Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda
Peltier, Cécile Alexandraa; Ndayisaba, Gilles Françoisa; Lepage, Philippeb; van Griensven, Johana; Leroy, Valérianec; Pharm, Christine Omesa; Ndimubanzi, Patrick Cyagaa; Courteille, Oliviera; Arendt, Vicd
aINT 108 ESTHER Phase 2 Project /Luxembourg (Lux-Development) in Kigali, Rwanda
bHôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
cINSERM, Unit 897, Institut de Santé Publique, Epidémiologie et Développement (ISPED), Université Victor Segalen Bordeaux 2, Bordeaux, France
dDepartment of Infectious Diseases, CHU, Luxembourg, Luxembourg.
Received 3 April, 2009
Accepted 21 May, 2009
Correspondence to Cécile Alexandra Peltier, MD, MMed (Ped), 35 Bd Professor Calmette, 24100 Bergerac, France. E-mail: firstname.lastname@example.org
Objective: To assess the 9-month HIV-free survival of children with two strategies to prevent HIV mother-to-child transmission.
Design: Nonrandomized interventional cohort study.
Setting: Four public health centres in Rwanda.
Participants: Between May 2005 and January 2007, all consenting HIV-infected pregnant women were included.
Intervention: Women could choose the mode of feeding for their infant: breastfeeding with maternal HAART for 6 months or formula feeding. All received HAART from 28 weeks of gestation. Nine-month cumulative probabilities of HIV transmission and HIV-free survival were determined using the Kaplan–Meier method and compared using the log-rank test. Determinants were analysed using a Cox model analysis.
Results: Of the 532 first-liveborn infants, 227 (43%) were breastfeeding and 305 (57%) were formula feeding. Overall, seven (1.3%) children were HIV-infected of whom six were infected in utero. Only one child in the breastfeeding group became infected between months 3 and 7, corresponding to a 9-month cumulative risk of postnatal infection of 0.5% [95% confidence interval (CI) 0.1–3.4%; P = 0.24] with breastfeeding. Nine-month cumulative mortality was 3.3% (95% CI 1.6–6.9%) in the breastfeeding arm group and 5.7% (95% CI 3.6–9.2%) for the formula feeding group (P = 0.20). HIV-free survival by 9 months was 95% (95% CI 91–97%) in the breastfeeding group and 94% (95% CI 91–96%) for the formula feeding group (P = 0.66), with no significant difference in the adjusted analysis (adjusted hazard ratio for breastfeeding: 1.2 (95% CI 0.5–2.9%).
Conclusion: Maternal HAART while breastfeeding could be a promising alternative strategy in resource-limited countries.
In developed countries, comprehensive prevention of mother-to-child transmission (PMTCT) programmes that use antiretroviral treatment (ART) prophylaxis and alternatives to breastfeeding have been shown to be very effective, resulting in overall HIV perinatal transmission rates of less than 2% . Similarly, low rates of perinatal transmission have been demonstrated in PMTCT programmes in low-income countries [2–4]. However, when breastfeeding is employed, especially for extended periods and mixed with formula feeding, subsequent transmission through breastfeeding clearly reduces the long-term efficacy of these prophylactic regimens [5–8]. Exclusive breastfeeding (EBF) with early cessation  and formula feeding are two conceivable alternatives to prevent postnatal HIV transmission . Several studies from low-income countries have reported postnatal transmission rates of less than 2% using alternatives to breastfeeding without a higher overall mortality rate [2,10]. However, in operational settings, these alternatives have shown a worrying increase in overall mortality among formula feeding children, probably due to the lack of access to clean water, incorrect dilution of formula and inadequate access to formula or postnatal follow-up [11,12]. As a result, current WHO guidelines recommended EBF with early weaning if replacement feeding is acceptable, feasible, affordable, sustainable and safe . Unfortunately, there are still concerns: EBF cannot completely avoid HIV transmission, but early weaning may lead to an increased morbidity in children . With access to antiretroviral in Africa, two other approaches could be conceivable as well: giving prophylactic ART to breastfed children born to HIV-positive mothers [14–16] or to provide maternal HAART while breastfeeding [2,17,18]. Although several studies provide indirect evidence for the efficacy of this latter intervention [19–21], well designed studies evaluating the efficacy of this strategy in poor countries are virtually nonexistent or ongoing. No single study has formally compared maternal breastfeeding with HAART with formula feeding within the same cohort in resource-limited countries. Therefore, we implemented an interventional cohort study to assess these two interventions to prevent postnatal mother-to-child transmission of HIV-1 in Rwanda: breastfeeding combined with maternal HAART for a maximum duration of 6 months versus formula feeding. The purpose of this article is to report the efficacy of these interventions based on HIV-1 transmission, mortality and HIV-free survival until 9 months of age.
