Department of Paediatrics and Child Health, School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa; HIV Prevention Research Unit, South African Medical Research Council, Durban, South Africa.
Department of Paediatrics and Child Health, School of Clinical Medicine, University of KwaZulu-Natal, Durban, South Africa.
Lancet Glob Health. 2019 Dec;7(12):e1717-e1727. doi: 10.1016/S2214-109X(19)30422-X.
WHO guidelines recommend co-trimoxazole prophylaxis for HIV-exposed, HIV-uninfected infants. These guidelines date back to an era in which HIV testing of infants was impossible and mothers had poor access to antiretroviral treatment. To determine whether this guideline requires revision in the current era of effective prevention of mother-to-child transmission and early infant diagnosis programmes, we aimed to investigate whether receiving no co-trimoxazole prophylaxis is inferior to receiving co-trimoxazole prophylaxis in the resulting incidence of grade 3 or 4 common childhood illnesses or mortality in breastfed HIV-exposed, HIV-uninfected infants.
We investigated our aim in a randomised controlled, non-inferiority trial. We enrolled the HIV-negative infants of mothers living with HIV who were actively involved in transmission prevention programmes in two clinics in Durban, South Africa. Infants were included in the study if they were breastfeeding at the screening and enrolment visits, and their mother was planning to breastfeed for at least 6 months; were a singleton birth and had a birthweight of 2 kg or more; had no clinically observed genetic disorders; and had no serious illnesses and had not received antibiotics or traditional medications (such as herbal remedies). Infants were randomly assigned (1:1) to receive co-trimoxazole or no co-trimoxazole. In the co-trimoxazole group, infants received the drug until all exposure to HIV had ceased (ie, 6 weeks after last exposure to breastmilk) and the infant was confirmed to be uninfected with HIV. The drug was administered by mothers in once-daily regimens of 20 mg trimethoprim and 100 mg sulfamethoxazole orally (age <6 months or bodyweight <5 kg), or 40 mg trimethoprim and 200 mg sulfamethoxazole orally (age >6 months or bodyweight >5 kg). Clinical and laboratory staff always remained masked to group assignment, but mothers and study counsellors were not. Infants and their mothers attended study visits at ages 6 weeks (for enrolment and randomisation), 10 weeks, 14 weeks, and then monthly from 4 to 12 months. Our primary outcome was the incidence of grade 3 or 4 common childhood illnesses (pneumonia or diarrhoea) or mortality in breastfed HIV-exposed, HIV-uninfected infants by age 12 months. A non-inferiority bound of 5% was used. The study is registered with the Pan African Clinical Trials Registry, number PACTR201311000621110, and the South African National Clinical Trials Registry, number DOH-27-0614-4728.
We screened 1570 mother-child pairs for study enrolment, from whom (78%) eligible infants were enrolled into the study between Oct 16, 2013, and May 23, 2018. Of the infants enrolled, 611 (50%) were randomly assigned to the co-trimoxazole group and 609 (50%) were randomly assigned to the no co-trimoxazole group. One (<1%) infant in the no co-trimoxazole group was excluded from the analysis of the final outcomes for having received traditional medicine (which only became apparent after randomisation); therefore, 611 (50%) infants in the co-trimoxazole group and 608 (50%) infants in the no co-trimoxazole group were included in the final intention-to-treat analysis. 136 (22%) infants in the co-trimoxazole group and 139 (23%) infants in the no co-trimoxazole group did not complete the 12-month study visit, predominantly because of loss to follow-up (93 [15%] infants in the co-trimoxazole group; 90 [15%] infants in the no co-trimoxazole group). The cumulative probability of the composite primary outcome was 0·114 (95% CI 0·076 to 0·147; 49 events) in the co-trimoxazole group versus 0·0795 (0·044 to 0·115; 39 events) in the no co-trimoxazole group. The risk difference (no co-trimoxazole group minus co-trimoxazole group) was -0·0319 (-0·075 to 0·011), meaning that the risk was around 3 percentage points lower in the no co-trimoxazole group on the additive scale.
We can conclude that no co-trimoxazole is not inferior to daily co-trimoxazole among breastfed HIV-exposed, HIV-uninfected infants whose mothers are accessing a prevention of mother-to-child transmission programme in an area unaffected by malaria. We therefore believe that WHO should revise the co-trimoxazole guidelines for HIV-exposed, HIV-uninfected infants in areas unaffected by malaria.
