Current status of HCV therapy

Major advances have been made in the treatment of chronic hepatitis C during the last 10 years, but major challenges remain, since treatment with pegylated interferons and ribavirin is effective in only around 55 percent of patients. Newer therapies are needed for the increasing numbers of patients who do not respond to relapse after current treatments with pegylated in interferons and ribavirin.

Polyethlene glycol (PEG) is nontoxic polymer that can be attached to interferons, a process termed "pegylation". Modification of proteins by pegylation can lead to prolonged absorption, delayed clearance and their longer half-life allow once-weekly rather than three times weekly dosages with standard interferon (IFN).

Two PEG-IFN formulations have been developed. Pegylated interferon alfa-b uses a 12-kDa polyethylene glycol, and pegylated interferon alfa-2a has a branched-chain PEG. Both are given with ribavirin in the treatment of chronic hepatitis C (HCV) infection. Pegylated interferon alfa-2b is administered as a weight-based regimen, whereas pegylated interferon alfa-2a is a fixed-dose regimen.

In several clinical trials, the response rates with pegylated inferferon monotherapy have been twice as high as those with unmodified interferon. Combinations of PEG-IFNs and ribavirin are the current standard of care for the treatment of hepatitis C, as this regimen has been shown to be more effective and equally well tolerated as unmodified IFN/ribavirin.

The variables that have been associated with associated with improved rates include genotypes other than 1, lower pretreatment viral loads, lower body weight of 75kg or less, younger age, and to a lesser extent the absence of cirrhosis. A post-hoc analysis of the virological data from the two large pivotal trials has led to the concept of evaluating an early virological response (FVR) in predicting the subsequent response to ongoing therapy. The absence of an EVR (defined either as a drop of 2 log or more in HCV RNA or negative HCV RNA findings at week 12 of therapy) has been associated with a very low probability of achieving a sustained virological response with continuing therapy. Overall, approximately 80 percent of patients receiving therapy achieve an EVP. More importantly, less than 2 percent of patients who do not achieve on EVR go on to have a sustained viral response (SVR) with ongoing therapy. Thus, it is reasonable to apply a "stop therapy" rule as week 12 in patients who do not achieve an EVR.

A multicenter global trial focusing on several important issues relevant to genotype, viral load, duration of therapy, and dose of ribavirin has validated the post-hoc analysis of PEG-IFB alfa-2b and ribavirin therapy and supports the use of a higher dosage of ribavirin in genotype 1 patients, particularly those with a high viral load, as opposed to the lower dose of 800mg uses in the clinical trial.

Increasing numbers of patients receiving the combination therapy with pegylated interferon and ribavirin do not respond, or relapse after treatment, Recognized that there is a potential histological benefit from interferon therapy, the use of maintenance therapy arises in virological nonresponders – particularly those with advanced fibrosis. The hypothesis that fibrosis can be reverses – particularly with a favorable impact on certain end points of cirrhosis, such as live failure and liver cancer – is currently being tested in a large multicenter trial (the HALT-C trial). Preliminary date have shown that treatment with pegylated interferon alfa-2 (180ug/week) and ribavirin (100-1200mg/day) in previous nonresponders to interferon treatment or interferon and ribavirin treatment led to an overall sustained virological response rate of 18 percent.

Ribavirin-like drugs. The mode of action of ribavirin is not well understood, but it is an effective drug in the treatment of chronic hepatitis C when used in combination with interferon. A combination with interferon. A combination of actions of the drug may exist – inhibiting viral replication and also enhancing the host’s immune response. The use of ribavirin is limited by the development of anemia, which not infrequently leads to dose reduction or discontinuation of the drug. Levovirin, a second-generation I-isomer of ribavirin, is associated with less anemia, presumably due to a lack of conversion of the agent in the erythrocytes to monophospate, diphosphate, and triphosphate intermediates. Clinical trials with this compound are awaited. Viramidine, a prodrug or ribavirin, has a longer residence time in the liver and produces less hemolysis owing to a comparatively lower uptake by the erythrocytes. Phase II trials are currently under way with viramidine in combination with pegylated interferon.

Clinical trials of several therapies for HCV are currently in progress, including molecular-based therapies. Direct inhibitors of HCV enzymes (protease, helicase, and polymerase) intuitively offer the best chance of clearing HCV infection. Several compounds are being evaluated in the replicon systems that have targeted inhibition against HCV polymerase, NS3 helicase, and NS2-3 and NS3-4A proteinases. These compound have not entered clinical trials, although it is expected that these drug groups will provide the next line of treatment for chronic hepatitis C, particularly with the goal of eradicating hepatitis C infection.

Summary. Treatment with pegylated interferon (either alfa-2b or alfa-2a) and ribavirin is the current standard of care for patients with chronic hepatitis C. To achieve the best response, genotype 1 patients need a longer period of therapy, at 48 week, with a higher dose of ribavirin of 1000/12000mg. Genotype 2 and 3 patients respond as well to a combination of pegylated interferon alfa-2a 180ug/week and ribavirin 800mg/day orally for 24 weeks as compared to 48 weeks of such combination therapy, even at a higher dose of ribavirin of 1000-1200mg; 24 weeks of therapy are therefore adequate in these patients. Current therapies are effective in approximately 55 percent of the overall population of patients with chronic hepatitis C. There are a number of special population groups in whom the role of treatment is leas well established. In addition, there is a significant number or nonresponders to current therapy for whom improved treatments need to be developed. A lack of an early virological response (defined either as a drop of 2 log or more in HCV RNA or negative HCV RNA findings at week 12 of therapy) is an important negative predictor of a sustained virological response to continued therapy.