TDF治疗LAM耐药的疗效和安全终获肯定

[AASLD 2012] 2012-11-21
尽管体外研究显示，对于拉米夫定耐药（Lamivudine Resistance，LAM-R）的HBV病毒株替诺福韦（Tenofovir DF，TDF）的活性好，但是关于它在治疗LAM-R患者的疗效方面缺乏一个前瞻性随机研究。

美国肝病研究学会（AASLD）第63届年会上，来自加拿大多伦多总医院的一项双盲、随机、3b期临床试验，比较了接受LAM治疗的慢性HBV感染者应用TDF与FTC/TDF的疗效。

研究发现，LAM-R的患者应用TDF治疗96周可以有效抑制HBV DNA复制，且并未检测出有TDF耐药。这类人群应用TDF单药与联合其他药物辅助TDF治疗的疗效相当。TDF的安全高，耐受性好，肾脏相关副反应发生率低和未发现临床有意义的骨丢失。

研究论文摘要

Efficacy and Safety of Tenofovir DF (TDF) in Chronic Hepatitis B Virus Infected Patients with Documented Lamivudine Resistance (LAM-R)

Background: TDF has demonstrated excellent efficacy and safety through 5 years in treatment-naïve chronic HBV patients in Studies 102/103. Although TDF is active in vitro vs. LAM-R HBV, its efficacy has not been established in LAM-R patients in a prospective, randomized trial.

Methods: Phase 3b, doubleblind, randomized (1:1) comparison of TDF and FTC/TDF in chronic HBV patients receiving LAM at time of screening with HBV DNA ≥103 copies/mL and documented LAM-R (INNOLiPA HBV, v2/v3). Patients were stratified at entry by ALT (≥ or< 2 x ULN) and HBeAg status and assessed for efficacy and
safety over 96 weeks including bone mineral density (BMD) monitoring by DXA.

Results: 280 patients were randomized and treated; 133/141 (94%) and 125/139 (90%) in the TDF and FTC/TDF groups, respectively, completed 96 weeks. Baseline(BL) demographics included: mean age 47 years, 75% males, 34% Asians; HBV genotypes: A 22%, B 14%, C 19%,and D 45%. Mean (SD) baseline HBV DNA was 6.5 (1.9) log10copies/mL; 42% had ALT ≤ ULN. Efficacy results (missing=failure) at Week 96 are shown in the table. Both treatments were well tolerated with 1% (3/280) discontinuing for an AE (1-TDF,2-FTC/TDF). No patients had a confirmed increase in serum creatinine of ≥ 0.5 mg/dL from BL, 1% (2-TDF) had serum phosphorus<2 mg/dL, and 3% (5-TDF, 4-FTC/TDF) had CrCL <50
mL/min (pre-treatment CrCL range for these 9 patients: 49-61mL/min). No clinically relevant bone loss was observed by assessment of spine and hip BMD T and Z scores, and there were no non-traumatic fractures reported. No resistance to TDF was detected through 96 weeks.

Conclusions: A high rate of HBV DNA suppression with no detectable TDF resistance was achieved with TDF in patients with documented LAM-R through 96 weeks. Similar efficacy between the mono- and combination therapy arms supports the use of TDF monotherapy in this population. TDF was safe and well tolerated, with a low rate of renal events and no evidence of clinically relevant bone loss.