1. Objectives

To collate the evidence and to assess the efficacy of interventions aiming to decrease late postnatal mother-to-child transmission of HIV on risk of HIV infection, overall survival, and HIV-free survival among children born to HIV-infected women

2. How studies were identified

The following databases were searched up to July 2008:

• CENTRAL (The Cochrane Library)
• PubMed
• EMBASE
• Gateway
• AIDSearch

Relevant conference proceedings and reference lists were also handsearched, and researchers in the field were contacted to identify ongoing or unpublished studies

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials (RCT), and, in cases where randomization was not feasible, non-randomized intervention cohort studies

3.2 Study participants

Pregnant or postpartum HIV-infected women and their children

3.3 Interventions

Interventions to prevent breast milk transmission of HIV by: i) decreasing the duration of exposure to breast milk; ii) decreasing maternal infectivity (e.g., lowering viral load in breast milk via maternal antiretroviral prophylaxis); iii) addressing factors affecting the transfer of virus from mother to child (e.g., preventing bleeding nipples); and iv) improving infants’ immune defenses against HIV infection (e.g., infant antiretroviral prophylaxis)

3.4 Primary outcomes

Among children born to HIV-infected women:

• HIV infection
• Overall survival
• HIV-free survival

4. Main results

4.1 Included studies

Seven trials involving 12,135 mother-infant pairs were included in this review:

• Six of the seven studies were RCT, and one was a non-randomized intervention cohort study in which exclusively breastfed infants were compared to those receiving mixed breastfeeding and those receiving formula feeding (n=1276 infants)
• One RCT in 401 mother-infant pairs compared breast milk to formula milk
• One study was a factorial RCT in 1078 HIV-infected women comparing maternal supplementation with vitamin A alone (30 mg beta-carotene plus 5000 IU preformed vitamin A), vitamin A plus multivitamins (vitamins C, E, B1, B2, B6, B12, niacin and folic acid), multivitamins alone, and placebo
• One RCT of 1200 HIV-infected women compared breastfeeding plus infant zidovudine prophylaxis for six months to formula feeding plus infant zidovudine for one month
• One RCT compared early abrupt cessation of exclusive breastfeeding at four months to exclusive breastfeeding for six months and continuation of breastfeeding as desired in 3276 HIV-exposed infants
• One three-armed RCT in 3016 infants compared infant neviradipine prophylaxis to extended neviradipine prophylaxis and dual extended neviradipine plus zidovudine prophylaxis
• A multi-centre RCT in 1887 infants compared varying regimens of infant prophylaxis with neviradipine

4.2 Study settings

• Botswana, Kenya, Malawi, South Africa, the United Republic of Tanzania, Zambia and a multi-centre study (Ethiopia, India, Uganda)
• Study settings included antenatal clinics and delivery facilities

4.3 Study settings

How the data were analysed
Data were collated according to type of intervention: i) decreasing the duration of exposure to breast milk; ii) decreasing maternal infectivity; iii) addressing factors affecting the transfer of virus from mother to child; and iv) improving infants’ immune defenses against HIV infection. No pooled analyses were performed.

Results
Decreasing the duration of exposure to breast milk
In one RCT of 401 mother-infant pairs, the cumulative probability of mother-to-child HIV transmission at 24 months was 20.5% (95% confidence interval (CI) [14.0 to 27.0]) in the formula arm versus 36.7% (95% CI [29.4 to 44.0]) in the breastfeeding arm (p=0.001). HIV-free survival at 24 months was also improved with formula feeding (58.0% versus 70.0%; p=0.02), although mortality rates were similar between groups (breastfeeding arm: 24.4%, 95% CI [18.2 to 30.7]; formula feeding arm: 20.0%, 95% CI [14.4 to 25.6]; p=0.30). Early cessation of exclusive breastfeeding at four months of age in 3276 infants had no effect on child mortality at 24 months, HIV-free survival at 24 months, or rates of postnatal HIV transmission between four and 24 months (all p≥0.13). Among HIV-uninfected children who were still breastfed at four months, there was no significant difference in HIV-free survival at 24 months (early cessation of breastfeeding: 83.9%; control group: 80.7%; p=0.27).

