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      Antiretroviral prophylaxis to prevent post-natal transmission of HIV through breastfeeding

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          Recently published results provide important new “proof of principle” that providing antiretroviral drugs to infants of HIV-infected mothers while breastfeeding can reduce postnatal HIV transmission.[1, 2] These are very encouraging results as they demonstrate that HIV infections can be reduced while preserving benefits of breastfeeding for these vulnerable infants. In the first study called SWEN (Six Week Extended-Dose Nevirapine) over 2000 mother-baby pairs in Ethiopia, India and Uganda were randomized to either single-dose nevirapine or to an extended regimen that included the standard maternal and newborn dose of nevirapine plus an extended course of nevirapine to the infant starting at 8 days of life and continuing daily to 42 days. After excluding those who were already infected at birth, the mother-to-child HIV transmission rate at 6 weeks was 5.3% in the single-dose nevirapine group and 2.5% in the six week extended-dose nevirapine group.[1] In the second study called PEPI (Post Exposure Prophylaxis of Infants) over 3000 mother-baby pairs in Malawi were randomized to either the control group that used single-dose nevirapine plus a week of zidovudine or to one of the two intervention groups: (1) daily nevirapine from 1 week to 14 weeks or (2) daily nevirapine and zidovudine from 1 week to 14 weeks. After excluding those who were already infected at birth, the mother-to-child HIV transmission rate at 14 weeks was 8.4% in the control group, and 2.8% and 2.8% in the extended prophylaxis arm using only nevirapine or using both nevirapine and zidovudine, respectively. [2] We should not be surprised if the response of policy-markers and communities to these results is one of puzzlement. How should these new results be translated into new policies? Should extended nevirapine prophylaxis for 6 or 14 weeks become a routine part of prevention of mother-to-child HIV transmission (PMTCT) programs in sub-Saharan Africa? In both studies there was an attenuation of the benefit of the extended nevirapine prophylaxis when children were tested some months after the prophylaxis had ended. In the SWEN study, transmission rates (excluding the birth infections) at 6 months were 9.0% in the control group and 6.9% in the extended prophylaxis group – a difference that was no longer statistically significant. [1] In PEPI, transmission rates (excluding the birth infections) at 9 months were 10.6% in the control group and 5.2% and 6.4% in the extended prophylaxis groups using only nevirapine or using both nevirapine and zidovudine, respectively. Although the benefit of extended prophylaxis remained statistically significant in PEPI, the magnitude of the benefit declined from a 3-fold decrease in transmission at 14 weeks to a 2-fold decrease at 9 months.[2] Although there had been some hope that the transmission-reducing action of nevirapine would continue after consumption of the drug had stopped, it appeared that later breastfeeding-acquired infections accrued at the same rate regardless of whether or not the extended prophylaxis had been offered. A naïve, but dangerous, conclusion from these observations might be that breastfeeding should end at the same time as extended prophylaxis ends, in other words, weaning should be encouraged at either 6 or 14 weeks. Highly disturbing findings in both of these studies are the extremely short durations of breastfeeding reported. In the SWEN study, only 32% of infants were still breastfeeding at 6 months. In PEPI, 90% were still breastfeeding at 6 months, but by 9 months almost 70% were not.[1, 2] Scientific studies of this magnitude take time to complete with the rigor required, and it should be noted that the SWEN study enrollment began in February 2001, PEPI in April 2004. At the time these studies were designed there was less appreciation of the risks of prematurely truncating the duration of breastfeeding. It was only in October 2006 that the World Health Organization (WHO) revised their guidelines to clearly encourage exclusive breastfeeding for the first 6 months of life as an option for HIV-infected mothers. It was also only at this time that WHO revised their guidelines to clearly state that early weaning should only be considered if there are affordable, feasible, acceptable, safe and sustainable (AFASS) replacement options for the infant or young child.[3] The latter recommendation, while a veiled one, is a recognition of the weak health service infrastructures, poor environmental conditions and high rates of other severe childhood infections in most communities in sub-Saharan Africa that make early weaning a dangerous proposition. We have recently published our results from the Zambia Exclusive Breastfeeding Study (ZEBS) in which we observed no benefit of in terms of HIV-free survival of early cessation of breastfeeding at 4 months compared to standard practice of breastfeeding to an average of 16 months. [4] The net benefit in terms of transmissions averted by stopping breastfeeding earlier than usual was cancelled out by the mortality caused by the absence of breastfeeding after 4 months. The ZEBS results are consistent with findings from Botswana that observed that HIV-free survival was not improved by formula feeding from birth compared to breastfeeding to about 6 months.[5] Weaning at 6 or even 14 weeks is therefore much too early! Might extended prophylaxis not simply be continued throughout the full duration of breastfeeding whatever its length? Both the SWEN and PEPI investigators encourage further study of this as an option and the ZEBS results clearly indicate the need to investigate interventions that allow the usual duration of breastfeeding (i.e. up to 18 months or greater) to occur. Theoretically, infant prophylaxis throughout breastfeeding should be safe and effective in at least reducing, if not entirely eliminating, transmission. But I would argue against implementation without evaluation. Too often reasonable inferences drawn from observational research are not borne out in clinical trials. A multi-site study is underway to investigate extended prophylaxis to 6 months.[6] Let us hope that investigation of extended prophylaxis to the full course of breastfeeding will not have to await small monthly increments until full duration of breastfeeding is reached. In the meantime, much could be gained by implementing 14 weeks of extended nevirapine prophylaxis as long as the program were not coupled with explicit or implicit messages to terminate breastfeeding as soon as feasible after the end of prophylaxis. Infant prophylaxis is an attractive approach to prevention of postnatal transmission as relatively simple, inexpensive and safe regimens can be used, and the risks of these interventions are accrued in the same population (infants) who stand to benefit. However, infant prophylaxis has one serious drawback in that it neglects the needs of the mother. Maternal prophylaxis, in contrast, stands to benefit both mother and child. One program that provided effective triple antiretroviral therapy to all pregnant women in Mozambique regardless of their clinical conditions or CD4 counts claims to have observed a very low transmission rate [7] but these data are difficult to interpret since the program was not set up to investigate the effects of this intervention on postnatal transmission. Others have raised concerns about short and long-term adverse effects of placing HIV-infected women on antiretroviral drugs before they are required on clinical grounds. However, for those HIV-infected pregnant women who do require effective antiretroviral therapy on clinical and CD4 count grounds, there is no dispute about the urgency of their receiving antiretroviral therapy. No-one disagrees that providing access to effective antiretroviral therapy for these women is an essential component of any comprehensive HIV prevention and treatment program as well as an essential component of any PMTCT program. Antiretroviral therapy can save the young mother’s life, can substantially reduce HIV-related morbidity, and has been shown (in observational studied only) to reduce the risk of transmitting the virus during pregnancy and delivery. This is a classic win-win public health intervention: providing a beautiful example of positive treatment-prevention synergy. Poor coordination between HIV care and PMTCT programs often, unfortunately, compromises optimal implementation of this logical recommendation. Effective maternal treatment is expected to reduce postnatal transmission but data demonstrating this are sparse. Investigation of this question poses challenges since treatment cannot be withheld from this group of women. As public health professionals, we welcome new findings that provide evidence of new interventions that have the capacity to improve our programs. As scientists, we have to stay attuned to what we still do not know, and have the foresight to design new studies to begin to address those gaps. Although antiretroviral drugs have a crucial role to play in prevention of mother-to-child HIV transmission through breastfeeding, we still have much to learn about how best to use these drugs taking into account the social and biological context of maternal and child health in the many disadvantaged sub-Saharan African settings where the HIV epidemic predominates.

