美国哈佛大学陈曾熙公共卫生学院Shahin Lockman团队研究了三种抗逆转录病毒治疗方案治疗艾滋病孕妇的疗效和安全性。2021年4月3日，该成果发表在《柳叶刀》杂志上。

妊娠期抗逆转录病毒治疗（ART）对孕产妇健康和预防围产期HIV-1传播都很重要；然而，关于孕妇可能使用的不同ART方案的安全性和有效性的足够数据却很少。

研究组在9个国家（博茨瓦纳、巴西、印度、南非、坦桑尼亚、泰国、乌干达、美国和津巴布韦）的22个临床研究机构进行了一项多中心、开放标签、随机对照的临床3期试验，2018年1月19日至2019年2月8日，研究组共招募了643名确诊感染HIV-1，怀孕14-28周的成年孕妇（年龄≥18岁）。以前服用过抗逆转录病毒药物的女性被排除在外，已知孕有多个胎儿的女性，或已知胎儿异常或有精神病史的女性也被排除在外。

将这些孕妇按1：1：1随机分组，并按孕龄（14-18周、19-23周和24-28周）和国家分层。其中217名接受多替拉韦+恩曲他滨+富马酸替诺福韦阿拉芬酰胺治疗，215名接受多替拉韦+恩曲他滨+富马酸替诺福韦二酯治疗，211名接受依法韦仑+恩曲他滨+富马酸替诺福韦二酯治疗。主要疗效结局为分娩后14天及以内，病毒抑制的受试者比例。主要安全性结果为复合不良妊娠结局（即早产、婴儿出生小于胎龄、死产或自然流产），以及发生3级及以上母婴所有随机参与者的不良事件。

入组时，中位胎龄为21.9周，受试者中位HIV-1 RNA浓度为902.5拷贝/mL，CD4中位计数为466个细胞/μL。605名（94%）受试者可获得分娩时的HIV-1 RNA水平数据。采用多替拉韦治疗的405名受试者中有395名（98%）在分娩时出现病毒抑制，而在依法韦仑+恩曲他滨+富马酸替诺福韦二酯组的200名受试者中有182名（91%）。

多替拉韦+恩曲他滨+富马酸替诺福韦阿拉芬酰胺组有52例（24%）患者出现复合不良妊娠结局，显著低于多替拉韦+恩曲他滨+富马酸替诺福韦二酯组（70例，33%）和依法韦仑+恩曲他滨+富马酸替诺福韦二酯组（69例，33%）。三组中发生3级及以上不良事件的参与者或婴儿比例没有差异。

多替拉韦+恩曲他滨+富马酸替诺福韦阿拉芬酰胺组的早产比率为6%，显著低于依法韦仑+恩曲他滨+富马酸替诺福韦二酯组（12%）。依法韦仑+恩曲他滨+富马酸替诺福韦二酯组的新生儿死亡率为5%，显著高于多替拉韦+恩曲他滨+富马酸替诺福韦阿拉芬酰胺组（1%）和多替拉韦+恩曲他滨+富马酸替诺福韦二酯组（2%）。

研究结果表明，在妊娠开始时，与依法韦仑+恩曲他滨+富马酸替诺福韦二酯方案相比，含多替拉韦的方案在分娩时具有更好的病毒学疗效。多替拉韦+恩曲他滨+富马酸替诺福韦阿拉芬酰胺方案可降低复合不良妊娠结局和新生儿死亡率。

附：英文原文

Title: Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial

Author: Shahin Lockman, Sean S Brummel, Lauren Ziemba, Lynda Stranix-Chibanda, Katie McCarthy, Anne Coletti, Patrick Jean-Philippe, Ben Johnston, Chelsea Krotje, Lee Fairlie, Risa M Hoffman, Paul E Sax, Sikhulile Moyo, Nahida Chakhtoura, Jeffrey SA Stringer, Gaerolwe Masheto, Violet Korutaro, Haseena Cassim, Blandina T Mmbaga, Esau Joo, Sherika Hanley, Lynette Purdue, Lewis B Holmes, Jeremiah D Momper, Roger L Shapiro, Navdeep K Thoofer, James F Rooney, Lisa M Frenkel, K Rivet Amico, Lameck Chinula, Judith Currier, Brookie M. Best, Cheryl Blanchette, Renee Browning, Yao Cheng, Andee Fox, Nagawa Jaliaah, Kevin Knowles, Mark Mirochnick, William A. Murtaugh, Emmanuel Patras, Mauricio Pinilla, Jean van Wyk, Frances Whalen

Issue&Volume: 2021/04/03

Abstract:

Background

Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

Methods

This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14–28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14–18, 19–23, and 24–28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of 10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422.

Findings

Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3–25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0–5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per μL (308–624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of 10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference 8·8% [95% CI 17·3 to 0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; 8·6% [–17·1 to 0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; 6·3% [–11·8 to 0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050).

Interpretation

When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths.

DOI: 10.1016/S0140-6736(21)00314-7

编辑：小柯机器人