Maternal Highly Active Antiretroviral Therapy Research Articles

Case Study: A Rapid Rollout of Universal Maternal HAART Improves Outcomes among HIV-Positive Women and Their Infants in Kenya.

Globally, countries have made significant achievements in reducing rates of mother-to-child transmission (MTCT) of HIV. In Kenya, MTCT rates were most recently estimated at 8%, with 220,000 children under 15 years of age living with HIV. In 2013, the World Health Organization recommended highly active antiretroviral therapy (HAART) for all HIV-infected pregnant and lactating women. APHIAPLUSKAMILI supported rollout of a county-level, targeted, rapid scale-up of HAART in 152 high-volume facilities in Kenya. A review and comparison of data from these facilities in 2013 and 2014 revealed a significant increase in the proportion of women started on HAART and a reduction in MTCT.

Maternal Highly Active Antiretroviral Therapy and Child HIV-Free Survival in Malawi, 2004-2009.

Highly active antiretroviral therapy (HAART) provision to eligible HIV-infected pregnant and post-partum women is critical for optimizing maternal health. We assessed the impact of maternal HAART on HIV-free survival of breastfed infants in Malawi. The post-exposure prophylaxis of infants-Malawi trial (2004-2009) enrolled mothers/infants during labor or immediately post-partum to evaluate 14-week extended infant antiretroviral prophylaxis for preventing HIV transmission through breastfeeding. Mothers meeting national HAART guidelines were referred for therapy. Child HIV-free survival-survival without HIV infection-was compared by maternal HAART status. Overall, 3022 mother-infant pairs contributed 4214 infant/person-years (PY) at-risk for HIV infection or death, with 532 events (incidence 12.6/100 PY, 95 % confidence interval [CI] 11.6-13.7). During follow-up, 349 mothers were HAART initiated; 581 remained HAART naïve with CD4 cell counts <250 cells/mm(3), and 2092 were never HAART-eligible. By 3 months, 11 % of infants with HAART naïve mothers (CD4 < 250) were infected with HIV or died versus 7 % of infants of HAART-initiated mothers and 4 % of infants of HAART-ineligible mothers. Maternal HAART was associated with a 46 % reduction in infant HIV infection or death as compared to infants with HAART naïve mothers (CD4 < 250) (adjusted hazards ratio 0.54, 95 % CI 0.36-0.81). Among HIV-exposed, uninfected infants, breastfeeding, but not HAART, was significantly associated with decreased child mortality. HIV infection and mortality are high during the first 3 months post-partum in infants of mothers with advanced HIV, and rapid maternal HAART initiation can significantly improve HIV-related infant outcomes. Clinical Trials Registration This study is registered at http://clinicaltrials.gov/ under trial number NCT00115648.

Implementation and Operational Research: Effects of Antenatal Care and HIV Treatment Integration on Elements of the PMTCT Cascade: Results From the SHAIP Cluster-Randomized Controlled Trial in Kenya.

Integrating antenatal care (ANC) and HIV care may improve uptake and retention in services along the prevention of mother-to-child transmission (PMTCT) cascade. This study aimed to determine whether integration of HIV services into ANC settings improves PMTCT service utilization outcomes. ANC clinics in rural Kenya were randomized to integrated (6 clinics, 569 women) or nonintegrated (6 clinics, 603 women) services. Intervention clinics provided all HIV services, including highly active antiretroviral therapy (HAART), whereas control clinics provided PMTCT services but referred women to HIV care clinics within the same facility. PMTCT utilization outcomes among HIV-infected women (maternal HIV care enrollment, HAART initiation, and 3-month infant HIV testing uptake) were compared using generalized estimating equations and Cox regression. HIV care enrollment was higher in intervention compared with control clinics [69% versus 36%; odds ratio = 3.94, 95% confidence interval (CI): 1.14 to 13.63]. Median time to enrollment was significantly shorter among intervention arm women (0 versus 8 days, hazard ratio = 2.20, 95% CI: 1.62 to 3.01). Eligible women in the intervention arm were more likely to initiate HAART (40% versus 17%; odds ratio = 3.22, 95% CI: 1.81 to 5.72). Infant testing was more common in the intervention arm (25% versus 18%), however, not statistically different. No significant differences were detected in postnatal service uptake or maternal retention. Service integration increased maternal HIV care enrollment and HAART uptake. However, PMTCT utilization outcomes were still suboptimal, and postnatal service utilization remained poor in both study arms. Further improvements in the PMTCT cascade will require additional research and interventions.

