Further evidence that 'breast is best' for children of mothers with HIV in sub-Saharan Africa

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Early weaning resulted in almost twice as many acute illnesses and hospitalisations among HIV-exposed uninfected infants when compared to infants who continued to be breastfed beyond six months of age, long-term follow-up of the PEPI-Malawi study of extended infant antiretroviral prophylaxis has shown.

However, the difference only became apparent after 12 months of age, suggesting that both breastfeeding and antiretroviral prophylaxis beyond 12 months of age - the currently recommended milestone for HIV-positive mothers to begin weaning uninfected infants - ought to be evaluated by studies of longer breastfeeding and prophylactic regimens.

The findings are published in the August 15 edition of Clinical Infectious Diseases.

Glossary

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

morbidity

Illness.

hypothesis

A tentative explanation for an observation, phenomenon, or scientific problem. The purpose of a research study is to test whether the hypothesis is true or not.

diarrhoea

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

At 15 months of age 6.4% of infants weaned early had died compared to 3.5% of those still breastfeeding (p= 0.03).

Improving the survival of infants born to mothers with HIV who remain uninfected is a serious challenge in sub-Saharan Africa.

Studies in Malawi, Uganda and Botswana have shown how early weaning (at 4-6 months of age) to prevent HIV transmission compared to breastfeeding for longer periods has resulted in severe diarrhoea and death, acute malnutrition and/or stunted growth. Additionally, stopping breastfeeding has not improved HIV-free survival (remaining alive and being free of HIV infection).

Balancing the risks and benefits of breastfeeding in resource-poor settings where safe alternatives are rare has been the subject of lengthy debate.

Breastfeeding provides many protective factors including complete nutritional requirements and is vital to survival in resource-poor settings especially in the first few months of life. The World Health Organization (WHO) recommends breastfeeding for 12 months or longer.

The authors note that while evidence from resource-poor setting shows the increased risk of death and disease from not breastfeeding, the timing of these events is poorly understood.

In the interests of programme planning and clinical management the authors stress the importance of knowing the immediate and long-term effects of early weaning.

They hypothesise that stopping breastfeeding to prevent HIV transmission “leads to early acute morbidity that occurs during the process of weaning or immediately after weaning.”  They recognise that death linked to weaning happens late and after the process of weaning is completed.

The authors chose to look at rates of illness and/or hospitalisation among HIV-exposed, uninfected Malawian infants in follow-up periods of three months after weaning took place and to determine the cumulative death rates over time. The infants were part of the PEPI-Malawi trial.

The PEPI-Malawi trial took place from 2004 to 2009 to determine the efficacy of extended infant antiretroviral prophylaxis for up to 14 weeks after birth to reduce HIV transmission after birth. The study showed that 14 weeks of infant antiretroviral prophylaxis had a greater protective effect than single dose nevirapine plus one week of AZT.

The infants and their mothers were seen at birth and at 1, 3, 6, 9 and 14 weeks of age. After 14 weeks follow-up visits were at six months of age and then every three months until 2 years of age.

Mothers in the trial were advised to stop breastfeeding by six months. The characteristics of the mothers in the groups were similar and remained constant over time. However, more women in the NBF group had CD4 cell counts at baseline under 250 cells/mm3 than in the BF group.

This analysis included HIV-uninfected infants at six months of age.  Breastfeeding and illness and or hospital admission and malnutrition (defined as weight for age Z score of or less than two) were compared during the age intervals of 6-9 months, 9-12 months and 12-15 months.

Breastfeeding (BF) was defined as any breastfeeding at the start and end of the interval, and no breastfeeding was defined as no breastfeeding (NBF) at any time during the interval.

Among 1761 infants, after controlling for extended antiretroviral infant prophylaxis, infant cotrimoxazole prophylaxis and maternal HIV disease stage, the rate ratios for illnesses and/or hospital admissions for NBF compared to BF at 6-9 months, 9-12 months and 12-15 months were 1.7, p<0.0001, 1.66, p=0.0001 and 1.75, p=0.0008, respectively.

No breastfeeding was consistently and significantly associated with a higher risk of illness and/or hospitalisation.

The authors note these findings support their hypothesis and suggest “that the adverse effects of weaning occur quickly and manifest as acute events resulting in clinic visit or hospital admission.”

While death rates were similar between the BF and NBF groups during the 6-12 month age interval the risk of death was significantly higher in the NBF group during 12-15 months of age. This finding, the authors note, reinforces that of another study, which showed that stopping BF early was associated with increased mortality that continued into the second year of life in HIV-exposed, uninfected African children.

The authors also note the apparent association of cotrimoxazole prophylaxis (CTXP) with lower frequency of illnesses and /or admissions at each age interval for these infants. Evidence has shown the benefits of CTXP in HIV-infected infants and adults, while studies in HIV-exposed, uninfected infants are lacking.

A clinical trial (the PROMISE study) will begin soon that will determine if extended CTXP can reduce death and disease after stopping breastfeeding among HIV-exposed, uninfected infants.

The authors suggest a potential bias of excluding infants who became HIV-infected during the follow-up period, as most of these were in the BF group.

They also note the issue of reverse causality that is common to breastfeeding studies. Illness, for example, may lead mothers to stop breastfeeding and as such is the cause of not breastfeeding rather than the result.

The authors conclude “with the introduction of maternal antiretrovirals for both prophylaxis and treatment, breastfeeding duration could be extended. The impact of these changes on child health needs to be evaluated. In settings similar to Malawi, where the background rates of illness and death are high, inexpensive preventive strategies such as cotrimoxazole prophylaxis of HIV-exposed, uninfected children during and after weaning, should be considered.”

References

Taha, TE et al.Effects of cessation of breastfeeding in HIV-1-exposed, uninfected children in Malawi. CID 53(4): 388-395, doi: 10.1093/cid/cir413, 2011. (View free full text article).