Onyango-Makumbi, Carolyne MBChB, MS*; Bagenda, Danstan PhD*†; Mwatha, Antony MS‡; Omer, Saad B MBBS, MPH, PhD§; Musoke, Philippa MBChB, FAAP*¶; Mmiro, Francis MBChB, FRCOG*††; Zwerski, Sheryl L RN, MSN, CRNP‖; Asiimwe Kateera, Brenda MBChB*; Musisi, Maria RN*; Fowler, Mary Glenn MD, MPH#; Brooks Jackson, J MD#; Guay, Laura A MD#

INTRODUCTION

Mother-to-child transmission of HIV accounts for nearly 90% of all pediatric HIV infections.¹ More than 95% of HIV-infected children live in resource-poor settings where breastfeeding is the norm. Without prophylaxis, the overall risk of HIV transmission in breastfeeding populations is estimated to be between 30% and 45% and is due to perinatal infection and postnatal exposure through breast milk.² The latter contributes 12%-16% of the cumulative absolute risk of acquisition among infants through 2 years of age.^3-6 This cumulative risk is considerably lower if exclusive breastfeeding is practiced for the first 3-6 months followed by weaning at 6 months of age; the estimated risk of HIV transmission through breastfeeding after 6 weeks of age is less than 1% per month.^4,7,8

This low but cumulative risk of HIV transmission through breast milk must be balanced against the high morbidity and mortality risk due to malnutrition and infectious diseases seen among infants in resource-limited settings who are not breast-fed. In resource-poor settings, increased rates of infant gastroenteritis have consistently been associated with early replacement feeding, likely due to lack of clean water, unsafe food preparation, and early introduction of contaminated weaning foods.⁹ Worldwide, diarrheal diseases account for a significant proportion (13%-21%) of all deaths among infants and children less than 5 years of age with many of them suffering from frequent episodes which significantly impact development, growth, and overall nutritional status.^10-12

The optimal time for an HIV-infected woman in resource-limited settings to cease breastfeeding is dependent on both her individual circumstances and locally available resources. Exclusive replacement feeding or early weaning are neither feasible nor safe options for the majority of HIV-infected women in resource-poor settings like Uganda. The ability to provide safe replacement feeding and the risks associated with it cannot be easily assessed, and adequate resources to ensure clean water and weaning foods are rarely available for the majority of mothers. In addition, formula and animal milk substitutes are expensive and failing to breast-feed is stigmatizing. Even in mid-level countries, water safety cannot always be guaranteed. An example of this was a severe diarrheal outbreak in Francistown and surrounding areas in Botswana in 2006, when heavy rains led to ground-water contamination and resulted in a severe outbreak of infant diarrhea with resultant high morbidity and mortality among HIV-exposed infants who had received government provided formula milk and were not being breast-fed.¹³

In these analyses from Kampala, Uganda, we assessed the risk of infant morbidity from serious gastroenteritis and mortality using data from 2 large perinatal HIV clinical trials-the HIV Network for Prevention Trials (HIVNET 012) trial and the HIV hyperimmune globulin (HIVIGLOB)/nevirapine (NVP) trial, both of which were conducted at the same site but at different periods. The 2 studies reflect differing World Health Organization (WHO) infant feeding recommendations for HIV-infected women that were current at the times of the 2 trials.

METHODS

Parent Trial Study Design and Participants

These analyses were based on serious gastroenteritis and mortality data from 2 perinatal HIV transmission trials, HIVNET 012 and HIVIGLOB/NVP, both of which enrolled HIV-infected women and their children from the Mulago National Referral Hospital located in Kampala, Uganda.

The HIVNET 012 trial was a phase IIB randomized perinatal HIV prevention trial conducted from November 1997 to January 2001, with the primary goal of comparing the efficacy of intrapartum and neonatal single-dose (SD) NVP versus zidovudine (ZDV) in reducing maternal-to-child transmission. Pregnant women were consecutively recruited from Mulago Hospital antenatal clinics. The women were counseled and HIV tested; those who were HIV seropositive, met eligibility criteria, and gave informed consent were enrolled into the study. Mother-infant pairs were randomly assigned to receive SD NVP (200 mg) at labor onset and NVP (2 mg/kg) was given to the infant within 72 hours of birth or ZDV (600 mg) at the onset of labor, then 300 mg every 3 hours until delivery, and to the newborn infant 4 mg/kg ZDV twice daily for 7 days. The duration of follow-up was through 18 months. Detailed description of the study design, methods, and results is provided elsewhere.^14,15

