南非金山大学Willem D.F. Venter研究团队取得一项新突破。他们分析了Dolutegravir（DTG）加两种不同的替诺福韦前药治疗人类免疫缺陷病毒（HIV）的疗效。 相关论文2019年8月29日发表于国际顶尖学术期刊《新英格兰医学杂志》。

2017年1月至2018年5月，该课题组在南非进行了一项为期96周、临床3期、研究者主导、开放标签的随机试验，共招募了1053名患者，年龄均在12岁及以上，平均年龄32岁，99%以上为黑人，59%为女性。所有患者在过去半年内未接受抗逆转录病毒治疗，肌酐清除率大于60 ml/min（19岁以下大于80 ml/min），HIV-1 RNA水平超过500拷贝/毫升，平均CD4计数为每立方毫米337个细胞。

1053例患者随机分为三组，恩曲他滨（FTC）+DTG+不同的替诺福韦前药（富马酸丙酚替诺福韦，TAF组；富马酸替诺福韦二吡呋酯，TDF组），以及当地的标准治疗方案TDF-FTC-依法韦仑（标准治疗组）。治疗48周后，TAF组中HIV-1 RNA水平低于50拷贝/毫升的患者占84%，TDF组为85%，标准护理组为79%，这表明，含有DTG的治疗方案并不比标准治疗组差。

标准治疗组中断试验的患者数高于其他两组，但三组的治疗效力相当。与其他治疗方案相比，TAF方案对骨密度和肾功能的影响较小。TAF组和女性患者体重增加最多，包括肌肉组织和脂肪组织，其中TAF组平均增重6.4千克，TDF组增重3.2千克，标准治疗组增重1.7千克。

综上，DTG联合两种替诺福韦前药（TAF和TDF）方案的疗效均不逊于标准治疗方案，但患者的体重增加明显，尤其是在TAF组。 

据悉，研究人员正考虑将DTG+TAF纳入HIV感染的抗逆转录病毒治疗方案，但该方案在中低收入国家应用较少。

附：英文原文

Title: Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV

Author: Willem D.F. Venter, Michelle Moorhouse, Simiso Sokhela, et al

Issue&Volume: Vol 381 No 9, 29 August 2019

Abstract: 

BACKGROUND
Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.

METHODS
We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data.

RESULTS
A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.

CONCLUSIONS
Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.)

DOI: 10.1056/NEJMoa1902824

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1902824