多替拉韦加利伟酯联合两种不同的替诺福韦前药治疗 HIV。

Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV.

机构信息

From Ezintsha (W.D.F.V., M. Moorhouse, S.S., N.M., C.S., G.A., N.C., N.A., A.V.), Wits Reproductive Health and HIV Institute, Faculty of Health Sciences (W.D.F.V., M. Moorhouse, S.S., L.F., N.M., M. Masenya, C.S., G.A., N.C., M.C., N.A., A.V.), and the South African Medical Research Council Developmental Pathways for Health Research Unit, Department of Pediatrics, School of Clinical Medicine, Faculty of Health Sciences (S.N.), University of the Witwatersrand, Johannesburg; the Faculty of Medicine, Imperial College London (A.Q., K.M., B.S.), and HIV i-Base (P.C.), London, and the Department of Translational Medicine, Liverpool University, Liverpool (A.H.) - all in the United Kingdom; ICAP at Columbia University, Mailman School of Public Health and Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York (E.A.); and the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands (A.V.).

出版信息

N Engl J Med. 2019 Aug 29;381(9):803-815. doi: 10.1056/NEJMoa1902824. Epub 2019 Jul 24.

DOI:10.1056/NEJMoa1902824

PMID:31339677

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.).

摘要

背景

两种正在考虑纳入抗逆转录病毒疗法（ART）方案治疗人类免疫缺陷病毒（HIV）感染的药物是多替拉韦（DTG）和富马酸替诺福韦艾拉酚胺（TAF）。在中低收入国家，这两种药物的使用数据有限。

方法

我们在南非进行了一项 96 周、由研究者主导的、开放标签、随机试验，比较了恩曲他滨（FTC）和 DTG 三联疗法加两种替诺福韦前药中的一种 - TAF（TAF 组）或替诺福韦二吡呋酯富马酸酯（TDF）（TDF 组）- 与当地的标准护理方案 TDF-FTC-依非韦伦（标准护理组）。纳入标准包括年龄在 12 岁及以上、在过去 6 个月内未接受过 ART、肌酐清除率每分钟超过 60 毫升（19 岁以下患者每分钟超过 80 毫升）以及 HIV-1 RNA 水平为每毫升 500 拷贝或更多。主要终点是 48 周时 HIV-1 RNA 水平低于每毫升 50 拷贝的患者比例（用 FDA 的 Snapshot 算法确定；非劣效性边界为-10 个百分点）。我们报告了主要（48 周）疗效和安全性数据。

结果

共有 1053 名患者于 2017 年 2 月至 2018 年 5 月期间接受了随机分组。超过 99%的患者为黑人，59%为女性。平均年龄为 32 岁，平均 CD4 计数为每立方毫米 337 个细胞。48 周时，HIV-1 RNA 水平低于每毫升 50 拷贝的患者比例在 TAF 组为 84%，在 TDF 组为 85%，在标准护理组为 79%，表明 DTG 包含的方案与标准护理方案非劣效。标准护理组中退出试验方案的患者人数多于其他两组。在符合方案人群中，标准护理方案与其他两种方案具有等效效力。TAF 组对骨密度和肾功能的影响较小。TAF 组的体重增加（包括瘦体重和脂肪体重）最大，在 TAF 组中增加了 6.4 公斤，在 TDF 组中增加了 3.2 公斤，在标准护理组中增加了 1.7 公斤。接受 DTG 包含方案的患者未发现整合酶抑制剂耐药。