HAART during pregnancy and during breastfeeding among HIV-infected women in the developing world: has the time come?

Abstract

There are as yet no definitive data from randomized controlled trials with clinical end points to inform when to optimally start HAART in asymptomatic HIV-infected patients [1,2]. However, the advent of more potent and better-tolerated antiretroviral drugs has led to a strong push toward earlier initiation of HAART. This trend has been driven primarily by findings from large prospective cohort studies [3–5] in the United States and elsewhere showing lower mortality and fewer adverse events associated with initiation of HAART at higher CD4 cell counts. During pregnancy, healthcare providers in high-income countries recommend initiation of HAART for all HIV-infected women in order to reduce viral load, improve maternal health, and prevent perinatal HIV transmission [1,6]. In resource-poor settings, initiating HAART has been recommended only for pregnant women with more advanced HIV disease [i.e., CD4 cell count < 200 cells/μl (<250 cells/μl in some countries such as Malawi) or HIV-related symptoms and CD4 cell count < 350 cells/μl] [7]. In this issue of AIDS, Ouyang et al. [8] challenge the notion that one commonly used antiretroviral drug – nevirapine (NVP) – is uniquely associated with hepatotoxicity during pregnancy [9]. The authors analyzed data from three large prospective cohort studies and found that pregnancy itself was significantly associated with increased hepatotoxicity in HIV-infected women. Contrary to previous reports [10–12], the investigators did not find an increase in hepatotoxicity among pregnant women exposed to NVP, including NVP-naive women with CD4 cell counts above 250 cells/μl. Pregnancy may provide a unique physiology that predisposes women to drug-induced hepatotoxicity [6,8]. Consequently, whenever feasible, liver enzymes should be monitored among pregnant HIV-infected women receiving antiretroviral drugs. The above findings are highly relevant for developing countries where NVP remains a common component of first-line HAART, including during pregnancy. For the reasons mentioned by Ouyang et al. [8], the risk and determinants of hepatotoxicity may differ for pregnant women in resource-poor settings. However, the strong association of hepatic abnormality with pregnancy and not with NVP in this large prospective study, and the fact that hepatic dysfunction was not demonstrably worse with higher CD4 cell count, could be of major consequence for pregnant HIV-infected women, especially in resource-poor settings. It is also important to emphasize that the hepatotoxicity previously noted in patients taking continuous NVP has not been seen when NVP is used as a single, intrapartum dose [13]. The paper by Peltier et al. [14] from the AMATA study in Kigali, Rwanda demonstrates that maternal HAART (from 28 weeks gestation till 7 months postpartum) among breastfeeding mothers was associated with a very low risk of mother-to-child transmission (MTCT) peripartum and during the first 9 months after birth. Similarly, low rates of MTCT of HIV have been observed in several other studies [15–20] of HAART among breastfeeding mothers in resource-poor settings in Africa. In the Kisumu Breastfeeding Study (KiBS), conducted in Nyanza Province, Kenya, women initiated HAART [zidovudine (AZT) + lamivudine + NVP, later changed to nelfinavir for those women with a CD4 cell count > 250 cells/μl due to concerns about hepatotoxicity] at 34 weeks gestation through 6 months postpartum [15]. Overall MTCT of HIV at 12 months was 5.9% (95% confidence interval = 4.0–8.5). Of particular interest, the higher risk of MTCT among women with CD4 cell count below 350 cells/μl was eliminated in the KiBS study with use of maternal HAART for eligible women. The Drug Resource Enhancement against AIDS and Malnutrition program in Mozambique [16,17], the multicenter Kesho Bora Study [18,19], and the MTCT-Plus treatment program in Côte d'Ivoire [20] also reported very low transmission rates when mothers received HAART during late pregnancy and breastfeeding. In the AMATA study in Rwanda [14], all women, regardless of CD4 cell count, received HAART in the third trimester of pregnancy. Those who elected breastfeeding also received HAART for 7 months postpartum. At 6 months, exposure to HIV was stopped by weaning from the breast. The other group (nonbreastfeeding mothers) received HAART until 6 weeks after delivery and infants received replacement feeding from birth. The two groups were nonrandomized and women self-selected into either the breastfeeding with HAART or the replacement-feeding group. The AMATA study found that the MTCT rate at 9 months of age was very low in both groups, similar to that in high-income countries, and HIV-free survival by 9 months was also high in both groups. The authors of the AMATA study [14] conclude that women in various resource-limited settings could be offered a choice between these two infant feeding options, both of which could be safe and effective, given