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1.  HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis 
PLoS Medicine  2011;8(3):e1000430.
Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.
Background
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
Methods and Findings
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Conclusions
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
Trial Registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.
Why Was This Study Done?
More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.
What Did the Researchers Do and Find?
In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.
What Do These Findings Mean?
These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.
The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT
doi:10.1371/journal.pmed.1000430
PMCID: PMC3066134  PMID: 21468304
2.  Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial 
Lancet  2012;379(9835):2449-2458.
Summary
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.
doi:10.1016/S0140-6736(12)60321-3
PMCID: PMC3661206  PMID: 22541418
3.  Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial 
PLoS Medicine  2011;8(3):e1001015.
Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.
Background
Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
Methods and Findings
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.
Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm3 were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).
Conclusions
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
Trial registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about half a million children become infected with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). Nearly all these newly infected children live in resource-limited countries and most acquire HIV from their mother, so-called mother-to-child transmission (MTCT). Without intervention, 25%–50% of babies born to HIV-positive mothers become infected with HIV during pregnancy, delivery, or breastfeeding. This infection rate can be reduced by treating mother and child with antiretroviral (ARV) drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to her baby soon after birth nearly halves the risk of MTCT. Further reductions in risk can be achieved by giving mother and baby three ARVs—an NNRTI and two nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and lamivudine)—during pregnancy and perinatally (around the time of birth).
Why Was This Study Done?
Breastfeeding is crucial for child survival in poor countries but it is also responsible for up to half of MTCT. Consequently, many researchers are investigating how various ARV regimens given to mothers and/or their infants during the first few months of life as well as during pregnancy and perinatally affect MTCT. In this single-arm trial, the researchers assess the feasibility and safety of using a triple-ARV regimen to suppress the maternal HIV load (amount of virus in the blood) from late pregnancy though 6 months of breastfeeding among HIV-positive women in Kisumu, Kenya, and ask whether this approach achieves a lower HIV transmission rate than other ARV regimens that have been tested in resource-limited settings. In a single-arm trial, all the participants are given the same treatment. By contrast, in a “randomized controlled” trial, half the participants chosen at random are given the treatment under investigation and the rest are given a control treatment. A randomized controlled trial provides a better comparison of treatments than a single-arm trial but is more costly.
What Did the Researchers Do and Find?
In the Kisumu Breastfeeding Study (KiBS), HIV-infected pregnant women took a triple-ARV regimen containing zidovudine and lamivudine and either nevirapine or the protease inhibitor nelfinavir from 34–36 weeks of pregnancy to 6 months after delivery. They were advised to breastfeed their babies (who received single-dose nevirapine at birth), and to wean them rapidly just before 6 months. The researchers then used Kaplan-Meier statistical methods to estimate HIV transmission and death rates among 487 live-born infants from delivery to 24 months. The cumulative HIV transmission rate rose from 2.5% at birth to 7.0% at 24 months. The cumulative HIV transmission or death rate at 24 months was 15.7%; no infant deaths were attributed to ARVs. At 24 months, 3.0% of babies born to mothers with a low viral load were HIV positive compared to 8.7% of babies born to mothers with a high viral load, a statistically significant difference. Similarly, at 24 months, 8.4% of babies born to mothers with low baseline CD4 cell counts (CD4 cells are immune system cells that are killed by HIV; CD4 cell counts indicate the level of HIV-inflicted immune system damage) were HIV positive compared to 4.1% of babies born to mothers with high baseline CD4 cell counts, although this difference did not achieve statistical significance.
What Do These Findings Mean?
Although these findings are limited by the single-arm design, they support the idea that giving breastfeeding women a triple-ARV regimen from late pregnancy to 6 months is a safe, feasible way to reduce MTCT in resource-limited settings. The HIV transmission rates in this study are comparable to those recorded in similar trials in other resource-limited settings and are lower than MTCT rates observed previously in Kisumu in a study in which no ARVs were used. Importantly, the KiBS mothers took most of the ARVs they were prescribed and most stopped breastfeeding by 6 months as advised. The intense follow-up employed in KiBS may be partly responsible for this good adherence to the trial protocol and thus this study's findings may not be generalizable to all resource-limited settings. Nevertheless, they suggest that a simple triple-ARV regimen given to HIV-positive pregnant women regardless of their baseline CD4 cell count can reduce MTCT during pregnancy and breastfeeding in resource-limited setting.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001015.
The accompanying PLoS Medicine Research article by Zeh and colleagues describes the emergence of resistance to ARVs in KiBS
Information on HIV and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/en/index.html (in several languages)
doi:10.1371/journal.pmed.1001015
PMCID: PMC3066129  PMID: 21468300
4.  Efficacy of Short-Course AZT Plus 3TC to Reduce Nevirapine Resistance in the Prevention of Mother-to-Child HIV Transmission: A Randomized Clinical Trial 
PLoS Medicine  2009;6(10):e1000172.
Neil Martinson and colleagues report a randomized trial of adding short-course zidovudine+lamivudine to reduce drug resistance from single-dose nevirapine used to prevent mother-to-child transmission of HIV.
Background
Single-dose nevirapine (sdNVP)—which prevents mother-to-child transmission of HIV—selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care.
Methods and Findings
sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1∶1∶1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit.
Conclusions
A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms.
Trial registration
www.ClinicalTrials.gov NCT 00144183
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV can be treated with combination antiretroviral therapy (ART), commonly three individual antiretroviral drugs that together efficiently suppress the replication of the virus. HIV infection of a child by an HIV-positive mother during pregnancy, labor, delivery, or breastfeeding is called mother-to-child transmission (MTCT). In 2007, an estimated 420,000 children were newly infected with HIV, the majority through MTCT. Most of these mothers and children live in sub-Saharan Africa where child and maternal mortality rates are high and mortality in HIV-infected children is extremely high. MTCT is preventable and there is a global commitment, agreed at the UN General Assembly Session on HIV/AIDS in 2001, to reduce the proportion of infants infected with HIV by 50% by 2010.
Why Was This Study Done?
