Horvath T, Madi BC, Iuppa IM, Kennedy GE, Rutherford G, Read JS. Interventions for preventing late postnatal mother-to-child transmission of HIV. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006734. DOI: 10.1002/14651858.CD006734.pub2.
The objectives of this systematic review were to assess the evidence for and determine the efficacy of interventions to decrease late postnatal mother-to-child transmission (MTCT) of HIV, and to determine whether they increase overall and HIV-free survival
Electronic searches were undertaken using PubMed, EMBASE, CENTRAL, and other databases to identify relevant studies from 1980-2008. Hand searches of the reference lists of all pertinent reviews and studies found were undertaken, as well as abstracts from relevant conferences, including the International AIDS Conferences and the annual Conference of Retroviruses and Opportunistic Infections. Experts in the field of HIV prevention were contacted to locate any further studies or relevant conference proceedings not included in the databases to ensure that unpublished studies were included. The search strategy was iterative. There were no restrictions on country or language. Identified studies were independently reviewed for eligibility, and differences of opinion were resolved by consensus
After screening 1,349 citations, 17 were identified as potentially relevant studies; seven of these met all the inclusion criteria and were included in the review (six randomized clinical trials and one intervention cohort study). Inclusion criteria consisted of randomized clinical trials of HIV-infected women and their infants that assessed the efficacy of interventions to prevent MTCT of HIV through breast milk; other trials and intervention cohort studies with relevant data, but only if randomization was not feasible due to the nature of the intervention; and studies performed in general or specific populations and in hospitals or clinics. Ecological studies and studies with historical controls were excluded.
The seven studies included were conducted in Botswana, Kenya, Malawi, Tanzania, South Africa. and Zambia, Three separate but coordinated randomized controlled trials, counting in the review as one study, were conducted in Ethiopia, India, and Uganda.
HIV-infected pregnant or postpartum women and their children were included. The studies in the review are Nduati 20001(1) ; Fawzi 20022(2) ; Thior 20063(3); Coovadia 20074(4); Kuhn 20085(5); Kumwenda 20086(6); and SWEN 20087(7). The number of participants in the included studies ranged from 401 to 3,276.
The types of interventions that the studies included were the following: interventions to prevent breast milk transmission of HIV through decreasing the duration of exposure to breast milk; decreasing maternal infectivity; addressing factors affecting the transfer of virus from mother to child; and improving infants' defenses against HIV infection.
Among children born to HIV-infected women, the outcome measures were HIV infection, overall survival, and HIV-free survival.
Among the randomized controlled trials, Nduati 2000 studied breastfeeding versus formula feeding; Fawzi 2002 studied vitamin supplements; Thior 2006 studied breastfeeding with infant zidovudine prophylaxis for six months versus formula feeding plus infant zidovudine for one month; Kuhn 2008 studied exclusive breastfeeding for four months with an abrupt or rapid stop versus breastfeeding exclusively for six months with a gradual introduction of complementary foods and continuation of breastfeeding; Kumwenda 2008 studied infant prophylaxis with nevirapine and zidovudine; and SWEN 2008 studied dosage of mother and infant prophylaxis. The intervention cohort study (Coovadia 2007) assessed the risk of HIV transmission and survival associated with exclusive breastfeeding and other types of infant feeding.
The review divided the effects of interventions in four categories: decreasing the duration of exposure to breast milk, decreasing maternal infectivity, modifying factors affecting the transfer of virus from mother to infant, and increasing infant defenses. In terms of decreasing the duration of exposure to breast milk, Nduati 2000 demonstrated the efficacy of complete avoidance of breastfeeding by formula feeding for preventing MTCT of HIV. The cumulative probability of HIV infection at 24 months was 36.7% (95% confidence interval [CI]: 29.4-44.05) in the breastfeeding arm versus 20.5% (95% CI: 14.0-27.0%) in the formula arm (P=0.001); however, mortality and malnutrition rates were similar in both arms during the first two years of life. Similarly, Kuhn 2008 demonstrated that HIV-free survival at two years was similar between children who ceased breastfeeding abruptly at around four months of age and those who continued breastfeeding.