The HIVIGLOB/NVP trial was a phase III randomized, 3-arm, partially blind trial comparing the efficacy of the SD NVP regimen with the addition of polyclonal HIVIGLOB or extended infant NVP dosing daily until 6 weeks of age compared with the SD NVP regimen alone for the prevention of perinatal and breast milk associated HIV transmission. HIVIGLOB, which is an experimental intravenous HIV hyperimmune globulin (HIV-GLOB) preparation containing antibodies against HIV (and others) was prepared by collecting the blood units from donors who were found to be HIV-1 antibody positive at the Nakasero Blood Bank in Kampala, Uganda. The HIVIGLOB product was tested in Sweden and Uganda in a phase I/II study and found to be safe.¹⁶ The 200 mg/kg dosage for the mothers was based on a dosage chosen for a US perinatal trial (PACTG 185) and the 400 mg/kg dosage for the infants was based on findings from the phase I/II study where it was associated with a lower transmission rate of HIV at 6 weeks of age and significant increases in HIV-1 p24 antibody titer after infusion in women and their infants.^16,17

Participant enrollment into the Phase III trial occurred between July 2004 and July 2006, and follow-up was completed in July 2007. Women were recruited from HIV-seropositive pregnant mothers participating in the Mulago Hospital prevention of mother-to-child transmission program. After infant feeding counseling, those HIV-infected women who chose to breast-feed were referred to the study for enrollment. Mothers who met the eligibility criteria and gave informed consent were enrolled in the trial between 32 and 35 weeks of gestation. All women were given a SD NVP tablet (200 mg) to take at the onset of labor and their newborns were given NVP syrup (2 mg/kg) within 72 hours of birth. In arm 1, mothers were randomized to receive a single intravenous infusion of 240 mL or 12 g (approximately 200 mg/kg) of HIVIGLOB at 36-37 weeks gestation, and the infants born to these mothers received a single intravenous infusion 24 mL or 1.2 g (approximately 400 mg/kg) of HIVIGLOB preferably within 18 hours of birth. In arm 2, infants received extended NVP prophylaxis (5 mg) daily from week 1 through 6 weeks of age while in arm 3, infants received only SD NVP after birth. All infants received multivitamins once daily from week 1 through 6 weeks of life. The HIVIGLOB/NVP trial was originally approved to follow-up infants through 18 months. However, in April 2007, by which time most infants had completed their scheduled study exit at 18 months, funding constraints by the sponsor necessitated that the length of follow-up be reduced to 12 months for the remaining few that had not completed their original study scheduled exit.

Cotrimoxazole Prophylaxis

In the HIVNET 012 trial, HIV-exposed infants did not routinely receive cotrimoxazole prophylaxis as there were no policy guidelines regarding this at the time. All infants in the HIVIGLOB/NVP trial were given prophylactic treatment with cotrimoxazole from 6 weeks of life to the time of confirmed negative HIV status after breastfeeding cessation as per the Ugandan Ministry of Health (MOH) guidelines.¹⁸ Children who were confirmed as HIV infected continued with cotrimoxazole prophylaxis after breastfeeding cessation.

Counseling Regarding Breastfeeding

In HIVNET 012, women were counseled according to Ugandan MOH/WHO guidelines at the time of the trial, which recommended exclusive breastfeeding for at least 6 months and to wean as early as possible thereafter.¹⁹ Women were not counseled to discontinue breastfeeding at any specific time point and many continued through the first year of life and some into the second year.

In contrast, mothers in the HIVIGLOB/NVP trial were counseled according to revised Ugandan MOH prevention of mother-to-child transmission guidelines at the time which recommended exclusive breastfeeding for 3-6 months, with early and abrupt weaning over a 2-week period to minimize mixed feeding, if an HIV-infected woman had to breast-feed because of social or economic reasons.^20,21 However, initiation of weaning was modified based on the mother's ability to provide adequate locally available nutritious foods and the nutritional status of the baby.

Determination of Infant HIV Infection

In HIVNET 012, qualitative HIV-1 RNA polymerase chain reaction (PCR) assays were done at age 1-3 days, 6 weeks, 14 weeks, and 12 months. If HIV-1 RNA was detected, a second sample was obtained at the earliest opportunity possible or at the next scheduled visit for confirmation by HIV-1 RNA PCR or HIV-1 culture. Infants were tested using HIV-enzyme immunoassay, with western blot confirmation if reactive at 18 months. Diagnosis of HIV infection in infants was based on a positive qualitative HIV-1 RNA PCR assay confirmed by either quantitative HIV-1 RNA assay or HIV-1 culture on a second blood sample. In the case of an infant death where there was only one positive RNA assay on the sample preceding death, the infant was considered to be infected.

