Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals
Expert Rev Gastroenterol Hepatol. 2013;7(2):171-185.
Topic Alert
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Abstract and Introduction
Abstract
Hepatitis C virus (HCV) infection is a major global health problem as it has a high propensity for establishing chronicity. Chronic HCV carriers are at risk of developing severe liver disease including fibrosis, cirrhosis and liver cancer. While treatment has considerably improved over the years, therapy is still only partially effective, and is plagued by side effects, which contribute to treatment failure and is expensive to manage. The drug development pipeline contains several compounds that hold promise to achieve the goal of a short and more tolerable therapy, and are also likely to improve treatment response rates. It remains to be seen, however, how potent antiviral drug cocktails will affect the hepatitis C burden worldwide. In resource-poor environments, considerable costs, inadequate infrastructure for medical supervision and distribution may diminish the impact of future therapies. Consequently, development of novel therapeutic and prophylactic strategies is imperative to contain HCV infection globally.
Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals
Expert Rev Gastroenterol Hepatol. 2013;7(2):171-185.
Topic Alert
"Hepatitis C" is already on your Topic Alert list.
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.
Information from Industry
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.
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