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      When Is Replacement Feeding Safe for Infants of HIV-Infected Women?

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          Abstract

          In this issue of PLoS Medicine, Renaud Becquet and colleagues report their findings from a new study looking at the long-term safety of infant feeding interventions aimed at reducing mother-to-child HIV transmission in Africa [1]. Over two years, the researchers studied the safety of infant feeding interventions (either formula feeding or shortened breast-feeding) among infants of HIV-infected mothers in Abidjan, Côte d'Ivoire. The UNAIDS Guidelines The authors chose to examine this issue because of the continued challenges faced by HIV-infected mothers regarding infant feeding. Breast-milk transmission of HIV contributes substantially to the risk of infant HIV infection; consequently HIV-infected mothers in Europe and the United States are counseled not to breast-feed their infants. However, avoiding breast-feeding or shortening the term of breast-feeding may be risky for infants in settings with inadequate sanitation, limited access to breast-milk substitutes, or unsafe water. Thus, UNAIDS (the Joint United Nations Programme on HIV/AIDS) recommends that HIV-infected women “replacement feed” their infants when it is acceptable, feasible, affordable, sustainable, and safe (“replacement feeding” is a term used to refer to feeding infants with milk other than breast milk, such as formula) [2]. Interpreting these guidelines is particularly challenging on the ground. When is replacement feeding safe for babies? This issue of safety is the focus of Becquet et al's study—by measuring severe morbidity and mortality, the authors determined how risky replacement feeding and shortened breast-feeding were for infants born to HIV-infected mothers in an urban African setting. The New Study The authors compared morbidity, hospitalization, and mortality over a two-year period among infants of HIV-infected women who had received peripartum antiretrovirals and elected to either breast-feed for four months or formula feed. In addition, the authors compared the infants in this cohort to infants in a historical cohort in the same setting with the same clinical and survival assessments who breast-fed for a prolonged duration. Breast-milk transmission of HIV contributes substantially to the risk of infant HIV infection. Becquet et al. found that at baseline, formula-feeding mothers were more educated and had better access to tap water and less shared housing than women who elected to breast-feed for a short duration. However, there was no evidence that formula-feeding mothers in this cohort had more advanced HIV disease than women who breast-fed. Overall, adverse events among HIV-uninfected infants were similar in the two groups. Formula-fed infants had significantly increased risk of diarrhea and acute respiratory illnesses, while short-term breast-fed infants tended to have a higher incidence of malnutrition. However, over two-year follow-up, the risk of hospitalization or mortality did not differ between the two feeding groups. In addition, when both groups of infants were compared to a historical cohort in which breast-feeding was prolonged, the authors found excellent two-year survival among HIV-uninfected children regardless of whether they breast-fed long-term (95%) or breast-fed for four months or never breast-fed (96%). The authors conclude that “given appropriate nutritional counseling and care, access to clean water, and a supply of breast-milk substitutes, these alternatives to prolonged breast-feeding can be safe interventions to prevent mother-to-child transmission of HIV in urban African settings.” Implications of the Study These conclusions may be slightly provocative in 2007—replacement feeding has been abandoned in many African settings as a viable intervention for prevention of breast-milk HIV transmission. The authors provide good data to suggest that with appropriate provisos, replacement feeding can be a safe option to consider for HIV-infected mothers in urban African settings. Are these conclusions valid? Yes. The study has several strengths—the authors have conducted meticulous and robust analyses with large cohorts including a long period of follow-up. The authors had adequate retention and detailed morbidity assessment, and they included independent assessment of morbidity. The authors made use of a closely linked historical cohort in order to compare prolonged breast-feeding with shortened or no breast-feeding. While exclusive breast-feeding was not practiced by the majority of women in the cohort despite counseling to do so, the proportion of predominantly breast-feeding women was similar to other African cohorts promoting exclusive breast-feeding and probably reflects the reality of breast-feeding practices in similar settings [3]. All in all, for a woman in Abidjan, the likelihood of having a baby neither acquire HIV nor die would be highest with peripartum antiretrovirals and no or limited breast-feeding. Are the conclusions generalizable? Perhaps not widely. The findings of this study are consistent with a clinical trial in Nairobi, in which infants of HIV-infected women randomized