Mills Anthony, Crofoot Gordon, McDonald Cheryl, Shalit Peter, Flamm Jason A, Gathe Joseph, Scribner Anita, Shamblaw David, Saag Michael, Cao Huyen, Martin Hal, Das Moupali, Thomas Anne, Liu Hui C, Yan Mingjin, Callebaut Christian, Custodio Joseph, Cheng Andrew, McCallister Scott
*Gordon Crofoot Research, Southern California Men's Medical Group/Men's Health Foundation, Assistant Professor of Clinical Medicine, Univeristy of California, Los Angeles, Los Angeles, CA; †Houston, TX; ‡Tarrant County Infectious Disease Associates, Fort Worth, TX; §Clinical Associate Professor in the Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA; ‖Kaiser Permanente, Sacramento, CA; ¶Therapeutic Concepts, Houston, TX; #DCOL Center for Clinical Research, Longview, TX; **La Playa Medical Group and Clinical Research, San Diego, CA; ††Center for AIDS Research, The University of Alabama at Birmingham, Birmingham, AL; and ‡‡Gilead Sciences, Foster City, CA.
J Acquir Immune Defic Syndr. 2015 Aug 1;69(4):439-45. doi: 10.1097/QAI.0000000000000618.
To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor-based single-tablet regimen (STR) for initial treatment of HIV-1 infection.
Antiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥ 70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAF: N = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDF: N = 50) once daily with matched placebos for 48 weeks.
At week 24, viral suppression (HIV-1 RNA <50 copies/mL) rates were similar (TAF 74.8% vs. TDF 74.0%). At week 48, rates were TAF 76.7% vs. TDF 84.0%; the difference was driven by higher rate of discontinuations in TAF (6.8%) vs. TDF (2%). Among those with virologic failure, none developed resistance. Most adverse events were of mild/moderate severity. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% confidence interval: 0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% confidence interval: 0.05 to 0.14) for TDF (P = 0.053). The % change in retinol binding protein/Cr ratio was +9 (TAF) vs. +54 (TDF), P = 0.003; the % change in urine β-2 microglobulin/Cr ratio was -42.0 (TAF) vs. +2.3 (TDF), P = 0.002. The % change in hip bone mineral density (BMD) was -0.84 (TAF) vs. -3.82 (TDF), P < 0.001 and in spine BMD was -1.57 (TAF) vs. -3.62 (TDF), P = 0.003. There were no fractures in either group.
The TAF arm had significantly improved renal and bone safety parameters: less proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir/C/F/TAF STR. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with TAF.
评估新型替诺福韦前药替诺福韦艾拉酚胺（TAF）作为首个基于蛋白酶抑制剂的单片复方制剂（STR）用于初治HIV-1感染的安全性和有效性。
估算肾小球滤过率≥70 mL/min的初治抗逆转录病毒治疗（ART）成人患者按2:1随机分组，接受每日一次的达芦那韦/考比司他/恩曲他滨/替诺福韦艾拉酚胺（D/C/F/TAF）STR（TAF组：N = 103）或达芦那韦+考比司他+恩曲他滨/富马酸替诺福韦二吡呋酯（TDF组：N = 50），并匹配安慰剂，治疗48周。
在第24周时，病毒抑制（HIV-1 RNA<50拷贝/mL）率相似（TAF组为74.8%，TDF组为74.0%）。在第48周时，TAF组为76.7%，TDF组为84.0%；差异是由于TAF组（6.8%）的停药率高于TDF组（2%）。在病毒学失败的患者中，无人产生耐药性。大多数不良事件为轻/中度严重程度。第48周时，TAF组血清肌酐相对于基线的平均变化为0.06 mg/dL（95%置信区间：0.04至0.08），TDF组为0.09 mg/dL（95%置信区间：0.05至0.14）（P = 0.053）。视黄醇结合蛋白/Cr比值的变化百分比为TAF组+9，TDF组+54，P = 0.003；尿β-2微球蛋白/Cr比值的变化百分比为TAF组-42.0，TDF组+2.3，P = 0.002。髋部骨密度（BMD）的变化百分比为TAF组-0.84，TDF组-3.82，P<0.001；脊柱BMD的变化百分比为TAF组-1.57，TDF组-3.62，P = 0.003。两组均无骨折发生。
TAF组在肾脏和骨骼安全性参数方面有显著改善：蛋白尿减少，髋部和脊柱BMD变化较小，这与elvitegravir/C/F/TAF STR的类似设计研究结果一致。这种D/C/F/TAF STR为初治HIV提供了一个有前景的选择，具有达芦那韦的高耐药屏障，以及TAF改善长期肾脏和骨骼安全性的潜力。
