Experimental Drugs for HBV Infection4

liver411

Entecavir



Early Study Results Suggest Experimental Drug Entecavir Is Safe and Effective for Treatment of Hepatitis B Virus (HBV) Infection, But Clinical Trials Now on Hold



By Brian Boyle, MD



Chronic hepatitis B virus (HBV) infection is a significant cause of morbidity and mortality worldwide. Current estimates are that there are more than 300 million HBV-infected persons and that many of these individuals will eventually suffer HBV-related cirrhosis or hepatocellular carcinoma.



Currently approved treatments for HBV include interferon and Epivir (lamivudine), but due to problems with efficacy and resistance, it is clear that additional therapies are needed. In the Woodchuck model, entecavir, a new deoxyguanine nucleoside analog, is an efficient inhibitor of HBV replication with low apparent toxicity.



To evaluate the safety and efficacy of entecavir in humans a multicenter, placebo-controlled, dose-escalating study was performed. Forty-two patients were enrolled and 34 patients were assigned to receive entecavir (either 0.05, 0.1, 0.5, or 1.0 mg once daily orally) and 8 a placebo for 4 weeks. Each enrolled patient had to have an HBV DNA greater than 20 MEq/mL by branched chain DNA (bDNA) assay on 2 different occasions at least 2 weeks apart and compensated liver disease. Patients were eligible regardless of the presence or absence HBeAg or prior therapy for HBV, but were excluded if positive for hepatitis C virus, hepatitis D virus or HIV.



All patients that received entecavir experienced a significant decline in HBV DNA while the group that received placebo experienced virtually no change in HBV DNA levels. Entecavir-treated patients that received 0.05, 0.1, 0.5, and 1.0 mg once daily had mean HBV DNA decreases of 2.21, 2.29, 2.81 and 2.55 log10 copies/mL, respectively, and 25%, 25%, 33% and 13%, respectively, achieved an undetectable HBV DNA during entecavir treatment.



Decreases of HBV viral load were similar between pretreated and naïve patients. In the first 4 weeks following therapy, HBV levels were significantly lower in the patients treated with higher doses of entecavir (0.5 and 1.0 mg daily) then in those patients treated with lower doses (0.05 and 0.1 mg daily). There were no significant differences in decreases in ALT between the treated and placebo patients. A transient loss of HBeAg occurred in 2 patients.



Overall, entecavir was well tolerated and no dose-related or dose-limiting side effects were observed. The most common side effects reported were fatigue and headache.



[Preliminary results of this study were presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Toronto, Canada, September 17-20, 2000].



Based upon these very short-term treatment data, entecavir appears to be a potent suppressor of HBV and to be very promising in the treatment of chronic HBV infection. Larger human studies are needed to clearly establish the efficacy and safety of entecavir, and given the limited treatment options available for chronic HBV, they will be anxiously awaited.



Editor's Note: Bristol-Myers Squibb (BMS) has put a temporary hold on clinical studies of entecavir pending an analysis of the results of animal studies of the drug's potential carcinogenecity. More information may become available within the next 60 days, according to BMS. RB



9/10/01



References

R DE Man and others. Safety and Efficacy of Oral Entecavir Given for 28 Days in Patients with Chronic Hepatitis B Virus Infection. Hepatology. 2001; 34:578-82.