Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals

Chao Shi; Alexander Ploss

Disclosures

Expert Rev Gastroenterol Hepatol. 2013;7(2):171-185. 

In This Article

Prospects in HCV Treatment

An estimated 170 million people, or 3% of the world population, are chronically infected with hepatitis C virus (HCV) (Figure 1). Persistent HCV infection leads to liver cirrhosis and can culminate eventually in hepatocellular carcinomas. Since the discovery of HCV as a causative agent for non-A non-B hepatitis in 1989, constant efforts have been made to improve the outcome of hepatitis C patients. Before 1990, HCV was an incurable disease and monotherapy with IFN-α resulted in a sustained virologic response (SVR) in only 10% of the treated patients.[1] Combination therapies of pegylated interferon (peg-IFN) with ribavirin (RBV) were later applied and became the standard-of-care for HCV. This combination treatment improved SVR rates, but fell short of curing HCV infection in more than 50% of patients with HCV genotype 1 and had an even worse outcome or was contraindicated in patients with comorbidities such as HIV infection, cirrhosis, transplant recipients or in African–Americans,[2,3] thus creating a need for more effective therapies. The introduction of direct-acting antivirals (DAAs), which are inhibitors of virally encoded protein functions, to the market represents a milestone in HCV therapy. Incivek® (generic name: telaprevir; Vertex, MA, USA) and Victrelis™ (generic name: boceprevir; Merck, NJ, USA), two drugs that interfere with the virally encoded NS3/4A protease, were approved by the US FDA in 2011. Addition of telaprevir or boceprevir to the peg-IFN/RBV regimen increases SVR rates in certain clinical trial cohorts to 60–70%.[4–7] In the meantime, many candidates of HCV DAAs, including the next generation of protease inhibitors, NS5A inhibitors and polymerase inhibitors, are at the late stage of development. Recent clinical trials have demonstrated that combinations of orally administered DAAs with different mechanisms of action can cure chronic HCV infection with 90% rate,[8–10] although the optimal results remain to be confirmed in larger patient cohorts. The availability of these new, presumably more potent DAAs is expected to revolutionize the standard-of-care of HCV infection, with a promise to cure HCV with an all-oral, IFN-free cocktail regimen. In addition, drugs targeting host factors that are essential for HCV replication, such as cyclophilin A and miR122, are also in the pipeline. A drastic expansion of the ammunition for treating HCV infection is expected in the next few years.

Figure 1.

Relative hepatitis C virus prevalence and distribution of common genotypes. The numbers in the figure indicate the most prevalent HCV genotype(s) in the respective regions. Data taken from WHO (2006) and [20,152].

Because HCV, unlike HIV and hepatitis B virus (HBV), does not integrate into the host genome, successful treatment with antiviral therapies is able to eradicate the virus from individuals. A 90% cure rate of new antiviral drugs suggests that the number of existing patients will shrink in the USA and other developed counties, where effective treatment can be applied. Moreover, as a consequence of implementation of rigorous blood supply screening for HCV since 1991, the number of new HCV infections in the USA fell from a peak of 180,000/year in the mid-1980s to 16,000/year in 2009 ([11] and CDC data). Currently, the most common cause of ongoing HCV transmission is the sharing of contaminated needles or syringes by injection drug users (IDUs; in the USA) and unsafe medical practices (globally). Some studies have projected the prevalence in the USA to decline from 3.2 million in 2005 to 2.5 million in the 2020s without considering the utilization of more effective antiviral regimens.[12,13] Using a similar but simplified approach, the authors predict that with the application of new DAAs, which can potentially improve the rate of SVR from 50 to 90%, the infected population in the USA will decline below 2 million in 2020s (Figure 2 & Table 1). Furthermore, since the new regimens can be applied to patients who were previously ineligible for the standard-of-care treatment due to their insensitivity or intolerance to interferons, the percentage of patients receiving treatment is expected to increase. Currently, only 10–27% of people diagnosed with HCV infection are offered treatment.[14] If we assume the treatment rate increases to 50% with the application of new DAAs, the projection of the US prevalence will be below half a million in 2020s (Figure 2). However, this optimistic outlook comes with caveats.

Figure 2.

A projection of hepatitis C virus burdens in the USA for the next decade. Assuming 50% sustained virologic response rate for peg-IFN/ribavirin regimen and 90% for DAAs combo regimen. DAA: Direct-acting antiviral; HCV: Hepatitis C virus; peg-IFN: Pegylated interferon; RBV: Ribavirin.

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