chronic hepatitis c, ind, interferons, ribavirin
R Kumar. The Present And Emerging Investigational Drugs For Chronic Hepatitis C: Current Status. The Internet Journal of Pharmacology. 2008 Volume 6 Number 2.
Chronic hepatitis C is caused by flavi virus (RNA virus) and is the leading cause for cirrhosis, hepatocellular carcinoma and liver transplantation. The standard therapy of chronic hepatitis C is peg interferon &#945; weekly plus oral-ribavirin daily is not effective in all patients and is limited by adverse effect. Therefore new investigational drugs are being developed and in pipeline. This article focuses on new investigational drugs that are presently in an advance stage of development also focuses on newer interferons, ribavirin analogue and anti apoptotic drug.
Viruses are obligate intracellular parasites, their replication depends on synthetic processes of the host cell. Hepatitis C caused by RNA flavi virus, 80% of individual will become chronically infected. Chronic hepatitis C is the leading cause for cirrhosis, hepatocellular carcinoma and liver transplantation 1 .
The goal of therapy patients with chronic hepatitis C is viral eradication and primary efficacy and point of treatment is achievement of SVR (Sustained Viral Response). SVR defined as the absence of detectable viremia for 6 months after completion of treatment. Sustained viral response is associated with improvement in liver pathology and reduction in risk of cirrhosis and hepatocellular carcinoma 2 .
The standard treatment in patients with chronic hepatitis C infection is once weekly pegylated interferon alpha with oral ribavirin (a synthetic nucleotide analogoue) daily. Combination therapy is more effective than monotherapy with interferon. Therefore monotherapy with pegylated interferon alpha is indicated in patients with chronic hepatitis C infection who can not tolerate oral ribavirin 12 . Side effects with the use of inteferon alfa include a flu like syndrome i.e. headache, fever, chills and myaligias occurs in more than 30% of patients within 6 hours after dosing and finds to resolve during therapy. During chronic therapy adverse effects include neurotoxicities (i.e. mood disorder, depression, seizures) pneumonitis, myelosuppression alopecia, tinnitus and retinopathy. Side effects with the use of ribavirin include dose dependent hemolytic anaemia, depression, instability, cough and insomnia 2 .
Currently available therapy for patient with chronic hepatitis C provides a cure rate of 40-90% and associated with significant adverse effects that often necessitate discontinuation. Therefore new drugs with higher efficacy and better tolerability are needed.
The availability of a full length HCV genome has enabled the identification of new targets and facilitates screening of new anti HCV drug 34 . Several targets have been identified in HCV genome for anti HCV drug, including IRES (Internal Ribosome Entry Site), E1/E2 (Envelop glycoprotein), P7 NS2, NS3, NS5 and NS5B (5-6). Many specifically targeted small molecule inhibitors are being developed and are emerging, future drug for patient with chronic hepatitis C infection 56 .
This article focuses on emerging future anti-HCV drugs that are currently in clinical trial and in advance stage of development.
Investigational New Drugs (IND)
NS3/4A Serine protease inhibitor
The combination treatment with telaprevir plus peginterferon-α–2a reduced the HCV RNA by 5.5 log after 14 days in previously untreated patients with chronic hepatitis C genotype-I 89 . Combination therapy causes more reduction in HCV RNA indicating additive effect of telaprevir with peginterferon-α-2a. HCV mutant resistant to telaprevir remained sensitive to peginterferon-α-2a. The triple combination treatment with telaprevir, peginterferon-α-2a and ribavirin in the PROVE trials (Phase II trials) yielded good results. At the EASL (Europian Association for the Study of the Liver) 2008 meeting in Milan, Italy, final results of the PROVE trials recently became available, both PROVE 1 and PROVE 2 trials had shown that the telaprevir based (triple combination) regimen resulted in a 20% higher SVR than previously achieved with standard treatment with peginterferon plus ribavirin in patients with chronic hepatitis C 1011 . Adverse effect with telaprevir therapy were rash and anaemia.
Currently available therapy for hepatitis C infection-Interferons
Interferon α-2a and interferon-α-2b are currently available for treatment of hepatitis C virus infection administered subcutaneously or intramuscularly, elimination help life is 2-5 hours and need to be administered daily or 3 times weekly.
Pegylated interferon-α is a fusion molecule of polyethylene glycolmolecule and interferon- α. Pegylated interferon α-2a and pegylated interferon α-2b need to be administered once weekly because of slower clearance of these drug result in longer terminal half life allowing for less frequent dosing 2 .
Newer Interferons in development
Investigational drug that reduces hepatic fibrosis:
Investigational drugs that have showed good antiviral effect in clinical trials in patient with chronic hepatitis C infection but further development has been stopped due to toxicity – includes.
Chronic hepatitis C is manageable disease the current treatment is peginterferon-α weekly plus oral ribavirin daily but this is not 100% effective (cure rate is 40% to 90%) also the adverse effects are the limiting factors. New specific anti HCV investigational drugs are in pipeline and in development.
Adding a new specifically targeted antiviral therapy on to peginterferon-α plus ribarivin standard treatment is the most promising strategy. Resistance due to mutation i.e. HCV polymeruse develops early limits the efficacy of investigational drugs. Combination of different antiviral drugs may reduce the development of resistance. Anti apoptotic inhibitor like caspase inhibitor may improve hepatic fibrosis. Optimal combination of drugs that result in-sustained viral response, reduce hepatic fibrosis, reduces adverse effects or better tolerability will be the more effective treatment.