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Objective: The primary aim of this serial cross-sectional analysis is to estimate the total number of prevented perinatal HIV transmissions from the time of the initial recommendation for perinatal zidovudine (ZDV) prophylaxis in 1994 through 2020 in the US., Methods: The estimated number of prevented transmissions was calculated as annual differences between expected and observed numbers of perinatal HIV transmissions. Annual expected number of transmissions was estimated by multiplying the annual number of births to women with HIV by 0.2255 (22.55%), i.e., the transmission rate of the control group in the ACTG Protocol 076 trial. We used published point estimates or, if only ranges were given, the midpoints of those ranges as the best estimates of the annual numbers of births to women with HIV and infants with perinatal HIV. When data were not available, we linearly interpolated or extrapolated the available data to obtain estimated numbers for each year., Results: Between 1978 and 2020, the approximate number of live births to women with HIV was 191 267 (95% confidence interval [CI] 190 392-192 110) and for infants with diagnosed perinatal HIV, it was 21 379 (95% CI 21 088-21 695). Since 1994, the annual number of infants born with HIV decreased from 1263 (95% CI 1194-1333) to 33 in 2019 (95% CI 22-45) and 36 in 2020 (95% CI 25-48), corresponding to a 97% reduction. Cumulatively, an estimated total of 22 732 (95% CI 21 340-24 462) perinatal HIV infections were prevented from 1994 through to 2020., Conclusion: The elimination of perinatal HIV transmission-accompanied by the cumulative number of prevented cases exceeding that of perinatal HIV infections-is a major public health achievement in the US., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

In a randomized, double-blind, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) use from 28 weeks gestational age to 2 months postpartum to prevent mother-to-child transmission of hepatitis B virus, there was no significant effect of maternal TDF use on maternal or infant bone mineral density 1 year after delivery/birth. Clinical Trials Registration. NCT01745822., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: To investigate potential risk factors for perinatal (intrauterine and intrapartum) mother-to-child transmission (MTCT) of HIV in women unexposed to antiretroviral therapy (ART) during pregnancy., Methods: We compared factors according to perinatal MTCT outcome among 2275 ART-naive (until the onset of labor) HIV-infected women in the Breastfeeding, Antiretrovirals and Nutrition study (2004-2010) in Lilongwe, Malawi. Factors included HIV viral load during pregnancy, food security, demographic characteristics, hematologic and blood chemistry measures, medical history and physical factors. Associations with perinatal MTCT and interactions with maternal viral load were assessed using simple and multivariable logistic regression., Results: There were 119 (115 intrauterine and 4 intrapartum) cases of perinatal MTCT, only one to a mother with <1000 HIV copies/mL. Maternal viral loads >10,000 copies/mL were common (63.1%). Lower maternal viral load (<1000 copies/mL and 1000.1-10,000 copies/mL) was associated with reduced odds of perinatal MTCT [adjusted odds ratio (aOR), 0.1; 95% confidence interval (CI): 0.01-0.4 and aOR, 0.2; 95% CI: 0.1-0.4, respectively), compared with maternal viral load >10,000 copies/mL. Low CD4+ T cell count (≤350 cells/μL) was only associated with perinatal MTCT in unadjusted models. Food shortage (aOR, 1.8; 95% CI: 1.2-2.6), sexually transmitted infection (STI) (past year; aOR, 1.9; 95% CI: 1.0-3.7), histories of herpes zoster (aOR, 3.0; 95% CI: 1.6-5.6) and tuberculosis (aOR, 2.5; 95% CI: 1.1-5.7) were associated with increased odds of perinatal MTCT., Conclusions: These findings confirm that lowering maternal HIV viral load is most important in preventing perinatal MTCT and support efforts to address food shortage, STI and tuberculosis prevention, while informing programs to improve ART coverage in pregnancy.

