新药跟踪:对于阿迪福韦用药48周以上的研究

liver411

(希望大家能帮助大家翻译,谢谢)

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

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.