Background

Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants.

Methods

DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181.

Findings

Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4·1 weeks (IQR 4·0–5·1) in the dolutegravir group compared with 12·1 weeks (10·7–13·3) in the efavirenz group (adjusted hazard ratio [HR] 1·93 [95% CI 1·5–2·5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life.

Interpretation

Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing.

Funding

Unitaid.

中文翻译：

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妊娠晚期开始的多替拉韦与依非韦伦的产后 72 周随访 (DolPHIN-2)：一项开放标签、随机对照研究

背景

妊娠期抗逆转录病毒药物使用晚与围产期传播风险增加和婴儿死亡率升高有关。我们报告了基于多替拉韦与基于依非韦伦的方案在母亲和婴儿中的疗效和安全性的最终产后 72 周结果。

方法

DolPHIN-2 是一项随机、开放标签试验。南非和乌干达年龄至少 18 岁、未经治疗但确诊 HIV 感染且估计妊娠至少 28 周、在妊娠晚期开始抗逆转录病毒治疗的孕妇有资格入选。符合条件的女性被随机分配 (1:1) 接受基于多替拉韦（50 mg 多替拉韦、300 mg 富马酸替诺福韦酯和 200 mg 恩曲他滨（南非）或 300 mg 拉米夫定（乌干达））或依非韦伦（固定剂量组合） 600 mg 富马酸替诺福韦酯加恩曲他滨（南非）或拉米夫定（乌干达））治疗。主要疗效结果是在 6、12、24、48 时测量的病毒载量低于 50 拷贝/mL 的时间。产后 72 周，使用 Cox 模型调整病毒载量和 CD4 细胞计数。安全性终点通过发生事件的妇女和婴儿的数量进行总结。该试验已在 ClinicalTrials.gov 注册，NCT03249181。

发现

在 2018 年 1 月 23 日至 8 月 15 日期间，对 280 名女性进行了筛选，其中 268 名（96%）女性被随机分配：133 名（50%）到依非韦伦组，135 名（50%）到多替拉韦组。250 名（93%；依非韦伦组 125 名 [50%] 和多替拉韦组 125 名 [50%]）女性被纳入疗效意向治疗分析。多替拉韦组病毒载量低于 50 拷贝/mL 的中位时间为 4·1 周（IQR 4·0-5·1），而依非韦伦组为 12·1 周（10·7-13·3） （调整后的风险比 [HR] 1·93 [95% CI 1·5–2·5]）。在产后 72 周，多替拉韦组 116 名 (93%) 母亲和依非韦伦组 114 名 (91%) 母亲的病毒载量低于 50 拷贝/mL。在有严重不良事件的 57 名 (21%) 母亲中，多替拉韦组中有 3 名（2%）和依非韦伦组有 5 名（4%）与药物有关（多替拉韦药物相关事件是有自杀意念、自杀未遂、带状疱疹脑膜炎的各一名妇女；依非韦伦药物相关事件有自杀未遂和肝硬化的妇女各有 1 人，药物性肝损伤的有 3 人）。在记录了严重不良事件的 136 名 (56%) 婴儿中，没有一个与研究药物有关。除了先前报道的多替拉韦组出生时检测到的三例婴儿 HIV 感染外，尽管母体病毒抑制最佳且出生后第一年婴儿连续检测呈阴性，但依非韦伦组在母乳喂养期间发生了额外的传播。

解释

Dolutegravir 安全且耐受性良好，支持世卫组织对孕妇和哺乳期妇女的最新治疗建议。尽管母体病毒载量持续无法检测到，突显出需要继续对婴儿进行检测，但母乳喂养期间仍可能发生婴儿 HIV 传播。

资金

统一援助。