Thior I, Lockman S, Smeaton LM, Shapiro RL, Wester C, Heymann SJ, Gilbert PB, Stevens L, Peter T, Kim S, van Widenfelt E, Moffat C, Ndase P, Arimi P, Kebaabetswe P, Mazonde P, Makhema J, McIntosh K, Novitsky V, Lee TH, Marlink R, Lagakos S, Essex M; Mashi Study Team. 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 Aug 16;296(7):794-805.
To compare the efficacy and safety of two infant feeding strategies (breastfeeding for six months plus zidovudine compared to formula feeding plus zidovudine) for the prevention of postnatal mother-to-child HIV transmission.
This is a two-by-two factorial randomized clinical trial conducted from March 2001 through October 2003.
The study took place at four district hospitals in Botswana. The hospitals were located in one city, one town, and two large villages.
Participants were 1200 pregnant women age 18 or older attending prenatal clinics between 33 and 35 weeks' gestation. All participants were HIV positive by ELISA on two separate samples, had acceptable levels of hemoglobin, neutrophils, alanine aminotransferase, aspartate aminotransferase, creatinine, and had no known intolerance to zidovudine (ZDV) or nevirapine (NVP).
All women in the study received 300mg of ZDV orally twice daily from 34 weeks' gestation until labor onset, and then every three hours until delivery. The intervention strategy differed at the beginning of the trial and was revised once efficacy data from Thailand became available. In the peripartum period, mother-infant pairs were randomized to both receive either a placebo, or single-dose nevirapine. Following results of Thailand trials, the study was revised so that all infants received single dose NVP, and the mother received either placebo or single dose NVP. In the post-partum period, infants were randomized to receive either six months of breastfeeding plus prophylactic ZDV, or formula feeding (formula was provided) plus one month of ZDV. In the formula-fed group, 4mg/kg of ZDV was administered to all infants every 12 hours from birth until one month. In the breastfed group, infants received 4mg/kg of ZDV every eight hours from one to two months of age, and 6mg/kg every eight hours from two to six months. HAART became available in October of 2002 and was offered to all women with an AIDS-defining illness or with CD4 counts of less than 200 cells/mm3.
Primary efficacy was based on lack of HIV infection in the infant by age seven months and HIV-free survival at age 18 months. Safety endpoints included adverse events in the infant by seven months of age. HIV testing was done by PCR up to 12 months of age and by ELISA at 18 months.
Of the 1200 pregnant women enrolled, 602 were assigned to the formula feeding arm and 598 were assigned to the breastfeeding arm. A total of 32 (5.6%) and 51 (9.0%) infants in the formula feeding and breastfeeding arms, respectively, became HIV-positive by seven months of age (p=0.04), with a treatment hazard ratio for time until HIV infection of 1.7 (CI: 1.07-2.55).
Those mother/infant pairs who both received placebo in the peripartum period showed a greater difference in seven-month infant HIV-infection rates (3.4% of formula-fed infants vs. 14.0% of breastfed infants) compared to mother-infant pairs who both received NVP in the peripartum period (8.6% HIV infection among formula fed vs. 11.0% of breastfed infants). This interaction was not noted among mother-infant pairs in the revised peripartum portion of the trial.
A total of 114 infants died after birth, 10.7% in the formula-feeding group and 8.7% in the breastfeeding group. The most common causes of infant death were pneumonia and diarrhea. The cumulative incidence of infant death by month seven was significantly higher in the formula-feeding group than in the breastfeeding group (9.3% vs. 4.9%, p=0.003). However, after month seven this difference disappeared. A total of 166 infants died or became HIV-positive through the 18-month visit (80 in the formula-feeding group and 86 in the breastfeeding group), for a cumulative 18-month rate of HIV infection or mortality of 13.9% (formula-fed) and 15.1% (breastfed) (p=0.6). In terms of safety, at seven months adverse events of grade three or higher and of hospitalization were significantly higher among infants in the formula fed group (p=0.04), while the rate of grade three or higher laboratory abnormalities associated with ZDV toxicity was significantly higher in the breastfed than in the formula-fed group (p<0.001).
Self-reported adherence to exclusive formula feeding was 93%. Self-reported adherence to exclusive breastfeeding was 57% in the first month, 31% at month three and 18% at month five. Exclusion of infants whose mothers initiated HAART before delivery and exclusion of the 56 infants who started HAART did not appreciably change feeding strategy comparisons for any of the main study outcomes.
The authors conclude that infants in the formula-fed group had lower rates of HIV infection but increased rates of early mortality and adverse events from infectious diseases than those in the breastfed group. As a result, HIV-free survival was not significantly different by group at 18 months. Rates of HIV infection and infant mortality in the formula-fed and breastfed groups were lower and more similar in the revised study than in the original study period; availability of HAART during the revised study period also may have lowered infant mortality. However, because infant HAART was initiated only after HIV infection was detected, it would not have affected the HIV-free survival outcome.
Using the Jadad Criteria, this study received a quality rating of 3. One point was received for describing the randomization, one point for adequate randomization, and one point for description of loss to follow-up. There was no blinding in this study.
This is an important study revealing lower HIV-infection rates among formula infants, offset by higher mortality due to other causes, compared to children who are breastfed. This study also provides important data on the effect of a combined perinatal/postpartum intervention. All but one other study has found higher rates of morbidity and mortality among formula-fed infants compared to breastfed infants. The HIV-free survival and HIV-infection rates achieved here using a combined perinatal/postpartum intervention were comparable or slightly better than other studies.(1,2,3,4) However, some studies using breastfeeding alone without the zidovudine prophylaxis showed similar results.(2,5,6)
Breastfeeding with zidovudine prophylaxis is a feasible method of preventing mother-to-child transmission, at least in Botswana. Further study is needed to determine the efficacy and safety of other strategies, such as the use of maternal HAART during breastfeeding, which could further improve outcomes. Before implementing formula-feeding strategies for PMTCT in developing countries, it is important to assess and improve the capacity to manage childhood illnesses. Because adherence to breastfeeding or formula feeding, and the epidemiology of childhood infections may differ across regions, comparisons across studies and divergent populations should be made with caution.
Coutsoudis A, Dabis F, Fawzi W, Gaillard P, Haverkamp G, Harris DR, Jackson JB, Leroy V, Meda N, Msellati P, Newell ML, Nsuati R, Read JS, Wiktor S; Breastfeeding and HIV International Transmission Study Group.
Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis. 2004 Jun 15;189(12):2154-66.
- Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. 2003 Sep 13;362(9387):859-68.
Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial.. Lancet. 2002 Apr 6;359(9313):1178-86.
Dabis F, Msellati P, Meda N, Welffens-Ekra C, You B, Manigart O, Leroy V, Simonon A, Cartoux M, Combe P, Ouangre A, Ramon R, Ky-Zerbo O, Montcho C, Salamon R, Rouzioux C, Van de Perre P, Mandelbrot L. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. DITRAME Study Group. DIminution de la Transmission Mere-Enfant.. Lancet. 1999 Mar 6;353(9155):786-92.
Leroy V, Karon JM, Alioum A, Ekpini ER, Meda N, Greenberg AE, Msellati P, Hudgens M, Dabis F, Wiktor SZ; West Africa PMTCT Study Group. Twenty-four month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission of HIV-1 in West Africa.. AIDS. 2002 Mar 8;16(4):631-41.
Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial.. Lancet. 2003 Sep 13;362(9387):859-68.