The key findings of the studies have been described recently on www.aidsmap.com. However, there were a number of smaller trials, mathematical models and sub-studies presented at the conference that may help bring the picture a little more into focus.
While the WHO guidelines recommend that HIV-infected mothers avoid breastfeeding whenever replacement-feeding options are “AFASS” (accessible, feasible, affordable, sustainable and safe), (see http://www.aidsmap.com/en/news/1C6972FE-B40B-42BC-BC71-2BA36589535E.asp) the recent outbreak of diarrhoea and increase in infant mortality in formula fed babies in Botswana demonstrated how difficult it is to for even middle-income developing countries to consistently meet AFASS criteria through their public health programmes. However, several speakers noted that there have been other studies in Africa that reported very good results with formula feeding, most notably the Ditrame Plus studies in the Ivory Coast (see http://www.aidsmap.com/en/news/4B3A0A9D-2500-48E2-8A5E-4C490E212AED.asp).
Furthermore, the rainy season in Botswana was particularly heavy that year, and may indicate a singular event. However, Dr Charles van der Horst, of the University of North Carolina Chapel Hill, and the primary investigator of the BAN study in Malawi, said that mortality increases after every rainy season in that setting. “Even if I didn’t have a calendar, I know when the rainy season starts in Lilongwe because all of a sudden I start seeing dead babies in my study. HIV-negative dead babies. And it’s because the rainy season is starting. They are crawling around getting mixed foods which are contaminated and outbreaks,” he said.
The other studies presented at the conference were performed in settings where formula feeding from birth was, for one reason or another, deemed impractical or inherently unsafe. The emphasis of these reports was when or how mothers should discontinue breastfeeding their infants.
The Zambia Exclusive Breastfeeding Study (ZEBS) concluded that early abrupt weaning (at four months) does not improve HIV-free survival among HIV-exposed infants — and is harmful to children who are already HIV-infected (full report here: http://www.aidsmap.com/en/news/4ACFB8CE-DF88-4385-9C18-33BBFD9FF24B.asp).
This conclusion differed somewhat from what had been predicted by mathematical models, one of which was presented in a poster session (Atashili). The model calculated HIV transmission, mortality and HIV-free survival rates for several different modes of infant feeding: exclusive formula feeding, exclusive breastfeeding for four months and exclusive breastfeeding for six months — based on perfect and imperfect adherence to each feeding model
Even though it derived its formulae on mortality risk at month 24 from studies that had been conducted in Kenya, Uganda and South Africa, this model could have under-estimated the risk of mortality associated with breastfeeding avoidance in most settings, given the findings of ZEBS and other reports of higher mortality in infants weaned before six months in areas where HIV was not a major public health problem. In fact, the model calculated roughly equivalent numbers of deaths would occur for each mode of infant feeding.
However, the model predicted that weaning at four months should have improved HIV-free survival at 24 months in comparison with prolonged breastfeeding — and this was plainly not the case in ZEBS. But this was not solely because survival in the abrupt weaning arm was so low, but because early weaning did not reduce HIV transmission as much as had been anticipated.
In fact, some experts suggested that abrupt weaning itself might directly increase the risk of transmission.
“Since breastfeeding is going to continue in the context of HIV, understanding the viral dynamics of HIV in breastmilk, and understanding the risk factors of MTCT of HIV is important,” said Katherine Semrau of Boston University, who presented an analysis of some of the factors associated with breastfeeding and MTCT in the first 138 mother/infant pairs in ZEBS.
32 out of the first 138 infants became HIV-infected (as measured by HIV-DNA PCR) over the course of the study). Several factors that have been previously noted in other studies were significantly associated with a higher risk of transmission, such as low haemoglobin levels (<10 g/dl), lower CD4 cell counts and higher plasma viral loads. Levels of HIV RNA (consistently above 50 copies per ml) in breastmilk were also highly associated with transmission (39% of women had consistently detectable viral load and a significantly higher risk of MTCT than women who were either inconsistent or non-shedders (OR = 4.3, 95%CI 2.04 to 9.44).
The breast is typically a conserved compartment to protect breastmilk, and viral load levels there do not always directly correlate with plasma viral load (although higher plasma viral load does tend to be associated with detectable virus in breastmilk). Approximately a third of the women in the study did not have detectable breastmilk viral load indicating that the breastmilk epithelium was effectively preventing HIV from entering the milk. None of the women without detectable viral load in their breastmilk transmitted HIV.
However, a relationship between levels of breast milk HIV RNA and breastmilk sodium (Na) levels was also observed. Na is a marker for epithelial permeability in breast tissue, and although it is typically elevated at the start of lactation, it later declines, typically until weaning. But in this study, when Na was elevated (≥13 mM/L) at four months (in 7% of the women), it was associated both with higher levels of viral load in breastmilk viral load and predicted transmission (p = 0.005).
Given that half of the women would have been randomised to abrupt weaning, the increased Na at this point could have been the result of abrupt weaning. If abrupt weaning reduces breast membrane integrity, then it could lead to increased viral load and the significantly increase the risk of transmission to an infant who is not yet entirely weaned.
According to another of the investigators of the ZEBS study, Dr Donald Thea of Boston University, “One of the observations that we had, when we looked at viral load in the breastmilk two weeks after weaning had occurred, we saw that there was a one log increase in the amount of virus in breastmilk, implying that there really are factors associated with the mode of weaning that we really need to look into further.”
The four other studies, demonstrated that rapid weaning could put HIV-negative infants at greater risk of life-threatening events than was seen in historical controls where mothers weaned infants normally. (full report here: http://www.aidsmap.com/en/news/5C963569-20A5-4077-94FF-AE4BE0911886.asp).
In one of these studies, conducted in Uganda, weaning occurred quite early (at a median of three months) — often just after the mother learned that her infant was HIV-negative. (Although in light of the high rate of transmission around the time of weaning in the ZEBS study, these infants should perhaps be retested). Dr Carolyne Onyango, who presented the findings from Uganda, noted that mothers were being advised to wean upon learning the infant’s status — or were often trying to devise other ways to prevent transmission. For example, one women said that she was going to give her infant black tea to try to keep the baby from becoming infected.
Finally, the three studies demonstrated similarly increased rates of life-threatening diarrhoea even in infants stopped breastfeeding at or shortly before six months — the period of time exclusive breastfeeding is now recommended for women who can’t use alternatives. While underscoring the dangers of weaning, it is unclear exactly what safer alternative there might be at this point in a child’s life. Furthermore, because these studies were not randomised or controlled, it is impossible to say whether such outcomes as HIV-free survival would have been better in children if exposed to long-term mixed feeding.
Rather, these studies underscore how crucial it is to provide HIV-positive mothers with adequate support. The investigators of these studies tended to stress the need to do more to improve hygiene, and access to safe, clean water. According to Dr Michael Thigden of the US Centre’s for Disease Control: “Counselling strategies to assist mothers in safe preparation of nutritional weaning foods in resource-limited settings are urgently needed.”
Meanwhile, Dr van der Horst stressed the necessity of providing infants extra sources of nutrition. “We asked the women before we started BAN about weaning at six months, and we also did a nutritional study about what they were giving the babies in terms of complementary feeds, and what they would give if they weaned, and it was clear that these babies would die if they didn’t get something in addition at six months,” he said.