Study design and setting
The present study was a nonrandomized, interventional cohort study, named ‘Amata’, which means ‘milk’ in the local language (Kinyarwanda). It was conducted at four government-run health facilities: one rural health centre (70 km from Kigali, the capital city), one semirural health centre (15 km from Kigali) and two urban sites in Kigali. Each of these four sites had antenatal care services with PMTCT programmes in place, providing access to treatment for HIV infection. Routine HIV testing and HAART are provided free of charge in Rwanda.
Between May 2005 and January 2007, all HIV-infected pregnant women entering the PMTCT programmes in these four centres were invited to participate in the study from 28 weeks of gestation. The women were counselled about the risk of higher morbidity with formula feeding and the risk of HIV through breastfeeding during two information prenatal sessions; those consenting to participate were given the choice of infant-feeding mode at inclusion, prior to delivery.
All enrolled women received HAART from 28 weeks of gestation irrespective of the study group. In line with the Rwandan national protocol, pregnant women with CD4 cell count less than 350 cells/μl or WHO clinical stage 4 or both were considered eligible for lifelong HAART, consisting (in 2005) of combined therapy with stavudine (D4T), lamivudine (3TC) and nevirapine (NVP). For the remainder (WHO clinical stage 1, 2, 3 and CD4 cell count >350 cells/μl), a prophylactic HAART regimen containing zidovudine (ZDV), 3TC and efavirenz (EFV) was started. EFV was chosen to avoid the hepatotoxicity due to NVP for women having high CD4 cell counts . ZDV was preferred over D4T in prophylactic HAART given its well documented efficacy in PMTCT.
After inclusion, those choosing formula feeding had specific education sessions with the counsellors on safe preparation of formula, which was provided free of charge until 6 months of age. These women were also informed that they would be given an injection of 5 mg oestradiol just after delivery, to help suppressing the breast milk production. In the breastfeeding group, women were counselled to exclusively breastfeed until 6 months and then to perform rapid weaning. A supplement of ‘sosoma’ (mixture of soya, sorghum and maize) was given during the weaning period for 1 month and was also given to the formula feeding group. All food supplementation was stopped at 7 months unless severe malnutrition (weight-for-age below the fifth percentile) was diagnosed, after excluding underlying medical problems. We used the Centers for Disease Control and Prevention curves , as the 2006 international WHO curves  were not available at the start of the study. After birth, prophylactic HAART was stopped for the nonlifelong eligible women who had opted for formula feeding unless they became eligible for HAART in between. For breastfeeding women, prophylactic HAART was given until 7 months of age (until 1 month after weaning) to protect infants against the risk of postnatal transmission associated with mixed feeding if abrupt weaning was not done. In each case, a backbone of ZDV and 3TC was given for 7 days after stopping NVP/EFV, to reduce the risk of resistance .
Following WHO recommendations, all newborn infants exposed to HIV received NVP 2 mg/kg at birth and ZDV 4 mg/kg twice daily for 7 days. At 6 weeks of age, cotrimoxazole was given to all infants until 9 months of age and continued after for those infected .
