Catherine M. Wilfert

Coverage of Nevirapine-Based Services to Prevent Mother-to-Child HIV Transmission in 4 African Countries

CONTEXTnFew studies have objectively evaluated the coverage of services to prevent transmission of human immunodeficiency virus (HIV) from mother to child.nnnOBJECTIVEnTo measure the coverage of services to prevent mother-to-child HIV transmission in 4 African countries.nnnDESIGN, SETTING, AND PATIENTSnCross-sectional surveillance study of mother-infant pairs using umbilical cord blood samples collected between June 10, 2007, and October 30, 2008, from 43 randomly selected facilities (grouped as 25 service clusters) providing delivery services in Cameroon, Côte dIvoire, South Africa, and Zambia. All sites used at least single-dose nevirapine to prevent mother-to-child HIV transmission and some sites used additional prophylaxis drugs.nnnMAIN OUTCOME MEASUREnPopulation nevirapine coverage, defined as the proportion of HIV-exposed infants in the sample with both maternal nevirapine ingestion (confirmed by cord blood chromatography) and infant nevirapine ingestion (confirmed by direct observation).nnnRESULTSnA total of 27,893 cord blood specimens were tested, of which 3324 were HIV seropositive (12%). Complete data for cord blood nevirapine results were available on 3196 HIV-seropositive mother-infant pairs. Nevirapine coverage varied significantly by site (range: 0%-82%). Adjusted for country, the overall coverage estimate was 51% (95% confidence interval [CI], 49%-53%). In multivariable analysis, failed coverage of nevirapine-based services was significantly associated with maternal age younger than 20 years (adjusted odds ratio [AOR], 1.44; 95% CI, 1.18-1.76) and maternal age between 20 and 25 years (AOR, 1.28; 95% CI, 1.07-1.54) vs maternal age of older than 30 years; 1 or fewer antenatal care visits (AOR, 2.91; 95% CI, 2.40-3.54), 2 or 3 antenatal care visits (AOR, 1.93; 95% CI, 1.60-2.33), and 4 or 5 antenatal care visits (AOR, 1.56; 95% CI, 1.34-1.80) vs 6 or more antenatal care visits; vaginal delivery (AOR, 1.22; 95% CI, 1.03-1.44) vs cesarean delivery; and infant birth weight of less than 2500 g (AOR, 1.34; 95% CI, 1.11-1.62) vs birth weight of 3500 g or greater.nnnCONCLUSIONnIn this random sampling of sites with services to prevent mother-to-child HIV transmission, only 51% of HIV-exposed infants received the minimal regimen of single-dose nevirapine.

Monitoring effectiveness of programmes to prevent mother-to-child HIV transmission in lower-income countries

Ambitious goals for paediatric AIDS control have been set by various international bodies, including a 50% reduction in new paediatric infections by 2010. While these goals are clearly appropriate in their scope, the lack of clarity and consensus around how to monitor the effectiveness of programmes to prevent mother-to-child HIV transmission (PMTCT) makes it difficult for policy-makers to mount a coordinated response. In this paper, we develop the case for using population HIV-free child survival as a gold standard metric to measure the effectiveness of PMTCT programmes, and go on to consider multiple study designs and source populations. Finally, we propose a novel community survey-based approach that could be implemented widely throughout the developing world with minor modifications to ongoing Demographic and Health Surveys.

Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine.

