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1.  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
2.  Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001608.
Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.
Please see later in the article for the Editors' Summary
Background
Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.
Methods and Findings
We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.
Conclusions
Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.
Why Was This Study Done?
The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.
What Did the Researchers Do and Find?
The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.
What Do These Findings Mean?
These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)
The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001608
PMCID: PMC3934828  PMID: 24586123
3.  HIV: prevention of mother-to-child transmission  
BMJ 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
4.  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
5.  HIV: mother-to-child transmission 
BMJ 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
6.  Impact of Round-the-Clock, Rapid Oral Fluid HIV Testing of Women in Labor in Rural India 
PLoS Medicine  2008;5(5):e92.
Background
Testing pregnant women for HIV at the time of labor and delivery is the last opportunity for prevention of mother-to-child HIV transmission (PMTCT) measures, particularly in settings where women do not receive adequate antenatal care. However, HIV testing and counseling of pregnant women in labor is a challenge, especially in resource-constrained settings. In India, many rural women present for delivery without any prior antenatal care. Those who do get antenatal care are not always tested for HIV, because of deficiencies in the provision of HIV testing and counseling services. In this context, we investigated the impact of introducing round-the-clock, rapid, point-of-care HIV testing and counseling in a busy labor ward at a tertiary care hospital in rural India.
Methods and Findings
After they provided written informed consent, women admitted to the labor ward of a rural teaching hospital in India were offered two rapid tests on oral fluid and finger-stick specimens (OraQuick Rapid HIV-1/HIV-2 tests, OraSure Technologies). Simultaneously, venous blood was drawn for conventional HIV ELISA testing. Western blot tests were performed for confirmatory testing if women were positive by both rapid tests and dual ELISA, or where test results were discordant. Round-the-clock (24 h, 7 d/wk) abbreviated prepartum and extended postpartum counseling sessions were offered as part of the testing strategy. HIV-positive women were administered PMTCT interventions. Of 1,252 eligible women (age range 18 y to 38 y) approached for consent over a 9 mo period in 2006, 1,222 (98%) accepted HIV testing in the labor ward. Of these, 1,003 (82%) women presented with either no reports or incomplete reports of prior HIV testing results at the time of admission to the labor ward. Of 1,222 women, 15 were diagnosed as HIV-positive (on the basis of two rapid tests, dual ELISA and Western blot), yielding a seroprevalence of 1.23% (95% confidence interval [CI] 0.61%–1.8%). Of the 15 HIV test–positive women, four (27%) had presented with reported HIV status, and 11 (73%) new cases of HIV infection were detected due to rapid testing in the labor room. Thus, 11 HIV-positive women received PMTCT interventions on account of round-the-clock rapid HIV testing and counseling in the labor room. While both OraQuick tests (oral and finger-stick) were 100% specific, one false-negative result was documented (with both oral fluid and finger-stick specimens). Of the 15 HIV-infected women who delivered, 13 infants were HIV seronegative at birth and at 1 and 4 mo after delivery; two HIV-positive infants died within a month of delivery.
Conclusions
In a busy rural labor ward setting in India, we demonstrated that it is feasible to introduce a program of round-the-clock rapid HIV testing, including prepartum and extended postpartum counseling sessions. Our data suggest that the availability of round-the-clock rapid HIV testing resulted in successful documentation of HIV serostatus in a large proportion (82%) of rural women who were unaware of their HIV status when admitted to the labor room. In addition, 11 (73%) of a total of 15 HIV-positive women received PMTCT interventions because of round-the-clock rapid testing in the labor ward. These findings are relevant for PMTCT programs in developing countries.
Nitika Pant Pai and colleagues report the results of offering a round-the-clock rapid HIV testing program in a rural labor ward setting in India.
Editors' Summary
Background.
Since the first reported case of AIDS (acquired immunodeficiency syndrome) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. Now, more than 33 million people are infected, almost half of them women. HIV is most often spread through unprotected sex with an infected partner, but mother-to-child transmission (MTCT) of HIV is also an important transmission route. HIV-positive women often pass the virus to their babies during pregnancy, labor and delivery, and breastfeeding, if nothing is done to prevent viral transmission. In developed countries, interventions such as voluntary testing and counseling, safe delivery practices (for example, offering cesarean delivery to HIV-positive women), and antiretroviral treatment of the mother during pregnancy and labor and of her newborn baby have minimized the risk of MTCT. In developing countries, the prevention of MTCT (PMTCT) is much less effective, in part because pregnant women often do not know their HIV status. Consequently, in 2007, nearly half a million children became infected with HIV mainly through MTCT.