In the HIVIGLOB/NVP trial, infants were tested at birth, at weeks 2, 6, 14 and at 6 and 12 months using qualitative DNA or quantitative RNA PCR. Infant HIV infection status was based on at least 2 positive PCRs (DNA or RNA) on separate infant specimens. At 18 months, HIV-uninfected infants were tested using HIV enzyme immunoassay with western blot confirmation if reactive. Infants who died or were lost to follow-up after only one positive PCR or antibody test were classified as infected. Infants were included in data analysis for this article if they remained HIV-uninfected through to 18 months or at the last visit.

Measurements of Serious Adverse Events

Gastroenteritis was defined as an episode of diarrhea (the passage of 3 or more loose or watery stools within a 24-hour period) with or without vomiting. For purposes of this analysis, we defined serious gastroenteritis events as those diarrheal events in the infant, as described above, which resulted in a hospitalization or death.

Data on serious adverse events (including serious gastroenteritis), HIV infection, and infant survival were collected systematically throughout the course of both the HIVNET 012 and HIVIGLOB/NVP trials. Adverse events grading was based on the NIH Division of AIDS Toxicity Tables for Grading Severity of Adverse Experiences, April 1994, for pediatric events.

Medical history, clinical examination, and routine laboratory tests were performed at scheduled protocol visits for both studies. For HIVNET 012, regular visits were scheduled at weeks 1, 6, 10, 14 and then at 6, 9, 12, and 18 months. In the HIVIGLOB/NVP trial, regular scheduled visits were weekly for the first 6 weeks, then at weeks 10, 14 and at 6, 12, and 18 months. In addition to the scheduled visits, mothers in both studies were encouraged to bring their infants to the clinic at any time in case of illness. At all visits, information on illnesses, hospitalizations, and vital status were collected. In the HIVNET 012 study, questions were asked about breastfeeding cessation only, whereas in the HIVIGLOB/NVP trial, standardized questions were asked about exclusive breastfeeding, mixed and replacement feeding, and timing of weaning. The complete cessation of breastfeeding was recorded as the date the mother or primary caretaker reported that the infant no longer received any breast milk.

Statistical Analyses

These analyses focused on rates and timing of gastroenteritis events that resulted in hospitalization or death and all cause mortality among HIV-uninfected exposed infants in the HIVIGLOB/NVP and the HIVNET 012 trials.

Baseline comparisons of continuous variables are presented using means, standard deviations, medians, and interquartile range (IQR). Means were evaluated using a 2-sided sample t test. Medians for duration of breastfeeding were based on Kaplan-Meier estimates to account for censoring over time. Categorical variables were compared using proportions and the corresponding cross-table Pearson chi-squared test (with Yates continuity correction).

Event rates were computed as the sum of the number of events of interest occurring for children seen within a 1-month age-interval band divided by the person-time at risk within that corresponding age-interval band, where risk time within each interval is indicated by the time during the interval that the child was still HIV uninfected. Thus, a child was dropped from the risk set for all the time within a specified age-band that follows HIV infection and for all that child's subsequent follow-up age intervals, but was considered for the length of time within the age interval when they were still regarded as HIV uninfected. Otherwise, each child contributes to events and person-time as indicated until their termination from the study. Associated 95% confidence intervals (CIs) were calculated under the assumption that the observed numbers of events follow a Poisson distribution, and by use of Byar approximation of Poisson exact limits which allow for asymmetric distribution of low event counts.^22,23

Graphs were generated depicting the event rates (per 1000 child-months) in each age-interval band and associated curves depicting 95% CIs. P values computed were based on Fisher exact 2-sided test, which were obtained by performing a uniformly most powerful unbiased test on the ratio of rates of 2 Poisson counts (divided by corresponding time at risk for each count) and defining the 2-sided P values as either 1 or twice the minimum of the 1-sided P values ensuring internally consistent P values.^24,25

Comparison of cumulative mortality between studies was based on the corresponding Kaplan-Meier (Aalen-Nelson) based cumulative hazard estimates of mortality over the follow-up period. Gastroenteritis-associated and overall mortality rates were also estimated using the overall number of events divided by the group respective child-months over an 18-month period. Statistical significance for all tests was evaluated against the 5% alpha critical level. All the analyses were done using R statistical program and Stata (College Station, TX).^26,27

Ethical Considerations

Institutional Review Board (IRB) approval was obtained from Uganda and US IRBs before each study commencement. Written informed consent was obtained from all study participants before enrollment after careful explanation of the studies.

