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A phase II dose‐escalating trial of clevudine in patients with chronic hepatitis B
Author(s) -
Marcellin Patrick,
MommejaMarin Herve,
Sacks Stephen L.,
Lau George K. K.,
Sereni Daniel,
Bronowicki JeanPierre,
Conway Brian,
Trepo Christian,
Blum M. Robert,
Yoo Byung Chul,
Mondou Elsa,
Sorbel Jeff,
Snow Andrea,
Rousseau Franck,
Lee HyoSuk
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20257
Subject(s) - medicine , hbeag , gastroenterology , hepatitis b virus , hepatitis b , coinfection , dosing , nucleoside analogue , immunology , hbsag , virology , nucleoside , virus , biology , biochemistry
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 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. (H EPATOLOGY 2004;40:140–148.)