Follow-up of mother–infant pairs was done by the Amata team, consisting of physicians, nurses and counsellors. Mother–infant pairs were examined clinically at birth (within 48 h) and follow-up visits were scheduled at 15 days, 6 weeks and 3, 6, 7 and 9 months postpartum. At each visit, adherence to HAART (pill count and questionnaires) and the feeding method were assessed by maternal interview and clinical examination and women were counselled accordingly. Breast health and feeding techniques were evaluated at each visit. If a breast-fed infant had received any liquids or solids even once (with the exception of drugs), they were then considered to have received ‘mixed feeding’, using the WHO definitions . In case of problematic or insufficient breastfeeding, the need to add additional feeding was discussed and mixed feeding was an acceptable option. All women were counselled about family planning; those on an EFV-containing regimen were given 3-monthly progesterone injections. All care was provided for free, and transportation costs were reimbursed by the project. CD4 cell count and HIV-RNA plasma viral load of all women were measured at inclusion, at delivery (less than 48 h after having given birth) and at 6 months postpartum. CD4 cell count was done using a FACSCalibur instrument (BD Bioscience, San Jose, California, USA; Becton, Dickinson and Company, Franklin Lakes, New Jersey, USA). Viral load tests were done with the rel-time PCR testing on COBAS TaqMan 48 Analyzer (Roche Molecular Diagnostics, Basel, Switzerland). The HIV status of the infant was established with a HIV-1 DNA PCR assay using the Amplicor technique (version 1.5; Roche Molecular Systems, Branchburg, New Jersey, USA).
Diagnosis of HIV infection in children
HIV DNA PCR tests were performed in children at birth, at 6 weeks, 3 months, 7 and 9 months of age. Infants were defined as having been infected in utero if the HIV-1 DNA PCR was positive within 48 h of life and confirmed to be positive in the next test. Transmission was considered to have occurred peripartum if a negative result at birth was followed by a positive result at 6 weeks of age. The blood test done at day 15 was stored and performed only in case of different results between birth and 6 weeks PCR tests. Children with a positive HIV DNA PCR after day 15 were considered infected through breast milk if blood samples from birth and day 15 were negative. Every positive HIV test for children was confirmed by a second positive test before a final diagnosis of HIV infection was accepted. Mortality and morbidity data were obtained through hospital inpatient and outpatient records or by interview of the family member at each scheduled visits.
Main outcome measures
Three main outcomes were measured at 9 months of age among the liveborn children:
1. Cumulative incidence of mother-to-child HIV transmission (perinatal and postnatal).
2. Cumulative infant mortality.
3. Cumulative incidence of HIV-free survival: HIV infection or death whichever came first.
Every first-born liveborn child was included in the analysis in an intent-to-feed analysis, breastfeeding + HAART or formula feeding. The allocation to a feeding group was based on the feeding option chosen before delivery. All newborns who died before 48 h of life linked to anoxia and prematurity before any feeding were not included in the analysis, to exclude deaths unrelated to the feeding option. The Student's t-test, Wilcoxon rank-sum test, χ2-test and Fisher's exact test were used to determine differences in means, median values and proportions between groups. Cumulative probability of events in the first 9 months of life was calculated using Kaplan–Meier estimates with 95% confidence intervals (CIs). This was appropriate as intervals between tests were less than 3 months . Comparisons were made using the log-rank test. Infants who were lost to follow-up (LTFU) before reaching study endpoints were recorded at the date of their last HIV test available. LTFU was defined as having missed planned appointments after having been actively sought at home. The timing of acquisition of infection was estimated to have occurred midway between the dates of the last-negative and the first-positive test. Determinants for 9-month HIV-free survival were explored using a Cox model adjusted on the following variables: infant-feeding modalities, and covariants: maternal CD4 cell count at delivery, time on HAART prior to delivery, access to clean water, level of the mother's education, mode of delivery and birth weight and sex of the infant. Viral load at delivery was not included, as data were missing for 18% of women. Data were entered and stored using Access (Microsoft, Redmond, Washington, USA) software; data analysis was done with Epi Info (version 3.3.2; Centers for Disease Control, Atlanta, Georgia, USA), SPSS (version 16; SPSS Inc., Chicago, Illinois, USA) and Stata (version 9; Stata Corp., College Station, Texas, USA).