Objective: To evaluate factors within the social-ecological framework associated with most or moderately effective contraception, condom and dual method use at last coitus among young, HIV-infected women in Atlanta., Methods: This is a cross-sectional study conducted from November, 2013 until August, 2015 at the Grady Infectious Disease Clinic in Atlanta, Georgia. We recruited perinatally and horizontally HIV-infected women of ages 14-30 years to complete an audio computer-assisted self-interview. We evaluated factors within a social-ecological framework associated with most or moderately effective contraceptive use (hormonal contraception or an IUD), condom use, and dual method use (use of condom and most or moderately effective contraceptive) at last coitus., Results: Of 103 women enrolled, 74 reported a history of sexual activity. The average age was 22.1; 89% were African American, 52% were perinatally infected, 89% received combination antiretroviral therapy, and 63% had undetectable viral loads. At last coitus, 46% reported most or moderately effective contraception, 62% reported condom use and 27% reporting dual-method use. The odds of most or moderately effective contraceptive use was significantly reduced among those with detectable viral loads (versus undetectable viral loads; aOR 0.13 [0.04, 0.38]). Older age (aOR 0.85 [0.74, 0.98] and more frequent coitus (>once/week versus < = once/week; aOR 0.24 [0.08, 0.72]) was significantly associated with reduced condom use. Having a detectable viral load (versus undetectable viral loads; aOR 0.13 [0.03, 0.69]) and more frequent coitus (>once/week versus < = once/week; aOR 0.14 [0.03,0.82]), was associated with reduced dual method use, while being enrolled in school (aOR 5.63 [1.53, 20.71]) was significantly associated with increased dual method use., Conclusions: Most or moderately effective contraception, condom and dual method use remained inadequate in this cohort of young HIV-infected women. Individual-level interventions are needed to increase the uptake of dual methods with user-independent contraceptives., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Hepatitis C virus (HCV) infection is an important contributor to the worldwide burden of liver-related morbidity and mortality. Mother-to-child transmission of HCV ranges from 6 to 11% in different populations globally, but accurate estimates on the burden of pediatric HCV infection are limited because screening approaches are not consistent. Areas covered: The advent of new direct-acting antiviral agents that achieve very high rates of sustained virologic response (representing virologic cure) with short (i.e. 8-12 weeks) regimens has revolutionized the field of HCV treatment and led to the development of global elimination goals for HCV transmission and mortality. However, information on their safety during pregnancy and efficacy in preventing mother-to-child transmission is lacking. Currently, there are no approved treatment regimens with these antiviral agents for children younger than 12 years of age. Expert commentary: If these agents are shown to be safe during pregnancy and effective in preventing transmission to the infant, screening of pregnant women and antenatal treatment of those infected, could pave the way for eliminating pediatric HCV infection- particularly as these drugs become less costly and more accessible. Treatment of infected children when indicated, along with universal safe health care practices, can further pediatric HCV elimination.

A significant number of infants acquire HIV-1 through their infected mother's breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers ( n = 63) against heterologous HIV-1 variants and the quasispecies present in the mother. HIV-exposed uninfected infants (HEU) ( n = 42), compared to those that eventually acquired infection ( n = 21), did not possess higher nAb responses against heterologous envelopes ( P = 0.46) or their mothers' variants ( P = 0.45). Transmitting compared to nontransmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes ( P = 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains ( P = 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event ( P = 0.03). These results imply that preexisting anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both the frequency of breast milk transmission and subsequent infant morbidity. IMPORTANCE Passive immunization trials are under way to understand if preexisting antibodies can decrease mother-to-child HIV-1 transmission and improve infant outcomes. We examined the influence of preexisting maternal and infant neutralizing activity on transmission and infant morbidity in a breastfeeding mother-infant cohort. Neutralization was examined against both the exposure strains circulating in the infected mothers and a standardized reference panel previously used to estimate breadth. HIV-exposed uninfected infants did not possess a broader and more potent response against both the exposure and heterologous strains compared to infants that acquired infection. Transmitting, compared to nontransmitting, mothers had significantly higher neutralization breadth and potency but similar responses against autologous variants. Infants born to mothers with higher neutralization responses were more likely to have a serious adverse event. Our results suggest that preexisting antibodies do not protect against breast milk HIV-1 acquisition and may have negative consequences for the baby., (Copyright © 2017 Ghulam-Smith et al.)

Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in sub-Saharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers ( n = 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was in utero (91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and in utero transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT., (Copyright © 2017 American Society for Microbiology.)