HIV Prevention Research Unit of the South African Medical Research Council and the Family Larsson-Rosenquist Foundation.
世界卫生组织（WHO）指南建议对感染艾滋病毒的婴儿（HIV 暴露但未感染的婴儿）进行复方新诺明预防。这些指南可以追溯到艾滋病毒检测对婴儿来说是不可能的，而且母亲获得抗逆转录病毒治疗的机会很少的时代。为了确定在当前有效预防母婴传播和早期婴儿诊断方案的时代，是否需要修订该指南，我们旨在研究在母乳喂养、HIV 暴露、HIV 未感染的婴儿中，不接受复方新诺明预防是否比接受复方新诺明预防导致的 3 级或 4 级常见儿童疾病的发生率或死亡率更低。
我们在一项随机对照、非劣效性试验中调查了我们的目的。我们招募了居住在南非德班的正在积极参与传播预防项目的 HIV 阳性母亲的 HIV 阴性婴儿。如果婴儿在筛查和入组时正在母乳喂养，并且其母亲计划母乳喂养至少 6 个月；是单胎出生，体重 2 公斤或以上；没有临床观察到的遗传疾病；没有严重疾病，没有接受抗生素或传统药物（如草药）治疗，则将婴儿纳入研究。婴儿被随机分配（1:1）接受复方新诺明或不接受复方新诺明。在复方新诺明组中，婴儿在所有接触 HIV 的情况结束后（即最后一次接触母乳后 6 周）并确认未感染 HIV 时停止服用该药。母亲每天以 20 毫克甲氧苄啶和 100 毫克磺胺甲恶唑口服（年龄 <6 个月或体重 <5 公斤），或 40 毫克甲氧苄啶和 200 毫克磺胺甲恶唑口服（年龄 >6 个月或体重 >5 公斤）的剂量服用该药。临床和实验室工作人员始终对分组分配保持盲法，但母亲和研究顾问则不然。婴儿及其母亲在 6 周（入组和随机分配）、10 周、14 周以及 4 至 12 个月时每月进行一次研究访问。我们的主要结局是母乳喂养、HIV 暴露、HIV 未感染的婴儿在 12 个月时发生 3 级或 4 级常见儿童疾病（肺炎或腹泻）或死亡率。使用 5%的非劣效性边界。该研究在泛非临床试验注册中心注册，编号为 PACTR201311000621110，在南非国家临床试验注册中心注册，编号为 DOH-27-0614-4728。
我们对 1570 对母婴进行了研究入组筛查，其中（78%）符合条件的婴儿于 2013 年 10 月 16 日至 2018 年 5 月 23 日被纳入研究。在入组的婴儿中，611（50%）被随机分配到复方新诺明组，609（50%）被随机分配到无复方新诺明组。无复方新诺明组中（1%）的 1 名婴儿因接受传统药物治疗而被排除在最终结局分析之外（只有在随机分配后才发现）；因此，611（50%）名接受复方新诺明治疗的婴儿和 608（50%）名接受无复方新诺明治疗的婴儿被纳入最终的意向治疗分析。复方新诺明组中有 136（22%）名婴儿和无复方新诺明组中有 139（23%）名婴儿未完成 12 个月的研究访问，主要是因为失访（93 [15%]名婴儿在复方新诺明组；90 [15%]名婴儿在无复方新诺明组）。在复方新诺明组中，复合主要结局的累积概率为 0.114（95%CI 0.076-0.147；49 例事件），而无复方新诺明组为 0.0795（0.044-0.115；39 例事件）。风险差异（无复方新诺明组减去复方新诺明组）为-0.0319（-0.075-0.011），这意味着在没有疟疾的地区，接受预防母婴传播方案的 HIV 暴露但未感染的母乳喂养婴儿中，无复方新诺明组的风险低约 3 个百分点。
我们可以得出结论，在没有疟疾的地区，接受预防母婴传播方案的 HIV 暴露但未感染的母乳喂养婴儿中，不接受复方新诺明治疗并不比每日接受复方新诺明治疗差。因此，我们认为，世界卫生组织应该修订针对无疟疾地区的 HIV 暴露但未感染的婴儿的复方新诺明指南。
南非医学研究理事会的 HIV 预防研究单位和家庭拉森-罗森奎斯特基金会。