In many resource-limited settings, MTCT is prevented by giving a single dose of nevirapine (an antiretroviral drug which has a long duration in the body and protects the fetus during labor and delivery only) to HIV-infected women in labor and also to a baby within 72 hours of birth. However, nevirapine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), which suppresses the replication of the virus, is associated with increased resistance of HIV, in mother and child, to NNRTI. This resistance reduces the effectiveness of future treatments of both mother and child with combination ART that includes an NNRTI; such regimens are the mainstay for long-term treatment of HIV in developing countries. The researchers investigated whether giving other antiretroviral drugs with nevirapine, during labor and delivery, to both mother and her newborn reduced the chances of them developing resistance to NNRTIs.
What Did the Researchers Do and Find?
The researchers selected 406 HIV-positive pregnant women for study across five sites in South Africa between February 2003 and May 2007. The women and their newborn babies were randomly assigned to receive, either (i) a single dose of nevirapine, (ii) a single dose of nevirapine plus combivir (zidovudine combined with lamivudine) for four days, or (iii) a single dose of nevirapine plus combivir for seven days. At two days, two weeks, and six weeks after delivery blood was collected from mothers and babies. HIV virus from blood samples was analyzed for resistance mutations, and mothers and children with resistance mutations were monitored for a further 96 weeks until no resistance was detected or combination ART (also called “HAART”) was started. Enrollment into the single-dose nevirapine arm was stopped early because a very high rate of NNRTI resistance mutations was found and other investigators reported long-term bad consequences of NNRTI-resistance on subsequent ART. The two nevirapine plus combivir arms were continued. The researchers found that selection of resistance mutations by single-dose nevirapine was reduced in mother and child by the addition of zidovudine and lamivudine for a short period; resistance mutations were found in 59.2% of women who got nevirapine only but only 11.7%, and 7.3% of women treated nevirapine plus four days combivir, and nevirapine plus seven days combivir respectively. A reduction was also seen in new NNRTI resistant mutations in the HIV-infected infants that received combivir. The study did not have enough women to show that there was a real difference between the resistance in the four-day and seven-day combivir regimens.
What Do These Findings Mean?
These findings show that a short-course treatment of zidovudine and lamivudine in addition to a single dose of nevirapine during labor and birth reduces the selection of NNRTI resistance mutations in both mother and child. The drug regimens appeared safe, and easy to provide and adhere to. Preliminary results from this study contributed to a change in clinical practice for the care of pregnant women with HIV; in 2004 the World Health Organisation guidelines introduced a short course of combivir with nevirapine for the management of pregnant HIV-infected women. However, the study had some limitations. It used HIV-positive women who were mainly infected with a subtype of HIV called HIV-1 clade C and who had a lot of virus in their blood. NNRTI resistance after treatment with nevirapine is more common in clade C than in others and this study does not address the effect of these combinations for preventing NNRTI resistance in other HIV subtypes. Also, World Health Organization, national, and international guidelines recommend combination ART during pregnancy, as it decreases HIV transmission from mother to child in the uterus to <2% in resource-limited settings. Although long-term combination treatment may not be available in all locations, this study does not tell us how the short-term combinations during and after delivery tested would compare to longer-term combinations given to pregnant women in reducing both HIV transmission and HIV drug resistance.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000172.
This study is further discussed in a PLoS Medicine Perspective by Lehman et al.
The US Centers for Disease Control and Prevention provide information for HIV treatment and prevention
MedlinePlus provides extensive information on symptoms and treatment for HIV/AIDS as well as access to related clinical trials and medical literature
aidsmap, a nonprofit, nongovernmental organization provides information on HIV and supporting those living with HIV
The World Health Organization gives information on the prevention of mother-to-child transmission of HIV
doi:10.1371/journal.pmed.1000172
PMCID: PMC2760761  PMID: 19859531
5.  Measuring Coverage in MNCH: Population HIV-Free Survival among Children under Two Years of Age in Four African Countries 
PLoS Medicine  2013;10(5):e1001424.
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 D'Ivoire, 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 D'Ivoire (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 D'Ivoire (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 (Pearson's r = 0.85), and moderately correlated with 24-mo HIV-free survival (Pearson's r = 0.29). 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
Editors' Summary
Background
For a pregnant woman who is HIV-positive, the discrepancy across the world in outlook for mother and child is stark. Mother-to-child transmission of HIV during pregnancy is now less than 1% in many high-income settings, but occurs much more often in low-income countries. Three interventions have a major impact on transmission of HIV to the baby: antiretroviral drugs, mode of delivery, and type of infant feeding. The latter two are complex, as the interventions commonly used in high-income countries (cesarean section if the maternal viral load is high; exclusive formula feeding) have their own risks in low-income settings. Minimizing the risks of transmitting HIV through effective drug regimes therefore becomes particularly important. Monitoring progress on reducing the incidence of mother-to-child HIV transmission is essential, but not always easy to achieve.
Why Was This Study Done?
A research group led by Stringer and colleagues recently reported a study from four countries in Africa: Cameroon, Côte D'Ivoire, South Africa, and Zambia. The study showed that even in the health facility setting (e.g., hospitals and clinics), only half of infants whose mothers were HIV-positive received the minimum recommended drug treatment (one dose of nevirapine during labor) to prevent HIV transmission. Across the population of these countries, it is possible that fewer receive antiretroviral drugs, as the study did not include women who did not access health facilities. Therefore, the next stage of the study by this research group, reported here, involved going into the communities around these health facilities to find out how many infants under two years old had been exposed to HIV, whether they had received drugs to prevent transmission, and what proportion were alive and not infected with HIV at two years old.
What Did the Researchers Do and Find?
The researchers tested all consenting women who had delivered a baby in the last two years in the surrounding communities. If the mother was found to be HIV-positive, then the infant was also tested for HIV. The researchers then calculated how many of the infants would be alive at two years and free of HIV infection.
Most mothers (78%) agreed to testing for themselves and their infants. There were 7,985 children under two years of age in this study, of whom 13% had been born to an HIV-positive mother. Less than half (46%) of the HIV-positive mothers had received any drugs to prevent HIV transmission. Of the children with HIV-positive mothers, 11% were HIV-infected, 84% were not infected with HIV, and 5% had died. Overall, the researchers estimated that around 80% of these children would be alive at two years without HIV infection. This proportion differed non-significantly between the four countries (ranging from 73% to 84%). The researchers found higher rates of infant survival than they had expected and knew that they might have missed some infant deaths (e.g., if households with infant deaths were less likely to take part in the study).