Background: Antiretroviral (ARV) interventions are used to reduce HIV viral replication and prevent mother-to-child transmission. Viral suppression relies on adherence to ARVs., Methods: A 2-phase study was conducted using data from the Breastfeeding, Antiretrovirals, and Nutrition study. We included mothers randomized to 28 weeks of postpartum ARVs with ≥1 plasma or breastmilk specimen. All mothers who transmitted HIV to their infants from 2-28 weeks (n = 31) and 15% of mothers who did not (n = 232) were included. Adherence was measured by pill count [categorized as poor (0%-80%), partial (81%-98%), and near perfect (>98%)]. Associations between adherence and breastmilk RNA were assessed using mixed-effects models. Cox models were used to estimate associations between breastmilk RNA and HIV transmission. Using Monte Carlo simulation, we estimated the number of transmissions that would occur had everyone randomized to maternal ARVs been 90% and 100% adherent., Results: Partial or near perfect ARV adherence significantly reduced the odds of having detectable (≥40 copies/mL) breastmilk RNA, compared with poor adherence (Odds Ratio (OR) 0.23, 95% CI: 0.08 to 0.67; OR 0.36, 95% CI: 0.16 to 0.81, respectively). Detectable breastmilk RNA was associated with increased breastmilk transmission compared with undetectable breastmilk RNA (hazard ratio 3.8, 95% CI: 1.2 to 12.1). All transmitting mothers had ≥1 plasma viral load specimen >100 copies per milliliter. An estimated similar number of transmissions would occur with 90% adherence compared with 100%., Conclusions: Helping patients adhere to ARVs throughout breastfeeding is important for realizing the full potential of recommended ARV interventions to prevent mother-to-child HIV transmission. Maintaining plasma viral load <100 copies per milliliter may prevent breastmilk transmission., Competing Interests: Dr. Davis, Dr. Rigdon, and Dr. Miller report grants from the National Institutes of Health (NIH) during the conduct of the study, and Dr. Davis is currently employed by the Centers for Disease Control and Prevention (CDC). Dr. Nelson reports grants from NIH and CDC during the conduct of the study; grants from Merck, GSK, and Janssen outside the submitted work. Dr. Hudgens reports grants from CDC, NIH, and Gates Foundation during the conduct of the study.

