恩替卡韦3期48周针对E阳性结果(11.1AASLD)

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Entecavir: new hepatitis B drug-phase III study results of 48-weeks therapy in HBeAg+ nucleoside-naïve patients Written by Jules Levin Results from 3 large phase III studies of entecavir are being presented at this conference (55th Annual American Association for the Study of Liver Diseases), as well as a number of substudies. At today's late afternoon oral sessions, Robert Gish reported results from ETV-022, a study in 700 patients comparing entecavir 0.5 mg once daily to lamivudine 100 mg once daily. This is an international randomized, double-dummy, double-blind study. Liver biopsies were performed within 52 weeks of randomization and at week 48. BRIEF SUMMARY: ETV showed superiority with histolpgic improvement (72% vs 62%; mean viral load reduction by PCR; -6.98 vs -5.46 log; undetectable HBV DNA by PCR: 69% vs 38%; ALT normalization: 78% vs 79% <400 c/ml; (all significant). Loss of HBeAg & seroconversion were similar for both groups; safety profile was similar for both; fewer discontinuations due to adverse events for ETV; fewer ALT flares observed both on & off treatment for ETV; entecavir resistance was not observed. Up to 14 log viral load reductions were observed. Patients were HBsAg+ for >24 weeks prior to screening for study; HBeAg-positive; HBV DNA >3 MEq/mL (by DNA); serum ALT 1.3-10 x ULN; compensated liver function; nucleoside-naïve (<12 weeks of therapy); last dose of anti-HBV therapy >24 weeks prior to randomization; I think Gish said 13% of patients had previously used IFN. 75% were men. Mean 35 yrs old. 40% Caucasian, 57% Asian. REGION: 24% Europe; 48% Asia; 13% North America; 13% South America. BASELINE HISTOLOGY: comparable between arms Knodell Necroinflammatory Score (0-18) Mean: --Entecavir 7.8 --Lamivudine 7,7 Knodell Fibrosis Score (0-4) Mean: ETV 1.7, LAM 1.7 score >=3 --entecavir 34% --lamivudine 32% score=4, cirrhosis --entecavir 8% --lamivudine 8% Ishak Fivbrosis Score (0-6) Mean Score >=5, cirrhosis --entecavir & LAM: 8% HISTOLOGIC IMPROVEMENT (primary efficacy endpoint) Week 48 Improvement in Knodell necroinflammatory score by at least two points, plus no worsening of Knodell fibrosis score IMPROVEMENT ETV (n=314): 72% LAM (n=314): 62% P=0.0085 NO IMPROVEMENT ETV: 21% LAM: 24% IMPROVEMENT IN ISHAK FIBROSIS SCORE Week 48 Secondary Histologic Endpoint ETV: 39% LAM: 35% NS NO CHANGE ETV: 46% LAM: 40% PROPORTION OF PATIENTS WORSENED ETV: 8% LAM: 10% MEAN CHANGE in HBV DNA from baseline by PCR ETV: -6.98 log copies/ml LAM: -5.46 log copies/ml P<0.0001 PROPORTION OF PATIENTS with HBV DNA <400 Copies/ml at Week 48 ETV: 69% LAM: 38% P<0.0001 PROPORTION of PATIENTS with ALT NORMALIZATION (<1.25 x ULN) ETV: 78% LAM: 70% P=0.014 LOSS of HBeAg & SEROCONVERSION at week 48 LOSS OF HBeAg ETV: 22% LAM: 20% NS SEROCONVERSION ETV: 21% LAM: 18% NS MOST FREQUENT ADVERSE EVENTS ON TREATMENT Comparable across arms Headache 21% URI 17-20% Cough 12-15% Nasopharyngitis 14% Abdominal pain, upper 10% Fatigue 10% Fever 10-9% CUMULATIVE SAFETY PROFILE ETV LAMAny AE 85% 83%SAE 7% 7%G3/4 AE 13% 15%D/C AE <1% 3%Deaths 0 1% ALT FLARES 12 (3%) patients treated with ETV had on treatment ALT flares: 9/12 occurred between day 9 & 98 of treatment; 11/12 were self-limiting on continued therapy, resolving in 2 to 7 weeks. None of the ETV-treated patients had hepatic decompensation. 2 off treatment ALT flares. 20 (6%) patients treated with LAM had on-treatment ALT flares. 8 off treatment ALT flares. On treatment ALT flare: ALT >2 x baseline and >10 x ULN Off treatment ALT flare: ALT >2 reference (minimum of baseline and dosing) and >10 x ULN PATIENT ENDPOINT MANAGEMENT Complete Virologic Response HBV DNA <0.7 q/mL by bDNA & loss of HBeAg ETV: 21% LAM: 19% Virologic response Only HBV DNA <0.7 MEq/mL by bDNA but positive for HBeAg ETV: 70% LAM: 46% Virologic Non-response HBV DNA >0.7 MEq/mL by bDNA ETV: 5% LAM: 26%

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恩替卡韦3期48周针对E阳性结果(11.1AASLD) Entecavir: new hepatitis B drug-phase III study results of 48-weeks therapy in HBeAg+ nucleoside-naïve patients

700位病人参加恩替卡韦 0.5 mg/天和拉米夫丁100 mg/天的试验. 本试验为国际型双盲试验.48周和52周随即进行肝脏活检.

简要概括: ETV 的组织学改善较拉米优越.(72% vs 62%; PCR法平均病毒载量; -6.98 vs -5.46 log; PCR法不可测得HBV DNA : 69% vs 38%; ALT 正常率: 78% vs 79% <400 c/ml; . 两组的E抗原&血清转换相近; 安全性相近; 少数由于副反应剧烈而中止; ETV治疗过程中或结束较少的发作; 恩替的耐药没有发现. 超过14 log 的病毒数消失.

研究前病人的表抗+必须超过24周; E抗原为阳; HBV DNA >3 MEq/mL (by DNA); serum ALT 1.3-10 x ULN; 肝功能代偿; 韦经过核苷类治疗 (12 周内的治疗); 随机前采用抗病毒治疗已超过24周; 我认为 Gish 说 13% 的病人曾经采用干扰素进行治疗. 75% 的男性中平均年龄为35岁. 40% 为高加索人, 57% 为亚洲人. 地区分布: 24% 欧洲; 48% 亚洲; 13% 北美; 13% 南美.