The researchers found that their estimates of the proportion of HIV-positive mothers who received drugs to prevent transmission were fairly similar between their previous study, looking at health facilities, and this study of the surrounding communities. However, in 14 out of 16 comparisons, the estimate from the community was lower than that from the facility.
What Do These Findings Mean?
This study shows that it would be possible to estimate how many infants are surviving free of HIV infection using a study based in the community, and that these estimates may be more accurate than those for studies based in health facilities. There are still a large proportion of HIV-positive mothers who are not receiving drugs to prevent transmission to the baby. The authors suggest that using two or three drugs to prevent HIV may help to reduce transmission.
There are already community surveys conducted in many low-income countries, but they have not included routine infant testing for HIV. It is now essential that organizations providing drugs, money, and infrastructure in this field consider more accurate means of monitoring incidence of HIV transmission from mother to infant, particularly at the community level.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001424.
The World Health Organization has more information on mother-to-child transmission of HIV
The United Nations Children's Fund has more information on the status of national PMTCT responses in the most affected countries
doi:10.1371/journal.pmed.1001424
PMCID: PMC3646218  PMID: 23667341
6.  What Will It Take to Eliminate Pediatric HIV? Reaching WHO Target Rates of Mother-to-Child HIV Transmission in Zimbabwe: A Model-Based Analysis 
PLoS Medicine  2012;9(1):e1001156.
Using a simulation model, Andrea Ciaranello and colleagues find that the latest WHO PMTCT (prevention of mother to child transmission of HIV) guidelines plus better access to PMTCT programs, better retention of women in care, and better adherence to drugs are needed to eliminate pediatric HIV in Zimbabwe.
Background
The World Health Organization (WHO) has called for the “virtual elimination” of pediatric HIV: a mother-to-child HIV transmission (MTCT) risk of less than 5%. We investigated uptake of prevention of MTCT (PMTCT) services, infant feeding recommendations, and specific drug regimens necessary to achieve this goal in Zimbabwe.
Methods and Findings
We used a computer model to simulate a cohort of HIV-infected, pregnant/breastfeeding women (mean age, 24 y; mean CD4, 451/µl; breastfeeding duration, 12 mo). Three PMTCT regimens were evaluated: (1) single-dose nevirapine (sdNVP), (2) WHO 2010 guidelines' “Option A” (zidovudine in pregnancy, infant nevirapine throughout breastfeeding for women without advanced disease, lifelong combination antiretroviral therapy for women with advanced disease), and (3) WHO “Option B” (pregnancy/breastfeeding-limited combination antiretroviral drug regimens without advanced disease; lifelong antiretroviral therapy with advanced disease). We examined four levels of PMTCT uptake (proportion of pregnant women accessing and adhering to PMTCT services): reported rates in 2008 and 2009 (36% and 56%, respectively) and target goals in 2008 and 2009 (80% and 95%, respectively). The primary model outcome was MTCT risk at weaning.
The 2008 sdNVP-based National PMTCT Program led to a projected 12-mo MTCT risk of 20.3%. Improved uptake in 2009 reduced projected risk to 18.0%. If sdNVP were replaced by more effective regimens, with 2009 (56%) uptake, estimated MTCT risk would be 14.4% (Option A) or 13.4% (Option B). Even with 95% uptake of Option A or B, projected transmission risks (6.1%–7.7%) would exceed the WHO goal of less than 5%. Only if the lowest published transmission risks were used for each drug regimen, or breastfeeding duration were shortened, would MTCT risks at 95% uptake fall below 5%.
Conclusions
Implementation of the WHO PMTCT guidelines must be accompanied by efforts to improve access to PMTCT services, retain women in care, and support medication adherence throughout pregnancy and breastfeeding, to approach the “virtual elimination” of pediatric HIV in Zimbabwe.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A woman who is infected with HIV can pass the virus to her baby during pregnancy, labor and delivery, or breastfeeding—mother-to-child HIV transmission (MTCT). Without treatment, up to 30% of babies born to HIV-infected women will become infected with HIV during pregnancy or at delivery, and a further 5%–20% will become infected through breastfeeding. In 2009, around 400,000 children under 15 years of age became infected with HIV, mainly through MTCT—90% of these MTCT infections occurred in Africa.
In addition to preventing HIV infection among prospective parents and avoiding unwanted pregnancies among HIV-positive women, effective prevention of MTCT (PMTCT) requires preventing the transmission of HIV from infected mothers to their infants during pregnancy, labor, delivery, and breastfeeding.
In 2010, the World Health Organization (WHO) published new guidelines for PMTCT based on combination antiretroviral therapy for women with advanced HIV disease, and two options for countries to select for women with less advanced disease. Option A includes zidovudine (ZDV) during pregnancy and single-dose nevirapine (sdNVP) at delivery, followed by daily nevirapine syrup for infants throughout the duration of breastfeeding; Option B includes maternal triple-drug ARV regimens throughout pregnancy and breastfeeding. However, WHO estimates that only 53% of pregnant women worldwide received any antiretroviral medicines for PMTCT in 2009.
Why Was This Study Done?
As in many sub-Saharan African countries where prolonged breastfeeding is common, and necessary to improve child health, Zimbabwe is implementing the 2010 WHO guidelines with Option A. However, because of the challenges of enrolling and retaining women in PMTCT programs, the effectiveness of this strategy is unknown. Therefore in this study, the researchers used a model to calculate the level of PMTCT uptake in Zimbabwe, the PMTCT drug regimens, and the duration of breastfeeding that would be necessary to reach the WHO goal of an MTCT risk below 5%.
What Did the Researchers Do and Find?
The researchers used a validated computer simulation model developed for analyzing the cost-effectiveness of preventing AIDS complications to measure risk of infant HIV transmission at the time of weaning, the HIV infection risk at 4–6 weeks of age, infant survival at two years of age, and 2-year HIV-free survival. The researchers used four scenarios of PMTCT uptake and linked the models to two populations of pregnant and breastfeeding women (mean age, 24 years) in Zimbabwe, and then analyzed the combinations of the factors necessary to reach MTCT risks less than 5%.