Objective:To determine whether prior exposure to single-dose nevirapine (NVP) for prevention of mother-to-child HIV transmission (PMTCT) is associated with attenuated CD4 cell response, death, or clinical treatment failure in women starting antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTI). Methods:Open cohort evaluation of outcomes for women in program sites across Zambia. HIV treatment was provided according to Zambian/World Health Organization guidelines. Results:Peripartum NVP exposure status was known for 6740 women initiating NNRTI-containing ART, of whom 751 (11%) reported prior use of NVP for PMTCT. There was no significant difference in mean CD4 cell change between those exposed or unexposed to NVP at 6 (+202 versus +182 cells/μl; P = 0.20) or 12 (+201 versus +211 cells/μl; P = 0.60) months. Multivariable analyses showed no significant differences in mortality [adjusted hazard ratio (HR), 1.2; 95% confidence interval (CI), 0.8–1.8] or clinical treatment failure (adjusted HR, 1.1; 95% CI, 0.8–1.5). Comparison of recent NVP exposure with remote exposure suggested a less favorable CD4 cell response at 6 (+150 versus +219 cells/μl; P = 0.06) and 12 (+149 versus +215 cells/μl; P = 0.39) months. Women with recent NVP exposure also had a trend towards elevated risk for clinical treatment failure (adjusted HR, 1.6; 95% CI, 0.9–2.7). Conclusion:Exposure to maternal single-dose NVP was not associated with substantially different short-term treatment outcomes. However, evidence was suggestive that exposure within 6 months of ART initiation may be a risk factor for poor treatment outcomes, highlighting the importance of ART screening and initiation early in pregnancy.

HIV, infant feeding and more perils for poor people: new WHO guidelines encourage review of formula milk policies

The release of the new WHO guidelines on HIV and infant feeding, in a global context of widespread impoverishment, requires countries to re-examine their infant-feeding policies in relation to broader socioeconomic issues. This widening scope is necessitated by compelling new reports on the scale of global underdevelopment in developing countries. This paper explores these issues by addressing feeding choices made by HIV-infected mothers and programmes supplying free formula milks within a global environment of persistent poverty. Accumulating evidence on the increase in malnutrition, morbidity and mortality associated with the avoidance or early cessation of breastfeeding by HIV-infected mothers, and the unanticipated hazards of formula feeding, demand a deeper assessment of the measures necessary for optimum policies on infant and child nutrition and for the amelioration of poverty. Piecemeal interventions that increase resources directed at only a fraction of a familys impoverishment, such as basic materials for preparation of hygienic formula feeds and making flawed decisions on choice of infant feeding, are bound to fail. These are not alternatives to taking fundamental steps to alleviate poverty. The economic opportunity costs of such programmes, the equity costs of providing resources to some and not others, and the leakages due to temptation to sell capital goods require careful evaluation. Providing formula to poor populations with high HIV prevalence cannot be justified by the evidence, by humanitarian considerations, by respect for local traditions or by economic outcomes. Exclusive breastfeeding, which is threatened by the HIV epidemic, remains an unfailing anchor of child survival.

Science, ethics, and future of research into maternal-infant transmission of HIV-1

Effective, feasible interventions to prevent perinatal transmission of HIV-1 in developing nations are an urgent necessity. Scientific issues of concern include a need to identify other effective antiretroviral agents; to define the shortest effective course of therapy; to assess interventions other than antiretroviral agents; and to investigate interventions that may reduce HIV-1 transmission via breastfeeding. Sound scientific design is fundamental to all research studies. Ethical standards must guide such studies and include the necessity that the problem studied be a health priority in the host country; that the highest standard of care attainable in the country be assured to participants; that the health-care resources of the country not be harmed; that the informed consent of participants be obtained; and that a process of discussion ensure that a successful intervention will be considered for implementation. There are circumstances in which a no-antiretroviral comparison may be ethically justified.

Measuring Coverage in MNCH: Population HIV-Free Survival among Children under Two Years of Age in Four African Countries

