Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Lancet. 2015 Jun 27;385(9987):2606-15. doi: 10.1016/S0140-6736(15)60616-X. Epub 2015 Apr 15.
Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens.
In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445.
We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks.
Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile.
Gilead Sciences.
富马酸替诺福韦二吡呋酯会引起与高血浆替诺福韦浓度相关的肾毒性和骨毒性作用。替诺福韦艾拉酚胺是一种新型的替诺福韦前药，其血浆替诺福韦浓度降低了 90%。与富马酸替诺福韦二吡呋酯相比，含替诺福韦艾拉酚胺的方案具有更好的肾安全性和骨安全性。
在这两项对照、双盲的 3 期研究中，我们从 16 个国家的 178 个门诊中心招募了估计肌酐清除率为 50 mL/min 或更高的未经治疗的 HIV 感染患者。患者被随机分配（1:1）接受每日一次口服片剂，包含 150 mg 艾维雷韦、150 mg 考比司他、200 mg 恩曲他滨和 10 mg 替诺福韦艾拉酚胺（E/C/F/替诺福韦艾拉酚胺）或 300 mg 富马酸替诺福韦二吡呋酯（E/C/F/富马酸替诺福韦二吡呋酯），并用匹配的安慰剂。随机化由计算机生成的分配序列（块大小 4）和 HIV-1 RNA、CD4 计数和区域（美国或非美国）分层。研究者、患者、研究人员和评估结果的人员对治疗组进行了盲法。所有接受一剂研究药物的参与者均纳入主要的意向治疗疗效和安全性分析。主要结局是 48 周时美国食品和药物管理局（FDA）快照算法（预先指定的非劣效性边界为 12%）定义的血浆 HIV-1 RNA 小于 50 拷贝/ml 的患者比例和预先指定的 48 周时的肾和骨终点。这些研究在 ClinicalTrials.gov 上注册，编号为 NCT01780506 和 NCT01797445。
我们于 2013 年 1 月 22 日至 2013 年 11 月 4 日招募了患者（筛选了 2175 人，随机分配了 1744 人），并给 1733 名患者进行了治疗（866 名给予 E/C/F/替诺福韦艾拉酚胺，867 名给予 E/C/F/富马酸替诺福韦二吡呋酯）。E/C/F/替诺福韦艾拉酚胺与 E/C/F/富马酸替诺福韦二吡呋酯相比不劣效，替诺福韦艾拉酚胺组的 866 名患者中有 800 名（92%）和富马酸替诺福韦二吡呋酯组的 867 名患者中有 784 名（90%）的血浆 HIV-1 RNA 小于 50 拷贝/ml（调整差异 2.0%，95%CI-0.7 至 4.7）。给予 E/C/F/替诺福韦艾拉酚胺的患者血清肌酐升高的平均幅度明显小于给予 E/C/F/富马酸替诺福韦二吡呋酯的患者（0.08 比 0.12 mg/dL；p<0.0001），蛋白尿的中位数变化明显较小（-3%比 20%；p<0.0001），在 48 周时脊柱（平均百分比变化-1.30 比-2.86；p<0.0001）和髋关节（-0.66 比-2.95；p<0.0001）的骨密度下降幅度明显较小。
通过 48 周，超过 90%的接受 E/C/F/替诺福韦艾拉酚胺或 E/C/F/富马酸替诺福韦二吡呋酯治疗的患者实现了病毒学成功。给予 E/C/F/替诺福韦艾拉酚胺的患者肾和骨的影响明显减轻。尽管这些研究没有评估肾衰竭和骨折等临床安全事件的能力，但我们的数据表明，E/C/F/替诺福韦艾拉酚胺将具有良好的长期肾和骨安全性。
吉利德科学公司。