Cytomegalovirus is highly prevalent worldwide and an important opportunistic pathogen in human immunodeficiency virus (HIV)-infected individuals. The effects of cytomegalovirus infection on HIV-exposed infants are poorly understood. We conducted a systematic review to assess the relationship between cytomegalovirus and HIV infections among HIV-exposed infants. Limited evidence suggests that HIV-induced immunosuppression in the mother increases the rate of congenital cytomegalovirus infection, while maternal antiretroviral therapy may reduce it. Limited information exists on the direction of the relationship between cytomegalovirus and HIV transmission among HIV-exposed infants. Only 2 studies have addressed this temporal sequence of events, and they suggest that cytomegalovirus can lead to subsequent HIV infection in HIV-exposed infants. Most evidence suggests that early cytomegalovirus infection accelerates HIV disease progression in infants. Gaps remain in understanding the role that cytomegalovirus infection plays in HIV-exposed infants. Decreasing cytomegalovirus transmission prenatally and in infancy might further decrease HIV transmission and lead to better health among HIV-exposed infants., (Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Unlabelled: Infants born to HIV-1-infected mothers in resource-limited areas where replacement feeding is unsafe and impractical are repeatedly exposed to HIV-1 throughout breastfeeding. Despite this, the majority of infants do not contract HIV-1 postnatally, even in the absence of maternal antiretroviral therapy. This suggests that immune factors in breast milk of HIV-1-infected mothers help to limit vertical transmission. We compared the HIV-1 envelope-specific breast milk and plasma antibody responses of clade C HIV-1-infected postnatally transmitting and nontransmitting mothers in the control arm of the Malawi-based Breastfeeding Antiretrovirals and Nutrition Study using multivariable logistic regression modeling. We found no association between milk or plasma neutralization activity, antibody-dependent cell-mediated cytotoxicity, or HIV-1 envelope-specific IgG responses and postnatal transmission risk. While the envelope-specific breast milk and plasma IgA responses also did not reach significance in predicting postnatal transmission risk in the primary model after correction for multiple comparisons, subsequent exploratory analysis using two distinct assay methodologies demonstrated that the magnitudes of breast milk total and secretory IgA responses against a consensus HIV-1 envelope gp140 (B.con env03) were associated with reduced postnatal transmission risk. These results suggest a protective role for mucosal HIV-1 envelope-specific IgA responses in the context of postnatal virus transmission. This finding supports further investigations into the mechanisms by which mucosal IgA reduces risk of HIV-1 transmission via breast milk and into immune interventions aimed at enhancing this response., Importance: Infants born to HIV-1-infected mothers are repeatedly exposed to the virus in breast milk. Remarkably, the transmission rate is low, suggesting that immune factors in the breast milk of HIV-1-infected mothers help to limit transmission. We compared the antibody responses in plasma and breast milk of HIV-1-transmitting and -nontransmitting mothers to identify responses that correlated with reduced risk of postnatal HIV-1 transmission. We found that neither plasma nor breast milk IgG antibody responses were associated with risk of HIV-1 transmission. In contrast, the magnitudes of the breast milk IgA and secretory IgA responses against HIV-1 envelope proteins were associated with reduced risk of postnatal HIV-1 transmission. The results of this study support further investigations of the mechanisms by which mucosal IgA may reduce the risk of HIV-1 transmission via breastfeeding and the development of strategies to enhance milk envelope-specific IgA responses to reduce mother-to-child HIV transmission and promote an HIV-free generation., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Objective: The objective of this study is to determine whether detection of HIV infection was delayed in infants exposed to antiretroviral prophylaxis to prevent HIV transmission during breastfeeding., Design: The Breastfeeding, Antiretrovirals and Nutrition (BAN) study was a randomized trial of 2369 mother-infant pairs conducted from 2004 to 2010. In addition to an intrapartum regimen, all mother-infant pairs were randomly assigned to three antiretroviral intervention arms during 28 weeks of breastfeeding: no further antiretroviral prophylaxis (control arm); infant-daily nevirapine (nevirapine arm); and maternal zidovudine, lamivudine and either nevirapine, nelfinavir or lopinavir-ritonavir (maternal arm). After breastfeeding cessation counselling and stopping the antiretroviral interventions by 28 weeks, 28 infant HIV infections occurred., Methods: To determine whether these infections occurred during the breastfeeding and antiretroviral intervention phase but had delayed detection on the antiretroviral arms, we performed ultrasensitive (droplet digital PCR) HIV testing on infants with stored peripheral blood mononuclear cell (PBMC) specimens at 24 weeks (n = 9)., Results: Of the nine infants, all three on the infant nevirapine arm had detectable HIV DNA at 24 weeks, compared with two of four on the maternal antiretroviral arm and one of two on the control arm. For infants with detectable HIV at 24 weeks, the median delay in detection between the ultrasensitive and standard assays was 18.3 weeks for the nevirapine arm, 15.4 weeks for the maternal arm and 9.4 weeks for the control arm., Conclusion: The prolonged inability to detect HIV with standard assays in the context of postnatal antiretroviral prophylaxis suggests that early antiretrovirals may restrict HIV replication sufficiently to lead to missed diagnosis among infected infants. Therefore, repeat virologic testing is warranted beyond the WHO-recommended point of testing at 6 weeks after breastfeeding cessation.

Background/aims: Retaining patients in prevention of mother-to-child transmission of HIV studies can be challenging in resource-limited settings, where high lost to follow-up rates have been reported. In this article, we describe the effectiveness of methods used to encourage retention in the Breastfeeding, Antiretrovirals, and Nutrition study and analyze factors associated with lost to follow-up in the study., Methods: The Breastfeeding, Antiretrovirals, and Nutrition clinical trial was designed to evaluate the efficacy of three different mother-to-child HIV transmission prevention strategies. Lower than expected participant retention prompted enhanced efforts to reduce lost to follow-up during the conduct of the trial. Following study completion, we employed regression modeling to determine predictors of perfect attendance and variables associated with being lost to follow-up., Results: During the study, intensive tracing efforts were initiated after the first 1686 mother-infant pairs had been enrolled, and 327 pairs were missing. Of these pairs, 60 were located and had complete data obtained. Among the 683 participants enrolling after initiation of intensive tracing efforts, the lost to follow-up rate was 3.4%. At study's end, 290 (12.2%) of the 2369 mother-infant pairs were lost to follow-up. Among successfully traced missing pairs, relocation was common and three were deceased. Log-binomial regression modeling revealed higher maternal hemoglobin and older maternal age to be significant predictors of perfect attendance. These factors and the presence of food insecurity were also significantly associated with lower rates of lost to follow-up., Conclusion: In this large HIV prevention trial, intensive tracing efforts centered on reaching study participants at their homes succeeded in finding a substantial proportion of lost to follow-up participants and were very effective in preventing further lost to follow-up during the remainder of the trial. The association between food insecurity and lower rates of lost to follow-up is likely related to the study's provision of nutritional support, including a family maize supplement, which may have contributed to patient retention., (© The Author(s) 2014.)