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          Most cited references 7

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          Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study.

          Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. A 2 x 2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. All of the mothers received zidovudine 300 mg orally twice daily from 34 weeks' gestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. The 7-month HIV infection rates were 5.6% (32 infants in the formula-fed group) vs 9.0% (51 infants in the breastfed plus zidovudine group) (P = .04; 95% confidence interval for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs 86 infants (15.1% breastfed plus zidovudine) (P = .60; 95% confidence interval for difference, -5.3% to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P = .003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = .21). Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. Identifier: NCT00197587.
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            Effects of early, abrupt weaning on HIV-free survival of children in Zambia.

            In low-resource settings, many programs recommend that women who are infected with the human immunodeficiency virus (HIV) stop breast-feeding early. We conducted a randomized trial to evaluate whether abrupt weaning at 4 months as compared with the standard practice has a net benefit for HIV-free survival of children. We enrolled 958 HIV-infected women and their infants in Lusaka, Zambia. All the women planned to breast-feed exclusively to 4 months; 481 were randomly assigned to a counseling program that encouraged abrupt weaning at 4 months, and 477 to a program that encouraged continued breast-feeding for as long as the women chose. The primary outcome was either HIV infection or death of the child by 24 months. In the intervention group, 69.0% of the mothers stopped breast-feeding at 5 months or earlier; 68.8% of these women reported the completion of weaning in less than 2 days. In the control group, the median duration of breast-feeding was 16 months. In the overall cohort, there was no significant difference between the groups in the rate of HIV-free survival among the children; 68.4% and 64.0% survived to 24 months without HIV infection in the intervention and control groups, respectively (P=0.13). Among infants who were still being breast-fed and were not infected with HIV at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months (83.9% and 80.7% in the intervention and control groups, respectively; P=0.27). Children who were infected with HIV by 4 months had a higher mortality by 24 months if they had been assigned to the intervention group than if they had been assigned to the control group (73.6% vs. 54.8%, P=0.007). Early, abrupt cessation of breast-feeding by HIV-infected women in a low-resource setting, such as Lusaka, Zambia, does not improve the rate of HIV-free survival among children born to HIV-infected mothers and is harmful to HIV-infected infants.( number, NCT00310726.) 2008 Massachusetts Medical Society
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              Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission.

              Effective strategies are urgently needed to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) through breast-feeding in resource-limited settings. Women with HIV-1 infection who were breast-feeding infants were enrolled in a randomized, phase 3 trial in Blantyre, Malawi. At birth, the infants were randomly assigned to one of three regimens: single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks. Using Kaplan-Meier analyses, we assessed the risk of HIV-1 infection among infants who were HIV-1-negative on DNA polymerase-chain-reaction assay at birth. Among 3016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P<0.001) and 6.4% in the extended-dual-prophylaxis group (P=0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug. Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants. ( number, NCT00115648.) 2008 Massachusetts Medical Society

                Author and article information

                Pan Afr Med J
                The Pan African medical journal
                African Field Epidemiology Network
                15 August 2008
                : 1
                [1 ] Department of Epidemiology, Mailman School of Public Health & Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York.
                Author notes

                About the author: Dr. Louise Kuhn is faculty in the Gertrude H. Sergievsky Center and in the Department of Epidemiology. She manages an international research program on HIV/AIDS among women and children. She has a Ph.D. from Columbia University, New York; and M.A. from the University of Cape Town, South Africa. She teaches courses and mentors graduate students in the Epidemiology program of the Mailman School of Public Health.

                Copyright © 2008 Louise Kuhn et al.

                The Pan African Medical Journal - ISSN 1937-8688. 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 work is properly cited.



                sub-saharan africa , pmtct , nevirapine , breastfeeding , zidovudine


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