to formula feed had significantly higher likelihood of not having an adverse outcome (either death or HIV infection) than the infants of women randomized to breast-feed [4]. Unfortunately, both studies may be hard to generalize to diverse settings in Africa. Supplying breast-milk substitutes is possible, but ensuring clean water is more problematic. In addition, the very strengths of the study (i.e., systematic frequent follow-up to ascertain morbidity and mortality) provided a safety net to prevent morbidity and mortality due to not breast-feeding that may be hard to replicate in a busy maternal–child health clinic in other settings. Thus, some prevention of mother-to-child transmission of HIV (PMTCT) programs that have provided replacement feeding have noted increased hospitalizations among infants who were replacement fed [5]. In addition, policy makers remain concerned about the potential impact of replacement feeding spillover from PMTCT programs to the general community, which could undermine efforts to promote breast-feeding [6]. Overall, translating safety for infant replacement feeding from closely observed research cohorts to programs can be problematic. The minimal mortality observed by Becquet and colleagues, however, may motivate PMTCT programs to think more carefully about optimizing child health in general. The high two-year survival in this cohort is laudable and reflects an important goal for PMTCT programs that may currently neglect child survival strategies in a narrow focus on HIV prevention. Incorporating frequent follow-up, growth assessment, and morbidity assessment and treatment within PMTCT follow-up clinics is essential to preserve child health benefits in addition to preventing infant HIV infection. While water safety and confidentiality issues may still pose challenges, strengthened infrastructure for infant/child surveillance may contribute to making replacement or shortened breast-feeding more safe. Conclusion Current research in prevention of breast-milk HIV transmission includes evaluation of a variety of approaches, including optimizing exclusive breast-feeding, providing antiretrovirals during shortened breast-feeding to mother or infant, and, ultimately, vaccination. Preserving breast-feeding is attractive because of nutritional, growth, safety, and confidentiality issues, and in the future these approaches may enable prolonged breast-feeding. However, some of the interventions currently under study may not be as promising as initially envisioned. For example, highly active antiretroviral therapy (HAART) during shortened breast-feeding is not the panacea hoped for—it may be associated with loss of confidentiality, toxicity, resistance, and infant morbidity and growth compromise when breast-feeding is stopped at six months. It is plausible that strategizing for not breast-feeding from birth would be less problematic than first starting to breast-feed on HAART, and then stopping after six months. Thus, replacement feeding should still be considered in the mix of strategies to prevent breast-milk transmission of HIV, particularly when water safety is assured and provision of breast-milk substitutes is an option. Becquet et al's data are reassuring that when appropriate support is provided and clean water is available, replacement feeding can be safe in an urban African setting.

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          Most cited references5

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          Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival.

          The promotion of exclusive breastfeeding (EBF) to reduce the postnatal transmission (PNT) of HIV is based on limited data. In the context of a trial of postpartum vitamin A supplementation, we provided education and counseling about infant feeding and HIV, prospectively collected information on infant feeding practices, and measured associated infant infections and deaths. A total of 14 110 mother-newborn pairs were enrolled, randomly assigned to vitamin A treatment group after delivery, and followed for 2 years. At baseline, 6 weeks and 3 months, mothers were asked whether they were still breastfeeding, and whether any of 22 liquids or foods had been given to the infant. Breastfed infants were classified as exclusive, predominant, or mixed breastfed. A total of 4495 mothers tested HIV positive at baseline; 2060 of their babies were alive, polymerase chain reaction negative at 6 weeks, and provided complete feeding information. All infants initiated breastfeeding. Overall PNT (defined by a positive HIV test after the 6-week negative test) was 12.1%, 68.2% of which occurred after 6 months. Compared with EBF, early mixed breastfeeding was associated with a 4.03 (95% CI 0.98, 16.61), 3.79 (95% CI 1.40-10.29), and 2.60 (95% CI 1.21-5.55) greater risk of PNT at 6, 12, and 18 months, respectively. Predominant breastfeeding was associated with a 2.63 (95% CI 0.59-11.67), 2.69 (95% CI 0.95-7.63) and 1.61 (95% CI 0.72-3.64) trend towards greater PNT risk at 6, 12, and 18 months, compared with EBF. EBF may substantially reduce breastfeeding-associated HIV transmission.
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            Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial.

