribution differs, as does their clinical impact with respect to the development of liver disease. HCV gt-1 is the most common genotype worldwide, with a prevalence of subtype 1b in Europe and of subtype 1a in the USA. Intravenous drug users are more frequently infected with gt-3a, especially in Europe. In the Mediterranean area, gt-2 prevails whereas gt-5 and gt-6 are rare.3 Gt-4 is also rare, although its prevalence is relatively high (22%) in the Egyptian population.4
Acute HCV infection is difficult to diagnose because it is usually asymptomatic. While it may resolve spontaneously, in 50–90% of the cases it progresses to chronic infection, with further evolution into cirrhosis in 10–40% of this latter group. Eventually, liver cancer may ensue, with an annual incidence of 1–5% per year.5 These complications are characterized by a high annual mortality rate: roughly 4% of the patients with cirrhosis and 30% of those with hepatocellular carcinoma will die from their disease.6 Thus, all efforts to eradicate the infection are fully justified and require a careful assessment of the many viral factors that promote infection and disease, with the aim of choosing the most appropriate therapeutic regimen. Several recent developments, including the identification of novel predictive factors and improvements in our knowledge of those already established, the adoption of new criteria to define both the duration of therapy and the therapeutic response, as well as the elucidation of resistance mechanisms, have remarkably changed the clinical scenario of HCV infection.
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Endpoints of treatment
The combination of pegylated interferon-α (pIFN-α) plus ribavirin (RBV) is the “historical” standard of care for patients with chronic hepatitis C (CHC). The primary goal of antiviral therapy is the achievement of a sustained virological response (SVR), defined as undetectable HCV RNA 24 weeks after the cessation of treatment. In non-cirrhotic patients, SVR is considered curative, whereas those with cirrhosis who have cleared the infection remain at risk of life-threatening complications. The
Potential targets for the development of new anti-HCV agents
The new antiviral agents can be subdivided into two categories: a) DAAs and b) host-targeting antivirals (HTAs). Both DAAs and HTAs target proteins that are essential for viral replication, albeit via different mechanisms (Table 2).
Boceprevir in treatment-naïve patients
SPRINT-2 (Serine Protease Inhibitor Therapy 2)22 was an international, phase III, double-blind, randomized study of HCV gt-1 treatment-naïve patients who received triple PI-based therapy or pIFN-α/RBV plus placebo. Non-Afro-American (n = 938) and Afro-American (n = 159) patients were analyzed separately because of racial differences in SVR rates. pIFN-α2b was administered subcutaneously at a dose of 1.5 μg/kg body weight once weekly; weight-based oral RBV was administered at a total dose of
Combinations of NS3/4A and HCV NS5A inhibitors
A preliminary phase IIa study110 involving patients with HCV gt-1 infection unresponsive to prior therapy showed SVR achievement with only two DAAs. In that study, 21 patients were divided into two groups. Group-1 patients received daclatasvir (60 mg once daily) plus asunaprevir (600 mg twice daily), and group-2 patients daclatasvir plus asunaprevir in combination with pIFN-α/RBV, both for 24 weeks. Almost all group-2 patients had an SVR, in contrast to 36% of the group-1 patients. Diarrhea and
HCV resistance to novel drugs
The RNA-dependent RNA polymerase of HCV is prone to error during the high rate of virion production (up to 1013 particles per day), resulting in the frequent emergence of resistant variants. In the majority of patients, these drug-resistant variants are present before treatment, accounting for minor populations within the quasispecies infecting the patient. Most resistant variants are relatively unfit and undetectable before therapy, even with currently available highly sensitive techniques
Antiviral treatment in HCV-related extrahepatic manifestations
HCV infection is responsible not only for the development of chronic liver disease, but also for the possible occurrence of extrahepatic manifestations. Among them, cryoglobulinemic vasculitis (CV) is of particular interest. This immune-complex-mediated vasculitis primarily involves small blood vessels in different tissues, including skin, kidney, and peripheral and central nervous systems.131, 132 HCV infection has also been reported in association with distinct histological patterns of
Conclusions
While pIFN-α/RBV still remains the SoC for non-gt-1 infections, on the basis of the experience gained with the recently introduced DAAs, the standard of care (SoC) for patients infected with HCV gt-1 is changing and now includes triple therapy with pIFN-α/RBV and either TPV or BOC. The most important studies that have been published so far with both DAAs as summarized in Table 5. However, these new anti-HCV drugs imply high costs and additional adverse events while demanding good compliance
Funding
“Fondazione Cassa di Risparmio di Puglia”, Bari, Italy (DS); Associazione Italiana per la Ricerca sul Cancro – AIRC, Milano, Italy (FD); Italian Ministry of University and Scientific and Technologic Research, National Project “Chronic liver damage induced by hepatitis C virus” (DS); AIFA – Agenzia Italiana del Farmaco, funds for independent studies, 2007, contract no. FARM7SJX (DS); University of Bari, Italy (DS). These funding sources had no role in the present study.
Conflict of interests
All authors declare no competing interests.
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