Why Was This Study Done?
In many developing countries, women do not receive adequate antenatal care. In India, for example, nearly half the women living in rural areas do not receive any antenatal care until they are in labor. This gives health care providers very little time in which to counsel women about HIV infection, test them for the virus, and start interventions to prevent MTCT. Furthermore, testing pregnant women in labor for HIV and counseling them is a challenge, particularly where resources are limited. In this study, therefore, the researchers investigate the feasibility and impact of introducing round-the-clock, rapid HIV testing and counseling in a busy labor ward in a rural teaching hospital in Sevagram, India.
What Did the Researchers Do and Find?
Women admitted to the labor ward between January and September 2006 were offered two rapid HIV tests—one that used a saliva sample and the other that used blood taken from a finger prick. Blood was also taken from a vein for conventional HIV testing. All the women were given a 15-minute counseling session about how HIV is transmitted, the importance of HIV testing, and information on PMTCT before their child was born (prepartum counseling), and a longer postpartum counseling session. HIV-positive women were given a cesarean delivery where possible and antiretroviral drug treatment to reduce MTCT. 1,222 women admitted to the labor ward during the study period (1,003 of whom did not know their HIV status) accepted HIV testing. Of 15 study participants who were HIV positive, 11 learnt of their HIV status in the labor room. Two babies born to these HIV-positive women were HIV positive and died within a month of delivery; the other 13 babies were HIV negative at birth and at 1 and 4 months after delivery. Finally, the rapid HIV tests missed only one HIV-positive woman (no false-positive results were given), and the time from enrolling a woman into the study through referring her for PMTCT intervention where necessary averaged 40–60 minutes.
What Do These Findings Mean?
These findings show the feasibility and positive impact of the introduction of round-the-clock pre- and postpartum HIV counseling and rapid HIV testing into a busy rural Indian labor ward. Few of the women entering this ward knew their HIV status previously but the introduction of these facilities in this setting successfully informed these women of their HIV status. In addition, the round-the-clock counseling and testing led to 11 women and their babies receiving PMTCT interventions who would otherwise have been missed. These findings need to be confirmed in other settings and the cost-effectiveness and sustainability of this approach for the improvement of PMTCT in developing countries needs to be investigated. Nevertheless, these findings suggest that round-the-clock rapid HIV testing might be an effective and acceptable way to reduce MTCT of HIV in many developing countries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050092.
Read a related PLoS Medicine Perspective article
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Women, Children, and HIV provides extensive information on the prevention of mother-to-child transmission of HIV in developing countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS in India, on women, HIV, and AIDS, and on HIV and AIDS prevention, including the prevention of mother-to-child transmission
AIDSinfo, a service of the US Department of Health and Human Services provides health information for HIV-positive pregnant women (in English and Spanish)
doi:10.1371/journal.pmed.0050092
PMCID: PMC2365974  PMID: 18462011
7.  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
8.  Maternal–Fetal Microtransfusions and HIV-1 Mother-to-Child Transmission in Malawi 
PLoS Medicine  2005;3(1):e10.
Background
Between 25% and 35% of infants born to HIV-infected mothers become HIV-1 infected. One potential route of mother-to-child transmission (MTCT) could be through a breakdown in the placental barrier (i.e., maternal–fetal microtransfusions).
Methods and Findings
Placental alkaline phosphatase (PLAP) is a 130-kD maternal enzyme that cannot cross the intact placental barrier. We measured PLAP activity in umbilical vein serum as an indicator of maternal–fetal microtransfusion, and related this to the risk of HIV-1 MTCT. A case-cohort study was conducted of 149 women randomly selected from a cohort of HIV-1-infected pregnant Malawians; these women served as a reference group for 36 cases of in utero MTCT and 43 cases of intrapartum (IP) MTCT. Cord PLAP activity was measured with an immunocatalytic assay. Infant HIV status was determined by real-time PCR. The association between cord PLAP activity and HIV-1 MTCT was measured with logistic regression using generalized estimating equations. Among vaginal deliveries, PLAP was associated with IP MTCT (risk ratio, 2.25 per log10 ng/ml PLAP; 95% confidence interval, 0.95–5.32) but not in utero MTCT. In a multivariable model adjusted for HIV-1 RNA load, chorioamnionitis, and self-reported fever, the risk of IP MTCT almost tripled for every log10 increase in cord PLAP activity (risk ratio, 2.87; 95% confidence interval, 1.05–7.83).