            Transmission of human immunodeficiency virus type 1 (HIV-1) is known to occur through breastfeeding, but the magnitude of risk has not been precisely defined. Whether breast milk HIV-1 transmission risk exceeds the potential risk of formula-associated diarrheal mortality in developing countries is unknown. To determine the frequency of breast milk transmission of HIV-1 and to compare mortality rates and HIV-1-free survival in breastfed and formula-fed infants. Randomized clinical trial conducted from November 1992 to July 1998 in antenatal clinics in Nairobi, Kenya, with a median follow-up period of 24 months. Of 425 HIV-1-seropositive, antiretroviral-naive pregnant women enrolled, 401 mother-infant pairs were included in the analysis of trial end points. Mother-infant pairs were randomized to breastfeeding (n = 212) vs formula feeding arms (n = 213). Infant HIV-1 infection and death during the first 2 years of life, compared between the 2 intervention groups. Compliance with the assigned feeding modality was 96% in the breastfeeding arm and 70% in the formula arm (P<.001). Median duration of breastfeeding was 17 months. Of the 401 infants included in the analysis, 94% were followed up to HIV-1 infection or mortality end points: 83% for the HIV-1 infection end point and 93% to the mortality end point. The cumulative probability of HIV-1 infection at 24 months was 36.7% (95% confidence interval [CI], 29.4%-44.0%) in the breastfeeding arm and 20.5% (95% CI, 14.0%-27.0%) in the formula arm (P = .001). The estimated rate of breast milk transmission was 16.2% (95% CI, 6.5%-25.9%). Forty-four percent of HIV-1 infection in the breastfeeding arm was attributable to breast milk. Most breast milk transmission occurred early, with 75% of the risk difference between the 2 arms occurring by 6 months, although transmission continued throughout the duration of exposure. The 2-year mortality rates in both arms were similar (breastfeeding arm, 24.4% [95% CI, 18.2%-30.7%] vs formula feeding arm, 20.0% [95% CI, 14.4%-25.6%]; P = .30). The rate of HIV-1-free survival at 2 years was significantly lower in the breastfeeding arm than in the formula feeding arm (58.0% vs 70.0%, respectively; P = .02). The frequency of breast milk transmission of HIV-1 was 16.2% in this randomized clinical trial, and the majority of infections occurred early during breastfeeding. The use of breast milk substitutes prevented 44% of infant infections and was associated with significantly improved HIV-1-free survival.
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              Two-Year Morbidity–Mortality and Alternatives to Prolonged Breast-Feeding among Children Born to HIV-Infected Mothers in Côte d'Ivoire

              Introduction In high human immunodeficiency virus (HIV) prevalence resource-constrained settings, HIV-infected pregnant women face a dilemma regarding the feeding practices of their forthcoming infant [1]. Indeed, in sub-Saharan Africa, where breast-feeding is widely practiced and usually prolonged at least 1 y after birth, the overall risk of HIV transmission through breast milk was estimated to be 8.9 new cases per 100 child-years of breast-feeding [2], and was thus responsible for 40% of perinatally acquired HIV infections [3]. On the other hand, in the absence of any specific nutritional counseling and adapted clinical management, nonbreast-fed children have a greater risk of dying from infectious diseases, especially early in infancy [4]. Current United Nations recommendations state that “when replacement feeding is acceptable, feasible, affordable, sustainable and safe, avoidance of all breast-feeding by HIV-infected mothers is recommended. Otherwise, exclusive breast-feeding is recommended during the first months of life and should then be discontinued as soon as it is feasible” [5]. Given the necessary support, complete avoidance of breast-feeding or exclusive breast-feeding with early cessation are conceivable nutritional interventions in urban African settings [6]. According to several African studies, the combined promotion of exclusivity of breast-feeding with early cessation could indeed reduce the cumulative risk of postnatal transmission while keeping the benefits of breast-feeding during the first months of life [7–10]. On the other hand, the postnatal risk of HIV transmission no longer exists when breast-feeding exposure is avoided [11]. However, little is known about the safety of these interventions. Compared to unrestricted breast-feeding, complete avoidance of breast-feeding was shown to be safe in an African clinical trial allocating infant feeding practices at random: morbidity and mortality were similar over a span of 2 y in breast-fed and formula-fed children [12]. But so far, child morbidity and mortality have never been studied in real-life situations in which HIV-infected pregnant women are able to choose either to breast-feed for a short period or to formula-feed, while being supported in their choice and counseled accordingly. The primary objective of this study was to assess the 2-y morbidity and mortality among short-term breast-fed and formula-fed children born to HIV-infected mothers in an urban West African setting with access to clean water. The secondary objective was to assess the 18-mo mortality among children exposed to these alternatives to prolonged breast-feeding and in long-term breast-fed children included in an historical cohort without infant feeding intervention. Methods The ANRS 1202/1202 Ditrame Plus study was an open-labeled cohort, based on patients attending community-run health facilities in Abobo and Yopougon, the two most-densely populated districts of Abidjan, the economic capital of Côte d'Ivoire. In this setting, HIV prevalence was around 11% among pregnant women in 2002 [13], municipal water is of generally good quality [14], and