Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda.
Lancet HIV. 2022 Aug;9(8):e534-e543. doi: 10.1016/S2352-3018(22)00173-4.
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.
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.
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.
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.
Unitaid.
在妊娠晚期开始抗逆转录病毒治疗与围产期传播风险增加和婴儿死亡率升高有关。我们报告了多替拉韦与依非韦伦为基础的方案在母亲和婴儿中的疗效和安全性的最终 72 周产后结果。
DolphIN-2 是一项随机、开放性标签试验。南非和乌干达的年龄至少为 18 岁、未经治疗但确认 HIV 感染且估计妊娠至少 28 周的孕妇有资格入组，他们在妊娠晚期开始抗逆转录病毒治疗。符合条件的妇女随机（1:1）接受多替拉韦（50mg 多替拉韦、300mg 富马酸替诺福韦二吡呋酯和南非 200mg 恩曲他滨或乌干达 300mg 拉米夫定）或依非韦伦（固定剂量组合 600mg 富马酸替诺福韦二吡呋酯加南非恩曲他滨或乌干达拉米夫定）为基础的治疗。主要疗效终点是在产后 6、12、24、48 和 72 周时测量的病毒载量小于 50 拷贝/ml 的时间，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数量进行总结。该试验在 ClinicalTrials.gov 注册，NCT03249181。
在 2018 年 1 月 23 日至 8 月 15 日期间，筛查了 280 名符合入组条件的妇女，其中 268 名（96%）妇女被随机分配：133 名（50%）接受依非韦伦组，135 名（50%）接受多替拉韦组。250 名（93%；依非韦伦组 125 名[50%]，多替拉韦组 125 名[50%]）妇女被纳入疗效意向治疗分析。多替拉韦组病毒载量小于 50 拷贝/ml 的中位时间为 4.1 周（IQR 4.0-5.1），依非韦伦组为 12.1 周（10.7-13.3）（调整后的危险比[HR] 1.93[95%CI 1.5-2.5]）。产后 72 周时，多替拉韦组 116 名（93%）母亲和依非韦伦组 114 名（91%）母亲的病毒载量小于 50 拷贝/ml。57 名（21%）母亲发生严重不良事件，多替拉韦组 3 名（2%）和依非韦伦组 5 名（4%）与药物有关（多替拉韦药物相关事件分别为 1 名妇女自杀意念、自杀企图、带状疱疹脑膜炎；依非韦伦药物相关事件分别为 1 名妇女自杀企图和肝硬化，3 人药物性肝损伤）。136 名（56%）婴儿中记录了严重不良事件，无一人与研究药物有关。除了多替拉韦组在之前报道的 3 例出生时感染 HIV 的婴儿外，在依非韦伦组中，尽管母亲的病毒载量持续不可检测，且婴儿在生命的第一年中连续进行了阴性检测，但在母乳喂养期间仍发生了传播。
多替拉韦安全且耐受良好，支持了更新后的世卫组织在孕妇和哺乳期妇女中的治疗建议。尽管母亲的病毒载量持续不可检测，但仍可在母乳喂养期间发生婴儿 HIV 传播，突出了需要继续对婴儿进行检测。
联合国艾滋病规划署。
