Hepsera(阿迪福韦)持续48周以上用药研究

Hepsera(阿迪福韦)10mg剂量用于HbeAG阳性慢性乙肝病人治疗：功效持续48周以上

　　慢性乙型肝炎(CHB)是一个重大的全球性健康问题，是导致肝硬化和肝细胞癌的首要原因。阿迪福韦(ADV)是一种核苷类似物，在体内和体外都有效，具有抗野生型和拉米夫定抗药性HBV活性。

　　当前研究的目的是评估采用ADV 10mg剂量，治疗HbeAg阳性的慢性乙肝病人48周以上的安全性和功效（研究437）。

　　试验选择HbeAg阳性、血清HBV DNA≧10⁶ copies/mL、ALT在1.2~10倍正常值上限(ULN)的病人，随机按1:1:1比例分为ADV（10mg或30mg每天）或者安慰剂(PLB)三组。48周后，安慰剂组病人切换到ADV 10mg；ADV 30mg病人组切换到使用安慰剂，ADV 10mg病人组再次随机分为两组：一组持续采用ADV 10mg，一组采用安慰剂，所有组都再进行第二个48周试验。

　　在第二个48周评定血清HBV DNA(Roche Amplicor, LLQ 400 copies/mL)、ALT和HbeAg。包含使用干扰素治疗失败或接受可达12周的拉米夫定治疗的病人，允许与本研究项目相隔6个月以上。(?)

　　全球范围内有78个试验点、515名具有肝功代偿功能的HbeAg阳性病人参加了此次试验。基线统计数据包括：380名男性(占74%)、135名女性(占26%)，平均年龄34.8±11.2岁。有306名亚裔(占59%)，185名白人(占36%)，17名黑人(占3%)及7名其他种族人(占1%)。

　　48周时，435名病人再次随机分为两组：持续采用ADV 10 mg (n =85) 或者安慰剂 (n =212)。138名病人从安慰剂切换到ADV 10 mg。此次分析中，48周以外附加治疗的中值时间是16.1周（范围从8.1到27.3周）。

　　持续采用ADV 10 mg治疗的中值持续时间为15.6周。基线统计ADV 10 mg组的HBV DNA中值为8.4 log10 copies/mL、中值ALT为2.3倍正常值上限，安慰剂组中值HBV DNA为8.4 log10 copies/mL、中值ALT为2.4倍正常值上限。

　　48周后，ADV 10 mg组中21%的病人HBV DNA小于400 copies/mL，对照安慰剂组中没有1人达到此效果。ADV 10 mg组48%的病人ALT恢复正常，对照安慰剂组中为16%。48周时ADV 10 mg组中12%的病人经历了HbeAg血清转化，对照安慰剂中为6%。

　　中期分析在60周时，从超过48周后持续使用ADV 10 mg的病人组中证明血清HBV DNA中值较48周基线值（中值5.17 log10 copies/mL）下降-0.13 log10 copies/mL(n = 54)，72周时下降-0.21 log10 copies/mL。

　　在接受第二个48周治疗中，71名血清HBV DNA水平大于400 copies/mL病人持续采用ADV 10 mg，在他们最终评估时有15名(21%)血清HBV DNA l降到400 copies/mL以下。

　　在第一个48周治疗后74名保持HbeAg阳性的病人中间，ADV组中另外有4名(占5%)经历了HbeAg血清转化。48周时ADV 10 mg组85人中41名ALT大于正常上限值的病人，在中期分析时有11人(27%)ALT正常化。

　　另外，在研究437中的预期病毒学子研究项目中鉴定出，在采用长达48周的ADV治疗的HbeAg阳性慢性乙肝病人中，没有产生与adefovir抗药性有关的HBV突变。

　　结论：对HbeAg阳性慢性乙肝病人采用ADV 10 mg持续治疗超过48周，可对HBV DNA和ALT水平产生额外的抑制效果，并促进HbeAg血清转化。病毒生化和血清学指标保持不变和持续改善，可能归因于没有抗药性发展。

　　本次研究将持续长达5年时间，以评估每日采用ADV 10 mg的安全性和功效，并观察可能的抗药性发展。

　　01/20/03

（此文由本站草译，若有纰漏敬请指出）

　　附英文原文：（Liver411发于HBVHBV论坛）

　　Hepsera (Adefovir Dipivoxil) 10 mg for Treatment of Patients with HBeAG+ Chronic Hepatitis B: Efficacy Continues Beyond 48 Weeks

　　Chronic hepatitis B (CHB) is an important global health issue and a leading cause of cirrhosis and hepatocellular carcinoma. ADV is a nucleotide analogue with potent in vivo and in vitro activity against wild type and lamivudine- resistant HBV.

