对LAM耐药E-的HBV,ETV比LAM能提供相对安全更高组织学病毒学生化学反应

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In Patients with Lamivudine-resistant, HBeAg- positive HBV, Switching to Entecavir Provides Comparative Safety and Superior Histologic, Virologic, and Biochemical Response Compared to Continuing Lamivudine

Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) polymerase. This Phase III trial compared ETV 1.0 mg QD to LVD 100 mg QD for 48 weeks in LVD-refractory, HBeAg (+) chronic hepatitis B patients.

ETV-026 is a multinational, randomized, double-blind, Phase III trial (N=286 treated) in which lamivudine/LVD (Epivir-HBV)-refractory patients either switched to ETV or continued LVD. Patients were HBeAg (+) with HBV DNA > 3 MEq/mL (bDNA assay) and ALT levels 1.3-10 x ULN. LVD-refractory was defined as persistent viremia while on LVD with or without documented YMDD mutation (present in 85% of pts).

Co-primary endpoints, assessed independently with a Bonferroni adjustment, were the proportion of patients achieving (1) Histologic Improvement: a > 2 point decrease in Knodell necroinflammatory score and no worsening of fibrosis (worsening: > 1-point increase in Knodell fibrosis score), and (2) a Composite Endpoint: HBV DNA < 0.7 MEq/mL and ALT normalization.

Results

Mean baseline viral loads by PCR were ETV: 9.48 log10 c/mL; LVD: 9.24 log10 c/mL. Mean baseline ALTs were ETV: 124 U/L; LVD: 132 U/L. Results of primary and major secondary endpoints are shown below.

Study Endpoints at Week 48 (non-completer = failure)

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*Co-primary endpoints ?/sup>n=124 for ETV group and n=116 for LVD group (pts with evaluable histology) 噉=133 for ETV and n=128 for LVD with baseline and Week 48 results

HBeAg loss occurred in 10% and 3% of ETV and LVD patients, respectively (p=0.0278). A greater proportion of LVD than ETV patients were observed to have virologic non-response (HBV DNA > 0.7 MEq/mL) at Wk 48, and met protocol criteria to discontinue treatment.

Mutations associated with ETV resistance were infrequently observed.

Safety was comparable between groups: 10% and 8% of patients had serious adverse events in the ETV and LVD groups, respectively.

Conclusion

In patients with LVD-refractory chronic hepatitis B, switching to ETV provided superior histologic, virologic, and biochemical response compared to continuing LVD, with comparable safety.

Commentary

In an announcement, Bristol-Myers Squibb provided the following commentary on the results of the ETV-026 study:

揚atients treated with entecavir experienced a significant mean reduction in HBV DNA

(-5.14 log10 copies/mL) from baseline (a secondary endpoint of the study, measured by a common assay梡olymerase chain reaction or PCR) compared to patients who continued treatment with lamivudine (-0.48 log10 copies/mL) (p-value less than 0.0001).?/span>

Additionally, through 48 weeks of treatment, 21 percent of people in the entecavir arm had HBV DNA less than 400 copies/mL compared to 1 percent of people in the lamivudine arm (p-value less than 0.0001). Liver function test improvement (ALT normalization) at Week 48 occurred more frequently in patients taking entecavir (75 percent ) versus lamivudine (23 percent) (p-value less than 0.0001).?/span>

揝ignificantly more patients treated with entecavir (n=141), when compared to lamivudine (n=145), achieved loss of HBeAg (10 percent vs. 3 percent; p=0.028) and complete virologic response (9 percent vs. 1 percent; p=0.0008); however, seroconversion (8 percent vs. 3 percent; p=0.06) did not reach statistical significance. Complete virologic response was defined as HBV DNA less than 0.7 MEq/mL by branched chain DNA and loss of HBeAg.

揝afety was comparable between the treatment groups, with similar incidence of serious adverse events (10 percent with entecavir, 8 percent with lamivudine) and total adverse events (85 percent with entecavir, 81 percent with lamivudine). The most frequent adverse events (greater than or equal to 10 percent of patients on treatment) in this study included: upper respiratory infection (18 percent for entecavir vs. 11 percent for lamivudine), headache (17 percent, 17 percent), fatigue (13 percent, 11 percent), cough (12 percent, 10 percent), upper abdominal pain (9 percent, 13 percent), nausea (8 percent, 10 percent) and nasopharyngitis (9 percent, 10 percent).?/span>

11/03/04

Reference M Sherman and others (the BEHoLD Study Group). ENTECAVIR IS SUPERIOR TO CONTINUED LAMIVUDINE FOR THE TREATMENT OF LAMIVUDINE-REFRACTORY, HBEAG(+) CHRONIC HEPATITIS B: RESULTS OF PHASE III STUDY ETV-026. Abstract 1152 (poster). 55th AASLD. October 29-November 2, 2004. Boston, MA

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