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Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi
Global Health Sciences Literature Digest
Published June 21, 2010
Journal Article

Kafulafula G, Hoover DR, Taha TE. Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi. J Acquir Immune Defic Syndr. 2009 Oct 20.

In Context

Prevention of postnatal mother-to-child HIV transmission remains challenging in resource-constrained areas. While breastfeeding carries the risk of HIV transmission, infants who are not breastfed are at increased risk of mortality.(1) Because the risk of HIV transmission increases with the duration of breastfeeding, the World Health Organization (WHO) recommends exclusive breastfeeding for six months followed by rapid weaning. To reduce HIV transmission while breastfeeding, several clinical trials are examining the efficacy of maternal and infant antiretroviral therapy (ART) to prevent HIV transmission. However, data from such trials suggest that weaning at six months places the infants at increased risk for severe gastroenteritis (GE) and GE-associated mortality.(2, 3)

Objective

To compare the rates of GE-related serious adverse events and mortality among HIV-exposed, uninfected infants enrolled in two clinical trials of infant ART prophylaxis. The treatment was for one week followed by breastfeeding for more than one year (the nevirapine [NVP]/AZT [NVAZ] trial) and for 14 weeks followed by rapid weaning at six months (the Post-Exposure Prophylaxis to the Infant [PEPI] trial).

Setting

Queen Elizabeth Central Hospital and clinics, Blantyre, Malawi

Study Design

Observational analysis of cohorts from two randomized clinical trials

Participants

A total of 1,810 infant-mother pairs from NVAZ and 2,035 mother-infant pairs from PEPI

Outcome

Frequency of severe GE, GE-associated mortality, and all cause mortality

Methods

Infants enrolled in the NAVI trial were randomized to one of three study arms. Infants in the control arm received oral single-dose NVP (2 mg/kg body weight once) plus AZT (4 mg/kg body weight twice a day) for one week. Infants in the second arm received the same regimen as those in the control arm for one week, followed by daily oral NVP to age 14 weeks (2 mg/kg body weight once daily from weeks one through two and 4 mg/kg body weight once daily for weeks three through 14). Infants in the third arm received the same regimen as those in the control arm followed by daily oral NVP (dosed as above) and oral AZT (4 mg/kg body weight twice daily from weeks one through five, 4 mg/kg body weight three times daily from weeks six through eight, and 6 mg/kg body weight three times daily from weeks nine through 14) to age 14 weeks. Infants in both trials were followed-up at one and six weeks, and 3, 6, 9, 12, 15, 18, and 24 months. Infants in PEPI were also seen at weeks 3, 9, and 14. Infants were tested for HIV at each visit (except three weeks) using DNA PCR until 15 months or older at which time serology was used. Women in PEPI were counseled to wean at six months and were provided with supplemental nutrition, equipment necessary for preparing supplemental feeds, and guidance regarding hygienic practices. Documentation of GE was through clinic visit or report from the mother.

The analysis was restricted to infants who were HIV-uninfected up through the study visit under consideration. NAVI had completed all follow-up visits, and data up to August 7, 2007 were included for infants in the PEPI study. PEPI participants were enrolled before August 7, 2006.

Results

Women enrolled in the two trials had significant differences: women in the NVAZ trial were younger, had fewer living children, were less educated, and a larger proportion had medical problems during pregnancy than women enrolled in the PEPI trial. Women in the PEPI trial were more likely to have electricity at home but less likely to have running water.

Among mothers of uninfected infants in the NVAZ trial, 89% were breastfeeding at nine months and 60% at 24 months. In the PEPI group, 90% weaned their uninfected infants between six and nine months and 3% were breastfeeding at 24 months.

The frequency of GE episodes among infants at the four- and six-month visit was higher in the NVAZ group than in the PEPI group (6.38% and 4.08%, respectively, P=0.01) and at the 10- and 12-month visit (8.02% and 5.62%, respectively, P=0.02), but at all other ages the frequencies did not differ significantly. The frequency of GE so severe that it required hospitalization was significantly higher in the PEPI group at the 7- and 12-month visit (P<0.001).

Through age six months, the cumulative overall mortality did not differ between the two groups, but by nine months, the probabilities were 62 and 54 per 1000 uninfected infants for PEPI and NVAZ trials, respectively. The cumulative overall mortality at age 12 months was significantly higher in infants in the PEPI trial than in the NVAZ trial (79 vs. 66 per 1000 uninfected infants, respectively, P=0.03).

Through age six months, the cumulative GE-associated mortality probabilities were similar among infants in the two groups. By age nine months, cumulative GE-associated mortality was 19 and 7 per 1000 uninfected children for the PEPI and NVAZ trials, respectively. The cumulative GE-associated mortality at age 12 months was significantly higher in uninfected infants in the PEPI trial compared with the NVAZ trial (24 vs. 12 per 1000 infants, P=0.0002).

Conclusions

Early weaning is associated with increased frequency of and mortality due to GE among HIV-exposed infants. Strategies that can permit breastfeeding without increasing the risk of HIV transmission are warranted.

Quality Rating

In general, this was a good study. Examining data from two similar clinical trials offered an opportunity to measure the association between duration of breastfeeding and GE-associated adverse outcomes. However, there were significant sociodemographic difference between the groups, and the studies were conducted at different times. These factors may have confounded the findings. Another limitation is that the methods by which mortality was ascertained were not provided. Infants lost to follow-up were excluded, and the duration of follow-up was adequate.

Programmatic Implications

The findings from this study offer further evidence of the morbidity and mortality associated with early cessation of breastfeeding to reduce HIV transmission.(2, 3, 4, 5, 6) The higher rates of GE, GE hospitalizations, and mortality in the PEPI group suggest that programs targeting early weaning have not yet provided sufficient evidence of decreased infant mortality. Provision of maternal ART during breastfeeding may offer one strategy that can both reduce post-natal HIV transmission and permit longer duration of breastfeeding to protect against intestinal pathogens.

References

  1. WHO Collaborative Study Team on the Role of Breastfeeding on the Prevention of Infant Mortality. Effect of breastfeeding on infant and child mortality due to infectious diseases in less developed countries: a pooled analysis. Lancet. 2000;355:451-5.
  2. National Statistical Office (NSO) [Malawi], and ORC Macro. Malawi Demographic and Health Survey 2004. Calverton, MD: NSO and ORC Macro; 2005. Abstract not available.
  3. Mermin J, Lule J, Ekwaru JP, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet. 2004;364:1428-34.
  4. Kuhn L, Aldrovandi GM, Sinkala M, et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med. 2008;359:130-41.
  5. Onyango C, Mmiro F, Bagenda D, et al. Early breastfeeding cessation among HIV-exposed negative infants and risk of serious gastroenteritis: findings from a perinatal prevention trial in Kampala, Uganda. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, CA. Abstract 775.
  6. Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy of formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda. AIDS 2009;23:2415-23.