Faculty Peer Reviewed
A healthy 61-year old man with a history of chronic genotype 1b hepatitis C virus infection of unknown duration arrives for his semiannual appointment in the Hepatology Clinic. The patient has previously been offered treatment with pegylated interferon and ribavirin, which he has declined on the basis of potential side effects and poor reported efficacy. He states that he has read that new treatment options for hepatitis C have recently become available…
Hepatitis C virus (HCV), first isolated in 1989, is a positive-stranded, enveloped RNA virus of the flaviviridae family. A recent survey estimates the prevalence of Americans with antibodies to HCV to be over 4 million, including 3.2 million with evidence of HCV viral load, indicating chronic infection. The majority of individuals with chronic HCV infection in the US are infected with genotype 1, which has proven difficult to treat. Risk factors for the acquisition of HCV include intravenous drug use, high-risk sexual behavior, and blood transfusion prior to the advent of HCV screening in 1992, although many infected individuals have no risk factors for transmission. While the incidence of acute HCV infection has decreased since its peak in the 1980s, estimates suggest that the prevalence of chronic HCV infection will not peak until 2015  and that as few as 25-30% of chronic HCV cases are being diagnosed due to the asymptomatic nature of HCV infection in its early stages.
HCV is the most common cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in the US. While many patients with chronic HCV infection will never experience any serious complications, data show that roughly one-third of patients with untreated chronic HCV will progress to cirrhosis within 20 years.[7,8] Identifying this third of chronic HCV patients has proven difficult, however, because of poor correlation between quantification of HCV viral load and clinical outcomes. Because of this, treatment may be initiated at any point in the natural history of HCV infection, although liver fibrosis is the best indication to initiate antiviral therapy to prevent progression. Thus, patients with chronic HCV infection should be regularly surveyed for abnormalities in liver biomarkers and with ultrasound to determine whether a liver biopsy to assess for fibrosis is indicated.
Treatment of chronic HCV infection with interferon-alpha predates the identification of HCV itself, but sustained responses were below 10% following a 6-month course. Improvements to this treatment regimen came in 2 forms: the addition of the antiviral compound ribavirin, which more than doubled the sustained response rate, and the covalent modification of interferon with polyethylene glycol (peg), which vastly improved the half-life of the molecule. However, pegylated interferon + ribavirin “double therapy” yielded a sustained virologic response, defined as undetectable HCV viral load 24 weeks following cessation of therapy, in only ~40% of patients infected with HCV genotype 1.
While the difficulty in generating models to study HCV infection has made analyses difficult, it is widely believed that exogenous interferon reduces HCV indirectly, by activating cell-surface interferon receptors and inducing JAK/STAT signaling. This subsequently alters transcription and translation of genes associated with inflammation and protein degradation to induce an “antiviral” state.[15,16] Several mechanisms have been proposed for the synergistic effect of ribavirin when paired with interferon therapy. Ribavirin is a guanosine analog and, as such, may be phosphorylated and subsequently incorporated into nascent RNA chains, causing early termination.[16,17] Other proposed mechanisms include ribavirin-dependent induction of catastrophic viral mutations, depletion of GTP required for RNA synthesis, and synergistic influence on the induction of interferon-dependent genes.[17,18] As a result of these indirect mechanisms of double therapy, there are considerable side effects associated with treatment, including cytopenias, fatigue, depression, pruritus, and anorexia. Furthermore, for genotype 1, this therapy is continued for 48 weeks and includes weekly subcutaneous injections of interferon. The poor efficacy and side effect profile paired with the length and mode of treatment administration underscore the need for direct therapies.
Recent advances in both in vitro and in vivo models of HCV infection have identified numerous candidates for drug targeting within the HCV proteome. The function of the nonstructural 3 (NS3) serine proteases is twofold. They are responsible for both the cleavage of the HCV polyprotein and for inhibition of innate immune signaling within hepatocytes via cleavage and inactivation of interferon-beta promoter stimulator 1. These NS3 molecules have been specifically targeted by 2 recently FDA-approved medications, telaprevir (Incivek, Vertex Pharmaceuticals, Boston, MA) and boceprevir (Victrelis, Merck, Whitehouse Station, NJ). Several recent clinical trials have highlighted the significant improvement in the efficacy of HCV treatment with “triple therapy” including an NS3 protease inhibitor in conjunction with peg-interferon and ribavirin.
The PROVE 1 randomized, controlled clinical trial found that while double therapy for 48 weeks achieved a sustained virologic response in only 41% of all patients with previously untreated genotype 1 chronic HCV, those who underwent triple therapy with telaprevir for the initial 12 weeks, followed by 36 weeks of double therapy, had a sustained virologic response in 67%, which was significantly greater. The PROVE 2 trial subsequently showed that a similar sustained virologic response of 69% (vs 46% for 48 weeks of double therapy alone) can be obtained in genotype 1-infected patients with only 12 additional weeks of double therapy following 12 weeks of triple therapy with telaprevir. The ADVANCE trial has shown that the treatment can be further simplified by response-guided therapy, in which an extended rapid virologic response (ie, undetectable HCV viral load between 4 and 12 weeks of triple therapy with telaprevir) can be used as an indication for cessation of therapy after only 12 additional weeks of pegylated interferon-ribavirin double therapy. These patients had similar sustained virologic responses (75% vs 44% for 48 weeks of double therapy alone) to the PROVE 1 and PROVE 2 trials, which included 36 weeks of double therapy following telaprevir. The SPRINT-1 trial found similarly promising results for boceprevir with the caveat that a 4-week lead-in of double therapy is required prior to 44 weeks of triple therapy with boceprevir in order to achieve the best results of 75% (vs 38% for 48 weeks of double therapy alone). The SPRINT-2 trial additionally showed that response-guided therapy, similar to that utilized in the ADVANCE trial for telaprevir, can be used with boceprevir, again with a 4-week lead-in of double therapy alone. While these results all apply to patients with chronic HCV genotype 1 infection who were previously untreated, like the patient in the initial case, additional randomized, controlled clinical trials have showed promising results for triple therapy for those patients who have previously failed double therapy.[26,27]
Thus, the current treatment guidelines for a patient like the one in the case above would be telaprevir 750 mg by mouth 3 times daily with peg-interferon and ribavirin for 12 weeks, with viral load assays between 4 and 12 weeks of treatment. Depending on the virologic response at these time points, double therapy would follow for either an additional 12 or 36 weeks. A 4-week lead-in of double therapy followed by either 24 or 44 weeks of boceprevir-based triple therapy, depending on virologic response between 8 and 24 weeks of therapy, would be an FDA-approved, albeit more complicated, alternative.
While the prospect of a curative 24-week regimen for genotype 1 HCV infection is certainly exciting, even the most generous predictions of sustained virologic response suggest that 20% of patients will fail to respond to the new regimens. Furthermore, there are considerable side effects associated with telaprevir and boceprevir, including anemia and rash; triple therapy combines the potential side effects of 3 agents. Initial data have, however, highlighted the fact that relapse is common in patients who receive NS3 protease inhibitors without double therapy. Thus, the precautions associated with double therapy and the indications for its initiation continue to be pertinent for the addition of these new agents. For patients like the one in this case, without any clinical signs of decompensated cirrhosis, the decision of whether to treat his HCV infection remains challenging.
Carl Gay, MD is a former medical student at NYU School of Medicine
Peer reviewed by Natalie Levy, MD, Department of Medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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