Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 ุ 10 6 copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log 10 copies/mL. After 28 days, the median HBV DNA log 10 change from baseline was ุ2.5, ุ2.7, ุ3.0, and ุ2.6 log 10 . Six months after dosing, median changes from baseline were ุ1.2, ุ1.4, ุ2.7 and ุ1.7 log 10 in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no doselimiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study. (HEPATOLOGY 2004;40: 140 -148.)
H epatitis B virus (HBV) can lead to chronic hepatitis and cirrhosis with 350 million carriers worldwide. 1 Currently approved antiviral regimens have been shown to improve the short-term outcome of the disease in some patients; however, they lack the ability to provide a cure or durable remission in most patients who are chronically infected with HBV. 1 Currently approved drugs include interferon, lamivudine, and adefovir. Interferon can be administered only subcutaneously and is associated with frequent side effects. Lamivudine is an oral drug with a favorable safety profile; however, long-term therapy is required with this drug, which leads to the selection of drug-resistant mutants. 2 Adefovir is another oral drug that also requires long-term therapy. It has been shown to select for resistant mutants in a very limited proportion of patients. 3 Therefore, there is a need for developing new agents for the treatment of HBV infection with improved efficacy.
Clevudine [1-(2-deoxy-2-fluoro-โค-L-arabinofuranosyl) thymine] is a nucleoside analog of the unnatural โค-L configuration. Clevudine has potent activity against HBV and some activity against Epstein-Barr virus in vitro. 4,5 The 50% effective concentration for HBV inhibition values ranged from 0.02 M to 0.84 M in a variety of systems used to evaluate the inhibitory effect of clevudine on wild-type HBV. These values are comparable with Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis Be antigen; LOD, limit of detection.