a safe water supply, availability of HAART, and regular postnatal follow-up and counseling. Current Rwandan guidelines use a CD4 cell count below 350 cells/μl as an indication to provide HAART in pregnancy. Pregnant Rwandan women with higher CD4 cell counts do not usually receive HAART, unless they arrive very late for antenatal care (after 34 weeks gestation). As the AMATA study provided HAART to all women, regardless of CD4 cell count, it is not possible to discern what the transmission rates (in utero and intrapartum) would have been if mothers had been managed according to the national guidelines before selection of the infant feeding method and antiretroviral regimen. It is, therefore, conceivable that treatment according to the above eligibility criteria might have accomplished similarly low transmission rates. We note that in the Kesho Bora Study [19], the effectiveness of maternal short-course AZT (starting at 28 weeks of pregnancy) combined with single-dose NVP appeared equivalent to HAART during pregnancy in reducing HIV transmission in utero and intrapartum among women with CD4 cell count between 200 and 500 cells/μl. The issue of breastfeeding among HIV-infected women in resource-limited settings continues to present major policy challenges [21–24]. Promotion of breastfeeding has been a cornerstone of child survival programs in resource-limited settings and, prior to the HIV epidemic, most African countries had nearly universal uptake of breastfeeding, usually for 2 years or more. Balancing the protective effect of breastfeeding on many causes of child mortality with the risk of HIV infection via breast milk remains a very difficult issue. Not breastfeeding is currently recommended in all high-income settings and wherever infant replacement feeding is affordable and sustainable, clean water is available, hygiene and sanitation conditions are good, and deaths due to diarrhea are relatively uncommon [25,26]. Although the infant mortality (till 9 months of age) in the AMATA study was not statistically different between infants who breastfed and those who received replacement feeding, mortality appeared higher in the replacement-feeding group [14]. Unfortunately, weight and growth data at 9 months of age were not provided in this paper. Given that, other studies [27–30] have found a substantial increase in morbidity and mortality with replacement feeding, it will be important to follow these infants until 2 years of age. In routine service programs, the risks of infant replacement feeding will likely be higher than in a controlled study environment [21,27]. Most clearly demonstrated in the Zambia Exclusive Breastfeeding Study [31], breastfed HIV-infected children also have a much better prognosis than nonbreastfed HIV-infected children. Considerable research efforts in the last decade have focused on making breastfeeding safer without diminishing the general health benefits [21,32]. Exclusive breastfeeding during the first 6 months has been shown to lower the risk substantially of postnatal HIV transmission, compared with mixed feeding but does not eliminate risk [31–35]. Three randomized controlled trials [36–38] have shown that daily NVP given to the infant during breastfeeding offers protection against HIV infection. Daily lamivudine may also provide protection to the breastfeeding infant, although the specific contribution of lamivudine could not be delineated [39]. Concerns have been expressed regarding the potential development of antiretroviral drug resistance among infants who become infected despite daily prophylaxis [25]. For treatment-eligible women (those with advanced HIV who meet existing criteria for treatment) in resource-poor settings there is an urgent need to make HAART available during pregnancy as well as postpartum. This intervention alone could have a large impact on maternal and child survival and health in resource-poor, high HIV prevalence areas. To do so, preventing MTCT (PMTCT) programs need to be transformed to address adequately the health needs of the mother and her family, integrating PMTCT with comprehensive family-focused HIV care and treatment services [40,41]. The optimal duration of breastfeeding while on HAART still needs to be defined to ensure optimal maternal and child health outcomes. The finding of a low transmission rate among both the breastfed and the replacement-feeding groups in the AMATA study [14] is very encouraging. However, for women who breastfeed and are not yet eligible for treatment for their own health, we cannot ascertain whether maternal HAART is preferable or better than antiretroviral drug prophylaxis provided to the infant. The benefits and safety of HAART used solely for prevention of perinatal transmission in healthy HIV-infected women remains under investigation. Recently presented findings from the Breastfeeding, Antiretroviral and Nutrition (BAN) study [38] in Malawi show that, for mothers with CD4 cell count above 250 cells/μl, either maternal HAART or daily infant NVP prophylaxis taken up to 28 weeks during