Background Population-based evaluations of programs for prevention of mother-to-child HIV transmission (PMTCT) are scarce. We measured PMTCT service coverage, regimen use, and HIV-free survival among children ≤24 mo of age in Cameroon, Côte DIvoire, South Africa, and Zambia. Methods and Findings We randomly sampled households in 26 communities and offered participation if a child had been born to a woman living there during the prior 24 mo. We tested consenting mothers with rapid HIV antibody tests and tested the children of seropositive mothers with HIV DNA PCR or rapid antibody tests. Our primary outcome was 24-mo HIV-free survival, estimated with survival analysis. In an individual-level analysis, we evaluated the effectiveness of various PMTCT regimens. In a community-level analysis, we evaluated the relationship between HIV-free survival and community PMTCT coverage (the proportion of HIV-exposed infants in each community that received any PMTCT intervention during gestation or breastfeeding). We also compared our community coverage results to those of a contemporaneous study conducted in the facilities serving each sampled community. Of 7,985 surveyed children under 2 y of age, 1,014 (12.7%) were HIV-exposed. Of these, 110 (10.9%) were HIV-infected, 851 (83.9%) were HIV-uninfected, and 53 (5.2%) were dead. HIV-free survival at 24 mo of age among all HIV-exposed children was 79.7% (95% CI: 76.4, 82.6) overall, with the following country-level estimates: Cameroon (72.6%; 95% CI: 62.3, 80.5), South Africa (77.7%; 95% CI: 72.5, 82.1), Zambia (83.1%; 95% CI: 78.4, 86.8), and Côte DIvoire (84.4%; 95% CI: 70.0, 92.2). In adjusted analyses, the risk of death or HIV infection was non-significantly lower in children whose mothers received a more complex regimen of either two or three antiretroviral drugs compared to those receiving no prophylaxis (adjusted hazard ratio: 0.60; 95% CI: 0.34, 1.06). Risk of death was not different for children whose mothers received a more complex regimen compared to those given single-dose nevirapine (adjusted hazard ratio: 0.88; 95% CI: 0.45, 1.72). Community PMTCT coverage was highest in Cameroon, where 75 of 114 HIV-exposed infants met criteria for coverage (66%; 95% CI: 56, 74), followed by Zambia (219 of 444, 49%; 95% CI: 45, 54), then South Africa (152 of 365, 42%; 95% CI: 37, 47), and then Côte DIvoire (3 of 53, 5.7%; 95% CI: 1.2, 16). In a cluster-level analysis, community PMTCT coverage was highly correlated with facility PMTCT coverage (Pearsons ru200a=u200a0.85), and moderately correlated with 24-mo HIV-free survival (Pearsons ru200a=u200a0.29). In 14 of 16 instances where both the facility and community samples were large enough for comparison, the facility-based coverage measure exceeded that observed in the community. Conclusions HIV-free survival can be estimated with community surveys and should be incorporated into ongoing country monitoring. Facility-based coverage measures correlate with those derived from community sampling, but may overestimate population coverage. The more complex regimens recommended by the World Health Organization seem to have measurable public health benefit at the population level, but power was limited and additional field validation is needed. Please see later in the article for the Editors Summary

Presumptive diagnosis of severe HIV infection to determine the need for antiretroviral therapy in children less than 18 months of age.

OBJECTIVEnTo develop a new algorithm for the presumptive diagnosis of severe disease associated with human immunodeficiency virus (HIV) infection in children less than 18 months of age for the purpose of identifying children who require antiretroviral therapy (ART).nnnMETHODSnA conditional probability model was constructed and non-virologic parameters in various combinations were tested in a hypothetical cohort of 1000 children aged 6xa0weeks, 6xa0months and 12 months to assess the sensitivity, specificity, and positive and negative predictive values of these algorithms for identifying children in need of ART. The modelled parameters consisted of clinical criteria, rapid HIV antibody testing and CD4+ T-lymphocyte (CD4) count.nnnFINDINGSnIn children younger than 18 months, the best-performing screening algorithm, consisting of clinical symptoms plus antibody testing plus CD4 count, showed a sensitivity ranging from 71% to 80% and a specificity ranging from 92% to 99%. Positive and negative predictive values were between 61% and 97% and between 95% and 96%, respectively. In the absence of virologic tests, this alternate algorithm for the presumptive diagnosis of severe HIV disease makes it possible to correctly initiate ART in 91% to 98% of HIV-positive children who are at highest risk of dying.nnnCONCLUSIONnThe algorithms presented in this paper have better sensitivity and specificity than clinical parameters, with or without rapid HIV testing, for the presumptive diagnosis of severe disease in HIV-positive children less than 18 months of age. If implemented, they can increase the number of HIV-positive children successfully initiated on ART.