RESULTS

In the HIVNET 012 study, 645 HIV-infected women were enrolled of whom 623 gave birth to HIV-uninfected babies whereas in the HIVIGLOB/NVP trial of the 722 women enrolled, 684 women gave birth to 698 HIV-uninfected babies who contribute risk time to the analysis. HIV-uninfected multiple births were included in this analysis.

Baseline Characteristics and Breastfeeding Cessation

Characteristics of mothers who gave birth to HIV-uninfected babies in the 2 trials are summarized in Table 1. The mothers in the HIVIGLOB/NVP trial were slightly older than mothers in HIVNET 012 by about a year. Parity of the mothers in the 2 trials was comparable with a median number of 3 children delivered (not including the study child). Marital status across the 2 studies was comparable with the majority of the women being married or in a stable union. The HIVNET 012 trial had a significantly higher proportion of women with less than secondary education [64.7% versus 56.2%, (P = 0.002)] and more women who described themselves as housewives [79.4% versus 69.6%, (P = 0.001)]. Of importance, there was a significant difference between the 2 trials with regard to breastfeeding cessation, with HIV-uninfected infants in the HIVIGLOB/NVP trial weaned at a median age of 4 months compared with 9.3 months in the HIVNET 012 trial (P < 0.001). Overall, the mothers were moderately immunosuppressed as evidenced by the absolute CD4 cell counts and viral load at enrollment, which were comparable between the 2 studies (Table 1).

Table 1

Rates of Serious Gastroenteritis

Table 2 presents age-specific rates of serious gastroenteritis events per 1000 child-months by month of age through 18 months of life among HIV-uninfected infants in the HIVIGLOB/NVP and the HIVNET 012 trials. In the HIVIGLOB/NVP trial, the highest rates of serious gastroenteritis events were 16.2 events per 1000 child-months at 3-4 months and 15.0 events per 1000 child-months at 7-8 months and thereafter remained relatively high up to 17 months. In the HIVNET 012 trial, serious gastroenteritis events increased at 7-8 months with a rate of 10.3 events per 1000 child-months, peaked at 9-10 months of age with a rate of 20.8 events per 1000 child-months, and then remained relatively low to 18 months of age.

Table 2

Across all age specified intervals, except the 9- to 10-month age interval, the rates of serious gastroenteritis were generally higher among infants in the HIVIGLOB/NVP trial when compared with the HIVNET 012 trial and reached statistical significance at 3-4 months (16.2 events per 1000 child-months versus 0 events per 1000 child-months, P = 0.005). Serious gastroenteritis events in the HIVIGLOB/NVP trial notably began at younger ages compared with infants in the HIVNET 012 trial (Fig. 1).

Figure 1

Overall rates of serious gastroenteritis events were highest in the HIVIGLOB/NVP trial at 8.0 events per 1000 child-months (95% CI 6.4-9.8) whereas the HIVNET 012 trial rates were 3.1 events per 1000 child-months (95% CI 2.1-4.4) which was statistically significant (P < 0.001).

Infant Mortality

The cumulative mortality for HIV negative infants was consistently although not statistically higher through 18 months of age in the HIVIGLOB/NVP trial when compared with the HIVNET 012 trial. The Kaplan-Meier (Aalen-Nelson) cumulative mortality hazard rates for the 2 studies are shown in Figure 2. The corresponding overall mortality rates in the HIVNET 012 trial versus the HIVIGLOB/NVP trial were 2.0 (95% CI 1.2-3.0) versus 3.2 (95% CI 2.1-4.6) per 1000 child-months, respectively (P = 0.10). In the course of follow-up, there were 6 gastroenteritis-associated deaths in the HIVIGLOB/NVP trial and only 1 gastroenteritis-related death in the HIVNET 012 trial. The overall gastroenteritis-related death rates in the HIVIGLOB/NVP trial versus the HIVNET 012 trial were 0.6 (95% CI 0.2-1.2) per 1000 child-months and 0.1 (95% CI 0.1-0.5), respectively (P = 0.18).