Conclusion
These results suggest that during vaginal deliveries, placental microtransfusions are a risk factor for IP HIV-1 MTCT. Future studies are needed to identify factors that increase the risk for microtransfusions in order to prevent IP HIV-1 MTCT.
Placental microtransfusions as measured by placental alkaline phosphatase levels in cord blood are a risk factor for mother-to-child transmission during vaginal deliveries.
doi:10.1371/journal.pmed.0030010
PMCID: PMC1285069  PMID: 16287342
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.  Impact of Maternal HIV Seroconversion during Pregnancy on Early Mother to Child Transmission of HIV (MTCT) Measured at 4-8 Weeks Postpartum in South Africa 2011-2012: A National Population-Based Evaluation 
PLoS ONE  2015;10(5):e0125525.
Background
Mother-to-child transmission of HIV (MTCT) depends on the timing of HIV infection. We estimated HIV-seroconversion during pregnancy (HSP) after having a HIV-negative result antenatally, and its contribution to early MTCT in South Africa (SA).
Methods and Findings
Between August 2011 and March 2012, we recruited a nationally representative sample of mother-infant pairs with infants aged 4-to-8 weeks from 578 health facilities. Data collection included mother interviews, child health-card reviews, and infant dried-blood-spots sample (iDBS). iDBS were tested for HIV antibodies and HIV-deoxyribonucleic-acid (HIV-DNA). HSP was defined as maternal self-report of an HIV-negative test during this pregnancy, no documented use of antiretroviral drugs and a matched HIV sero-positive iDBS. We used 20 imputations from a uniform distribution for time from reported antenatal HIV-negative result to delivery to estimate time of HSP. Early MTCT was defined based on detection of HIV-DNA in iDBS. Estimates were adjusted for clustering, nonresponse, and weighted by SA’s 2011 live-births.
Results
Of 9802 mother-infant pairs, 2738 iDBS were HIV sero-positive, including 212 HSP, resulting in a nationally weighted estimate of 3.3% HSP (95% Confidence Interval: 2.8%-3.8%). Median time of HIV-seroconversion was 32.8weeks gestation;28.3% (19.7%- 36.9%) estimated to be >36 weeks. Early MTCT was 10.7% for HSP (6.2%-16.8%) vs. 2.2% (1.7%-2.8%) for mothers with known HIV-positive status. Although they represent 2.2% of all mothers and 6.7% of HIV-infected mothers, HSP accounted for 26% of early MTCT. Multivariable analysis indicated the highest risk for HSP was among women who knew the baby’s father was HIV-infected (adjusted-hazard ratio (aHR) 4.71; 1.49-14.99), or who had been screened for tuberculosis (aHR 1.82; 1.43-2.32).
Conclusions
HSP risk is high and contributes significantly to early MTCT. Identification of HSP by repeat-testing at 32 weeks gestation, during labor, 6 weeks postpartum, in tuberculosis-exposed women, and in discordant couples might reduce MTCT.
doi:10.1371/journal.pone.0125525
PMCID: PMC4420458  PMID: 25942423
11.  Estimating mother-to-child HIV transmission rates in Cameroon in 2011: a computer simulation approach 
Background
Despite the progress in the Prevention of the Mother-to-Child Transmission of HIV (PMTCT), the paediatric HIV epidemic remains worrying in Cameroon. HIV prevalence rate for the population of pregnant women was 7.6 % in 2010 in Cameroon. The extent of the paediatric HIV epidemic is needed to inform policymakers. We developed a stochastic simulation model to estimate the number of new paediatric HIV infections through MTCT based on the observed uptake of services during the different steps of the PMTCT cascade in Cameroon in 2011. Different levels of PMTCT uptake was also assessed.