At baseline, the researchers found that the 2008 National PMTCT Program in Zimbabwe led to a projected 12-month MTCT risk of 20.3%. The projected risk in 2009 was 18.0% because of improved uptake. The estimated MTCT risk with Option A at 56% uptake (2009 levels) was 14.4% and with Option B was 13.4%. However, even with greatly increased uptake, such as 95% levels, the researchers found that projected transmission risks would exceed the WHO goal of less than 5% MTCT, and that the MTCT risk would fall below 5% at the 95% uptake level only if the lowest transmission risks were used for each drug regimen, or if breastfeeding duration were shortened.
What Do These Findings Mean?
These findings show that the planned implementation of the 2010 WHO PMTCT guidelines with Option A in Zimbabwe could substantially reduce infant HIV infection risk compared to the 2009 national program with sdNVP. Furthermore, in order to reach a MTCT risk of less than 5%, a national program based on either Option A or Option B will also need to include strategies to improve access to PMTCT services (to almost 100% uptake), retain women in care, and support medication adherence throughout pregnancy and breastfeeding. These findings from a resource-limited country with high HIV prevalence and prolonged breastfeeding may be useful for other countries in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001156.
Avert gives some more information on MTCT and PMTCT.
The United Nations Children's Fund has factsheets on national PMTCT responses in the most affected countries.
WHO's strategic vision for PMTCT for 2010–2015 is also available.
doi:10.1371/journal.pmed.1001156
PMCID: PMC3254654  PMID: 22253579
7.  HIV: prevention of mother-to-child transmission  
Clinical Evidence  2011;2011:0909.
Introduction
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
Results
We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breastfeeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15% to 30% during pregnancy and labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads, advanced HIV disease, or both.Without antiretroviral treatment (ART), 15% to 35% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the complications associated with life-long treatment, including adverse effects of antiretroviral drugs, difficulties of adherence across the developmental trajectory of childhood and adolescence, and the development of resistance.From a paediatric perspective, successful prevention of MTCT and HIV-free survival for infants remain the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, to the baby immediately after birth, or to the mother and baby reduce the risk of intrauterine and intrapartum MTCT of HIV-1 and when given to the infant after birth and to the mother or infant during breastfeeding reduce the risk of postpartum MTCT of HIV-1.
Reductions in MTCT are possible using multidrug ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1% to 2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. There is evidence that short courses of antiretroviral drugs have confirmed efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.The development of viral resistance in mothers and infants after single-dose nevirapine and other short-course regimens that include single-dose nevirapine is of concern. An additional short-course of antiretrovirals with a different regimen during labour and early postpartum, and the use of HAART, may decrease the risk of viral resistance in mothers, and in infants who become HIV-infected despite prophylaxis.World Health Organization guidelines recommend starting prophylaxis with antiretroviral drugs from as early as 14 weeks' gestation, or as soon as possible if women present late in pregnancy, in labour, or at delivery.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin seems no more effective than immunoglobulin without HIV antibody at reducing HIV-1 MTCT risk.
Vaginal microbicides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that supplementation with vitamin A reduces the risk of HIV-1 MTCT, and there is concern that postnatal vitamin A supplementation for mother and infant may be associated with increased risk of mortality.
We don't know whether micronutrients are effective in prevention of MTCT of HIV as we found no RCT evidence on this outcome.
Avoidance of breastfeeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breastfeeding-related HIV transmission needs to be balanced against the multiple benefits that breastfeeding offers. In resource-poor countries, breastfeeding is strongly associated with reduced infant morbidity and improved child survival. Exclusive breastfeeding during the first 6 months may reduce the risk of HIV transmission compared with mixed feeding, while retaining most of its associated benefits.In a population where prolonged breastfeeding is usual, early, abrupt weaning may not reduce MTCT or HIV-free survival at 2 years compared with prolonged breastfeeding, and may be associated with a higher rate of infant mortality for those infants diagnosed as HIV-infected at <4 months of age. Antiretrovirals given to the mother or the infant during breastfeeding can reduce the risk of HIV transmission in the postpartum period. World Health Organization guidelines recommend that HIV-positive mothers should exclusively breastfeed for the first 6 months, after which time appropriate complementary foods can be introduced. Breastfeeding should be continued for the first 12 months of the infant's life, and stopped only when an adequate diet without breast milk can be provided. Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
PMCID: PMC3217724  PMID: 21477392
8.  Pooled Individual Data Analysis of 5 Randomized Trials of Infant Nevirapine Prophylaxis to Prevent Breast-Milk HIV-1 Transmission 
A pooled analysis of individual data from >5000 human immunodeficiency virus type 1 (HIV-1)–infected mothers and their infants from Africa and India who participated in 5 randomized trials shows that extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection.
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.
doi:10.1093/cid/cis808
PMCID: PMC3518881  PMID: 22997212
breast milk; HIV; nevirapine
9.  Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study 
PLoS Medicine  2010;7(2):e1000233.
In a comparative cohort study, Jeffrey Stringer and colleagues investigate the risk of ART failure in women who received single-dose nevirapine for PMTCT, and assess the duration of increased risk.
Background
Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure.
Methods and Findings
We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load ≥400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%–13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7–12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval.
Conclusions
Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, acquired immunodeficiency syndrome (AIDS) kills nearly 300,000 children. At the end of 2008, 2.1 million children were positive for the human immunodeficiency virus (HIV), the cause of AIDS, and in that year alone more than 400,000 children were newly infected with HIV. Most HIV-positive children acquire the virus from their mothers during pregnancy or birth or through breastfeeding, so-called mother-to-child transmission (MTCT). Without intervention, 15%–30% of babies born to HIV-positive women become infected with HIV during pregnancy and delivery, and a further 5%–20% become infected through breastfeeding. These rates of infection can be greatly reduced by treating the mother and her newborn baby with antiretroviral drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to the baby soon after birth reduces the risk of MTCT by nearly a half; a further reduction in risk can be achieved by giving the mother and her baby additional antiretroviral drugs during pregnancy, around the time of birth, and while breast-feeding.
Why Was This Study Done?
