Infant feeding strategies and PMTCT - Mashi trial from Botswana
Summary of published research1
Arecently published paper compares the efficacy and safety of two infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. Conducted in Botswana, the Mashi (milk) Study was designed as a randomised 2x2 factorial clinical trial, to compare interventions for both preventing perinatal HIV transmission (part 1) and reducing postnatal HIV infection and mortality (Part 2). The findings from Part 2 are summarised here.
Between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomised from four district hospitals in Southern Botswana (located in one city, one town and two villages). Amongst the 11,388 women originally screened, the prevalence of HIV was 33% of whom 30% participated in the trial. All of the mothers received zidovudine from 34 weeks' gestation and during labour. Mothers and infants were randomised to receive single-dose nevirapine or placebo.
Infants were randomised to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). In the breastfed group, exclusive breastfeeding was recommended (as per Botswana guidelines), however non-exclusive breastfeeding was not considered non-adherence to breastfeeding. In the breastfeeding group, mothers were instructed to begin and complete weaning between 5 and 6 months of age and free infant formula was provided from 5 to 12 months of age. Mothers randomised to the formula- fed group were supplied with formula for 12 months. All mothers were educated about safe formula preparation and administration, and provided with high-protein food for infants from 6 through to 12 months of age.
Adherence to infant feeding strategy and zidovudine was assessed by maternal report at each scheduled visit using standardized questionnaires. For zidovudine, adherence was assessed by collecting information on study drug intake and the primary reason for any missed doses. For infant feeding strategy, adherence was assessed by questioning mothers on food and fluid intakes, frequency of breastfeeding and water source since the previous visit.
Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month until 18 months of age. Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants.
Of the 1200 women, 1193 reached delivery resulting in 591 and 588 live first-born infants in the formula-fed and breastfed plus zidovudine groups, respectively. Maternal and infant characteristics were well balanced between both groups (P>0.05) for all comparisons other than sanitation facilities (P=0.04)
HIV infection rates and mortality
The 7-month HIV infection rates were 5.6% (n=32) in the formula-fed group and 9.0% (n=51) infants in the breastfed plus zidovudine group (P=0.04; 95% confidence interval (CI) for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 13.9% in the formula fed group (n=80) and 15.1% in the breastfed plus zidovudine group (n=86) (P=0.60; 95% CI, -5.3% to 2.9%).
The cumulative infant mortality at 7 months was significantly higher for the formula fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P=0.003). However this difference diminished beyond month 7, so that by the age of 18 months there was no significant difference (P=0.21).
One hundred and fourteen infants died after birth, 10.7% (63/591) from the formula-fed group and 8.7% (51/588) from the breastfed plus zidovudine group. Of the 77 infants who died with a HIV negative status, over half (58%) had a negative HIV test result within the 2 weeks preceding death, and the vast majority (95%) had a negative HIV test result within the 3 months preceding death. A total of 5 infants died before an initial PCR result was obtained. The remaining 32 infant deaths were among babies who had tested HIV positive - 15 from the formula-fed group and 17 from the breastfed plus zidovudine group. The most common causes of infant death were diarrhoea and pneumonia. The deaths in the breastfed plus zidovudine group were more likely to be in HIV-infected infants and at older ages as compared with the deaths in the formula-fed group.
The morbidity and mortality rates amongst formula fed infants are greater than those reported previously in another randomised trial2 in Nairobi, Kenya which showed a similar 2-year mortality rate but a significantly lower HIV-free survival rate in the breastfeeding group. The authors suggest this difference may be explained by the access to clean municipal water that the Nairobi women had.
Adherence to drug regimen and feeding strategy
Of the 1179 live-born babies, 1172 (99.4%) initiated zidovudine following birth. The median duration of infant zidovudine was 5.9 months in the breastfed plus zidovudine group, and 84% (479 of 567) of responding mothers in the breastfed plus zidovudine group reported never missing 1 or more full days of infant zidovudine. In the formula fed group, 95% (562 of 591) received at least 2 weeks dosage of zidovudine.
Full adherence to exclusive formula feeding was self-reported by 93% of mothers in the formula- fed group. Three infants in the formulafed group were infected between months 1 and 7, presumably because they were exposed to breast milk.
Among mothers in the breastfed plus zidovudine group, self-reported adherence to exclusive breastfeeding was 57.1% at month 1, 31.3% at month 3, and 17.5% at month 5. Predominant breastfeeding was practiced by 21.2%, 20.1%, and 7.5% of mothers by 1 month, 3 months, and 5 months, respectively and mixed breastfeeding was practiced by 21.7%, 48.6%, and 75.0% for the same age groups.
The authors suggest that the low rates of exclusive breastfeeding may have influenced the results, if mixed or non-exclusive breastfeeding were associated with increased risk of HIV transmission as previously reported by Coutsoudis et al3. The transmission rates due to breastmilk were similar to other studies4 whose mother's breastfed and received short course zidovudine.
A total of 166 infants died or became HIV positive through the 18-month visit. This corresponded to a cumulative 18-month rate of HIV infection or mortality of 13.9% (n=80) in the formula fed group and 15.1% (n=86) in the breastfed plus zidovudine groups (P=0.60; 95% CI for difference, -5.3% to 2.9%).
Although virtually all women in the breastfed plus zidovudine group breastfed, many did not do so exclusively, despite educational efforts.
Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIVfree survival at 18 months. The study revealed relatively high morbidity and mortality rates associated with formula feeding among infants of HIV-infected mothers, with deaths largely due to pneumonia and diarrhoea. This demonstrates the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. The authors highlight the need for a careful assessment of the local management of childhood illnesses (mostly diarrhoeal and respiratory diseases) before the implementation of a formula feeding strategy for the prevention of mother-to-child transmission of HIV in developing countries.
1Thior et al (2006). 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 Randomised Trial: The Mashi Study. JAMA, 296: 7, 794-805
2Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1. JAMA. 2000;283:1167-1174.
3Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa. Lancet. 1999;354:471-476. and Coutsoudis A. Influence of infant feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa. Ann N Y Acad Sci. 2000;918: 136-144.
4Dabis F, Msellati P, Meda N, et al. 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. Lancet. 1999;353:786-792.
Taken from Field Exchange Issue 29, December 2006