Methods
A discrete events computer simulation-based approach with stochastic structure was proposed to generate a cohort of pregnant women followed-up until 6 weeks post-partum, and optionally until complete breastfeeding cessation in both prevalent and incident lactating HIV-infected women. The different parameters of the simulation model were fixed using data sources available from the 2011 national registry surveys, and from external cohorts in Cameroon. Different PMTCT coverages were simulated to assess their impact on MTCT. Available data show a low coverage of PMTCT services in Cameroon in 2011.
Results
Based on a simulation approach on a population of 995, 533 pregnant women, the overall residual MTCT rate in 2011 was estimated to be 22.1 % (95 % CI: 18.6 %–25.2 %), the 6-week perinatal MTCT rate among prevalent HIV-infected mothers at delivery is estimated at 12.1 % (95 % CI: 8.1 %–15.1 %), with an additional postnatal MTCT rate estimated at 13.3 % (95 % CI: 9.3 %–17.8 %). The MTCT rate among children whose mothers seroconverted during breastfeeding was estimated at 20.8 % (95 % CI: 14.1 %–26.9 %). Overall, we estimated the number of new HIV infections in children in Cameroon to be 10, 403 (95 % CI: 9, 054–13, 345) in 2011. When PMTCT uptake have been fixed at 100 %, 90 % and 80 %, global MTCT rate failed to 0.9 % (95 % CI: 0.5 %–1.7 %), 2.0 % (95 % CI: 0.9 %–3.2 %) and 4.3 % (95 % CI: 2.4 %–6.7 %) respectively.
Conclusions
This model is helpful to provide MTCT estimates to guide the national HIV policy in Cameroon. Increasing supply and uptake of PMTCT services among prevalent HIV infected pregnant women, as well as HIV-prevention interventions including the offer and acceptance of HIV testing and counselling in lactating women could reduce significantly the residual HIV MTCT in Cameroon. A public health effort should be made to encourage health care workers and pregnant women to use PMTCT services until complete breastfeeding cessation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-1336-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-016-1336-2
PMCID: PMC4709976  PMID: 26754155
HIV; Mother-to-child transmission; Africa; Children; Breastfeeding; Modelling
12.  Awareness and knowledge on timing of mother-to-child transmission of HIV among antenatal care attending women in Southern Ethiopia: a cross sectional study 
Reproductive Health  2013;10:66.
Background
Mother-to-child transmission (MTCT) of HIV infection remains a major public health problem and constitutes the most important cause of HIV infection in children under the age of 15 years old. Awareness on MTCT of HIV and knowledge of its timing usually pose a direct effect on utilization of PMTCT services (mainly HIV testing, infant feeding options and antiretroviral use). The objective of this study is to assess pregnant women’s knowledge on timing of MTCT of HIV in Southern Ethiopia.
Methods
A cross sectional study was conducted in 62 health centers in Southern Ethiopia from February 25 to March 24, 2012. A total of 1325 antenatal care attending women were included in the survey by using a multistage sampling technique. Data were collected using a structured and pre-tested questionnaire. Multiple logistic regression analysis was employed to identify variables associated with women’s knowledge on timing of MTCT of HIV.
Results
All interviewed pregnant women were aware of HIV/AIDS transmission, but only 60.7% were aware of the risk of MTCT. The possibility of MTCT during pregnancy, delivery and breastfeeding was known by 48.4%, 58.6% and 40.7% of the respondents, respectively. The proportion of women who were fully knowledgeable on timing of MTCT was 11.5%. Women’s full knowledge on timing of MTCT was associated with maternal education [AOR = 3.68, 95% CI: 1.49-9.08], and being government employee [AOR = 2.50, 95% CI: 1.23- 5.07]. Whereas, there was a negative association between full knowledge of women on timing of MTCT and no offer of information on MTCT/PMTCT by antenatal care (ANC) service provider [AOR = 0.44, 95% CI: 0.30-0.64], lack of discussion on ANC with male partner [AOR = 0.30, 95% CI: 0.12-0.72], and lack of discussion on HIV/AIDS with male partner [AOR = 0.17, 95% CI: 0.07-0.43].
