title: A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B.
abstract: 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 x 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 dose-limiting 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.
authors.affiliation: Service d'Hépatologie, Hopital Beaujon, Clichy, France. marcellin@bichat.inserm.fr
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Herve
authors.initials: H
authors.lastname: Mommeja-Marin
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sacks
authors.forename: George K K
authors.initials: GK
authors.lastname: Lau
authors.forename: Daniel
authors.initials: D
authors.lastname: Sereni
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.forename: Brian
authors.initials: B
authors.lastname: Conway
authors.forename: Christian
authors.initials: C
authors.lastname: Trepo
authors.forename: M Robert
authors.initials: MR
authors.lastname: Blum
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Yoo
authors.forename: Elsa
authors.initials: E
authors.lastname: Mondou
authors.forename: Jeff
authors.initials: J
authors.lastname: Sorbel
authors.forename: Andrea
authors.initials: A
authors.lastname: Snow
authors.forename: Franck
authors.initials: F
authors.lastname: Rousseau
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000914:Antibodies, Viral / Q000032:analysis; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001086:Arabinofuranosyluracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019540:Area Under Curve; D004279:DNA, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D005838:Genotype; D006513:Hepatitis B e Antigens / Q000032:analysis / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D001086:Arabinofuranosyluracil; D000410:Alanine Transaminase; C034935:clevudine