Single-dose nevirapine is the mainstay of MTCT prevention programs in many poor countries but can induce resistance to nevirapine and to other NNRTIs. The drugs used to treat HIV infections fall into several different classes defined by how they stop viral growth. HIV can become resistant to any of these drugs and a virus strain that is resistant to one member of a drug class is often also resistant to other members of the same class. Because most first-line antiretroviral therapies (ARTs; cocktails of antiretroviral drugs) used in developing countries contain an NNRTI and because HIV-positive mothers eventually need ART to safeguard their own health, the resistance to NNRTIs that is induced in women by single-dose nevirapine might decrease the chances that ART will work for them later. In this multi-country, prospective cohort study, the researchers compare the effectiveness of NNRTI-containing ART in a group (cohort) of women previously exposed to single-dose nevirapine during childbirth to its effectiveness in a group of unexposed women. They also investigate whether the length of time between nevirapine exposure and ART initiation affects ART effectiveness.
What Did the Researchers Do and Find?
The researchers enrolled 355 HIV-positive nevirapine-exposed women and 523 HIV-positive nevirapine-unexposed women in Zambia, Kenya, and Thailand who were just starting NNRTI-containing ART and followed them for 48 weeks. They defined ART failure as death, discontinuation of NNRTI-containing ART, or a high virus load in the blood (virologic failure) at 24 or 48 weeks. ART failed in nearly a third of the nevirapine-exposed women but in only a quarter of the nevirapine-unexposed women. Women who began ART within 6 months of taking single-dose nevirapine to prevent MTCT were twice as likely to experience ART failure as women not exposed to single-dose nevirapine. Women who began ART 7–12 months after single-dose nevirapine had a slightly increased risk of ART failure compared to unexposed women but this increased risk was not statistically significant; that is, it could have occurred by chance. Women who began ART more than 12 months after single-dose nevirapine did not have an increased risk of ART failure compared to unexposed women. Finally, the researchers used a statistical method called locally weighted regression analysis to confirm that an increase in the interval between single-dose nevirapine and ART initiation decreased the risk of virologic failure.
What Do These Findings Mean?
These findings, which confirm and extend the results of previous studies and which are likely to be generalizable to other resource-poor countries, indicate that single-dose nevirapine given to women to prevent MTCT increases their risk of subsequent ART failure. More positively, they also show that this increased failure risk is largely confined to women who begin ART within a year of exposure to nevirapine. Because of the study design, it is possible that the nevirapine-exposed women share some additional, undefined characteristic that makes them more likely to fail ART than unexposed women. Even so, these findings suggest that, provided NNRTI-containing ART is not given to HIV-positive women within a year of nevirapine exposure, single-dose nevirapine can be safely used to prevent MTCT without compromising the mother's future antiretroviral treatment options.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000233.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS, on treatments for HIV/AIDS, and on HIV infection in infants and children
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health Organization has information on mother-to-child transmission of HIV
doi:10.1371/journal.pmed.1000233
PMCID: PMC2821896  PMID: 20169113
10.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
11.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
12.  Three Postpartum Antiretroviral Regimens to Prevent Intrapartum HIV Infection 
The New England journal of medicine  2012;366(25):2368-2379.
Background
The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants.
Methods
Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth.
Results
A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan–Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intra-partum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P = 0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P = 0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P = 0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups).
Conclusions
In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.)
doi:10.1056/NEJMoa1108275
PMCID: PMC3590113  PMID: 22716975
13.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
14.  Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial 
Lancet  2011;379(9812):221-228.
Summary
Background
Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months.
Methods
In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primaryefficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412.
Findings
Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1.1% (95% CI 0.3–1.8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2.4% (1.3–3.6) of controls (difference 1.3%, 95% CI 0–2.6), equating to a 54% reduction in transmission (p=0.049). However, mortality (1.2% for nevirapine vs 1.1% for placebo; p=0.81) and combined HIV infection and mortality rates (2.3% vs 3.2%; p=0.27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.
Interpretation
Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age.
Funding
US National Institutes of Health.
doi:10.1016/S0140-6736(11)61653-X
PMCID: PMC3539769  PMID: 22196945
15.  Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174 
BMC Infectious Diseases  2012;12:246.
Background
Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age.
Methods
The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms.
HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants.
The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and growth) until 50 weeks and HIV-1-free survival until 50 weeks.
Discussion
This study will provide a new evidence-based intervention to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies.
Trial registration number ( http://www.clinicaltrials.gov)
NCT00640263
doi:10.1186/1471-2334-12-246
PMCID: PMC3482558  PMID: 23039034
16.  18-Month Effectiveness of Short-Course Antiretroviral Regimens Combined with Alternatives to Breastfeeding to Prevent HIV Mother-to-Child Transmission 
PLoS ONE  2008;3(2):e1645.
Objective
We assessed the 18-month effectiveness of short-course (sc) antiretroviral peripartum regimens combined with alternatives to prolonged breastfeeding to prevent mother-to-child transmission (MTCT) of HIV-1 in Abidjan, Côte d'Ivoire.
Methodology
HIV-1 infected pregnant women received from ≥32–36 weeks of gestation scZidovudine (ZDV)+/−Lamivudine (3TC)+single-dose Nevirapine (sdNVP) at delivery within the ANRS 1201/1202 DITRAME-Plus cohort (2001–2003). Neonates received a sdNVP+7-day ZDV prophylaxis. Two infant-feeding interventions were systematically offered free of charge: formula-feeding or exclusive shortened breastfeeding with early cessation from four months. The reference group was the ANRS 049a DITRAME cohort (1994–2000) exposed to scZDV from 36 weeks, then to prolonged breastfeeding. Pediatric HIV infection was defined by a positive plasma HIV-1 RNA at any age, or if aged ≥18 months, a positive HIV-1 serology. Turnbull estimates of cumulative transmission risks (CTR) and effectiveness (HIV-free survival) were compared by exposure group using a Cox model.