Conclusion
There was low awareness and knowledge on timing of MTCT of HIV in this study. Hence, strengthening the level of PMTCT services in ANC settings and devising mechanisms to promote involvement of men in PMTCT services is needed.
doi:10.1186/1742-4755-10-66
PMCID: PMC3866506  PMID: 24330487
13.  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
14.  Higher risks of mother-to-child HIV transmission in countries with lower HIV prevalence: UNAIDS 2013 results for 32 countries with generalised epidemics 
Journal of Virus Eradication  null;1(4):257-263.
Abstract
Objectives
Diagnosis and treatment of HIV-infected mothers significantly lower rates of mother-to-child transmission (MTCT) of HIV. Early infant diagnosis (EID) is required to monitor success of prevention of MTCT (pMTCT) programmes. Our aim was to compare rates of MTCT, EID and pMTCT in countries with generalised epidemics.
Methods
The UNAIDSinfo database includes country-level information on epidemic size, prevalence of HIV infection, EID rates and pMTCT coverage. The AIDS Spectrum model was used to estimate the number of children infected with HIV in 2013, for 32 countries with generalised epidemics. Least squares linear regression, weighted by epidemic size and controlling for GDP/capita, was used to correlate national adult HIV prevalence with estimated MTCT rates.
Results
There were 32 countries with generalised epidemics included in the analysis (31 in Africa). Higher-prevalence countries (≥5%) had significantly lower rates of MTCT (P<0.01) than lower-prevalence countries (<5%). For 20 lower-prevalence countries (total 7.4 million HIV-infected people), there were 105,300 childhood (0–14 years) infections in 2013. In 12 higher-prevalence countries (total 17.1 million HIV-infected people), there were an estimated 107,500 childhood infections in 2013. Regression analysis suggests that if all countries achieved the same MTCT rate as Botswana (2.0%), childhood HIV infections could be cut by 88% (from 105,300 to 12,300 per year) in lower-prevalence countries, and by 82% (from 107,500 to 19,700 per year) in higher-prevalence countries.
Conclusions
In this analysis of 32 countries with generalised HIV epidemics, 49.5% (105,500/213,000) of childhood HIV infections in 2013 were in lower-prevalence countries. Targeting of prevention of MTCT in lower-prevalence countries needs to be prioritised, despite challenges, to reduce the number of children infected.
PMCID: PMC4946657  PMID: 27482423
MTCT; pMTCT; mother-to-child transmission; HIV; Option B+
15.  The contribution of maternal HIV seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of HIV 
Background
The prevention of mother-to-child transmission (PMTCT) of HIV has been focused mainly on women who are HIV-positive at their first antenatal visit, but there is uncertainty regarding the contribution to overall transmission from mothers who seroconvert after their first antenatal visit and before weaning.
Method
A mathematical model was developed to simulate changes in mother-to-child transmission of HIV over time, in South Africa. The model allows for changes in infant feeding practices as infants age, temporal changes in the provision of antiretroviral prophylaxis and counselling on infant feeding, as well as temporal changes in maternal HIV prevalence and incidence.
Results
The proportion of MTCT from mothers who seroconverted after their first antenatal visit was 26% (95% CI: 22-30%) in 2008, or 15 000 out of 57 000 infections. It is estimated that by 2014, total MTCT will reduce to 39 000 per annum, and transmission from mothers seroconverting after their first antenatal visit will reduce to 13 000 per annum, accounting for 34% (95% CI: 29-39%) of MTCT. If maternal HIV incidence during late pregnancy and breastfeeding were reduced by 50% after 2010, and HIV screening were repeated in late pregnancy and at 6-week immunization visits after 2010, the average annual number of MTCT cases over the 2010-15 period would reduce by 28% (95% CI: 25-31%), from 39 000 to 28 000 per annum.
Conclusion
Maternal seroconversion during late pregnancy and breastfeeding contributes significantly to the paediatric HIV burden, and needs greater attention in the planning of PMTCT programmes.
doi:10.1097/QAI.0b013e3182432f27
PMCID: PMC3378499  PMID: 22193774
HIV/AIDS; vertical transmission; mathematical model; South Africa
16.  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
17.  When Do HIV-Infected Women Disclose Their HIV Status to Their Male Partner and Why? A Study in a PMTCT Programme, Abidjan 
PLoS Medicine  2007;4(12):e342.
