Two studies presented on Thursday at the Twelfth Annual Retrovirus Conference in Boston have shown that the use of prophylaxis in babies breast-fed by HIV-positive mothers can reduce HIV transmission to comparable rates to formula-fed babies. However, this approach can increase the risk of the child developing resistance to the drugs used, at least temporarily.
A trial in Botswana of various AZT, 3TC and nevirapine combinations has succeeded in bringing the HIV mother-to-baby transmission down to below four per cent, as reported previously.
However up to half of HIV transmission to babies is via breast milk, and the ‘Mashi’ trial, whose name means ‘milk’ in Tswana, included a second phase which randomised babies to receive either formula feed, or breast-feeding plus AZT, up to seven months of age. All of the babies were given AZT until they were one month old.
There was little difference in the ultimate fate of the children in this trial. By the age of 18 months, 14% of formula-fed and 16% of breast-fed babies were HIV-positive, including those who had HIV at birth.
However at seven months, when AZT was stopped, there was a larger difference, with 6% of formula-fed babies being positive, and 9% of those breast-fed.
Set against this were higher mortality rates in the formula-fed babies. Nine per cent of formula-fed babies had died by eight months as opposed to 5% of breast-fed babies. However by 18 months the ‘mortality and morbidity’ rates were similar: 14% in formula-fed and 16% in breast-fed babies.
The original study design had also randomised mother / baby pairs to receive nevirapine or placebo at birth. The drug was given to the mothers during labour and to the infants no more than three days after birth.
This increased the difference between formula feeding and breast feeding, with a 3% difference between breast and formula feeding in the placebo arm, but a 12% advantage to formula feeding by seven months in the nevirapine arm. Only 3% of babies given both formula feed and nevirapine were HIV-positive by seven months. This advantage disappeared during the second phase of the trial when all babies, but only half of the mothers received nevirapine.
One encouraging finding was that mothers were adherent to formula feeding. Only 9% of these mothers said they had sometimes breast-fed, despite 75% of trial participants having no mains electricity, 69% no fridge, and 45% no source of water on their premises. Formula-feeding mothers reported giving 95% of AZT doses to their babies, and breast-feeding mums 86%.
In contrast only 18% of women in the breast-feeding arm said they exclusively breast-fed up to 18 months and only 50% to seven months.
The study had previously reported a 44% nevirapine resistance rate in mothers.
In another study, resistance rates among babies given nevirapine or 3TC prophylaxis while breast-feeding were documented.
In the Ugandan SIMBA trial, 26 (6%) of 404 children acquired HIV up to six weeks after birth.
Drug resistance was documented in these children. Twelve (92%) of the 13 receiving nevirapine had a nevirapine resistance mutation, nine with Y181C plus seven other mutations, with three infants having multiple mutations. None of the mothers had these mutations and the mutations were still present six to nine months later in nine infants tested later.
The M184V 3TC mutation was present in nine (69%) of the 13 children who took it. It faded over time – only two of the infants still had the mutation detectable three to six months later.
In response to an audience member calling the use of drugs with a low resistance barrier ‘unethical’ in infants, presenter Marina Giuliano commented that the decision to use 3TC monotherapy as prophylaxis in children was made with the best available information at the time.
The investigators concluded: “Post-partum prophylaxis with nevirapine or 3TC leads almost invariably to the selection of resistance mutations in children [with HIV] receiving them. This should be considered when choosing antiretroviral regimens.”
Thior I et al. Breastfeeding with 6 months of infant zidovudine prophylaxis versus formula feeding for reducing postnatal HIV transmission and infant mortality: a randomized trial in Southern Africa. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 75LB, 2005.
Giuliano M et al. Selection of resistance mutations in children receiving prophylaxis with lamivudine or nevirapine for the prevention of postnatal transmission of HIV. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 99, 2005.