Findings
Among 926 live-born children enrolled, 107 (11.6%) were HIV-infected at 18 months. CTRs were 22.3% (95% confidence interval[CI]:16–30%) in the 238 ZDV long-term breastfed reference group, 15.9% (CI:10–27%) in the 169 ZDV+sdNVP shortened breastfed group; 9.4% (CI:6–14%) in the 195 ZDV+sdNVP formula-fed group; 6.8% (CI:4–11%) in the 198 ZDV+3TC+sdNVP shortened breastfed group, and 5.6% (CI:2–10%) in the 126 ZDV+3TC+sdNVP formula-fed group. Each combination had a significantly higher effectiveness than the ZDV long-term breastfed group except for ZDV+sdNVP shortened breastfed children, ranging from 51% (CI:20–70%) for ZDV+sdNVP formula fed children to 63% (CI:40–80%) for ZDV+3TC+NVPsd shortened breastfed children, after adjustment for maternal eligibility for antiretroviral therapy (ART), home delivery and low birth-weight. Substantial MTCT risk reductions are reachable in Africa, even in short-term breastfed children. The two sc antiretroviral combinations associated to any of the two infant feeding interventions, formula-feeding and shortened breastfeeding, reduce significantly MTCT with long-term benefit until age 18 months and without increasing mortality.
doi:10.1371/journal.pone.0001645
PMCID: PMC2237904  PMID: 18286200
17.  Cumulative Exposure to Cell-Free HIV in Breast Milk, Rather Than Feeding Pattern per se, Identifies Postnatally Infected Infants 
In a nested case-control study, postnatal HIV infection was strongly associated with cumulative HIV RNA breastmilk exposure, even after allowing for maternal CD4 and plasma viral load; cases ingested approximately 15 times more HIV-1 RNA particles than controls.
Background. We quantified the relationship between human immunodeficiency virus (HIV) RNA shedding in breast milk, cumulative RNA exposure, and postnatal transmission, relating timing of infection in the infant to estimated total volume of milk exposure.
Methods. Nested case-control study of 36 infants of HIV-infected mothers. Case patients were infants who acquired HIV infection through breastfeeding from age 6 through 28 weeks, and control subjects were uninfected infants matched on age at obtainment of a breast milk sample. Mothers and infants received peripartum single-dose nevirapine prophylaxis. Feeding data were collected daily; breast milk samples were collected and infant anthropometry was performed at 6 weeks and monthly thereafter. Volume of milk ingested was estimated using infant weight and feeding pattern.
Results. Before HIV acquisition in case patients, feeding pattern (exclusive breastfeeding; median duration, 65 vs 70 days; P = .6) and daily milk intake (mean volume, 638 vs 637 mL; P = .97) did not differ significantly between case patients and control subjects. Case mothers were more likely to shed virus (64% vs 9% always, 22% vs 20.5% intermittently, 14% vs 70.5% never shed; overall, P < .001). Case patients ingested ∼15 times more HIV-1 RNA particles than did control subjects (196.5 vs 13 × 106 copies; P < .001). Allowing for maternal antenatal CD4 cell count and plasma HIV-1 load, child sex and duration of mixed breastfeeding, the association between HIV RNA exposure and infection remained statistically significant (P < .001).
Conclusions. Postnatal acquisition of HIV-1 is more strongly associated with cumulative exposure to cell-free particles in breast milk than with feeding mode. Reducing breast milk viral load through antiretroviral therapy to mother or child can further decrease postnatal transmission in exclusively breastfed infants.
doi:10.1093/cid/ciq203
PMCID: PMC3049337  PMID: 21367736
18.  Two-Year Morbidity–Mortality and Alternatives to Prolonged Breast-Feeding among Children Born to HIV-Infected Mothers in Côte d'Ivoire 
PLoS Medicine  2007;4(1):e17.
Background
Little is known about the long-term safety of infant feeding interventions aimed at reducing breast milk HIV transmission in Africa.
Methods and Findings
In 2001–2005, HIV-infected pregnant women having received in Abidjan, Côte d'Ivoire, a peripartum antiretroviral prophylaxis were presented antenatally with infant feeding interventions: either artificial feeding, or exclusive breast-feeding and then early cessation from 4 mo of age. Nutritional counseling and clinical management were provided for 2 y. Breast-milk substitutes were provided for free. The primary outcome was the occurrence of adverse health outcomes in children, defined as validated morbid events (diarrhea, acute respiratory infections, or malnutrition) or severe events (hospitalization or death). Hazards ratios to compare formula-fed versus short-term breast-fed (reference) children were adjusted for confounders (baseline covariates and pediatric HIV status as a time-dependant covariate). The 18-mo mortality rates were also compared to those observed in the Ditrame historical trial, which was conducted at the same sites in 1995–1998, and in which long-term breast-feeding was practiced in the absence of any specific infant feeding intervention. Of the 557 live-born children, 262 (47%) were breast-fed for a median of 4 mo, whereas 295 were formula-fed. Over the 2-y follow-up period, 37% of the formula-fed and 34% of the short-term breast-fed children remained free from any adverse health outcome (adjusted hazard ratio [HR]: 1.10; 95% confidence interval [CI], 0.87–1.38; p = 0.43). The 2-y probability of presenting with a severe event was the same among formula-fed (14%) and short-term breast-fed children (15%) (adjusted HR, 1.19; 95% CI, 0.75–1.91; p = 0.44). An overall 18-mo probability of survival of 96% was observed among both HIV-uninfected short-term and formula-fed children, which was similar to the 95% probability observed in the long-term breast-fed ones of the Ditrame trial.
Conclusions
The 2-y rates of adverse health outcomes were similar among short-term breast-fed and formula-fed children. Mortality rates did not differ significantly between these two groups and, after adjustment for pediatric HIV status, were similar to those observed among long-term breast-fed children. Given appropriate nutritional counseling and care, access to clean water, and a supply of breast-milk substitutes, these alternatives to prolonged breast-feeding can be safe interventions to prevent mother-to-child transmission of HIV in urban African settings.
Given appropriate nutritional counseling and care, access to clean water, and supply of breast milk substitutes, replacing prolonged breast-feeding with formula-feeding appears to be a safe intervention to prevent mother-to-child transmission of HIV in this setting.
Editors' Summary
Background.
The HIV virus can be transmitted from infected mothers to their babies during pregnancy and birth as well as after birth through breast milk. Mother-to-child transmission in developed countries has been all but eliminated by treatment of mothers with the best available combination of antiretroviral drugs and by asking them to avoid breast-feeding. However, in many developing countries, the best drug treatments are not available to mothers. Moreover, breast-feeding is generally the best nutritional choice for infants, especially in areas where resources such as clean water, formula feed, and provision of healthcare are scarce. And even if formula feed is available, formula-fed babies might be at higher risk of dying from diarrhea and chest infections, which are more common in infants who are not breast-fed. International guidelines say that HIV-positive mothers should avoid all breast-feeding and adopt formula feeding instead if this option is practical and safe for them, which would require that they can afford formula feed and have easy access to clean water. If formula-feeding is not feasible, guidelines recommend that mothers should breast-feed only for the first few months and then stop and switch the baby to solid food. One of these two alternative options should be feasible in most African cities if mothers are given the right support.