The main judgement criterion was HIV-free survival, expected to be 95% overall at 9-months of age. To be able to detect a 7.5% difference in HIV-free survival (a constant hazard ratio of 0.38) with a power of 80% , 205 patients needed to be included in each group. Allowing for 10% LTFU, we decided to include at least 225 pregnant women in each group.
The study was designed and conducted in collaboration with the Rwandan Ministry of Health. The National Ethical Committee of Rwanda, having an international registration, approved the study with annual evaluation of the study progress reports and reevaluation of the protocol. An informed consent has been obtained for all patients included in this cohort.
From May 2005 to January 2007, 562 HIV-positive pregnant women were included in the study, of whom 240 (42.7%) preferred breastfeeding under HAART and 322 (57.3%) women chose formula feeding. Eleven (2.0%) women were LTFU prior to delivery, and 551 infants were born during the study, of whom 11 were twins (second born excluded) and 14 (2.5%) were stillborns. Overall, five (1.0%) newborns died within 48 h of life (four were premature and one infant died on the second day of a neonatal infection that was clinically present at the time of birth; the mother had fever during expulsion). None of these five deaths were related to feeding exposure and were excluded from further analysis. Therefore, 532 mother–infant pairs were included in this analysis (Fig. 1).
Delivery characteristics of these women and infants are summarized in Table 1. Women choosing breastfeeding were slightly younger, had higher CD4 cell count and were less likely to be eligible for lifelong HAART than women choosing formula feeding. They had also less access to clean water. Viral load at delivery was similar in both groups, but 95 (17.8%) viral loads were missing at delivery due to laboratory technical problems. Women in the formula feeding were also more likely to have started lifelong ART prior to inclusion in the study. Overall, 256 (48.1%) women were on HAART for life after inclusion.
Tolerance of and adherence to the interventions
No mother interrupted her HAART treatment, although 11 (2.1%) required drug substitution due to toxicity, one during pregnancy and 10 after delivery. Of all these side effects, seven were due to ZDV-related anaemia and two were due to D4T-related lipodystrophy. In addition, one woman interrupted EFV treatment due to a severe depression and one case of rash due to NVP was observed. No HIV-related deaths were reported. Adherence to EBF was very good (94.2%). None of the infants of the 13 women who practiced mixed feeding were infected.
Overall, seven children were infected with HIV-1 of which six in utero (three in each infant-feeding group). Only one child in the breastfeeding group became infected between months 3 and 7, and no child acquired HIV infection between birth and 9 months in the formula feeding group. In the breastfeeding group, the cumulative probability of HIV-1 transmission at 6 weeks and 9 months was 1.3% (95% CI 0.4–4.1%) and 1.8% (95% CI 0.7–4.8%), respectively. In the formula feeding group, these cumulative probabilities were similar at 6 weeks and 9 months estimated to be 1% (95% CI 0.3–3.0%). Over the first 9 months, the probability of HIV-1 transmission was not statistically different between both groups (log-rank test, P = 0.43). The one infant who acquired HIV infection in the breastfeeding group represented a cumulative risk of postnatal infection of 0.5% (95% CI 0.1–3.4%; P = 0.24) at 9 months of life. Although the infecting breastfeeding mother was receiving HAART, she had been suffering from gastritis with severe vomiting from 4 months postpartum. This, in combination with prolonged fasting for religious reasons, made her adherence and drug absorption questionable. Finally, while hospitalized for severe vomiting, she suddenly ceased breastfeeding at 5 months. Her plasma viral load result at 6 months postpartum showed a viral load of 1600 copies/ml.