The Effect of Prenatal Highly Active Antiretroviral Therapy on the Transmission of Congenital and Perinatal/Early Postnatal Cytomegalovirus Among HIV-Infected and HIV-Exposed Infants

Before highly active antiretroviral therapy (HAART), congenital cytomegalovirus (CMV) rates were higher among human immunodeficiency virus (HIV)-exposed infants than unexposed infants. This study examines congenital and perinatal/early postnatal (P/EP) CMV among HIV-exposed infants pre- and post- HAART. Infants born to HIV-infected women were evaluated for congenital CMV (CMV-positive culture in first 3 weeks of life) and P/EP CMV (positive culture in first 6 months of life). Prenatal maternal HAART was defined as triple antiretroviral therapy (ART) with at least 1 nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. Among 414 infants evaluated, 1678 CMV assessment days were completed (mean = 3 assessment days per infant). Congenital CMV rates did not differ by time period, HAART use, or infant HIV infection status. P/EP CMV rates were greater for the 1988-1996 birth cohort (17.9%) compared with the 1997-2002 birth cohort (8.9%) (P < .01), HIV-infected versus uninfected infants (P < .01), and infants with no maternal ART versus those with ART (P < .01). Controlling for potential confounders, P/EP CMV was associated with no maternal ART (odds ratio = 4.7; P < .01), and among those with no maternal ART, P/EP CMV was associated with maternal CD4 count ≤200 cells/μL (P < .01). For HIV-uninfected infants with P/EP CMV, symptoms including splenomegaly, lymphadenopathy, and hepatomegaly were associated with no maternal HAART versus those with HAART (41% vs 6%; P < .05). Although congenital CMV rates did not change, the post-HAART era showed reduced P/EP CMV and occurrence of related clinical symptoms. These findings underscore the importance of prenatal HAART for all HIV-infected pregnant women.

Highly Active Antiretroviral Therapy Versus Zidovudine for Prevention of Mother-to-Child Transmission in a Programmatic Setting, Botswana

Few studies have compared the programmatic effectiveness of the recommended strategies of antenatal highly active antiretroviral therapy (HAART) and zidovudine for prevention of mother-to-child transmission. We prospectively followed infants (93% formula fed) whose mothers who took either HAART (258 infants) or zidovudine (170 infants) during pregnancy in the Botswana national program. Overall, 10 infants (2.5%) acquired HIV--9 infants in the zidovudine group (5.5%, 95% confidence interval: 2.6% to 10.2%) and 1 infant in the HAART group (0.4%, 95% confidence interval: 0.0% to 2.2%). Maternal HAART was associated with decreased prevention of mother-to-child transmission (P = 0.001) and improved HIV-free survival (P = 0.040) compared with zidovudine (with or without single-dose nevirapine) in a programmatic setting.

Increased Risk of Severe Infant Anemia After Exposure to Maternal HAART, Botswana

Maternal highly-active antiretroviral therapy (HAART) reduces mother-to-child HIV transmission but may increase the risk for infant anemia. The incidence of first severe anemia (grade 3 or 4, Division of AIDS 2004 Toxicity Table) was assessed among HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana. Severe anemia rates were compared between 3 groups: infants exposed to maternal HAART in utero and during breastfeeding (BF) and 1 month of postnatal zidovudine (ZDV) (HAART-BF); infants exposed to maternal ZDV in utero, 6 months of postnatal ZDV, and BF (ZDV-BF); and infants exposed to maternal ZDV in utero, 1 month of postnatal ZDV, and formula-feeding (ZDV-FF). A total of 1719 infants were analyzed-691 HAART-BF, 503 ZDV-BF, and 525 ZDV-FF. Severe anemia was detected in 118 infants (7.4%). By 6 months, 12.5% of HAART-BF infants experienced severe anemia, compared with 5.3% of ZDV-BF (P < 0.001) and 2.5% of ZDV-FF infants (P < 0.001). In adjusted analysis, HAART-BF infants were at greater risk of severe anemia than ZDV-BF or ZDV-FF infants (adjusted odds ratios 2.6 and 5.8, respectively; P < 0.001). Most anemias were asymptomatic and improved with iron/multivitamin supplementation and cessation of ZDV exposure. However, 11 infants (0.6% of all infants) required transfusion for symptomatic anemia. Microcytosis and hypochromia were common among infants with severe anemia. Exposure to maternal HAART starting in utero was associated with severe infant anemia. Confirmation of this finding and possible strategies to mitigate hematologic toxicity warrant further study.

