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A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B

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Title: A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B
Authors: Yoo, BC, Marcellin, P, Mommeja-Marin, H, Sacks, SL, Lau, GKK, Sereni, D, Bronowicki, JP, Conway, B, Trepo, C, Blum, MR, Mondou, E, Sorbel, Jeff, Snow, A, Rousseau, F, Lee, HS
Source: Hepatology. 40:140-148
Publisher Information: Ovid Technologies (Wolters Kluwer Health), 2004.
Publication Year: 2004
Subject Terms: Adult, Male, Hepatitis B virus, Genotype, Gene Dosage, Antiviral Agents - administration & dosage - adverse effects - pharmacokinetics, Chronic - blood - drug therapy - immunology - virology, Antibodies, Viral, Antiviral Agents, Antibodies, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Arabinofuranosyluracil - administration & dosage - adverse effects - analogs & derivatives - pharmacokinetics, Predictive Value of Tests, Viral analysis, Humans, Hepatitis B e Antigens, Hepatitis B, Chronic - blood - drug therapy - immunology - virology, Dose-Response Relationship, Drug, Antibodies, Viral analysis, Arabinofuranosyluracil, Alanine Transaminase, Middle Aged, Hepatitis B, 3. Good health, Alanine Transaminase blood, Treatment Outcome, Area Under Curve, DNA, Viral, Female, Follow-Up Studies
Description: 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 × 106 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 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 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. (Hepatology 2004;40:140-148.)
Document Type: Article
Language: English
ISSN: 0270-9139
DOI: 10.1002/hep.20257
Access URL: https://aasldpubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hep.20257
https://pubmed.ncbi.nlm.nih.gov/15239097
https://pubmed.ncbi.nlm.nih.gov/15239097/
https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20257
https://onlinelibrary.wiley.com/doi/abs/10.1002/hep.20257
https://www.ncbi.nlm.nih.gov/pubmed/15239097
https://hub.hku.hk/handle/10722/224813
https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.20257
http://hdl.handle.net/10722/224813
Rights: Wiley TDM
Accession Number: edsair.doi.dedup.....100f804130c75f10b749cf34a9275cba
Database: OpenAIRE
Description
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 × 106 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 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 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. (Hepatology 2004;40:140-148.)
ISSN:02709139
DOI:10.1002/hep.20257