Marcellin Patrick, Mommeja-Marin Herve, Sacks Stephen L, Lau George K K, Sereni Daniel, Bronowicki Jean-Pierre, Conway Brian, Trepo Christian, Blum M Robert, Yoo Byung Chul, Mondou Elsa, Sorbel Jeff, Snow Andrea, Rousseau Franck, Lee Hyo-Suk
Service d'Hépatologie, Hopital Beaujon, Clichy, France.
Hepatology. 2004 Jul;40(1):140-8. doi: 10.1002/hep.20257.
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.
目前可用于治疗慢性乙型肝炎的疗法在实现治愈方面的能力有限。克来夫定是一种新型嘧啶类似物，在体外具有强大的抗乙型肝炎病毒（HBV）活性。一项多中心剂量递增研究评估了克来夫定每日一次，剂量分别为10、50、100和200毫克，持续28天。符合条件的患者HBV DNA水平为3×10⁶拷贝/毫升或更高，未接受过核苷治疗，且未合并人类免疫缺陷病毒或丙型肝炎病毒感染。共纳入32例患者（10毫克、50毫克、100毫克和200毫克剂量组分别为5例、10例、10例和7例），81%为男性，81%为亚洲人，88%在基线时乙肝e抗原（HBeAg）呈阳性。治疗前血清HBV DNA水平中位数在7.3至8.8 log₁₀拷贝/毫升之间。28天后，HBV DNA log₁₀较基线的变化中位数分别为-2.5、-2.7、-3.0和-2.6 log₁₀。给药6个月后，10毫克、50毫克、100毫克和200毫克队列较基线的变化中位数分别为-1.2、-1.4、-2.7和-1.7 log₁₀。27例患者中有6例HBeAg消失，27例患者中有3例血清转换为HBe抗体。克来夫定耐受性良好，无剂量限制性毒性。在100毫克队列的6例患者中观察到谷丙转氨酶短暂升高至正常上限的7.8倍（升高范围为20至186 IU/L），无肝衰竭迹象。这些升高与病毒抑制改善相关。克来夫定的药代动力学特征与剂量成正比。总之，这些结果证明了克来夫定在HBV感染患者中的耐受性和强大活性，并支持进一步的临床研究。