Structural violence and clinical medicine: free infant formula for HIV-exposed infants.

We wholeheartedly agree with Paul Farmer and colleagues [1] that it is vitally important to examine social, as well as molecular, causes of disease. Unless we carefully consider the full range of factors that underlie a given problem, we may produce “solutions” with unintended and deleterious consequences. In this light we express our concern about the infant feeding approach advocated in their article to reduce mother-to-child transmission of HIV in Rwanda. n nWhile exclusive replacement feeding reduces the risk of transmission between HIV-positive mothers and their infants, it does not adequately address the specters of infection and undernutrition that accompany avoidance of breast-feeding. We are convinced—by data from regions that are similar to Rwanda and even from African countries with higher standards of living—that replacement feeding from birth is a dangerous and inappropriate approach for HIV-affected families in countries like Rwanda. n nIn addition, avoiding breast-feeding from birth can be exceedingly risky, particularly in the same regions where the risk of mother-to-child transmission of HIV is highest. While Partners in Health (PIH) offers high-quality health-care support and financial assistance to reduce the risks associated with breast-feeding avoidance in two districts in Rwanda, it is impossible to eliminate those risks. Researchers have found that children in Ghana, Peru, and India who are not breast-fed between the ages of six weeks and six months have a ten-fold higher risk of death [2]. A multi-country analysis by the World Health Organization (WHO) showed that infants who were born to mothers with little education and were not breast-fed had a five-fold increased risk of death from six to 11 months of age. Since about 5% of breast-fed Rwandan babies already die in the first six months of life and another 3.5% from six to12 months [3], it is essential that PIH substantiate the mortality, nutrition, and morbidity outcomes resulting from their approach before promoting it more widely. n nGiven that breast-feeding avoidance increases the risk of death from other causes, even as it decreases the risk of HIV transmission, is there a net gain? The concept of “HIV-free survival” combines the likelihood of surviving with the likelihood of not becoming HIV infected, allowing a more comprehensive assessment of the risks and benefits of infant feeding. In Botswana [4] and the Ivory Coast [5], rates of HIV-free survival were no better among formula-fed infants than among infants breast-fed for three to six months. At this years WHO Consultation on HIV and Infant Feeding in Geneva, reports showed high death rates in ongoing trials in Kenya, Uganda, and Malawi associated with breast-feeding cessation at three to six months. These results were despite earlier assumptions that breast-feeding cessation at this age might be safe, while avoiding most of the HIV transmission associated with prolonged breast-feeding [6]. Since these carefully controlled studies represent best-case scenarios for replacement feeding, most actual program settings will favor breast-feeding (actually, disfavor replacement feeding). n nThe risk of mother-to-child HIV transmission in the first six months in a country like Rwanda, where 81% of women are still exclusively breast-feeding at four to six months [3], is relatively low—probably approximately 0.3% per month [7]. It may be even lower in districts like those in which PIH works, where eligible HIV-positive mothers begin receiving highly active antiretroviral therapy during pregnancy, because the majority of postnatal HIV transmission is from mothers with low CD4+ cell counts [8]. n nScientific evidence amply demonstrates the significant risks that accompany replacement feeding and the safety and effectiveness of exclusive breast-feeding for the first six months, and continued breast-feeding thereafter as appropriate and safe. Around the world, researchers, programmers, and policy makers are becoming increasingly convinced that the infant feeding counseling component of prevention of mother-to-child transmission of HIV programs must focus on optimizing HIV-free survival rates, not simply on HIV transmission. Accomplishing this means taking full account of all factors, both social and molecular, that are at work in a particular context, and tailoring responses to meet them.

