Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Infectious Diseases, College of Health Sciences at Makerere University, Kampala, Uganda.
J Acquir Immune Defic Syndr. 2019 Feb 1;80(2):224-233. doi: 10.1097/QAI.0000000000001908.
Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF).
HIV-1-infected treatment-naive adults in India, South Africa, and Uganda.
A phase-4, 96-week, randomized, double-blind, noninferiority trial compared d4T 20 mg twice daily and TDF, taken in combination with lamivudine (3TC) and efavirenz (EFV). The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies per milliliter at 48 weeks. Adverse events assessments included measures of bone density and body fat. The trial is registered on Clinicaltrials.gov (NCT02670772).
Between 2012 and 2014, 536 participants were recruited per arm. At week 96, trial completion rates were 75.7% with d4T/3TC/EFV (n = 406) and 82.1% with TDF/3TC/EFV (n = 440, P = 0.011). Noncompletion was largely due to virological failure [6.2% (33) with d4T/3TC/EFV versus 5.4% (29) with TDF/3TC/EFV; P = 0.60]. For the primary endpoint, d4T/3TC/EFV was noninferior to TDF/3TC/EFV (79.3%, 425/536 versus 80.8% 433/536; difference = -1.49%, 95% CI: -6.3 to 3.3; P < 0.001). Drug-related adverse event discontinuations were higher with d4T (6.7%, 36), than TDF (1.1%, 6; P < 0.001). Lipodystrophy was more common with d4T (5.6%, 30) than TDF (0.2%, 1; P < 0.001). Creatinine clearance increased in both arms, by 18.1 mL/min in the d4T arm and 14.2 mL/min with TDF (P = 0.03). Hip bone density measures, however, showed greater loss with TDF.
Low-dose d4T combined with 3TC/EFV demonstrated noninferior virological efficacy compared with TDF/3TC/EFV, but mitochondrial toxicity remained high. Little renal toxicity occurred in either arm. Implications of bone mineral density changes with TDF warrant investigation.
降低包括司他夫定（d4T）在内的抗逆转录病毒药物剂量可能会降低毒性，同时保持疗效。替诺福韦二吡呋酯富马酸（TDF）存在严重的肾毒性和骨毒性担忧。
印度、南非和乌干达的未经治疗的 HIV-1 感染成人。
一项为期 96 周的 4 期、随机、双盲、非劣效性试验比较了每日两次 20 毫克司他夫定和 TDF，与拉米夫定（3TC）和依非韦伦（EFV）联合使用。主要终点是第 48 周时 HIV-1 RNA<50 拷贝/毫升的参与者比例。不良事件评估包括骨密度和体脂测量。该试验在 Clinicaltrials.gov 注册（NCT02670772）。
在 2012 年至 2014 年间，每个手臂招募了 536 名参与者。在第 96 周时，d4T/3TC/EFV 组的试验完成率为 75.7%（n=406），TDF/3TC/EFV 组为 82.1%（n=440，P=0.011）。未完成主要原因是病毒学失败[6.2%（33）与 d4T/3TC/EFV 相比，5.4%（29）与 TDF/3TC/EFV；P=0.60]。对于主要终点，d4T/3TC/EFV 与 TDF/3TC/EFV 相当（79.3%，425/536 与 80.8%，433/536；差异=-1.49%，95%CI：-6.3 至 3.3；P<0.001）。与 TDF 相比，d4T（6.7%，36）相关的药物不良反应停药率更高（1.1%，6；P<0.001）。脂肪营养不良在 d4T 组更常见（5.6%，30），而 TDF 组（0.2%，1）更常见（P<0.001）。两个治疗组的肌酐清除率都有所增加，d4T 组增加了 18.1ml/min，而 TDF 组增加了 14.2ml/min（P=0.03）。然而，髋骨密度测量显示 TDF 组骨密度损失更大。
低剂量 d4T 联合 3TC/EFV 与 TDF/3TC/EFV 相比显示出非劣效的病毒学疗效，但线粒体毒性仍然很高。两个治疗组均未发生明显的肾毒性。需要进一步研究 TDF 引起的骨矿物质密度变化的意义。