Background
In Africa, women tested for HIV during antenatal care are counselled to share with their partner their HIV test result and to encourage partners to undertake HIV testing. We investigate, among women tested for HIV within a prevention of mother-to-child transmission of HIV (PMTCT) programme, the key moments for disclosure of their own HIV status to their partner and the impact on partner HIV testing.
Methods and Findings
Within the Ditrame Plus PMTCT project in Abidjan, 546 HIV-positive and 393 HIV-negative women were tested during pregnancy and followed-up for two years after delivery. Circumstances, frequency, and determinants of disclosure to the male partner were estimated according to HIV status. The determinants of partner HIV testing were identified according to women's HIV status. During the two-year follow-up, disclosure to the partner was reported by 96.7% of the HIV-negative women, compared to 46.2% of HIV-positive women (χ2 = 265.2, degrees of freedom [df] = 1, p < 0.001). Among HIV-infected women, privileged circumstances for disclosure were just before delivery, during early weaning (at 4 mo to prevent HIV postnatal transmission), or upon resumption of sexual activity. Formula feeding by HIV-infected women increased the probability of disclosure (adjusted odds ratio 1.54, 95% confidence interval 1.04–2.27, Wald test = 4.649, df = 1, p = 0.031), whereas household factors such as having a co-spouse or living with family reduced the probability of disclosure. The proportion of male partners tested for HIV was 23.1% among HIV-positive women and 14.8% among HIV-negative women (χ2 = 10.04, df = 1, p = 0.002). Partners of HIV-positive women who were informed of their wife's HIV status were more likely to undertake HIV testing than those not informed (37.7% versus 10.5%, χ2 = 56.36, df = 1, p < 0.001).
Conclusions
In PMTCT programmes, specific psychosocial counselling and support should be provided to women during the key moments of disclosure of HIV status to their partners (end of pregnancy, weaning, and resumption of sexual activity). This support could contribute to improving women's adherence to the advice given to prevent postnatal and sexual HIV transmission.
In a mother-to-child HIV prevention program in Côte d'Ivoire, Annabel Desgrées-du-Loû and colleagues identify three junctures at which women tend to disclose their HIV status to partners.
Editors' Summary
Background.
Since the first reported case of AIDS (acquired immunodeficiency syndrome) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. By the end of 2006, nearly 40 million people were infected, 25 million of them in sub-Saharan Africa. HIV is most often spread by having unprotected sex with an infected partner. In Africa, most sexual transmission of HIV is between partners in stable relationships—many such couples do not adopt measures that prevent viral transmission, such as knowing the HIV status of both partners and using condoms if one partner is HIV-positive. HIV can also pass from a mother to her baby during pregnancy, labor, or delivery, or through breastfeeding. Mother-to-child transmission (MTCT) of HIV can be reduced by giving anti-HIV drugs to the mother during pregnancy and labor and to her newborn baby, and by avoiding breastfeeding or weaning the baby early.
Why Was This Study Done?
Many African countries have programs for prevention of MTCT (PMTCT) that offer pregnant women prenatal HIV counseling and testing. As a result, women are often the first member of a stable relationship to know their HIV status. PMTCT programs advise women to disclose their HIV test result to their partner and to encourage him to have an HIV test. But for many women, particularly those who are HIV-positive, talking to their partner about HIV/AIDS is hard because of fears of rejection (which could mean loss of housing and food) or accusations of infidelity. Knowing more about when women disclose their HIV status and what makes them decide to do so would help the people running PMTCT programs to support women during the difficult process of disclosure. In this study, the researchers have investigated when and why women participating in a PMTCT research project in Abidjan (Côte d'Ivoire) told their partner about their HIV status and the impact this disclosure had on their partner's uptake of HIV testing.
What Did the Researchers Do and Find?
At regular follow-up visits, the researchers asked women in the Abidjan PMTCT project whether they had told their partners their HIV status and whether they were breast-feeding or had resumed sexual activity. Nearly all the women who tested negative for HIV, but slightly fewer than half of the HIV-positive (infected) women had told their partner about their HIV status by two years after childbirth. Two-thirds of the HIV-positive women who disclosed their status did so before delivery. Other key times for disclosure were at early weaning (4 months after birth) for women who breast-fed their babies, and when sexual activity resumed. HIV-positive women who bottle fed their babies from birth were more likely to tell their partners of their status than women who breast-fed. Factors that prevented women disclosing their HIV status included living in a polygamous relationship or living separately from their partners. Finally, the researchers report that the partners of HIV-positive women who disclosed their HIV status were about three times more likely to take an HIV test than the partners of HIV-positive women who did not disclose.