The prevention of mother-to-child transmission (PMTCT) of HIV is one of the great public health successes of the past 20 years. Much concerted research efforts and dedicated work have led to the achievement of very low rates of PMTCT of HIV in settings that can implement optimal prophylaxis. Though several implementation challenges remain, global elimination of pediatric HIV infection seems now more than ever to be an attainable goal. Often overlooked, the role of prophylaxis of the newborn is nevertheless a very important component of PMTCT. In this paper, we focus on the role of neonatal and infant prophylaxis, discuss mechanisms of protection, and present the clinical trial-generated evidence that led to the current recommendations for preventing infections in breastfed and non-breastfed infants. PMTCT of HIV should not end at birth; a continuum of care extending postpartum and postnatally is required to minimize the risk of new pediatric HIV infections.

Background & Aims: The extent of HBV infection to infants of HBV/HIV-coinfected pregnant women in sub-Saharan Africa is unknown. The aim of this study was to assess prevalence of HBV infection among antiretroviral-naïve, HIV-infected pregnant women in Malawi and examine HBV transmission to their infants., Methods: Plasma from 2048 HIV-infected, Malawian women and their infants were tested for markers of HBV infection. Study participants were provided standard-of-care health services, which included administration of pentavalent vaccine to infants at 6, 10, and 14 weeks of age., Results: One-hundred and three women (5%) were HBsAg-positive; 70 of these HBsAg-positive women were also HBV-DNA-positive. Sixteen women (0.8%) were HBV-DNA-positive but HBsAg-negative. Five of 51 infants (9.8%) born to HBsAg-positive and/or HBV-DNA-positive women were HBV-DNA-positive by 48 weeks of age.HBV DNA concentrations of two infants of mothers who received extended lamivudine-containing anti-HIV prophylaxis were <4 log10 IU/ml compared to ⩾ 8 log10 IU/ml in three infants of mothers who did not., Conclusions: HBV DNA was detected in nearly 10% of infants born to HBV/HIV-coinfected women. Antenatal testing for HIV and HBV, if instituted, can facilitate implementation of prophylactic measures against infant infection by both viruses., (Published by Elsevier B.V.)

Background: Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS)., Methods: We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study., Results: Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02)., Conclusions: These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV.

Objectives: To evaluate severe (grade 3/4) morbidity and mortality in HIV-exposed, uninfected infants., Design: : Secondary data analysis of The Breastfeeding, Antiretrovirals, and Nutrition (BAN) clinical trial., Methods: BAN randomized 2369 mother-infant pairs to maternal, infant, or no extended antiretroviral prophylaxis during breastfeeding. Morbidity outcomes examined were pneumonia/serious febrile illness, diarrhea/growth faltering, and malaria. Infant death was defined as neonatal (≤30 days of life), and postneonatal (31 days to 48 weeks of life). Cox proportional hazards models were used to evaluate the effect of covariates on infant morbidity and mortality., Results: The rate of pneumonia/serious febrile illness was highest in the first 12 weeks (0.83/100 person-weeks) before rapidly decreasing; rates of all morbidity outcomes increased after 24 weeks. Rates of pneumonia/serious febrile illness and diarrhea/growth faltering were higher during the rainy season. Prophylactic infant cotrimoxazole significantly decreased the rates of all morbidity outcomes. White blood cell (WBC) count less than 9000/μl at birth was associated with increased diarrhea/growth faltering [adjusted hazard ratio (aHR) 1.73, P = 0.04] and malaria (aHR 2.18, P = 0.02). Low birth weight (2000-2499 g) was associated with neonatal death (aHR 12.3, P < 0.001). Factors associated with postneonatal death included rainy season (aHR 4.24, P = 0.002), infant cotrimoxazole (aHR 0.48, P = 0.03), and low infant WBC count at birth (aHR 2.53, P = 0.02)., Conclusion: Infant morbidity rates increased after 24 weeks, when BAN infants weaned. Introduction of prophylactic cotrimoxazole was associated with reduced rates of morbidity and mortality in HIV-exposed uninfected infants. Unexpectedly, a low WBC count at birth was significantly associated with later infant morbidity and mortality in this cohort.