breast-feeding is widely practiced long term [15,16]. The Ditrame Plus study was granted ethical permission in Côte d'Ivoire from the ethical committee of the National AIDS Control Programme, and in France from the institutional review board of the French Agence Nationale de Recherches sur le Sida (ANRS). Inclusion Procedures and Research Design The inclusion procedures and research design undertaken in the Ditrame Plus study were described in detail in previous publications [17,18]. Briefly, from March 2001 to March 2003, any pregnant woman aged 18 y and over, diagnosed as HIV infected within one of the selected community-run health facilities, was proposed for entry into the study. Women included were systematically presented with both peripartum antiretroviral and postpartum nutritional interventions to prevent mother-to-child transmission of HIV. First, they received a short peripartum drug combination of zidovudine with or without lamivudine and nevirapine single dose [17]. Second, they were systematically and antenatally proposed to practice either complete avoidance of breast-feeding or exclusive breast-feeding with early cessation from the fourth month. Replacement feeding from birth or from breast-feeding cessation until 9 mo of age, as well as the material needed, were provided free of charge. In all cases, the staff supported the choice expressed by the women and counseled them accordingly [18]. Follow-up Procedures and Data Collection Two centers were exclusively dedicated to the follow-up of the mother–infant pairs. From birth up to the second birthday, 19 visits were scheduled on study sites for clinical, nutritional, psychosocial, and biological follow-up of both mothers and infants. Mother–infant pairs were seen at birth, 48 h after delivery, weekly until age 6 wk, monthly until age 9 mo, and every 3 mo until the second birthday. At each contact, the medical staff documented clinical events that occurred in children since the last visit. At each scheduled visit, infant feeding practices were recorded via structured questionnaires [19]. Patients who did not keep scheduled appointments were traced and encouraged to return to the study sites. At each scheduled visit, anthropometric measurements, including height and weight, were taken by trained staff according to standard procedures [20]. Infant feeding counseling was made available at study sites whenever needed [18]. Children requiring intravenous treatment were managed at the day-care hospital units linked to the study sites. For life-threatening diseases or diseases requiring overnight care, children were immediately referred to the pediatric unit of the University Hospital of Yopougon. All transport costs were reimbursed, and all care expenses related to any clinical event were entirely supported by the project. Pediatric Diagnosis of HIV Infection Blood samples were collected at day 2, weeks 4, 6, and 12, and then every 3 mo until 18 mo of age or until 2 mo after complete cessation of breast-feeding if the child was ever breast-fed. A serology examination was systematically performed at age 18 mo in all children. Pediatric HIV infection was defined as a positive RNA PCR at any age or positive HIV serology if aged 18 mo or more [21]. HIV-infected children received cotrimoxazole chemoprophylaxis from the time of their HIV diagnosis. Clinical Definitions Special attention was given to the collection of data on child morbidity potentially linked to inadequate infant feeding practices: diarrhea, acute respiratory infections, or malnutrition. During the study, all reports of potential outcomes were referred for independent review and classification by an event documentation committee unaware of the child's feeding practices. This committee used all clinical information available, including hospital records if the child had been hospitalized. The following definitions were used to validate morbidity. Diarrhea was defined as the passage of three or more loose or watery stools during a 24-h period for at least 2 d, or any reported diarrhea associated with at least one clinical sign of dehydration, or any reported diarrhea requiring care and followed by at least a second consultation for the same reason during a 72-h period. A diagnosis of acute respiratory infection was made if the child presented a cough, fever (axillary temperature greater than 37.5 °C), and focal pulmonary findings on physical examination. A diagnosis of malnutrition was considered when the child presented with growth faltering (no change or a decrease in measurements on growth charts from one visit to another) and was referred to the nutritionists to receive appropriate nutritional care, including provision of protein-enriched food. In case of child death, verbal autopsies were systematically conducted by trained psychosociologists to assign a possible cause of death [22]. The potential contributing causes of death were independently assessed by two pediatricians, unaware of the child's feeding practices, on the basis of all the clinical information collected (including hospital records) and the verbal autopsy. In case of conflicting diagnosis between the two pediatricians, the opinion of a third one was sought. Causes of death were codified using the 10th revision of the International Statistical Classification of Diseases and Related Health Problems [23]. Study Outcomes The primary outcome of the study was the 2-y occurrence in children according to infant feeding practices and HIV status of adverse health outcomes: any severe event (death, or hospital admission related to any cause or in any location) or validated morbid event as defined above. The two components of this definition were also investigated separately as secondary outcomes (severe events and validated morbidity). A secondary analysis was performed to compare the 18-mo mortality