Initiation of Antiretroviral Treatment in Women After Delivery Can Induce Multiclass Drug Resistance in Breastfeeding HIV-Infected Infants

The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-infected lactating women with CD4+ cell counts <350 cells/μL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis. We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests. Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P = .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P = .003). Postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.

Impact of maternal HAART on the prevention of mother-to-child transmission of HIV: results of an 18-month follow-up study in Ouagadougou, Burkina Faso

Mother-to-child transmission remains the main cause of global pediatric HIV infections, especially in sub-Saharan Africa. Many interventions based on single-dose antiretroviral therapy have been implemented to reduce the mother-to-child transmission of HIV. In resource-limited settings, highly active antiretroviral therapy (HAART) has only been recommended for HIV-infected pregnant women requiring treatment for their own health. Here, we assessed the efficacy over 18 months of maternal HAART versus peripartum short-course antiretroviral therapy (SCART) regimens for the prevention of mother-to-child transmission (PMTCT) of HIV. We conducted a retrospective cohort study of patients from two medical centers in Ouagadougou, Burkina Faso. The PMTCT files and registers from 1 January 2003 to 31 December 2006 were obtained from routine data collected at these sites. The main assessment criterion was the rate of HIV-1 positivity in children born to HIV-positive mothers as measured with HIV-1 rapid tests at 18 months. A total of 586 pregnant HIV-1-infected women in PMTCT programs were selected. Among these women, 260 were undergoing HAART and 326 received single-dose nevirapine (91.3%) or single-dose zidovudine (8.7%) at delivery. HIV-1 serological tests were performed on 454 children at 18 months old. The rate of HIV-1 vertical transmission was 0% (0/195) in the HAART group and 4.6% (12/259) in the single-dose monotherapy group (P<0.01). Eight infants in the HAART cohort and 30 in the SCART cohort were breastfed; three in the SCART group were HIV-positive. A total of 62 children died, 19 in the HAART group and 43 in the single-dose monotherapy group. Our study confirms that HAART for mothers effectively reduces the risk of infant HIV infection while preserving the breastfeeding option for mothers.

Postnatal Human Immunodeficiency Virus-1 Transmission After Cessation of Infant Extended Antiretroviral Prophylaxis and Effect of Maternal Highly Active Antiretroviral Therapy

A randomized clinical trial, the PostExposure Prophylaxis of Infants trial in Blantyre, Malawi, (PEPI-Malawi), which was carried out in a resource-limited setting showed that antiretroviral prophylaxis (nevirapine alone or nevirapine plus zidovu- dine) extended to age 14 weeks in infants who were breast-fed by human immunodeficiency virus (HIV)-infected mothers, reduced the risk of HIV-1 infection by 67%. In a similar setting, use of maternal highly active antiretroviral therapy (HAART) has also reduced postnatal HIV transmission; its efficacy, however, has not been confirmed in a randomized trial. The availability of antiretroviral therapy in 2006 provided the opportunity to evaluate, in the PEPI-Malawi trial, the complementary effects of infant prophylaxis and maternal HAART in reducing transmission of HIV through breast milk. This follow-up observational study determined the incidence of HIV infection and the association between postnatal HIV transmission and maternal HAART among breast-fed infants born to HIV-1-infected women in the PEPI-Malawi trial who were HIV negative after 14 weeks of extended antiretroviral prophylaxis. The infants were randomized at birth to receive either oral single-dose nevirapine plus 1 week of zidovudine (control), control plus nevirapine daily to age 14 weeks, or control followed by nevirapine plus zidovudine daily to age 14 weeks. Three maternal exposure categories were examined as follows: The HAART-eligible/untreated category consisted of infants whose mothers were eligible (defined as CD4 cell count <250 cells/μL) but had not received HAART. The HAART eligible/treated category included infants with eligible mothers who had started to receive HAART. The HAART-ineligible category was comprised of infants whose mothers were ineligible for HAART because all prior CD4 cell counts were ≥250 cells/μL. Of the 2318 infants in the study, 130 (5.6%) acquired an HIV infection; a total of 310 of their mothers (13.4%) received HAART. The postnatal transmission rates (cases per 100 person-years) were as follows: HAART eligible, untreated (10.56, with a 95% confidence interval [CI] of 7.91-13.82); HAART eligible, treated (1.79, with a 95% CI of 0.58-4.18); and HAART ineligible (3.66 with a 95% CI of 2.86-4.61). The use of postpartum HAART in women with low CD4 cell counts was associated with an 82% reduction in postnatal HIV transmission, compared to those with similar low CD4 cell counts who had not been given HAART (hazard ratio, 0.18; 95% CI, 0.07-0.44). These findings suggest that there are 2 options for preventing viral transmission from HIV-infected mothers who breast-feed their infants: (1) Continue extended infant prophylaxis beyond 14 weeks with an expected protective effectiveness of 67%, or (2) administer maternal HAART with an expected protective effectiveness of 82%.