In HIV-infected women, co-infections that target the placenta, fetal membranes, genital tract, and breast tissue, as well as systemic maternal and infant infections, have been shown to increase the risk for mother-to-child transmission of HIV (MTCT). Active co-infection stimulates the release of cytokines and inflammatory agents that enhance HIV replication locally or systemically and increase tissue permeability, which weakens natural defenses to MTCT. Many maternal or infant co-infections can affect MTCT of HIV, and particular ones, such as genital tract infection with herpes simplex virus, or systemic infections such as hepatitis B, can have substantial epidemiologic impact on MTCT. Screening and treatment for co-infections that can make infants susceptible to MTCT in utero, peripartum, or postpartum can help reduce the incidence of HIV infection among infants and improve the health of mothers and infants worldwide.

Background: In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission., Methods: Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks., Results: The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%-7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%-5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%-6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%-3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%-80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%-69%; P < .001)., Conclusions: Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.

Background: In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks., Methods: The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736., Findings: 676 mother-infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5-9) than in the maternal-antiretroviral (4%, 3-6; p=0·0273) or the infant-nevirapine (4%, 2-5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29-48 weeks than during the intervention phase (1·1 [95% CI 1·0-1·2] vs 0·7 [0·7-0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group)., Interpretation: In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity., Funding: US Centers for Disease Control and Prevention., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Breastfeeding increases metabolic demands on the mother, and excessive postnatal weight loss increases maternal mortality., Objective: We evaluated the efficacy of a lipid-based nutrient supplement (LNS) for prevention of excess weight loss in breastfeeding, HIV-infected women., Design: The BAN (Breastfeeding, Antiretrovirals, and Nutrition) Study was a randomized controlled trial in Lilongwe, Malawi. At delivery, HIV-infected mothers and their infants were randomly assigned according to a 2-arm (with and without LNS) by 3-arm (maternal triple-antiretroviral prophylaxis, infant-nevirapine prophylaxis, or neither) factorial design. The 28-wk LNS intervention provided daily energy (700 kcal), protein (20 g), and micronutrients (except for vitamin A) to meet lactation needs. Women were counseled to breastfeed exclusively for 24 wk and to wean by 28 wk. Weight change (0-28 wk) was tested in an intent-to-treat analysis by using 2-factor ANOVA and with longitudinal mixed-effects models., Results: At delivery, the LNS (n = 1184) and control (n = 1185) groups had similar mean weights and BMIs. Women receiving the LNS had less 0-28-wk weight loss (-1.97 compared with -2.56 kg, P = 0.003). This difference remained significant after adjustment for maternal antiretroviral drug therapy and baseline BMI. Women receiving antiretroviral drugs had more weight loss than did those not receiving antiretroviral drugs (-2.93 compared with -1.90 kg, P < 0.001). The benefit of the LNS for reducing weight loss was observed both in those receiving antiretroviral drugs (-2.56 compared with -3.32 kg, P = 0.019) and in those not receiving antiretroviral drugs (-1.63 compared with -2.16 kg, P = 0.034)., Conclusions: The LNS reduced weight loss among HIV-infected, breastfeeding women, both in those taking maternal antiretroviral prophylaxis to prevent postnatal HIV transmission and in those not receiving antiretroviral prophylaxis. Provision of an LNS may benefit HIV-infected, breastfeeding women in resource-limited settings. This trial was registered at clinicaltrials.gov as NCT00164762.

Perinatal HIV transmission occurs in utero or intrapartum. The mechanisms and timing of transmission are not clearly understood. To compare the genetic sequences of the V3 envelope region of infant's plasma HIV to that of the mother's plasma, peripheral blood mononuclear cells (PBMC) and vaginal secretions, and correlate with timing of transmission. All 3 infants had a positive HIV PCR in the first days of life, thus classified as in utero infections. In the first mother-infant pair, two different variants were present in the infant, one correlating with maternal PBMC virus and highly homologous to virus from vaginal secretions and the other identical to sequences in maternal plasma. In the second pair, the infant plasma virus was similar to that of maternal PBMC. In the third pair, the cord blood and infant plasma virus were highly similar to maternal vaginal virus. The presence of more than one HIV variant from the maternal blood and from the vaginal compartment in the cord blood of infants presumably infected in utero could point to more than one episode of transmission or, alternatively, to transmission of PBMC virus.

