We compared rates of serious gastroenteritis events and death among HIV-exposed uninfected children from two trials in Uganda conducted at the same clinic but at periods of time where there were different infant feeding counseling guidelines in place. Prior to the HIV/AIDS era, Ugandan women were encouraged to exclusively breastfeed their children for 6 months and to continue thereafter to 2 years of age. This is still the practice among HIV-uninfected mothers in Uganda. In the HIVIGLOB/NVP trial, infants were weaned at a median age of 4 months with almost all ceasing breastfeeding by 6 months of age compared to the HIVNET 012 trial where weaning was at a median age of 9.3 months; and with some infants breastfeeding into the second year of life. Breastfeeding duration among HIV exposed infants was much shorter in both the two studies when compared to the median duration of 19.9 months of any breastfeeding among children in the general Ugandan population born in the three 3 years preceding the Uganda Demographic Health Survey (2000) [28
Infant morbidity from serious gastroenteritis and mortality for HIV-uninfected infants was consistently higher in the HIVIGLOB/NVP trial with early breastfeeding cessation (4 months) than the HIVNET 012 trial with a later (9 months) median age of breastfeeding cessation. Likewise the serious gastroenteritis rates were significantly higher at 3 to 4 months of age in HIVIGLOB/NVP compared to HIVNET 012 around the time of early breastfeeding cessation. These results are highly concerning considering the fact that mothers in the HIVIGLOB/NVP study generally had higher levels of education and employment as compared to the mothers in the HIVNET 012 trial; and that cotrimoxazole prophylaxis which has been found to be beneficial against diarrhea was given to all HIV-exposed infants in the HIVIGLOB/NVP trial from 6 weeks of life to the time of confirmed negative HIV status following breastfeeding cessation [29
]. Based on these two facts, we would have anticipated that the infant rates of serious gastroenteritis events in the HIVIGLOB/NVP trial would be lower than in the earlier HIVNET 012 trial- but this was not the case. These findings are consistent with recent reports from perinatal HIV prevention trials in Blantyre, Malawi and Kisumu, Kenya, which also reported higher rates of serious gastroenteritis events and/or infant mortality for HIV-exposed uninfected infants around the time of early breastfeeding cessation when compared to historical controls at the same sites but where breastfeeding went into the second year of life [30
]. The early breastfeeding cessation for HIV exposed infants at the time of the trials was based on MOH and 2000 WHO guidance on HIV and infant feeding which were in effect during the trials [20
Recent data from the MITRA Study in Tanzania and the PEPI trial in Malawi show that HIV- free survival through 6 and 9 months respectively, is significantly associated with extended prophylactic antiretroviral treatment of the infant during the breastfeeding period [32
]. However, the Zambia Exclusive Breastfeeding study (ZEBS) reported no overall difference in HIV-free survival for infants who were randomized to abrupt weaning at 4 months versus continued exclusive breastfeeding to 6 months with gradual introduction of complementary foods thereafter and complete cessation of breastfeeding on average by 16 months. Of importance in that study, for healthier women with CD4 cell counts over 350/μL and who comprise the majority of HIV-infected mothers in most settings, HIV-free survival of the infants was significantly better for women who continued breastfeeding into the second year of life [34
]. Likewise, data from the MASHI trial in Botswana found significantly higher overall infant mortality through 7 months for infants who were formula-fed from birth compared to those who were breastfed and prophylaxed with daily infant ZDV; but with no difference in overall HIV-free survival by intervention arm at 12 or 18 months [35
While HIV-free survival is generally one of the most important endpoints to assess, overall all-cause survival is also important in the context of resource limited settings and is closely linked to duration of breastfeeding. The general child-survival literature has consistently shown the protective effects of breastfeeding against early infant mortality with a 3-6 fold decreased risk of mortality in the first 6 months of life and a 1.4-1.8 fold protective effect of breastfeeding against mortality in the second 6 months of life [36
]. There may be a number of reasons for the protective effects of breastfeeding during the first year of life. First, breast milk is known to be rich in immunoglobulin A (IgA) which has a protective mechanism against enteropathic gut infections, along with other innate immune protection and nutritional benefits provided by breast milk. The babies in the HIVIGLOB/NVP study stopped breastfeeding at an early age before they were likely to have high levels of protective IgA along their epithelial linings [37
]. Mixed-feeding prior to complete breastfeeding cessation could also have contributed to the early onset episodes of serious gastroenteritis that is seen in the HIVIGLOB/NVP trial through introduction of contaminated weaning foods when the infant’s natural immunity was not yet sufficient to control the infections. Recent data from studies conducted in Uganda and South Africa, also found formula- feeding was associated with a six- and almost four-fold higher infant mortality risk respectively, when compared to breastfeeding among infants of HIV-infected mothers. These findings reinforce the crucial role of extended breastfeeding in promoting overall infant survival including among HIV exposed infants living in resource limited settings [40
In both the HIVIGLOB/NVP and HIVNET 012 trials, the rates of serious gastroenteritis events were higher around the time of breastfeeding cessation when compared to the rate of serious gastroenteritis prior to stopping breastfeeding. This is consistent with other studies which show that the timing of introduction of weaning foods is frequently associated with increased gastroenteritis morbidity/ mortality events. This increase in severe gastroenteritis is presumed to be precipitated by poor hygienic practices and use of contaminated water around the time of weaning [42
]. It has also been documented that the weaning foods usually selected by mothers in Uganda are inadequate to provide caloric, nutritional and immunological needs of the infant [44
]. This in turn predisposes infants to immunological compromise which can lead to increased episodes of serious gastroenteritis especially without the immunologic protection provided by breast milk.