Decreasing maternal infectivity
Maternal multiple micronutrient supplementation had no effect on the overall risk of mother-to-child HIV transmission in one factorial trial enrolling 1078 HIV-infected women (relative risk (RR) 1.04, 95% CI [0.82 to 1.32], p=0.76), while vitamin A supplementation increased the risk of transmission (RR 1.38, 95% CI [1.09 to 1.76], p=0.009). Non-statistically significant reductions in mortality at 24 months of age among HIV-infected infants alive at six weeks, and in the transmission of HIV via breastfeeding, were observed with maternal multiple micronutrient supplementation.

Modifying factors affecting the transfer of virus from mother to infant
In the intervention cohort study including 1276 infants, breastfed children who also received solids during the first six months of life were ten times more likely to become HIV-infected than exclusively breastfed children (hazard ratio (HR) 10.87, 95% CI [1.51 to 78.00], p=0.018). Exclusively breastfed infants had lower cumulative three-month mortality rates than those given replacement feeds, although this was not statistically significant (6% versus 15%; HR 2.06, 95% CI [1.00 to 4.27], p=0.051).

Increasing infant defenses
Breastfeeding plus zidovudine prophylaxis for six months in comparison to formula feeding plus zidovudine prophylaxis for one month resulted in an increased rate of HIV infection at seven months (breastfeeding plus zidovudine group: 9.0%; formula group: 5.6%; p=0.04). However, cumulative infant mortality at seven months was statistically significantly higher in the formula-fed group than in the breastfed plus zidovudine group (9.3% versus 4.9%; p=0.003). No differences between groups were found for cumulative mortality or HIV infection rates at 18 months. Extended infant prophylaxis with neviradipine and extended dual prophylaxis with neviradipine plus zidovudine in one RCT of 3016 infants was found to reduce the rate of HIV infection at nine months (10.6% in the control group; 5.2% in the extended nevirapine group; 6.4% in the extended dual prophylaxis group; p<0.001). In addition, HIV-free survival was significantly improved to nine months of age in both extended prophylaxis groups, and to 15 months of age in the extended neviradipine group. In a multi-centre trial comparing neviradipine to extended neviradipine prophylaxis in 1887 infants, extended-dose neviradipine reduced the risk of HIV transmission at six weeks of age by 46% (RR 0.54, 95% CI [0.34 to 0.86], p=0.009), although at six months, the risk of transmission was not different between groups (RR 0.80, 95% CI [0.58 to 1.10], p=0.16). Extended prophylaxis also increased HIV-free survival at both six weeks (p=0.008) and at six months (p=0.03).

Adverse effects
Adverse effects were not considered separately in this review; however, rate of grade 3 or higher laboratory abnormality associated with zidovudine toxicity was significantly higher in the breastfed plus zidovudine group than in the formula-fed group (24.7% versus 14.8%; p<0.001).

5. Additional author observations*

In general, the methodological quality of the included studies was poor, with most studies being at high risk of selection bias due to inadequate allocation concealment, and at high risk of performance and detection bias due to lack of blinding. In addition, one included trial was a non-randomized intervention cohort study.

The trials reviewed here provide evidence that complete avoidance of breastfeeding is efficacious in preventing mother-to-child transmission of HIV, and that if breastfeeding is initiated, exclusive breastfeeding and extended antiretroviral prophylaxis are effective in preventing mother-to-child transmission of HIV in comparison to partial breastfeeding and limited antiretroviral prophylaxis. The authors also note that the benefits of breastfeeding, particularly in resource-poor regions, are well recognized, and include significantly decreased infant morbidity and mortality by providing optimal nutrition, protecting against common childhood infections, and promoting child spacing.

Further research is warranted investigating the mechanism(s) of breast milk transmission of HIV, the safety of current antiretroviral interventions, and the effective implementation of interventions known to be efficacious in the prevention of postnatal mother-to-child transmission of HIV.