Formula-feeding is not a sustainable solution

We agree with the authors Binagwaho et al.1 that sustainable access to safe drinking water is important and will go a long way to reducing the dangers associated with formula feeding. However, even if we meet the United Nations’ Millennium Development Goal (MDG) of halving the proportion of people without sustainable access to safe drinking water by 2015, there will still remain some 600 million people without safe water.2 According to current trends Sub-Saharan Africa, which bears the brunt of HIV, is estimated to only reach this MDG goal by 2040.2 We submit, however, that even in situations where one does have access to clean water, there are inherent risks, such as pneumonia and diarrhoea, associated with the absence of breast milk, probably related in part to the role that breast milk plays in stimulating maturation of the infant’s innate gastrointestinal immunity.3 These dangers are exacerbated in resource-poor settings resulting in the documented increase in mortality when young infants are not breastfed.4 In HIV-prevalent settings, as we previously, and the authors now mention, there are indeed a few settings where formula feeding has been shown to reduce the potential threat of mortality among formula-fed infants. Of note is that the study quoted5 and other similar studies all have shown equivalence in HIV-free survival. If breast- and formula-feeding (in these few settings) have similar outcomes in terms of HIV-free survival of infants, why would a developing country invest in a technology that comes at significant cost to public health budgets? In KwaZulu-Natal province, which has the highest HIV prevalence in South Africa, supply of formula has accounted for up to 50% of the provincial budget for prevention of mother-to-child transmission of HIV (PMCT). Would it not be more directly cost effective to invest in safe water for all? A major outbreak of diarrhoea that caused a spike in mortality, particularly among formula-fed infants, in Botswana (one of the wealthiest sub-Saharan African countries) illustrates the complexities of continuously providing an adequate formula supply and recognizes the inherent dangers of a contaminated water supply in a national PMTCT programme.6 This highlights the importance of following the latest UNAIDS/UNICEF/WHO guidelines (2007) of only using replacement feeding when it is “acceptable, feasible, affordable, sustainable and safe” – having clean water only satisfies one of these criteria. n nWe need to bear in mind that breast milk remains a very important food source in food-insecure households and we need to be more imaginative in looking for ways of preserving it while rendering it safe. A stark reminder of the need to preserve household food security comes from the 2009 Millennium Development Goals Report7 where it is reported that the current economic and food crises are endangering the recent gains that have been made in eradicating hunger and poverty. The threat of food insecurity is not only to the formula-fed newborn but also at 6xa0months and older when milk still constitutes a significant portion of the infant’s food intake. n nThe issues on breastfeeding and HIV transmission are now “stale, flat and unprofitable” as there are proven interventions to simultaneously reduce HIV transmission, improve survival of infants and preserve the multiple benefits of breastfeeding. These interventions include: promotion and support of exclusive breastfeeding during the first 6xa0months;8 maternal highly active antiretroviral therapy (HAART) and infant antiretroviral prophylaxis;9 and the use of a simple home-based method of flash heating breast milk which destroys the HIV virus while maintaining the majority of nutritional and immunological properties of breastmilk.10 n nThe search for sustainable solutions that also implement sensible emergency measures, supersedes short-term answers such as formula-feeding. In emergencies, the use of formula is neither a sustainable solution nor a sensible immediate option. ■

Prevention of Vertical Transmission of HIV in Resource-Limited Countries

Prevention of vertical (i.e., mother-to-child) transmission of HIV is essential to reduce significant HIV-related child morbidity and mortality in developing countries. Globally, pediatric infections comprise about 15% of all new HIV infections each year and virtually all pediatric infections can be prevented by eliminating vertical transmission [1]. The World Health Organization (WHO) recommendations (revised in 2006) for prevention of mother-to-child transmission (PMTCT)1 include a four-pronged comprehensive strategy [2]. Although we acknowledge the critical role that all approaches play in reducing pediatric HIV infection, the focus of this chapter is on strategies that address the third prong: preventing HIV transmission from infected mothers to their infants. Considerable achievements have been made on this front, including many clinical trials demonstrating good efficacy.