among children exposed to alternatives to prolonged breast-feeding with the mortality of long-term breast-fed children using the ANRS 049 Ditrame trial. This historical trial was conducted in Abidjan, Côte d'Ivoire, and Bobo-Dioulasso, Burkina Faso, in 1995–1998, and it evaluated the efficacy of zidovudine to reduce mother-to-child transmission of HIV [24,25]. For the present analysis, we have included women from the Ditrame trial recruited in Côte d'Ivoire only. These women were recruited at the same sites and in the same population as the Ditrame Plus study. No strategy was proposed at that time to prevent the postnatal transmission of HIV: infants were long-term breast-fed as they usually are in Abidjan [9]. Statistical Analysis All live-born infants were available for analysis. In the case of multiple births, only the first born was included. Live-born infants fed at least once were classified in either the breast-fed or formula-fed group on the basis of the infant feeding practices recorded at the visit 2 d after birth, i.e., according to the feeding practice that had been actually initiated. Infants who died or were lost to follow-up before having been fed at least once were unclassified. Baseline characteristics were compared between these two groups using the Pearson χ2 test or the Fisher exact test to compare categorical variables, and the Mann-Whitney U test to compare continuous variables. Compliance with the infant feeding choice was assessed and defined as follows: breast-feeding mothers were considered noncompliant if they had ceased breast-feeding before the third month, and nonbreast-feeding mothers were considered noncompliant if they had breast-fed at least once over the study period. Total effective follow-up time expressed in person-years was compared to total expected follow-up time in both groups. The causes reported for stopping follow-up before the expected 24 mo were described. The cumulative probabilities of remaining free from an adverse health outcome, a severe event or a validated morbid event, were compared between short-term breast-fed and formula-fed infants using time-to-failure methods, including the Kaplan-Meier estimation and log-rank testing. Multivariate analysis used Cox proportional-hazard models. This approach allowed for the estimation of HRs for mortality and morbidity between the two groups, with adjustment for pediatric HIV status (time-dependent variable) and other covariates at baseline (maternal education, type of housing, type of water supply, baseline maternal CD4 count, living or not with one's partner, study site, and low birth weight). Incidence rates of diarrhea, acute respiratory infection, and malnutrition were expressed per 100 person-year at risk, according to infant feeding practices and HIV status. Estimates were reported with their 95% confidence intervals (CIs). All statistical analyses were carried out with the use of SAS software (version 8.2; SAS Institute, http://www.sas.com). Results The cohort profile from acceptance of HIV testing to enrollment in the Ditrame Plus study is described elsewhere [17,18]. Among the 643 HIV-infected pregnant women consecutively enrolled between March 2001 and March 2003, 19 with a nonconfirmed HIV-1 status, or infected with HIV-2 only, were excluded, 44 were lost to follow-up before delivery, and 580 gave birth to 612 children [18]. After exclusion of second- and third-born babies of multiple births, 580 mother–infant pairs were included in the present analysis. Of these, 11 (1.9%) were stillbirths, 11 (1.9%) died within the first 72 h of life without having received any food, and one (0.2%) was lost to follow-up before recording information on first feed. Among the 557 live-born children fed at least once, 295 (53%) constituted the formula-fed group and 262 (47%) the short-term breast-fed group. Baseline Study Population Characteristics Baseline characteristics of mother–infant pairs in the Ditrame Plus short-term breast-fed and formula-fed groups are summarized in Table 1. Compared to breast-feeding mothers, formula-feeding mothers had a significantly higher level of education, were less likely to have cospouses or live-in typical shared housing, and were more likely to have tap water access at home. The other sociodemographic, clinical, and biological characteristics were comparable between the two groups. Compliance with the Initial Infant Feeding Maternal Choice In the breast-feeding group, 24 women (9%) were not compliant with the nutritional intervention agreed upon with the study team because they ceased breast-feeding before age 3 mo and switched to feeding their infants with artificial foods. Among the 262 breast-feeding mothers, complete cessation of breast-feeding occurred a median of 4 mo after delivery (interquartile range [IQR], 3–5 mo). In this group, 91% of the children were breast-fed for at least 3 mo, and 47% were still being breast-fed at age 6 mo. Women were encouraged to practice exclusive breast-feeding, but they failed; instead, most of the infants were predominantly breast-fed during the first 3 mo of life (i.e., children were given small amounts of water or water-based drinks in addition to breast milk) [18]. In the formula-feeding group, 44 women (15%) were noncompliant because they were found to have practiced breast-feeding at least once, 83% of them before their child was 1 mo of age. They thereafter switched to predominant breast-feeding. Mother–Infant Pair Follow-up Total follow-up time was 421 person-years among short-term breast-fed children and 517 person-years among formula-fed children, yielding, respectively, 85% and 92% of expected follow-up times (Table 2). Follow-up was stopped before age 24 mo for 107 children, accounting for 22% of the breast-fed children and 16% of the formula-fed children (p = 0.06). For these 107 lost-to-follow-up children, the