Overall, by 9 months of age, seven (3.1%) children had died in the breastfeeding group and 17 (5.6%) in the formula feeding group. For the 22 infants who died before 9 months of age and were HIV-negative at birth, a negative PCR result was available for all of them by 3 months prior to death. The 9-month cumulative probability of death for the breastfeeding group was 3.3% (95% CI 1.6–6.9%) and 5.7% (95% CI 3.6–9.2%) for the formula feeding group, with no statistically significant difference (log-rank test, P = 0.20). Among the 532 exposed liveborn children, 29 were HIV-1 infected or dead at 9 month of age. As shown in Fig. 2, the 9-month cumulative HIV-free survival was 95% (95% CI 91–97%) in the breastfeeding group and 94% (95% CI 91–96%) in the formula feeding group (log-rank test, P = 0.66).
After adjustment for potential confounders in the adjusted analysis, no significant difference in HIV-free survival was seen between the two intervention groups, with an adjusted hazard ratio of 1.2 (95% CI 0.5–2.9%) for breastfeeding versus formula feeding (Table 2). The only statistically significant factors retained were maternal CD4 cell count below 350 cells/μl and birth weight below 2.5 kg. If LTFU was considered as dead/infected in a sensitivity analysis, an adjusted hazard ratio of 1.9 (95% CI 0.9–4.0%) for breastfeeding compared to formula feeding was found (data not shown).
This is the first study reporting the field efficacy of two concomitant PMTCT interventions to reduce postnatal transmission of HIV. Although formula feeding has been the recommended option in developed countries, this intervention is not feasible for many African women and carries a higher risk of morbidity and mortality in resource-limited settings that needs to be balanced against its benefits in preventing postnatal transmission. With the antiretroviral era present in Africa since 2004, providing HAART to women while breastfeeding is another conceivable option, offering a culturally appropriate alternative. In our study, following a backbone of maternal HAART according to 2006 WHO criteria , both postnatal approaches were found to be safe and effective, with similar 9-month HIV-free survival of about 95%. The overall 9-month transmission rate was about 1.3%, one of the lowest mother-to-child transmission rate ever reported from low-income countries  and similar to those reported from industrialized countries. We attribute this strong effect to the combination of starting HAART prior to delivery, antiretroviral prophylaxis to the newborn and continued HAART for 6 months while breastfeeding.
In a meta-analysis, the risk of HIV transmission by EBF was estimated around 0.7% per child-month of breastfeeding follow-up . In other recent African studies, the lowest reported rates of transmission with EBF by 3–6 months have varied between 1.3 and 5.6% [2,3,30,31]. Although these studies are difficult to compare directly, our postnatal transmission rate for women breastfeeding under HAART would suggest a significant reduction in postnatal transmission. We found only one other published report [Drug Resource Enhancement against AIDS in Mozambique (DREAM) Program], assessing the efficacy of breastfeeding combined with maternal HAART to reduce postnatal transmission (additional 0.8% postnatal transmission in the breastfeeding group with HAART), but without a formula feeding comparison group at the same period .
The results with formula feeding were also encouraging, showing an overall mortality lower than in infants born to HIV-uninfected mothers in Rwanda . The total mortality of children followed in the Amata trial was 4.7% at 9 months, without statistically significant differences between the breastfeeding and formula feeding groups. This is in contrast with some studies that have shown an overall increased mortality in formula feeding infants, and we suggest that this is because both studies (DREAM and Amata) were strongly focused on patients' counselling, education, and good quality of care and adaptation of the feeding option to the mother's choice. These data also confirm the importance of postnatal follow-up for exposed children, very often neglected when PCR-testing is not available, resulting in limited access to care and information.