In terms of decreasing maternal infectivity, Fawzi 2002 found that multivitamins, excluding vitamin A, had no effect on the overall risk of HIV transmission. Vitamin A increased the risk of transmission (RR=1.38; 95% CI: 1.09-1.76; P=0.009).
In terms of modifying factors affecting the transfer of virus from mother to infant, Coovadia 2007 found increased risks of MTCT among breastfed children who also received solids any time after birth versus exclusively breastfed children (hazard ratio [HR]=10.87; 95% CI: 1.51-78; P=0.018). Likewise, cumulative three-month mortality in exclusively breastfed infants was 6.1% (95% CI: 4.74-7.92%) vs. 15.1% (7.63-28.73%) in infants given replacement feeds (HR=2.06; 95% CI: 1.00-4.27, P=0.051).
In terms of increasing infant defenses, three trials evaluated giving antiretroviral prophylaxis to the breastfeeding infant. Thior 2006 found breastfeeding plus zidovudine (transmission rate=9.0%) was not as effective as formula plus zidovudine (transmission rate=5.6%) in preventing HIV transmission (P=0.04) in the first six months of life. At 18 months, however, the cumulative mortality or HIV-infection rates were comparable in both arms (P=0.60). Two trials of extended infant nevirapine prophylaxis on breastfeeding infants demonstrated efficacy. In SWEN 2008, a six-week course of nevirapine resulted in a lower risk of HIV transmission by six weeks of age (RR=0.54; 95% CI: 0.34-0.86; P=0.009) but not at six months of age (RR=0.80; 95% CI: 0.58-1.10; P=0.016). At nine months, Kumwenda 2008 showed that the estimated rate of HIV infection was 10.6% in a control regimen of two-dose nevirapine prophylaxis, 5.2% in the extended nevirpaine group (P<0.001), and 6.4% in the extended dual prophylaxis group (nevirapine with zidovudine until 14 weeks of age) (P=0.002). HIV-free survival was significantly better through the age of nine months in both extended prophylaxis groups and through the age of 15 months in the extended nevirapine group.
The authors conclude that complete avoidance of breastfeeding is efficacious in preventing MTCT of HIV, but this intervention has significant associated morbidity (e.g., diarrheal morbidity if formula is prepared without clean water). If breastfeeding is initiated, two interventions: 1) exclusive breastfeeding during the first few months of life; and 2) extended antiretroviral prophylaxis to the infant (nevirapine alone, or nevirapine with zidovudine) are efficacious in preventing transmission.
Using the QUOROM checklist for assessing the quality of systematic reviews, this study was of good quality. The search was globally comprehensive and efforts were made to contact experts in the field and authors of studies in question. Outcome measures were subject to biological specimen testing and therefore less susceptible to bias. The authors assessed the risk of bias in each study with the Cochrane Handbook's bias assessment tool.(8)
Although there have been Cochrane reviews regarding interventions for the prevention of in utero and intrapartum MTCT, this is the first systematic review displaying the evidence of three main interventions for the prevention of late postnatal MTCT of HIV: complete avoidance of breastfeeding, exclusive breastfeeding, and antiretroviral prophylaxis to the breastfeeding infant. It is important to identify methods to prevent HIV transmission through breastfeeding because complete elimination of breastfeeding in developing countries may not be feasible or practical or it may result in increased mortality from causes other than HIV.
Unfortunately, none of the studies to date provide an ideal solution to HIV transmission via breast milk, and HIV transmission occurred in every arm of each study and in every study. Trials evaluating the efficacy of reducing transmission by reducing maternal HIV viral load or treatment of breast milk with chemicals or heat are underway and may result in more effective options than the studies conducted to date. Until then, exclusive breastfeeding with infant antiretroviral therapy appears to be the most efficacious intervention.
- Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000;283(9):1167-74.
- Fawzi WW, Msamanga GI, Hunter D, et al. Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality. AIDS 2002;16(14):1935-44.
- Thior I, Lockman S, Smeaton LM, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA 2006;296(7):794-805.
- Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007;369(9567):1107-16.
- Kuhn L, Aldrovandi GM, Sinkala M, et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med 2008;359(2):130-41.
- Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008;359(2):119-29.
- Bedri A, Gudetta B, Isehak A, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet 2008;372(9635):300-13.
- Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Chichester (UK): Wiley-Blackwell, 2008.