median age at the end of their observation time was 364 d (IQR, 92–508 d), and was significantly higher in formula-fed (415 d in median, IQR, 260–547 d) than breast-fed children (245 d, IQR, 42–456 d). The reported causes for stopping follow-up before age 24 mo did not differ between the two groups and were as follows: relocation outside the Abidjan limits (40%), refusal linked to the study protocol (too many scheduled visits or blood samples collected, 15%), family problems (mother ill or deceased, child with the father outside Abidjan, or widowhood, 9%), fear of stigmatization linked to the study participation (7%), and unspecified for the remainder (29%). Occurrence of Adverse Health Outcomes As shown in Figure 1, 37% of the formula-fed and 34% of the short-term breast-fed children remained free from an adverse health outcome, yielding an unadjusted HR among formula-fed children compared to breast-fed children of 1.09 (95% CI, 0.87–1.35; p = 0.43). After adjustment for pediatric HIV status and baseline covariates described in Methods, this HR was 1.10 (95% CI, 0.87–1.38, p = 0.43). In a multivariate analysis, the occurrence of an adverse health outcome was only significantly associated with the diagnosis of pediatric HIV infection (HR, 3.1; 95% CI, 2.3–4.1). Occurrence of Severe Events The overall 2-y probability of survival in the Ditrame Plus study was 90%. Mortality rates did not differ significantly between short-term breast-fed and formula-fed children. Over the 2-y period, short-term breast-fed and formula-fed children were comparable for cause of death; however, the frequency of diarrhea tended to be higher in formula-fed children (p = 0.10) (Table 3). Among the 557 children, 75 died or were hospitalized: 39 were in the formula-fed group and 36 in the breast-fed group. As detailed in Figure 2, the probability of remaining free from hospitalization or death over the first 2-y of life was the same in the two groups, even after adjustment for potential confounders. The unadjusted and adjusted HRs among formula-fed children compared to short-term breast-fed children were 0.89 (95% CI, 0.57–1.40; p = 0.62) and 1.19 (95% CI, 0.75–1.91; p = 0.44), respectively. In a multivariate analysis, the occurrence of death or hospitalization was significantly associated with the diagnosis of pediatric HIV infection (HR, 15.2; 95% CI, 9.4–24.6), low birth weight (HR, 1.8; 95% CI, 1.1–3.3) and mother's illiteracy (HR, 2.0; 95% CI, 1.2–3.2), but not with infant's mode of feeding (HR, 1.2; 95% CI, 0.7–1.9). Very similar results were obtained when performing this analysis among HIV-uninfected children alone. Occurrence of Validated Morbidity Over the 2-y period, 36% of the children remained free from diarrhea, acute respiratory infection, or malnutrition (Figure 3). This percentage was slightly higher in formula-fed compared to short-term breast-fed children, but the difference never reached statistical significance, even after adjustment for potential confounders. The unadjusted and adjusted HRs among formula-fed children compared to breast-fed children were 1.15 (95% CI, 0.92–1.43; p = 0.22) and 1.16 (95% CI, 0.92–1.46; p = 0.21), respectively. The incidence rates of diarrhea, acute respiratory infection, and malnutrition are reported in Table 4. Compared to short-term breast-fed children, the incidences of diarrhea and acute respiratory infection were higher among formula-fed children (27 versus 22 cases and nine versus six cases per 100 person-years, respectively), yielding adjusted HRs of 1.4 and 1.7 (p = 0.03 and p = 0.04, respectively). The incidence of malnutrition tended to be higher in breast-fed than formula-fed children (14 versus 11 cases per 100 person-years), but this difference was not statistically significant, even after adjustment. Comparison of Mortality Rates with Long-Term Breast-Fed Infants In 1995–1998, 240 women delivered 243 children in the Abidjan site of the Ditrame trial. After exclusion of three second-born babies of multiple births, four stillbirths, four children who died within the first 72 h of life without having received any food, three lost to follow-up before recording information on first feed, and ten nonbreast-fed children, 219 long-term breast-fed children were included in the present analysis. Baseline characteristics of these mother–infant pairs are presented in Table 1 and compared with the patients of the Ditrame Plus study. Women used for historical comparison were significantly younger, had higher CD4 counts, and were more likely to be at World Health Organization (WHO) clinical stage 1–2, whereas their children had lower birth weight than in the Ditrame Plus study. The median duration of breast-feeding in the Ditrame trial was 8 mo (IQR, 6–10 mo), and 80% of the children were still being breast-fed at age 6 mo. As detailed in Table 5, the overall 18-mo probability of survival was significantly higher in the Ditrame Plus study than in the Ditrame trial: unadjusted HR of 2.24 (95% CI, 1.41–3.56; p < 0.001). But the 18-mo probability of survival was similar among formula-fed and short-term and long-term breast-fed HIV-uninfected children. In a multivariate analysis, the occurrence of death was significantly associated with the diagnosis of pediatric HIV infection (HR, 14.4; 95% CI, 8.5–25.5), low birth weight (HR, 1.9; 95% CI, 1.1–3.3), mother's WHO clinical stage 3 (HR, 1.7; 95% CI, 1.1–2.9), mother's illiteracy (HR, 1.7; 95% CI, 1.1–2.8), but not with infant's mode of feeding (long-term breast-fed versus short-term breast-fed and formula-fed: HR, 1.3; 95% CI, 0.8–2.1). Discussion In this large prospective cohort study, we found no difference in 2-y rates of adverse health outcomes between early weaned breast-fed and formula-fed children born to HIV-infected mothers. Moreover, the 2-y probabilities of remaining free from severe events (hospitalization