Drugs That Treat Hepatitis C - Essay Example

Drugs for Hepatitis C" Introduction Hepatitis C is one of the most common infections in the developed world and is related with considerable morbidity and mortality. If untreated, virus is capable of causing progressive hepatocellular injury with fibrosis and subsequent cirrhosis. Chronic HCV is also the chief risk factor for hepatocellular carcinoma. HCV is a RNA virus that does not integrate into chromosomal DNA and does not establish latency per se. The virus is highly replicative and generates billions of its replicas every few days in an infected individuals. Theoretically, infection is curable in all affected patients. The current modality of care for treatment is the combination of peginterferon alfa and ribavirin, which produces high cure rate in selected virus genotypes only (McHutchinson, et al, 2009). Advent of highly efficient oral agents that are selective for HCV like HCV protease inhibitors and polymerase inhibitors, bring hope for curative combinations of oral agents. It is likely that treatment recommendation for this infection will change drastically in the coming years. Drugs for HCV Interferons (IFNs) Interferons (IFNs) are potent cytokines that possesses antiviral, immunomodulatory and antiproliferative activities (Biron, 2001; Samuel, 2001). These proteins are synthesized by the host cells in response to various inducers and, in turn cause biochemical modifications leading to antiviral state in cells. Three major classes of interferons with significant antiviral activities are being recognized: 1. Interferon α- non-glycosylated 2. Interferon β 3. Interferon γ. In chronic Hepatitis C virus infection, IFN alfa-2B monotherapy (3MU, 3 times a week) is associated with an approximate 50-70% rate of aminotransferase normalization and loss of plasma viral RNA, but relapse rates are high, and sustained virological remissions is observed only in 10-25% of the patients. Sustained viral responses are associated with long term histological improvement and probably reduce the risk of hepatocellular carcinoma and hepatic failure (Coverdale et al, 2004). Viral genotype and pre-treatment RNA level influence response to treatment, but viral clearance is the best predictor of the sustained response. Failure to attain early viral response predicts lack of sustained viral response with continued treatment. Non-responders generally do not benefit from IFN monotherapy retreatment, but they and patients relapsing after monotherapy often respond to combined pegylated IFN and ribavirin treatment. IFN treatment may benefit HCV associated cryoglobulinemia and glomerulonephritis. IFN administration during acute HCV infection reduces the risk of chronicity (Alberti, et al, 2002). Pegylated IFNs are superior to conventional thrice weekly IFN monotherapy in inducing sustained remissions in treatment naive patients. Monotherapy with pegIFN alfa-2A (180 µg subcutaneously weekly for 48 weeks) or pegIFN alfa-2B (1.5 µg/kg/week for 1 year) is associated with sustained response in 30-39%, including stable cirrhotic patients (Heathcote, et al, 2000). Moreover, it is the treatment option for the patients unable to take ribavirin. Studies are being carried out to establish the prolonged (4 years) maintenance monotherapy with pegylated IFNs and also for those not responding to IFN-ribavirin combinations. Although a large randomized relationship of pegIFN alfa-2A versus alfa-2B combined with ribavirin found no difference in the response rate (McHutchinson, et al, 2009). The efficacy of conventional and pegylated IFNs is enhanced by the addition of ribavirin particularly for genotype I infections. Combined therapy with pegIFN alfa-2A (180 µg once weekly for 48 weeks) and ribavirin (1000-1200 mg/day in divided doses) gives higher sustained viral response rates than IFN-ribavirin combinations in previously untreated patients (Fried, et al, 2002). For genotype 2 and 3 infections a shorter duration of therapy (24 weeks) with lower dose of ribavirin (800 mg/day) is effective. For genotype 1 and 4 infections, prolonged therapy and higher ribavirin doses are needed (Hadziyannis, et al, 2004). Around 15-20% of those failing to respond to combined IFN-ribavirin will have sustained response to pegIFN-ribavirin. Histological improvement may occur in patients who do not achieve sustained viral responses. In patients with compensated cirrhosis, treatment may reverse the cirrhotic changes and possibly minimize the risk of hepatocellular carcinoma (Poynard, et al, 2002). Mechanism of Action of IFNs The binding of IFN to specific cell surface receptor molecules, signals the cells to produce a series of antiviral proteins. IFN effects- 1. Inhibition of transcription- Activates Mx proteins and blocks mRNA synthesis. 2. Inhibition of translation- Activates methylase, thereby reduces mRNA cap methylation. Activates phosphodiesterase and blocks t-RNA function. Activates protein kinase P1, inhibits initiation of mRNA translation. 3. Inhibition of post-transitional processing- inhibits glycosyltransferase thereby reduces protein glycosylation. 4. Inhibits viral maturation- inhibits glycosyltransferase, thereby reduces glycoprotein maturation. 5. Inhibition of viral release- causes membrane changes and blocks binding (Samuel, 2001). Adverse Drug Reaction of IFN It may cause fever, chills, headache, myalgia, arthralgia, nausea, vomiting, diarrhoea. Dose limiting toxicities of IFN are- depression, myelosuppression- granulocytopenia, thrombocytopenia; neurotoxicity- confusion, behavioral disturbances and rarely seizures. Risk of depression is higher in chronically infected HCV patients (Marcellin, et al, 2004). Pegylated are better tolerated than standard IFNs. Ribavirin: Chemistry & Antiviral activity Ribavirin is a purine nucleosides analogue with a modified base and D-ribose sugar. Ribavirin inhibits the replication of wide range of RNA and DNA viruses. Mechanism of Action Although not completely understood, but it alters cellular nucleotide pools and inhibits viral m-RNA synthesis (Tam, et al,2002). It undergoes the process of intracellular phosphorylation and gets converted into its mono, di, tri-phosphate derivatives through the host cell enzymes. Ribavirin mono-phosphate competitively inhibits cellular inosine-5-phophate dehydrogenase and interferes with the synthesis of GTP and thus nucleic acid synthesis in general. Ribavirin tri-phosphate also competitively inhibits GTP-dependent 5- capping of viral mRNA and specifically influences the influenza virus transcriptase activity. Ribavirin appears to have multiple sites of action and some of these (e.g. inhibition of GTP synthesis) may potentiate others (e.g. inhibition of GTP-dependent enzymes). Ribavirin induces viral mutagenesis and may inhibit viral replication. This is called lethal mutagenesis (Hong & Cameron, 2002). Pharmacokinetics of ribavirin Bioavailability averages 50%. Accumulates in plasma and steady state is reached by 4 weeks. Food enhances plasma level of ribavirin. With aerosol administration plasma level increases with the duration of exposure and range from 0.2 to 1µg/ml after 5 days. Apparent volume of distribution of ribavirin is large (10 L/ kg). Poor plasma protein binding. Drug should be cautiously used in patients with creatinine clearance of Read More