breastfeeding was effective in reducing HIV transmission during breastfeeding. Although not statistically significant, there was a trend (P = 0.07) favoring daily NVP infant prophylaxis in promoting HIV-free survival in the BAN study [38]. The long-term impact of daily NVP infant prophylaxis, antiretroviral exposure through breast milk, or both on HIV-infected and uninfected children will require thoughtful study and demonstration of the large-scale feasibility of either of these approaches in diverse settings. The quantities of NVP and lamivudine, although probably not AZT, an infant ingests through exclusive breastfeeding (when the mother receives HAART) may not only reduce maternal viral load in breast milk but could also potentially provide infants with drug levels sufficient for prophylaxis against transmission [42–44]. We believe that infants born to mothers receiving HAART while breastfeeding do not need to receive infant NVP prophylaxis. However, the antiretroviral drug quantities are likely to be insufficient for treatment of a child who becomes HIV infected and could put the infected infant at risk for development of resistant virus based on inadequate therapeutic levels to suppress HIV-1 replication. Thus, infected infants should themselves be treated with HAART (protease inhibitor-based, if at all possible) independent of the antiretroviral drugs ingested through breast milk. The past 5 years have seen striking advances in access to HAART in many resource-limited settings [45–53]. Nevertheless, immunologic assessment is not universally available and pregnant HIV-infected women are still often not treated with HAART if they are eligible [54,55]. AZT administered from 28 weeks of pregnancy along with NVP during labor given to women with high CD4 cell count (and combined with 1 week of postnatal AZT and lamivudine to prevent NVP resistance) achieves antepartum and intrapartum protection for the baby comparable to that achieved with HAART [19]. In resource-rich countries, HAART in pregnancy has been associated with a higher risk of preterm birth in several large cohorts [56–59]. We have also learned that pregnancy appears to be a period of increased vulnerability to hepatotoxicity due to antiretroviral drugs [8]. Successful prevention of HIV transmission during breastfeeding is achievable either by administration of HAART to the mother or daily NVP prophylaxis to the infant during breastfeeding [36–38]. It is still unknown whether HAART administered only during pregnancy and the breastfeeding period and then stopped alters the long-term progression of maternal HIV disease [60]. There are finite resources to provide treatment for all HIV-infected persons, including those with a high CD4 cell count. Resource-poor countries especially will consider how to achieve maximal benefits from antiretroviral therapy. In the mean time, comprehensive coverage of PMTCT programs must continue to expand [61]. Treatment-eligible women should be treated during pregnancy and lactation [55]. With increasing familiarity of many healthcare workers with the use of HAART and wider availability of combination pills and once-daily regimens, certain countries in the developing world may decide to provide HAART for PMTCT to all women during pregnancy and breastfeeding. Clear guidance from the WHO and national programs concerning the optimal duration of HAART, education of health workers, and adherence counseling for women will be indispensable. Would the choice of HAART to all HIV-infected pregnant women, regardless of CD4 cell count, deprive other HIV-infected patients from access to treatment? Could it enhance routine service delivery without compromising maternal health in the long run? These questions will be answered in due course. While awaiting further data, an excellent strategy would be to ensure that women with CD4 cell count below 350 cells/μl in resource-limited settings receive HAART that would then be continued after breastfeeding cessation for maternal health. Use of daily infant prophylaxis (in addition to maternal AZT prophylaxis administered from 28 weeks of pregnancy along with NVP during labor) should be considered to reduce breastfeeding-related HIV transmission in infants born to women with CD4 cell count above 350 cells/μl. Acknowledgements Our work on PMTCT and pediatric HIV/AIDS care and treatment in resource-limited settings has been supported by the Elizabeth Glaser Pediatric AIDS Foundation, the Centers for Disease Control and Prevention, the President's Emergency Plan for AIDS Relief, and the National Institute for Child Health and Human Development. We are particularly grateful to Drs Chipepo Kankasa, Elaine Abrams, Chin-Yih Ou, Taha Taha, Omotayo Bolu, Pius Tih, Tom and Edie Welty, Sten Vermund, Ann Chao, Fujie Zhang, Christine Korhonen, Athena Kourtis, Russ Van Dyke, Tim Dondero, Wendy Wei, and R.J. Simonds for thoughtful feedback and discussion. The conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Elizabeth Glaser Pediatric AIDS Foundation. There are no conflicts of interest.