or death) and from morbidity validated by an independent committee were comparable in these two groups. However, compared to short-term breast-fed children and after adjustment for potential confounders, the formula-fed ones had a slightly increased risk of diarrhea or acute respiratory infections, but this difference materialized into neither differences in malnutrition rates nor hospitalization or death rates. Another important issue was whether these two modified infant feeding practices were safe as opposed to the standard, more prolonged breast-feeding. For that purpose, we compared 18-mo mortality among these short-term breast-fed and formula-fed children with the mortality observed in long-term breast-fed children within a historical trial conducted in the same population. No excess in mortality was observed in children exposed to alternatives to prolonged breast-feeding when taking into account HIV status: an overall 18-mo probability of survival of 96% was observed among HIV-uninfected short-term and formula-fed children, which was similar to the 95% probability observed in the long-term breast-fed ones. At first glance, a randomized clinical trial allocating infant feeding modalities at random would have been the ideal design for investigating adverse health outcomes. We, however, believe the way of feeding one's forthcoming child has to follow an informed and reasoned choice, and thus depends on individual situations. The choice of the infant feeding modality was thus left to the mother in a real-life situation in which alternatives to prolonged breast-feeding were available. The corollary of this nonrandomized design was that breast-feeding women of the Ditrame Plus study were different from those who did not breast-feed. The comparison between the feeding groups could have thus been biased by these differences. The breast-feeding group indeed had lower maternal education, lived in more crowded housing, and was less likely to have in-house access to tap water. All of these factors could be expected to be associated with greater morbidity and mortality in the breast-fed group, but all our analyses adjusted for these potential confounders to minimize this bias. The Ditrame trial was used as a group of comparison because no alternatives to prolonged breast-feeding had been proposed within that study. The strength of this strategy was that the women had been recruited at the same sites, with the same criteria, and in the same population as the Ditrame Plus study, and both of these studies were coordinated by the same study group. Morbidity data had not been collected and validated as in the Ditrame Plus study, however, limiting our present analysis to mortality. Because the Ditrame trial and the Ditrame Plus study were performed in the same setting by the same team, we cannot exclude the possibility that the medical team was less knowledgeable about managing infants born to HIV-infected women in the earlier period of the research program. We also acknowledge that there may have been confounding factors that had not been taken into account by our design, but we consider that the most important ones were controlled for. We had previously reported that the women included in the Ditrame Plus cohort were representative of the general population of pregnant women in Abidjan because they had been prenatally recruited among all attendees of community-run health facilities located in poor areas, with no other selection criteria than being HIV infected and at least 18 y old, and having accepted the study protocol [18]. All the women included in the study had access to tap water. But because two-thirds of them lived in typical shared housing, the tap was mainly outside the home. It had been previously reported that the quality of municipal water in Abidjan was good, but that household water storage was a common practice that contributed to contaminated drinking water [14]. Within our study, women were encouraged to avoid water storage, but one-third of them reported having given stored water to their child [26]. Such a practice might have had adverse consequences on infant health. Emphasis was made in the study protocol on the quality of follow-up of mother–infant pairs. Overall, 88% of the expected follow-up had been completed, and lost-to-follow-up children had participated in the study for a median of 1 y. The reasons for stopping follow-up earlier than expected was recorded for two-thirds of these women, which means that they had come to study sites to explain their intent or that they had been traced at home. In all cases, the vital status of the child was recorded at this last contact. Most of these women were unable to continue their study participation because they moved outside Abidjan to return to the north part of Côte d'Ivoire or to their birth country (mainly Mali or Burkina Faso), which might have been linked to the current political crisis in Côte d'Ivoire. As reported within another study, the follow-up was better among nonbreast-feeding mothers [12]. This could be explained by the mother's sociodemographic characteristics or the health care workers' attitude toward this latter group, and could be a possible source of bias [27]. Given the relatively high standard of care proposed within our study (closed clinical follow-up adapted to the child's age with free provision of care), our primary outcome was the occurrence of adverse health outcomes, defined as morbidity, hospitalization, or death. Emphasis was thus made on the collection and validation of morbidity. The same criteria were used for breast-fed and formula-fed children because the event validation committee was blinded to the exact child feeding practices. Because most of the women in our study were illiterate, we have extended the WHO definition of diarrhea to any diarrhea associated with dehydration or