BAN study: Giving ART to mothers or ARV prophylaxis to infants during breastfeeding equally effective at reducing HIV transmission

Maternal antiretroviral therapy (ART) or infant prophylaxis during the time of breastfeeding are equally safe and effective in reducing post-natal mother-to-child transmission of HIV, Dr Charles Chasela of the University of North Carolina Project in Lilongwe, Malawi, reported to the Fifth International AIDS Society conference on Wednesday.

He presented the findings of the Breastfeeding, Antiretroviral and Nutrition (BAN) Study as a late-breaker at IAS 2009 in Cape Town - making it the fifth major study at the conference evaluating ways to make it possible for an HIV-infected mother to breastfeed her infant without passing on HIV.

Breastfeeding in HIV

Breastfeeding is generally the best way of feeding a baby, but when the mother is HIV-positive there is a risk of vertical transmission of the virus to her infant. WHO guidelines recommend exclusive breastfeeding for HIV-infected women for the first six months of life unless replacement feeding is acceptable, feasible, affordable, sustainable and safe (AFASS) for them and their infants before that time.

Unfortunately, replacement feeding is rarely possible in resource-limited settings. Formula is expensive and reliable supplies are difficult to maintain in countries with limited infrastructure for transport and storage. Even when formula feed is freely provided it may not be culturally acceptable and often puts the mother at risk of having her HIV status disclosed involuntarily to her family and community and of being stigmatised.

Glossary

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

mother-to-child transmission (MTCT)

Transmission of HIV from a mother to her unborn child in the womb or during birth, or to infants via breast milk. Also known as vertical transmission.

diarrhoea

Abnormal bowel movements, characterised by loose, watery or frequent stools, three or more times a day.

hypersensitivity

An allergic reaction.

morbidity

Illness.

Finally, the water to prepare it with may not always be safe or it may be difficult to keep the babies’ environment hygienic. As a result, some programmes have reported diarrhoea outbreaks.

Breastfeeding reduces diarrhoea-related morbidity and mortality. Even early weaning poses problems. In fact, in another presentation at the conference, Dr Ashraf Fawzy of Columbia University reported that diarrhoea and morbidity increased among uninfected infants of HIV-infected mothers in the Zambia Exclusive Breastfeeding Study (ZEBS). The effect was most pronounced in children who stopped breastfeeding earlier. What was worse? “Among children who weaned early, severe diarrhoeal morbidity and mortality continued to be higher between 6 and 18 months,” Dr Fawzy reported.

“Formula is not recommended in Malawi since it is expensive, and if used in the first six months, yields high infant mortality. Therefore, there is an urgent need for interventions to make breastfeeding safer for infants of HIV-infected women,” said Dr Chasela.

The BAN Study

So investigators from Malawi, the University of North Carolina and the US Centers for Disease Control (CDC) launched the BAN study, a randomised controlled trial to evaluate two interventions given to HIV-infected mothers or their infants during a 24-week period of exclusive breastfeeding.

To prevent mother-to-child transmission of HIV, all the mothers were treated with a single dose of nevirapine during labour, followed by a week of twice-daily treatment with 3TC and AZT. All the women participating in the study were given nutritional supplementation to prevent maternal depletion.

To be eligible for the study, all the mothers had a CD4 cell count above 250 cells/mm3 and the infants weighed at least 2 kg. Then within the first week after delivery, the mothers and their infants were randomised into one of three treatment arms:

  • Maternal daily treatment with nevirapine (after they were switched to nelfinavir, then the protease inhibitor lopinavir/ritonavir) in combination with 3TC and AZT
  • Infant nevirapine (NVP) that the mother administered to her infant through 28 weeks
  • A control arm. No antiretroviral treatment, but nutritional support.

All the mothers breastfed for 24 weeks, followed by rapid weaning by 28 weeks. Weaning food Plumpy Nut was provided until week 48.

The study outcomes were HIV infection or death in infants at week 28 amongst those who were HIV-uninfected a week after birth.