　　The objectives of the current study are to evaluate the safety and efficacy of treatment with adefovir dipivoxil (ADV) 10 mg beyond 48 weeks in patients with HBeAg+ chronic hepatitis B (Study 437).

　　Patients with HBeAg+ CHB and serum HBV DNA >=106 copies/mL with ALT 1.2-10 x the upper limit of normal (ULN) were randomized to ADV (10 mg or 30 mg daily) or placebo (PLB) in a 1:1:1 ratio. After 48 weeks (wk) PLB patients switched to ADV 10 mg; ADV 30 mg patients switched to PLB and ADV 10 mg patients were re-randomized to continued ADV 10 mg or to PLB, all for an additional 48 wk.

　　Serum HBV DNA (Roche Amplicor, LLQ 400 copies/mL), ALT and HBeAg were assessed in the second 48 wk. Inclusion of patients who previously failed interferon therapy or received up to 12 wk lamivudine therapy > 6 months prior to study entry was allowed.

　　Five hundred fifteen HBeAg+ patients with compensated liver function were enrolled at 78 sites worldwide. Baseline demographics included: 380 males (74%) and 135 females (26%) with a mean age of 34.8+/-11.2 years. There were 306 (59%) Asian patients,185 Caucasian (36%), 17 Black (3%) and 7 other (1%).

　　At wk 48, 435 patients were re-randomized to continued ADV 10 mg (n =85) or PLB (n =212). 138 patients switched from PLB to ADV 10 mg. For this analysis, the median time of additional treatment beyond 48 wk was 16.1 wk (range of 8.1 to 27.3 wk).

　　The median duration of continued treatment with ADV 10 mg was 15.6 wk (range of 7.6 to 24.3 wk). At baseline in the ADV 10 mg group the median HBV DNA was 8.4 log10 copies/mL and the median ALT was 2.3 x ULN and in the PLB group the median HBV DNA was 8.4 log10 copies/mL and ALT 2.4 x ULN.

　　After 48 wk, 21% of ADV 10 mg patients had HBV DNA < 400 copies/mL compared to none receiving PLB. ALT normalized in 48% of the ADV 10 mg group compared to 16% in PLB. At wk 48 12% of ADV 10 mg patients had undergone HBeAg seroconversion compared to 6% of PLB patients.

　　At the time of the interim analysis, patients continuing ADV 10 mg beyond wk 48 demonstrated a median decline in serum HBV DNA from the 48 wk baseline (median 5.17 log10 copies/mL) of -0.13 log10 copies/mL at wk 60 (n = 54) and -0.21 log10 copies/mL at wk 72 (n = 29).

　　Among 71 patients with serum HBV DNA levels > 400 copies/mL at the beginning of the second 48 wk, 15 (21%) on continued ADV 10 mg had serum HBV DNA levels < 400 copies/mL at their last evaluation.

　　Among 74 patients who remained HBeAg positive during the first 48 wk, an additional 4 (5%) in the ADV group had undergone HBeAg seroconversion. ALT values were > ULN in 41 of 85 patients on ADV 10 mg at wk 48 but normalized in 11 (27%) at the time of the interim analysis.

　　In addition, the prospective virology surveillance substudy of Study 437 identified no HBV mutations associated with resistance to adefovir in HBeAg positive CHB patients with up to 48 wk of treatment with ADV.

　　Conclusion: Continued treatment of HBeAg positive CHB patients with ADV 10 mg beyond 48 weeks resulted in additional suppression in serum HBV DNA and ALT levels, and further HBeAg seroconversion. The sustained and continued improvement in virological, biochemical, and serological parameters may be due to the absence of resistance development.

　　This study will continue for up to 5 years duration to evaluate the long-term safety and efficacy of daily ADV 10 mg and to observe for the potential development of resistance.

　　01/20/03

　　Reference

　　Patrick Marcellin and others. ADEFOVIR DIPIVOXIL (ADV) 10 MG FOR THE TREATMENT OF PATIENTS WITH HBeAG+ CHRONIC HEPATITIS B: CONTINUED EFFICACY BEYOND 48 WEEKS. Abstract 840. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.