Why Was This Study Done?
Several completed and ongoing studies are assessing the relative risks and benefits of the two recommended strategies for different developing country locations, and this is one of them. The study, the “Ditrame Plus” trial by researchers from France and Côte d'Ivoire, was conducted in Abidjan, an urban West African setting. The goal was to compare death rates and rates of certain diseases (such as diarrhea and chest infections) between babies born to HIV-positive mothers that were formula-fed and those that were breast-fed for a short time after birth.
What Did the Researchers Do and Find?
HIV-positive pregnant women were invited to enter the study, and they received short-term drug treatments intended to reduce the risk of HIV transmission to their babies. Women in the trial were then asked to choose one of the two feeding options and offered support and counseling for either one. This support included free formula, transport, and healthcare provision. Babies were followed up to their second birthday, and data were collected on death rates and any serious illnesses. A total of 643 women were enrolled into the study, and safety data were collected for 557 babies, of whom 295 were in the formula group and 262 were in the short-term breast-feeding group. The researchers corrected for HIV infection in the babies and found no evidence that the risk of other negative health outcomes and death rates was any different between the formula-fed babies and short-term breast-fed babies. Looking specifically at individual diseases, the researchers found that the risks for diarrhea and chest infections were slightly higher among formula-fed babies, but this did not translate into a greater risk of death or worse overall health. They also compared the death rates in this study with some historical data from a previous research project done in the same area on children born to HIV-positive mothers who had practiced long-term breast-feeding. The mother-to-child transmission rate of HIV had been much higher in that earlier trial, but looking only at the HIV-negative children, the researchers found no difference in risk for death or serious disease between the formula-fed or short-term breast-fed babies from the Ditrame Plus trial and the long-term breast-fed babies from the earlier trial.
What Do These Findings Mean?
This study shows that if HIV-positive mothers are well supported, either of the two feeding options currently recommended (formula-only feed, or short-term breast-feeding) are likely to be equivalent in terms of the baby's chances for survival and health. However, women in this study were offered a great deal of support and the findings may not necessarily apply to real-life situations in other settings in Africa, or outside the context of a research project. In addition to routine care after birth, access to better drugs to prevent mother-to-child transmission in developing countries remains an important goal.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040017.
Resources from Avert (an AIDS charity) on HIV and infant feeding.
Information from the US Centers for Disease Control on mother-to-child transmission of HIV
Guidelines from the World Health Organization on mother-to-child transmission of HIV
AIDSMap pages on breast-feeding and HIV
HIV Care and PMTCT in Resource-Limited Setting contains monthly bulletins and a database devoted to HIV/AIDS infections and prevention of the mother-to-child transmission of HIV
The Ghent group is a network of researchers and policymakers in the area of prevention of mother-to-child transmission of HIV
doi:10.1371/journal.pmed.0040017
PMCID: PMC1769413  PMID: 17227132
19.  Initiation of Antiretroviral Treatment in Women After Delivery Can Induce Multiclass Drug Resistance in Breastfeeding HIV-Infected Infants 
HIV-infected breastfeeding infants acquired multi-class drug resistance (MCR) after their mothers started highly active antiretroviral therapy (HAART). MCR was more frequent in infants whose mothers started HAART by 6 months post-partum or were exclusively breastfeeding when they reported HAART use.
Background. 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.
Methods. 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.
Results. 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).
Conclusions. 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.
doi:10.1093/cid/cir008
PMCID: PMC3070029  PMID: 21460326
20.  Nevirapine Resistance by Timing of HIV Type 1 Infection in Infants Treated with Single-Dose Nevirapine 
Background
In women, single-dose nevirapine for prophylaxis against mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) selects for nevirapine-resistant HIV-1, which subsequently decays rapidly. We hypothesized that the selection, acquisition, and decay of nevirapine-resistant HIV-1 differs in infants, varying by the timing of HIV-1 infection.
Methods
We conducted a prospective, observational study of 740 Mozambican infants receiving single-dose nevirapine prophylaxis and determined the timing of infection and concentrations of nevirapine-resistant HIV-1 over time.
Results
Infants with established in utero infection had a high rate (87.0%) of selection of nevirapine-resistant HIV-1 mutants, which rapidly decayed to undetectable levels. The few without nevirapine resistance received zidovudine with single-dose nevirapine and/or their mothers took alternative antiretroviral drugs. Infants with acute in utero infection had a lower rate of nevirapine-resistant HIV-1 (33.3%; P =.006, compared with established in utero infection), but mutants persisted over time. Infants with peripartum infection also had a lower rate of nevirapine-resistant HIV-1 (38.1%; P =.001, compared with established in utero infection) but often acquired 100% mutant virus that persisted over time (P =.017, compared with established in utero infection).
Conclusions
The detection and persistence of nevirapine-resistant HIV-1 in infants after single-dose nevirapine therapy vary by the timing of infection and the antiretroviral regimen. In infants with persistent high-level nevirapine-resistant HIV-1, nevirapine-based antiretroviral therapy is unlikely to ever be efficacious because of concentrations in long-lived viral reservoirs. However, the absence or decay of nevirapine-resistant HIV-1 in many infants suggests that nevirapine antiretroviral therapy may be effective if testing can identify these individuals.
doi:10.1086/652151
PMCID: PMC3038662  PMID: 20384494
21.  Maternal Tuberculosis: A Risk Factor for Mother-to-Child Transmission of Human Immunodeficiency Virus 
The Journal of Infectious Diseases  2011;203(3):358-362.
Background. Maternal human immunodeficiency virus (HIV) RNA load, CD4 cell count, breast-feeding, antiretroviral use, and malaria are well-established factors associated with mother-to-child transmission (MTCT) of HIV; the role of maternal tuberculosis (TB), however, has not been well established.