Breastfeeding in HIV-Positive Women

Breastfeeding remains a common practice in parts of the world where the burden of HIV is highest and the fewest alternative feeding options exist. The impossible dilemma faced by HIV-positive mothers is whether to breastfeed their infants in keeping with cultural norms but in doing so risk transmitting the virus through breast milk, or to pursue formula feeding, which comes with its own set of risks, including a higher rate of infant mortality from diarrheal illnesses, while reducing transmission of HIV. Treatment of mothers and/or their infants with antiretroviral drugs is a strategy that has been employed for several decades to reduce HIV transmission through pregnancy and delivery, but the effect of these agents when taken during breastfeeding is a newer field of study. In this article we evaluate the latest clinical research, from trials that encourage exclusive breastfeeding to trials of antiretroviral therapy (ART) for either the mother or infant, in an attempt to prevent transmission of HIV through breast milk. Additionally, we discuss research that is in progress, with results anticipated in the next few years that will further shape clinical guidelines and practice. Exclusive breastfeeding is much safer than mixed feeding (the supplementation of breastfeeding with other foods), and should be encouraged even in settings where ART for either the mother or infant is not readily available. The research published regarding maternal treatment with highly active antiretroviral therapy (HAART) during pregnancy and the breastfeeding period has all been non-randomized with relatively little statistical power, but suggests maternal HAART can drastically reduce the risk of transmission of HIV. Infant prophylaxis has been intensively studied in several trials and has been shown to be as effective as maternal treatment with antiretrovirals, reducing the transmission rate after 6 weeks to as low as 1.2%. Research that is in progress will provide us with more answers about the relative contribution of maternal treatment and infant prophylaxis in preventing transmission, and the results of such research may be expected as early as this year through 2013. There is hope that perinatal HIV transmission may be greatly reduced in breastfeeding populations worldwide through a combination of behavioral interventions that encourage exclusive breastfeeding and pharmacologic interventions with antiretrovirals for mothers and/or their infants.

The Risks of Not Breastfeeding

The Risks of Not Breastfeeding

Postnatal HIV‐1 Transmission after Cessation of Infant Extended Antiretroviral Prophylaxis and Effect of Maternal Highly Active Antiretroviral Therapy

The association between postnatal human immunodeficiency virus type 1 (HIV-1) transmission and maternal highly active antiretroviral therapy (HAART) after infant extended antiretroviral prophylaxis was assessed. A follow-up study was conducted for the Post-Exposure Prophylaxis of Infants trial in Blantyre, Malawi (PEPI-Malawi). In PEPI-Malawi, breast-feeding infants of HIV-infected women were randomized at birth to receive a either control regimen (single-dose nevirapine plus 1 week of zidovudine); the control regimen plus nevirapine to age 14 weeks; or the control regimen plus nevirapine and zidovudine to age 14 weeks. Infant HIV infection, maternal CD4 cell count, and HAART use were determined. Maternal HAART use was categorized as HAART eligible but untreated (CD4 cell count of <250 cells/microL, no HAART received), HAART eligible and treated (CD4 cell count of <250 cells/microL, HAART received), and HAART ineligible (CD4 cell count of 250 cells/microL). The incidence of HIV infection and the association between postnatal HIV transmission and maternal HAART were calculated among infants who were HIV negative at 14 weeks. Of 2318 infants, 130 (5.6%) acquired HIV infection, and 310 mothers (13.4%) received HAART. The rates of HIV transmission (in cases per 100 person-years) were as follows: for the HAART-eligible/untreated category, 10.56 (95% confidence interval [CI], 7.91-13.82); for the HAART-eligible/treated category, 1.79 (95% CI, 0.58-4.18); and for the HAART-ineligible category, 3.66 (95% CI, 2.86-4.61). The HIV transmission rate ratio for the HAART-eligible/treated category versus the HAART-eligible/untreated category, adjusted for infant prophylaxis, was 0.18 (95% CI, 0.07-0.44). Postnatal HIV transmission continues after cessation of infant prophylaxis. HAART-eligible women should start treatment early for their own health and to reduce postnatal HIV transmission to their infants.

Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants

To assess hematologic and hepatic toxicities associated with in utero and breastfeeding exposure to maternal highly active antiretroviral therapy (HAART) among infants in Botswana. A nested cohort study within a randomized clinical trial (the Mashi Study). Laboratory toxicities among infants born to women who initiated HAART before delivery were compared with toxicities among those born to women who received zidovudine and a single dose of nevirapine or placebo in labor. Infants were randomized to breastfeed with extended zidovudine or to formula-feed. Hemoglobin concentrations, absolute neutrophil and platelet counts, and alanine aminotransferase and aspartate aminotransferase levels were recorded from birth to 7 months of age in infants. Grade 3 and 4 toxicities were compared by infant antiretroviral exposure status. In-utero exposure to maternal HAART was associated with increased risk for neutropenia in infants up to 1 month of age; 21.7% of HAART-exposed infants were neutropenic, compared with 5.5% of the infants exposed to zidovudine (P < 0.01). However, neutropenia was no longer associated with antenatal exposure to HAART after 1 month of age. Postnatal exposure to HAART was not associated with hematologic or hepatic toxicities. Laboratory toxicities were clinically asymptomatic in all but one infant. Exposure to maternal HAART in utero may increase the risk for infant neutropenia, particularly among breastfed infants, but the clinical significance of this finding is uncertain. The lack of association between exposure to HAART through breastfeeding and long-term toxicities in infants is reassuring but deserves study in larger cohorts.

Antiretroviral Therapy Among HIV-Infected Breastfeeding Mothers: A Promising Strategy to Prevent HIV Postnatal Transmission in Africa

Evaluation of: Giuliano M, Guidotti G, Andreotti M et al.: Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load: a study within the Drug Resource Enhancement Against AIDS and Malnutrition Program. J. Acquir. Immune Defic. Syndr. 44(3), 286–291 (2007). Maternal highly active antiretroviral therapy (HAART) starting during the late prenatal period and prolonged during lactation is a potentially interesting strategy to prevent mother-to-child transmission of HIV through breastfeeding in Africa. In this report, Giuliano and colleagues demonstrated that HIV-infected women treated with HAART from before delivery had lower cell-free HIV RNA load in breast milk and were less likely to have a detectable viral load in this compartment 1 week after delivery, when compared with untreated women. Antiretroviral therapy among HIV-infected breastfeeding mothers could thus be a promising strategy to prevent HIV transmission through breast milk in Africa if further larger studies confirm its safety. This strategy could also provide a link between prevention and care, since maternal HAART provided in pregnancy and during the breastfeeding period can be thereafter continued among women who meet the criteria for their own health.

Triple Antiretroviral Prophylaxis Administered During Pregnancy and After Delivery Significantly Reduces Breast Milk Viral Load

The administration of antiretroviral therapy to lactating women could represent a possible strategy to reduce postnatal HIV transmission. In this study, we assessed the effect of antiretroviral treatment on breast milk viral load and determined plasma and breast milk drug concentrations in pregnant women receiving highly active antiretroviral therapy (HAART). We studied 40 women receiving zidovudine, lamivudine, and nevirapine from 28 weeks of gestation to 1 month postpartum (group A) and 40 untreated pregnant women (group B). Blood and breast milk samples were collected at delivery and 7 days postpartum. Women in group A had received a median of 85 days of therapy before delivery. Median breast milk concentrations of nevirapine, lamivudine, and zidovudine were 0.6, 1.8, and 1.1 times, respectively, those in maternal plasma. HIV RNA levels in breast milk were significantly lower in group A than in group B (median of 2.3 vs. 3.4 log at delivery and 1.9 vs. 3.6 log at day 7; P < 0.001 for both comparisons). Antiretroviral drugs administered during the last trimester of pregnancy and after delivery reach levels similar to or higher than plasma concentrations in breast milk and can significantly reduce HIV RNA levels. Our data support the potential role of maternal HAART prophylaxis in reducing the risk of breast-feeding-associated transmission.