Results

A total of 2367 HIV-positive mothers and their infants were included in the study: 851 were on maternal ART, 848 were randomised to infant NVP, and 668 to the enhanced control. Fewer women were in the enhanced control arm since randomisation to the control arm was stopped after March 2008 based on a Data Safety and Monitoring Board recommendation.

There were no statistical significant differences in age, body mass index, CD4 count, haemoglobin and infant birth weight at baseline.

Severe side-effects were rare. There were no significant differences in terms of grade three or four toxicities except for low neutrophil count in mothers on the maternal ART arm (this is a known side-effect of AZT). And out of the 848 infants on the infant NVP arm, there were 16 possible cases of NVP hypersensitivity that were mild and all were resolved when NVP was discontinued. There appeared to be one additional case of NVP hypersensitivity in a breastfeeding infant whose mother was receiving NVP.

According to Dr Chasela, there had been concerns about NVP hypersensitivity (reactions that includes rash, eosonophilia, sometimes liver toxicity and Stevens Johnson Syndrome), which has been well documented in NVP use in adults, usually within the first weeks of treatment, but there is less information on its use in infants.

HIV infection status was assessed by testing the infant at birth, 2, 12, 28 and 48 weeks by DNA PCR. Dried Blood Spots (DBS) were obtained at each visit and tested to narrow the window of transmission to less than four weeks. All positives were confirmed with a second specimen. The rate of mother-to-child transmission of HIV one week after delivery (before randomisation) was 5%.

“Using standard survival methods - both the infant NVP and maternal ART regimens significantly reduced 28 week HIV transmission, compared with the enhanced control arm,” said Dr Chasela.

At the end of the study, 6.4% of the infants in the control arm were HIV-positive. This was significantly higher (p = 0.003) than the 3% rate of mother-to-child transmission observed in the infants of mothers who took antiretroviral therapy during breastfeeding, and the 1.8% transmission rate seen in infants treated with nevirapine (p

The overall risk of HIV transmission or death was 7.6% for infants in the control arm, compared to 4.7% for the maternal HIV treatment arm (p = 0.03) and 2.9% for the nevirapine arm (p

The study was not powered to directly compare the maternal and infant interventions, but there was some suggestion that HIV-free survival was lower among infants who were treated with NVP for 28 weeks (p = 0.07).

Implications

“The BAN results give global and national policy makers the choice of which interventions to implement: either maternal ART or infant NVP, based on the appropriateness of their particular setting,” said Dr Chasela.

Indeed, this was just one of five studies presented at IAS on interventions that could make breastfeeding safer for women with HIV and their infants. The first was a retrospective analysis of the DREAM cohort in Malawi and Mozambique, which found that giving ART during pregnancy and breastfeeding reduces the risk of a woman transmitting HIV to her infant to just 2%.

The other studies were all randomised controlled studies.

In the Mma Bana study in Botswana, there was about a half a percent risk of transmission during breastfeeding.

The PEPI-Malawi study was presented as a poster, and showed that extended antiretroviral prophylaxis of breastfeeding HIV-exposed infants for 14 weeks reduced postnatal transmission by 67% at age 14 weeks and 50% at age 9 months (Mofenson). However, continued transmission after 14 weeks suggested that infant prophylaxis needs to last at least as long as the mother continues to breastfeed.

Finally the Kesho Bora study used the same regimen as the BAN Study but commenced treatment between week 28 and 36 of pregnancy, rather than after delivery, and showed about a two percent risk of transmission during breastfeeding.

Taken together these findings have clear policy implications. Noting that transmission from women with CD4 counts of 200-350 cells/mm3 is still unacceptably high, Mofenson et al. wrote: Use of infant prophylaxis should be considered to reduce breast milk transmission risk in infants born to women with CD4 [cell counts] over 350, while women with CD4s [below] 350 should receive ART for their own health… which would be continued after breastfeeding cessation for maternal health.”

Further information

A powerpoint presentation by Charles Chasela and a webcast of the conference session in which it was presented are available on the IAS 2009 website.

A powerpoint presentation by Ashraf Fawzy and a webcast of the conference session in which it was presented are also available on the IAS 2009 website.