requiring at least a second consultation for the same reason. This may have contributed to a slightly overestimated incidence of diarrhea. Overall, we believe follow-up quality was high enough and sufficiently unbiased so that estimates of the incidence of adverse health outcomes are adequately made with the same definitions in both groups. When compared with the Ditrame trial in which no specific infant feeding counseling was made available, the provision of peripartum antiretroviral prophylaxis combined with the promotion of two alternatives to prolonged breast-feeding within Ditrame Plus considerably reduced the number of HIV-infected children: mother-to-child transmission of HIV was significantly reduced with a long-term benefit sustained until age 18-mo. For instance, 18-mo HIV transmission rates as low as 7% (95% CI, 4%–11%) and 6% (95% CI, 2%–10%) were obtained in short-term breast-fed and formula-fed children, respectively, whose mothers had received a peripartum short-course combination of zidovudine and 3TC in addition to single-dose nevirapine [28]. In comparison, the HIV transmission rate was 22% (95% CI, 16%–30%) at age 18 mo among the long-term breast-fed children of the Ditrame trial. Moreover, the mortality among HIV-uninfected children exposed to short-term breast-feeding or formula feeding was similar to the mortality observed among long-term breast-fed uninfected children. Hence, the overall probability of survival was improved among early weaned and formula-fed children in comparison to the long-term breast-fed ones. Given appropriate nutritional counseling and care, access to clean water, and an adequate supply of breast-milk substitutes, early weaning and formula feeding were not harmful for infant health among HIV-exposed children. Given these constraints, these alternatives to prolonged breast-feeding were not only safe, but socially acceptable and feasible within our population-based study. These results need to be balanced with the evaluation of other outcomes such as the assessment of child growth according to infant feeding practices and maternal perceptions of stigma given different infant feeding strategies. These findings of the Ditrame Plus study are consistent with a previous clinical trial of randomly allocated infant feeding practices in Kenya, with the preliminary results of a cohort study in Uganda and with a large African pooled analysis [12,29,30]. However, these findings differ from operational research suggesting that formula feeding was associated with higher mortality, morbidity, and stigma in field settings [31,32]. More recently, a clinical trial conducted in Botswana allocated at random 6 mo of breast-feeding plus prophylactic infant zidovudine, or formula feeding plus 1 mo of zidovudine [33]. In that trial, the probability of infant death by month 7 was significantly higher in the formula-fed group than in the breast-fed group (9.3% versus 4.9%; p = 0.003), but this difference diminished beyond month 7, such that the time-to-mortality distributions through 18 mo of age were not significantly different (10.7% versus 8.5%; p = 0.21). The access to care, support, and counseling, the provision of the breast-milk substitutes, and the clean water availability, as well as the good follow-up observed within the Ditrame Plus study, would all be expected to lead to more optimal outcomes for alternatives to prolonged breast-feeding in contrast to what was observed in less well-structured or well-supported programs. However, the clean water access, the education level of the mothers, and the economic status of the families included in our cohort appear representative of many urban settings in Africa and lead to a cautious but possible generalization of our results to contexts with appropriate political and structural supports. In conclusion, we urge the operational implementation in urban African settings of programs aimed at the overall reduction of mother-to-child transmission of HIV. HIV-infected pregnant women could be offered several alternatives to prolonged and predominant breast-feeding so that they could find the one adapted to their individual situation: either complete avoidance of breast-feeding or exclusive breast-feeding with early cessation. The recent rollout in Africa of programs of access to care for people living with HIV could provide a unique opportunity to routinely implement these infant feeding strategies. Both women and children could be given appropriate nutritional counseling and care within these initiatives. Moreover, the clinical support available in such infrastructures could contribute to minimizing infant mortality. The place of heavily subsidized breast-milk substitutes within these programs should, however, be politically discussed. At the same time, more research is needed to improve on safe infant feeding options for resource-constrained settings. Supporting Information Alternative Language Abstract S1 Translation of the Abstract into French by Renaud Becquet (22 KB DOC) Click here for additional data file.
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                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                January 2007
                16 January 2007
                : 4
                : 1
                : e30
                Article
                10.1371/journal.pmed.0040030
                1769417
                17227137
                de8b0c8a-58ad-4746-bae9-1f36f89b16e7
                Copyright: © 2007 Grace C. John-Stewart. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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                GC John-Stewart (2007) When is replacement feeding safe for infants of HIV-infected women? PLoS Med 4(1): e30. doi: 10.1371/journal.pmed.0040030

                Medicine
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