We chose a cohort design instead of a randomized clinical trial to avoid the ethical problems associated with a fixed allocation of the infant-feeding practices . In addition, this design helped to assess the mother's choice of feeding method with formula feeding with a close follow-up and education for the preparation of milk. We believe this was a key factor in encouraging good adherence . To be able to offer women a culturally acceptable method of feeding, that matched HIV transmission rates using formula feeding, resulted in very important public health implications.
This study had several limitations. First, while adjusting for the cohort design our findings remained essentially unchanged in multivariate analysis, residual confounding may still be possible. Second, these outcomes were obtained within a specific study research setting with high quality of care and follow-up. Consequently, these findings could not be generalized to the country level. Third, even though the overall tolerance of HAART was very good in this study, toxicity of HAART could be problematic in settings with fewer resources for follow-up. Finally, this study did not have the power to detect small differences in postnatal HIV-1 infection or mortality between the two approaches.
There are some public health caveats, as well. In most low-income countries, access to HAART services is still limited and particularly challenging for pregnant women during the last trimester of pregnancy. Even if accessible everywhere, cost implications of dissemination of this PMTCT model will have to be considered in each country. There is also the potential of an increased risk of infection with resistant viruses for those newborns infected while breastfed from mothers taking HAART . This issue may become less problematic now since, based on a recent paediatric study, WHO currently recommends to treat all young HIV-infected children with protease inhibitors in case of recent exposure to NVP [36,37].
Several relevant questions remain to be addressed. How will mixed feeding affect the postnatal transmission rate, even if HAART is taken? If HAART does protect against transmission during mixed feeding, then could HAART be continued for longer periods (e.g. up to 1 year) or during all the breastfeeding period? It also remains to be seen whether sufficient levels of adherence to prophylactic HAART can be achieved to avoid emergence of drug-resistance, especially when HAART is given for a longer period. There may be several alternatives to replacement feedings such as diluted, boiled cow's milk or heated expressed breast milk  that might be more easily implemented in remote places where provision of HAART or formula feeding can be problematic.
We conclude that breastfeeding when combined with maternal HAART can be associated with a minimal risk of postnatal transmission, similar to the formula feeding one in our cohort, and with HIV transmission rates as low as those in high-income countries. A key implication of this study is that women can be offered a choice in infant-feeding options, both of which could be safe and effective, given regular postnatal follow-up and counselling. This information would be useful in guiding recommendations on the safest and best infant-feeding modalities according to the different African contexts combined with the full spectrum of antiretroviral strategies, including ART for those in need.
We thank all families of children enrolled in the study. We appreciated the constant collaboration of Ministry of Health of Rwanda. We thank Joseph Viankandondera for his advice and for sharing with us his valuable experience in PMTCT clinical trials in Rwanda. We also thank Tony Reid for reviewing the manuscript in detail.
Contributors: Cécile Alexandra Peltier (C.A.P.), Gilles François Ndayisaba (G.F.N.), Philippe Lepage (P.L.), Johan van Griensven (J.vG.), Valériane Leroy (V.L.), Christine Omes (C.O.), Patrick Cyaga Ndimubanzi (P.C.N.), Olivier Courteille (O.C.) and Vic Arendt (V.A.).
Role of contributors: V.A., C.O. and C.A.P. designed and conceived the study; G.F.N., P.C.N., O.C., C.O. and C.A.P. implemented the study. J.vG. and G.F.N. analysed the data; V.L., P.L., C.A.P., J.vG. wrote the article; O.C. coordinated laboratory collection and quality of analysis; P.C.N. and G.F.N. coordinated data collection and conceived the database and V.L., P.L. and V.A. also checked the methodology and results of statistical analysis. All authors read and approved the final version of the report.
This study was funded by the Ministry of Foreign Affairs of Grand-Duché of Luxembourg (Lux-Development, projects RWA 021, INT 107, INT108 ESTHER Phase 2 Luxembourg).
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