Treatment of Hepatitis C Infection

TREATMENT OF HEPATITIS C INFECTION

In contrast to the treatment of patients with chronic HBV infection, the primary goal of treatment in patients with HCV infection is viral eradication. In clinical trials, the primary efficacy end point is typi-cally achievement of sustained viral response (SVR), defined as the absence of detectable viremia for 6 months after completion of therapy. SVR is associated with improvement in liver histology, reduction in risk of hepatocellular carcinoma, and, occasionally, with regression of cirrhosis as well. Late relapse occurs in less than 5% of patients who achieve SVR.

In acute hepatitis C, the rate of clearance of the virus without therapy is estimated at 15–30%. In one (uncontrolled) study, treatment of acute infection with interferon alfa-2b, in doses higher than those used for chronic hepatitis C, resulted in a sus-tained rate of clearance of 95% at 6 months. Therefore, if HCV RNA testing documents persistent viremia 12 weeks after initial seroconversion, antiviral therapy is recommended.

Treatment of patients with chronic HCV infection is recom-mended for those with an increased risk for progression to cirrhosis. The parameters for selection are complex. In those who are to be treated, the current standard of treatment is once-weekly pegylated interferon alfa in combination with daily oral ribavirin. Pegylated interferon alfa-2a and -2b have replaced their unmodified inter-feron alfa counterparts because of superior efficacy in combination with ribavirin, regardless of genotype. It is also clear that combina-tion therapy with oral ribavirin is more effective than monother-apy with either interferon or ribavirin alone. Therefore, monotherapy with pegylated interferon alfa is recommended only in patients who cannot tolerate ribavirin. Factors associated with a favorable therapeutic response include HCV genotype 2 or 3, absence of cirrhosis on liver biopsy, and low pretreatment HCV RNA levels.

RIBAVIRIN

Ribavirin is a guanosine analog that is phosphorylated intracellu-larly by host cell enzymes. Although its mechanism of action has not been fully elucidated, it appears to interfere with the synthesis of guanosine triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the viral RNA-dependent polymerase of certain viruses. Ribavirin triphosphate inhibits the replication of a wide range of DNA and RNA viruses, including influenza A and B, parainfluenza, respiratory syncytial virus, paramyxoviruses, HCV, and HIV-1.

The absolute oral bioavailability of ribavirin is 45–64%, increases with high-fat meals, and decreases with co-administration of antacids. Plasma protein binding is negligible, volume of distri-bution is large, and cerebrospinal fluid levels are about 70% of those in plasma. Ribavirin elimination is primarily through the urine; therefore, clearance is decreased in patients with creatinine clearances less than 30 mL/min.

Higher doses of ribavirin (ie, 1000–1200 mg/d, according to weight, rather than 800 mg/d) or a longer duration of therapy or both may be more efficacious in those with a lower likelihood of response to therapy (eg, those with genotype 1 or 4) or in those who have relapsed. This must be balanced with an increased likeli-hood of toxicity. A dose-dependent hemolytic anemia occurs in 10–20% of patients. Other potential adverse effects are depres-sion, fatigue, irritability, rash, cough, insomnia, nausea, and pruritus. Contraindications to ribavirin therapy include anemia, end-stage renal failure, ischemic vascular disease, and pregnancy. Ribavirin is teratogenic and embryotoxic in animals as well as mutagenic in mammalian cells. Patients exposed to the drug should not conceive children for at least 6 months thereafter.

NEW & INVESTIGATIONAL AGENTS

Among the agents for the treatment of HCV infection, those holding the greatest promise currently are the HCV NS3 protease inhibitors telaprevir and boceprevir. These highly potent agents are likely to decrease the overall duration of therapy, with possibly greater tolerability than current regimens. Another class of prom-ising agents is the HCV NS5B polymerase inhibitors, including both nucleoside and nonnucleoside analogs.