Current and future therapies for hepatitis C virus infection

Abstract

Only 20 years after the discovery of the Hepatitis C Virus (HCV), a cure is now likely for most people affected by this chronic infection, which carries a substantial disease burden, not only in the United States but also worldwide. The recent approval of two direct-acting antiviral agents that specifically inhibit viral replication has dramatically increased the viral clearance rate, from less than 10% with the initial regimen of interferon monotherapy to more than 70% with current therapy. Moreover, many other drugs targeting viral or host factors are in development, and some will almost certainly be approved in the coming years. The questions of who should be treated and with what regimen will be increasingly complex to address and will require careful consideration. As therapy improves, systemwide identification and care of patients who need treatment will be the next challenge. Because most infected persons are unaware of their diagnosis, the Centers for Disease Control and Prevention recently recommended screening for HCV all persons born between 1945 and 1965.^, It is anticipated that in the course of such a screening process, a large number of persons will be found to be infected with the virus; whether it will be possible to treat all these people is unclear. This article reviews the current therapy for HCV infection and the landscape of drug development.

Figure 1. Life Cycle of the Hepatitis C Virus (HCV) and Targets of Therapy

The sequential steps of HCV propagation in a hepatocyte are shown in Panel A. The virus forms complexes with lipoproteins and circulates in the blood. HCV entry factors include scavenger receptor B1 (SCARB1), CD81, claudin 1 (CLDN1), occludin, epidermal growth factor receptor (EGFR), and Niemann-Pick C1-like protein 1 (NPC1L1). Panel B shows the virus-encoded gene products displayed topologically on the endoplasmic reticulum membrane, as well as the major viral and host targets that are the focus of agents in advanced clinical development. Other targets in the HCV life cycle, such as viral proteins p7 and NS4B (Panel B), and host targets, including HCV entry factors, lipid metabolism, and membrane signaling pathway involved in replication (Panel A), are also being targeted for HCV therapeutic development. Inhibitors against some of the entry factors have already been developed for other purposes and are currently being tested as treatment for HCV infection.^– The symbols (+) and (−) refer to the positive and negative strand, respectively, of the viral genome. CypA denotes cyclophilin A, E envelope glycoprotein, GAG glycosaminoglycan, LDLR low-density lipoprotein receptor, NI nucleoside analogue inhibitor, NNI non-nucleoside analogue inhibitor, and NS nonstructural protein.

Figure 2. Boceprevir- and Telaprevir-Based Regimens for Treatment of HCV Infection

The boceprevir-based regimen and the telaprevir-based regimen differ in several aspects: first, with respect to the specific therapeutic regimen for each type of patient (those who have not received prior therapy vs. those who have received prior therapy, including patients with a relapse after an initial response, those with a partial response, and those with no response); second, with respect to the schedule and duration of the combination therapy; and third, with respect to the points at which therapy is changed, depending on the patient’s response, and the points at which therapy is stopped. Typically, telaprevir is given together with peginterferon and ribavirin (peginterferon alfa-2a, 180 µg per week, or peginterferon alfa-2b, 1.5 µg per kilogram of body weight per week, in combination with ribavirin, 1000 mg daily for a patient with a body weight of ≤75 kg and 1200 mg daily for a patient with a body weight of >75 kg) during the first 12 weeks of therapy; peginterferon and ribavirin are then continued without the protease inhibitor for a total of either 24 or 48 weeks, depending on the virologic response to the triple therapy (response-guided therapy). In contrast, boceprevir is administered starting 4 weeks after the initiation of peginterferon and ribavirin (at the same doses as above) and is continued for a total of 28 or 48 weeks, again depending on the virologic response. In general, with both regimens, patients with cirrhosis should receive the same treatment as patients who have not had a response to previous therapy. The stopping rules were as follows: for the telaprevir-based regimen, patients with an HCV RNA level greater than 1000 IU/ml at week 4 or week 12 should discontinue all three drugs; for the boceprevir-based regimen, patients with an HCV RNA level greater than or equal to 100 IU/ml at week 12 should discontinue all three drugs. For both regimens, patients with detectable HCV RNA at week 24 should discontinue therapy. Boc denotes boceprevir, PIFN peginterferon alfa, R ribavirin, and Tpv telaprevir.

Figure 3. Treatment Algorithm for HCV Infection, According to Genotype

A treatment algorithm is shown for patients who have not received prior therapy and for those who have received prior therapy, including patients with a relapse after an initial response and those with no response. Special pretreatment assessment refers to special considerations, such as genetic testing (for interleukin-28B genotype), liver biopsy, or noninvasive testing to determine the stage of liver fibrosis. Partial response is defined as an early virologic response (>2 log₁₀ reduction in the HCV RNA level or undetectable HCV RNA at week 12) but detectable HCV RNA at the end of treatment, and no response is defined as the lack of an early virologic response to standard therapy with peginterferon and ribavirin. Treatment for HCV genotype 2 or 3 infection is peginterferon-alfa-2a, 180 µg per week, or peginterferon-alfa-2b, 1.5 µg per kilogram of body weight per week, in combination with ribavirin, 800 mg daily, for 24 weeks; for genotype 4, 5, or 6 infection, the treatment is the same combination with weight-based ribavirin dosing (1000 mg daily for a patient with a body weight of ≤75 kg and 1200 mg daily for a patient with a body weight of >75 kg) for 48 weeks. For patients with HCV genotype 2 infection who do not have cirrhosis and who have a low viral level and a rapid virologic response (undetectable HCV RNA at week 4 of therapy), a shorter duration of therapy with weight-based ribavirin for 12 to 16 weeks may be equally effective. A newer, all-oral regimen, for which phase 3 studies have now been completed, shows promise in the treatment of patients with genotype 2 or 3 infection who have not received prior treatment and those who have not had a response to prior treatment with interferon.^, SVR denotes sustained virologic response.