More than 400,000 children were infected with (HIV-1) worldwide in 2008, or more than 1000 children per day. Mother-to-child transmission (MTCT) of HIV-1 is the most important mode of HIV acquisition in infants and children. MTCT of HIV-1 can occur in utero, intrapartum, and postnatally through breastfeeding. Great progress has been made in preventing such transmission, through the use of antiretroviral prophylactic regimens to the mother during gestation and labor and delivery and to either mother or infant during breast feeding. The timing and mechanisms of transmission, however, are multifactorial and remain incompletely understood. This article summarizes what is known about the pathogenetic mechanisms and routes of MTCT of HIV-1, and includes virologic, immunologic, genetic, and mucosal aspects of transmission., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi., Methods: We randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test., Results: Among mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction., Conclusions: The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.), (2010 Massachusetts Medical Society)

Two studies that were published in 1999 demonstrated that cesarean delivery before labor and before the rupture of membranes (elective cesarean delivery) reduces the risk of mother-to-child transmission of the human immunodeficiency virus (HIV). On the basis of these results, the American College of Obstetricians and Gynecologists and the US Public Health Service recommend that HIV-infected pregnant women with plasma viral loads of >1000 copies per milliliter be counseled regarding the benefits of elective cesarean delivery. Since the release of these guidelines, the cesarean delivery rate among HIV-infected women in the United States has increased dramatically. Major postpartum morbidity is uncommon, and cesarean delivery among HIV-infected women is relatively safe and cost-effective. However, a number of important questions remain unanswered, including whether cesarean delivery has a role among HIV-infected women with low plasma viral loads or who receive combination antiretroviral regimens.

Nevirapine resistance has been detected in a considerable proportion of women after single-dose nevirapine (SD-NVP) for the prevention of mother-to-child human immunodeficiency virus-1 transmission. As a result, concern has been raised about the effectiveness of subsequent nevirapine-based treatment. Studies in Thailand, Botswana, and South Africa have assessed virologic treatment response after SD-NVP. These studies did not find any significant difference in virologic response for women who began treatment >6 months after SD-NVP exposure. Two studies found worse response rates in women when treatment was initiated within 6 months of SD-NVP exposure. Furthermore, 2 studies found no difference in human immunodeficiency virus transmission rates from mother to child after the receipt of SD-NVP in repeat pregnancies. These data support the use of SD-NVP as 1 option for the prevention of mother-to-child human immunodeficiency virus-1 transmission in resource-limited settings, particularly in settings where more complex regimens are not yet available. Further research in the optimization of perinatal prevention regimens is needed.

In the United States, current human immunodeficiency virus (HIV) testing guidelines recommend an opt-out approach for pregnant women, whereby HIV testing is incorporated routinely into the standard panel of prenatal tests with the option to decline. Current recommendations for the initiation of treatment of HIV infection in pregnant women are the same as those for nonpregnant women. However, the special circumstances of pregnancy raise additional issues that are related to potential drug toxicity to the mother and fetus, which affect the choice of antiretroviral drugs to be used. For HIV-infected pregnant women who do not require therapy for their own health, antiretroviral drugs are recommended for prevention of mother-to-child transmission. Highly active antiretroviral therapy is recommended for all women with HIV RNA levels of > or = 1000 copies/mL, along with consideration of elective cesarean delivery. For women with HIV RNA levels of < 1000 copies/mL, a 3-part zidovudine prophylaxis regimen (prenatal, intrapartum, and neonatal) should be used alone or in combination with other antiretroviral drugs.

Prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) in the United States and Europe has been a tremendous success, such that transmission rates of less than 2% have been achieved. Some key successes have also been demonstrated in resource-poor countries; however, the translation of successful interventions into public health policy has been slow because of a variety of factors such as inadequate funding and cultural, social, and institutional barriers. The issue of HIV and infant feeding in settings that lack culturally acceptable, feasible, affordable, safe, and sustainable nutritional substitutes for breast milk is a continuing dilemma. An effective preventive infant HIV vaccine would be an optimal approach to reduce HIV acquisition in the first year of life among breast-feeding infants. The challenges to eliminate new perinatal HIV infections worldwide will depend on both sustaining and expanding PMTCT interventions and effective primary HIV prevention for women, adolescents, and young adults.