Figure 2

DISCUSSION

We compared rates of serious gastroenteritis events and death among HIV-exposed uninfected children from 2 trials in Uganda conducted at the same clinic but at periods where there were different infant feeding counseling guidelines in place. Before the HIV/AIDS era, Ugandan women were encouraged to exclusively breast-feed 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 with 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 2 studies when compared with 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 in the HIVNET 012 trial with a later (9 months) median age of breastfeeding cessation. Likewise, the serious gastroenteritis rates were significantly higher at 3-4 months of age in HIVIGLOB/NVP compared with 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 with 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 after breastfeeding cessation.²⁹ Based on these 2 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 with historical controls at the same sites but where breastfeeding went into the second year of life.^30,31 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.^20,21

Recent data from the MITRA Study in Tanzania and the Post-Exposure Prophylaxis of Infants (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.^32,33 However, the Zambia Exclusive Breastfeeding study 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 with those who were breast-fed and prophylaxed with daily infant ZDV; but with no difference in overall HIV-free survival by intervention arm at 12 or 18 months.³⁵

Although 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- to 6-fold decreased risk of mortality in the first 6 months of life and a 1.4- to 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.^37-39 Mixed-feeding before 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 6- and almost 4-fold higher infant mortality risk, respectively, when compared with 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.^40,41

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 with the rate of serious gastroenteritis before 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.^42,43 It has also been documented that the weaning foods usually selected by mothers in Uganda are inadequate to provide caloric, nutritional, and immunologic 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 with the HIVNET 012 data. Second, the HIVNET 012 findings are based on historic 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 2 studies. Given the relatively low mortality events, the analyses were underpowered to assess statistical differences in mortality between the 2 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 with 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, and more consistent cotrimoxazole prophylaxis, which would have reduced their risk of severe gastroenteritis compared with the earlier HIVNET 012 study infants. This would tend to mitigate any differences in severe gastroenteritis between the groups (ie, bias the magnitude of effect towards the null). However, despite this bias toward the null, the results demonstrated a significantly higher rate of serious gastroenteritis for the HIVIGLOB/NVP group compared with 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 Division of AIDS/National Institutes of Health (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; and reflecting the negative effects of early breastfeeding cessation reported in the general child survival literature.

These data from the HIVIGLOB/NVP trial in Uganda and 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 with more prolonged breastfeeding of HIV exposed infants.^30,31 In October 2006, WHO refined its HIV and infant feeding guidance and in February 2007, released revised guidelines to help policy makers and program managers clarify earlier recommendations.⁴⁵ The findings from HIVIGLOB/NVP and the studies in Malawi (PEPI), Kenya (Kisumu Breast-feeding Study [KIBS]), and Zambia (Zambia Exclusive Breastfeeding study) led to revised recommendations for most HIV-infected women to exclusively breast-feed for the first 6 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.^30,31,34 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 to provide optimal infant nutrition and to reduce the risk of severe infant gastroenteritis and mortality, although at the same time decreasing the risk of postnatal HIV transmission to maximize the lifesaving protective benefits of breast milk.

ACKNOWLEDGMENTS

Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (U01 AI068632).

The HIVNET 012 Trial was supported by the HIVNET and sponsored by NIAID, NIH, Department of Health, and Human Services, through contracts NO1-AI-35173 with Family Health International, NO1-AI-45200 with Fred Hutchinson Cancer Research Center, and subcontract NO1-AI-35173- 417 with Johns Hopkins University. In addition, the trial was supported by the HIV Prevention Trials Network and sponsored by NIAID and the Eunice Kennedy Shriver NICHD. Nevirapine (Viramune) for the study was provided by Boehringer Ingelheim Pharmaceuticals Inc. Other support was provided by Statistical Center for HIV/AIDS Research and Prevention at the Fred Hutchinson Cancer Research Center under 2 mechanisms: HIV Prevention Trials Network cooperative group agreement UO1 AI068617 and most recently through the subcontract with the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network BRS-IMPCT-Q-06-00126-T001 under their Prime grant number UO1 AI068632.

The HIVIGLOB/NVP study was sponsored by NIAID/NIH [RO1-AI34235, UO1 AI038576, UO1 AI048054 and UO1 AI69530. The content is the sole responsibility of the authors and does not necessarily represent the official views of the NIAID, NICHD, or NIH.

The authors sincerely thank the mothers and children who volunteered and participated in the 2 trials and all the staff of Makerere University-Johns Hopkins University Research Collaboration/MU-JHU CARE LTD for their participation in and support of the 2 trials.

REFERENCES

APPENDIX

C. Onyango-Makumbi coordinated the HIVIGLOB/NVP trial, contributed to the data analysis, and wrote the manuscript. D. Bagenda, S.B. Omer, and A. Mwatha provided data management and statistical support for analysis. M. Musisi and B. Kateera contributed to monitoring of adverse events and writing of the manuscript. S.L. Zwerski, P. Musoke, F. Mmiro, M.G. Fowler, L.A. Guay, and J.B. Jackson contributed to protocol development, conduct of the trial including monitoring of adverse events, and also with analyses and writing of the manuscript.