Both the HIVNET 012 and HIVIGLOB/NVP studies had some limitations relevant to the above analyses. The HIVIGLOB/NVP did not have HIV-free survival to compare to the HIVNET 012 data. Secondly, the HIVNET 012 findings are based on historical data and there may be unknown biases and temporal trends that could have contributed to the differences in rates of serious gastroenteritis events noted in the two studies. Given the relatively low mortality events, the analyses were underpowered to assess statistical differences in mortality between the two studies. There were also significant differences in the length of breastfeeding between the trials with infants in the HIVIGLOB/NVP trial stopping on average at about 4 months of age. The shorter period of breast feeding placed the HIVIGLOB/NVP group at increased risk of severe gastroenteritis morbidity/mortality when compared to most infants in HIVNET 012 who generally breast fed till about 9 months of age. In balance, the HIVIGLOB/NVP infants also had access to more potent recent antibiotics, as well as more consistent cotrimoxazole prophylaxis which would have reduced their risk of severe gastroenteritis compared to the earlier HIVNET 012 study infants. This would tend to mitigate any differences in severe gastroenteritis between the groups (i.e. bias the magnitude of effect towards the null). However, in spite of this bias towards the null, the results demonstrated a significantly higher rate of serious gastroenteritis for the HIVIGLOB/NVP group compared to the HIVNET 012 group which we attribute in large part to the early breastfeeding cessation.
Inherent strengths of the analyses include that the data on adverse events were consistently and carefully captured by site clinicians using the same standardized DAIDS/NIH Toxicity Tables; and that there was excellent follow up of participants in both trials so that late infant outcomes were well documented. The results are likewise consistent with findings from other recent trials in Malawi and Kenya; as well as reflecting the negative effects of early breastfeeding cessation reported in the general child survival literature.
These data from the HIVIGLOB/NVP trial in Uganda as well as the PEPI Malawi trial and the Kisumu, Kenya trials raise concerns that early breastfeeding cessation among HIV-infected women in resource-limited settings may lead to increased rates of serious gastroenteritis adverse events among infants and to increased overall infant mortality when compared to more prolonged breastfeeding of HIV exposed infants [30
]. In October 2006 WHO refined its HIV and infant feeding guidance and in February 2007, released revised guidelines to help policy makers and programme managers clarify earlier recommendations [45
]. The findings from HIVIGLOB/NVP as well as the studies in Malawi (PEPI), Kenya (KIBS) and Zambia (ZEBS) led to revised recommendations for most HIV-infected women to exclusively breastfeed for the first six months and then to continue breastfeeding through the first year of life with introduction of complementary foods in situations where safe nutritional alternatives are not readily accessible [30
]. Further data are needed on HIV-free survival outcomes at 18-24 months in relation to infant feeding choices; with careful assessment of competing causes of infant mortality associated with early breastfeeding cessation.
The ultimate goal of infant feeding strategies for HIV-infected women should be to develop interventions which allow longer, safer breastfeeding in order to provide optimal infant nutrition and to reduce the risk of severe infant gastroenteritis and mortality; while at the same time decreasing the risk of post-natal HIV transmission in order to maximize the lifesaving protective benefits of breast milk.