Breastfeeding accounts for up to half of all infant human immunodeficiency virus (HIV) infections worldwide and carries an estimated transmission risk of about 15% when continued into the second year of life. Because replacement feeding is not safely available, culturally acceptable, or affordable in many parts of the world and because breastfeeding provides protection against other causes of infant mortality, approaches that reduce breastfeeding mother-to child transmission of HIV are being explored. These include exclusive breastfeeding for the infant's first few months of life followed by rapid weaning, treatments of expressed milk to inactivate the virus, and antiretroviral prophylaxis taken by the infant or mother during breastfeeding, which are strategies currently being tested in clinical trials. Passive (antibodies) and active (vaccine) immunoprophylaxis will also soon begin to be tested. This paper focuses on current and planned research on strategies to prevent breastfeeding transmission of HIV.

This article provides a synthesis of clinical trial data with an aim to deduce the timing of mother-to-child transmission of HIV-1. Because transmission of the infection to the infant through breastfeeding is one of the main challenges in fighting paediatric HIV/AIDS in the developing world, we present separate estimates for the timing of HIV transmission for non-breastfeeding and breastfeeding populations. Our estimates predict that, for non-breastfeeding populations, 50% of HIV infections are transmitted to the infant at the very end of pregnancy, near to the time of labour. For breastfeeding populations, the postnatal period accounts for most of the HIV infections transmitted to the infant. We discuss the potential benefit of exclusive breastfeeding for the first 6 months of life as a policy to decrease the magnitude of HIV transmission. Furthermore, we present the hypothesis, based on recent research findings of viral latency, that the time when a fetus initially encounters the virus might not be when infection is established. We discuss the implications of this hypothesis and how it could lead to new interventions for the prevention of mother-to-child HIV transmission.

Transmission of HIV-1 to the infant through breastfeeding is a major cause of new paediatric HIV-1 infections worldwide. Although extended breastfeeding accounts for approximately 40% of infant HIV infections worldwide, most breastfed infants remain uninfected, despite prolonged and repeated exposure to HIV-1. Mechanisms associated with transmission of HIV-1 through breastfeeding and factors related to protection from such transmission remain poorly understood. Here we focus on the cellular origin of HIV in breast milk and on immune factors within the milk that may offer protection from transmission of HIV infection. The presence of innate immunity and induction of adaptive immunity against HIV is explored: in particular, specific antibodies, cellular responses, and their significance. The role of mucosal immune activation and epithelial integrity in HIV transmission is also addressed. We are of the opinion that advances in laboratory methods that study specific aspects of immunity will help open new areas of understanding of HIV transmission through breastfeeding and mechanisms of protection, and contribute to the development of novel prevention strategies.

Significant progress has been made in preventing transmission of HIV-1 from mother to infant. With combination antiretroviral therapies, transmission rates lower than 2% have been achieved in clinical studies. Abbreviated regimens covering labour and the first few days of neonatal life have shown considerable promise in the developing world. Several questions and challenges remain, however. These include choice of the optimal antiretroviral agent(s) and duration of the regimens, availability of antiretroviral agents in developing countries, long-term safety of antiretrovirals during pregnancy and early neonatal life and the problem of breastfeeding transmission in countries where alternatives to breastfeeding are not available. A wider array of strategies for prevention of mother-to-child transmission of HIV-1 during breastfeeding, including passive and active immunisation, may offer much needed answers to the problem of continued HIV transmission from mother to infant.

Significant progress has been made in the battle against transmission of HIV-1 from mother to infant. Antiretroviral regimens covering the later part of gestation, labour and the first few weeks of neonatal life have shown great efficacy in reducing such transmission. With the advent of combination antiretroviral therapies, transmission rates lower than 2% have been achieved in clinical studies. Elective caesarean delivery has been shown to enhance the benefit of antiretroviral regimens; however, the risks associated with this approach in many resource-poor settings in developing countries limit its role worldwide. Abbreviated antiretroviral regimens covering labour and the first few days of neonatal life have shown considerable promise in the developing world, resulting in 50% reduction in transmission. Several questions and challenges remain, however. Amongst them, choice of the optimal antiretroviral agent(s), evaluation of purely post-exposure neonatal prophylaxis, availability of antiretroviral agents in developing countries, long-term safety of antiretroviral therapy during pregnancy and early neonatal life, and the problem of breastfeeding transmission in the developing world are some issues that need urgent attention.