Methods. The study population was 783 HIV-infected Indian mother-infant pair participants in randomized and ancillary HIV-infected cohorts of the Six Week Extended-Dose Nevirapine (SWEN) Study, a study comparing extended nevirapine versus single-dose nevirapine, to reduce MTCT of HIV among breast-fed infants. Using multivariable logistic regression, we assessed the impact of maternal TB occurring during pregnancy and through 12 months after delivery on risk of MTCT.
Results. Of 783 mothers, 3 had prevalent TB and 30 had incident TB at 12 months after delivery. Of 33 mothers with TB, 10 (30%) transmitted HIV to their infants in comparison with 87 of 750 mothers without TB (12%; odds ratio [OR], 3.31; 95% confidence interval [CI], 1.53–7.29; P = .02). In multivariable analysis, maternal TB was associated with 2.51-fold (95% CI, 1.05–6.02; P = .04) increased odds of HIV transmission adjusting for maternal factors (viral load, CD4 cell count, and antiretroviral therapy) and infant factors (breast-feeding duration, infant nevirapine administration, gestational age, and birth weight) associated with MTCT of HIV.
Conclusions. Maternal TB is associated with increased MTCT of HIV. Prevention of TB among HIV-infected mothers should be a high priority for communities with significant HIV/TB burden.
doi:10.1093/jinfdis/jiq064
PMCID: PMC3071111  PMID: 21208928
22.  Impact of Maternal and Infant Antiretroviral Drug Regimens on Drug Resistance in HIV-Infected Breastfeeding Infants 
The Pediatric infectious disease journal  2013;32(4):10.1097/INF.0b013e31827f44ee.
BACKGROUND
The HPTN 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV-infection despite prophylaxis.
METHODS
HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher’s exact tests were used to evaluate associations between categorical variables.
RESULTS
NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in seven (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8=75% in the NVP arm, 1/17=5.9% in the placebo arm, P=0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral (ARV) treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all four of those infants by 6 months of age (4/4=100%). In contrast, only three (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate ARV treatment developed NVP resistance (P=0.003).
CONCLUSIONS
Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.
doi:10.1097/INF.0b013e31827f44ee
PMCID: PMC3826537  PMID: 23249916
Nevirapine resistance; prevention of mother-to-child transmission; extended nevirapine; HIV
23.  Independent Effects of Nevirapine Prophylaxis and HIV-1 RNA Suppression in Breast Milk on Early Perinatal HIV-1 Transmission 
Background
The mechanism of action of single-dose nevirapine on reducing mother-to-child transmission of HIV-1 may involve reduction of maternal HIV-1 or prophylaxis of infants.
Methods
In a study that randomized pregnant mothers to HIVNET 012 nevirapine versus short-course antenatal zidovudine, we compared breast milk HIV-1 RNA viral shedding and administration of single-dose nevirapine between mothers who transmitted HIV-1 to their infants at 6 weeks postpartum and those who did not.
Results
In multivariate analyses, maximum breast milk HIV-1 RNA levels (hazard ratio [HR] = 2.50, 95% confidence interval [CI]: 1.25 to 4.99; P = 0.01) and nevirapine use (HR = 0.12, 95% CI: 0.02 to 0.97; P = 0.05) were each independently associated with perinatal transmission at 6 weeks postpartum. Mothers who transmitted HIV-1 to their infants had significantly higher HIV-1 RNA levels in their breast milk between the second day and sixth week postpartum. Among mothers with maximum breast milk virus levels less than a median of 3.5 log10 copies/mL, the administration of nevirapine further decreased HIV-1 transmission risk from 22.2% to 0.0% (P = 0.04).
Conclusions
Peripartum administration of single-dose nevirapine to mother and infant decreases early perinatal HIV-1 transmission by means of breast milk HIV-1 RNA suppression and, independently, by providing the infant with exposure prophylaxis.
PMCID: PMC3310242  PMID: 18077838
Africa; breast milk; HIV-1; mother-to-child transmission; nevirapine; prevention of perinatal transmission
24.  HIV: mother-to-child transmission 
Clinical Evidence  2008;2008:0909.
Introduction
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without anti-retroviral treatment, the risk of HIV transmission from infected mothers to their children is 15-30% during gestation or labour, and 15-20% during breast feeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads and/or advanced disease, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother to child transmission of HIV? We searched: Medline, Embase, The Cochrane Library and other important databases up to January 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
Results
We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breast feeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15-30% during pregnancy and labour, with an additional 10-20% transmission risk attributed to prolonged breast feeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads and/or advanced HIV disease.Without antiretroviral treatment (ART), 15-30% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the development of resistance, and adverse effects.From a paediatric perspective, successful prevention of MTCT remains the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, and/or to the baby immediately after birth, reduce the risk of MTCT of HIV-1.
Reductions in MTCT are possible using simple ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1-2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. RCTs demonstrate that short courses of antiretroviral drugs have proven efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.
Avoidance of breast feeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breast feeding-related HIV transmission needs to be balanced against the multiple benefits that breast feeding offers. In resource-poor countries, breast feeding is strongly associated with reduced infant morbidity and improved child survival. Modified breastfeeding practices may reduce the risk of HIV transmission while retaining some of its associated benefits.In settings where formula feeding is not feasible (no clean water, insufficient health education, significant cultural barriers) modified breastfeeding practices may offer the best compromise.Early breast feeding with weaning around age 4-6 months may offer an HIV-free survival benefit compared with either formula, mixed feeding, or prolonged breast feeding.Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin or immunoglobulin without HIV antibody does not reduce HIV-1 MTCT risk.
Vaginal microbiocides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that vitamin A or multivitamin supplementation reduces the risk of HIV-1 MTCT or infant mortality.
PMCID: PMC2907958  PMID: 19450331
25.  Antiretroviral Regimens in Pregnancy and Breast-Feeding in Botswana 
The New England journal of medicine  2010;362(24):2282-2294.
BACKGROUND
The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown.
METHODS
We randomly assigned 560 HIV-1–infected pregnant women (CD4+ count, ≥200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir–ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks’ gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine–lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine.
RESULTS
The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group.
CONCLUSIONS
All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.)
doi:10.1056/NEJMoa0907736
PMCID: PMC2999916  PMID: 20554983

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