What Do These Findings Mean?
These findings identify three key times when women who have had an HIV test during pregnancy are likely to disclose their HIV status to their partner. The main one is before delivery and relates, in part, to how the mother plans to feed her baby. To bottle feed in Abidjan, women need considerable support from their partners and this may be the impetus for disclosing their HIV status. Disclosure at early weaning may reflect the woman's need to enlist her partner's support for this unusual decision—the normal time for weaning in Abidjan is 17 months. Finally, disclosure when sexual activity resumes may be necessary so that the woman can explain why she wants to use condoms. Although these findings need confirmation in other settings, targeting counseling and support within PMTCT programs to these key moments might help HIV-positive women to tell their partners about their status. This, hopefully, would help to reduce sexual transmission of HIV within stable relationships in sub-Saharan Africa.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040342.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS and on HIV infection in women
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Women Children and HIV provides extensive information on prevention of mother-to-child transmission of HIV in developing countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on HIV and AIDS prevention
AIDSinfo, a service of the US Department of Health and Human Services provideshealth information for HIV-positive pregnant women (in English and Spanish)
doi:10.1371/journal.pmed.0040342
PMCID: PMC2100145  PMID: 18052603
18.  Clinical Malaria Diagnosis in Pregnancy in Relation to Early Perinatal Mother-to-Child-Transmission of HIV: A Prospective Cohort Study 
HIV medicine  2013;15(5):276-285.
Objectives
We prospectively investigated fever symptoms and maternal diagnosis of malaria in pregnancy (MIP) in relation to child HIV infection among 2,368 pregnant HIV-positive women and their infants, followed-up from pregnancy until birth and 6 weeks post-delivery in Tanzania.
Methods
Doctors clinically diagnosed and treated MIP and fever symptoms during prenatal healthcare. Child HIV status was determined via DNA-PCR. Multivariable logistic regression models estimated relative risks (RR) and 95% confidence intervals (CI) for HIV mother-to-child-transmission (MTCT) by 6th week of life.
Results
Mean gestational age at enrollment was 22.2 weeks. During follow-up, 16.6% had ≥1 MIP diagnosis, 15.9% reported fever symptoms and 8.7% had both fever and MIP diagnosis. Eleven percent of HIV-exposed infants were HIV-positive by 6 weeks. The RR of HIV MTCT was statistically similar for infants whose mothers were ever vs. never clinical MIP diagnosed (RR=1.24, 95%CI:0.94–1.64), were diagnosed with 1 vs. 0 clinical MIP episode (RR=1.07;95%CI:0.77–1.48) and had ever vs. never reported fever symptoms (RR=1.04, 95%CI:0.78,1.38) in pregnancy. However, HIV MTCT risk increased by 29% (95%CI:4–58%) per MIP episode. Infants of women with ≥2 vs. 0 MIP diagnoses were 2.1 times more likely to be HIV infected by 6weeks old (95%CI:1.31–3.45).
Conclusions
Clinical MIP diagnosis, but not fevers, in HIV-positive pregnant women was associated with elevated risk of early HIV MTCT suggesting that malaria prevention and treatment in pregnant HIV-positive women may enhance the effectiveness of HIV prevention in MTCT programs in this setting. Future studies using laboratory confirmed malaria is needed to confirm this association.
doi:10.1111/hiv.12111
PMCID: PMC4299572  PMID: 24215465
Co-infection; Malaria; AIDS; HIV mother-to-child-transmission; HIV-exposed Infant
19.  First population-level effectiveness evaluation of a national programme to prevent HIV transmission from mother to child, South Africa 
Background
There is a paucity of data on the national population-level effectiveness of preventing mother-to-child transmission (PMTCT) programmes in high-HIV-prevalence, resource-limited settings. We assessed national PMTCT impact in South Africa (SA), 2010.
Methods
A facility-based survey was conducted using a stratified multistage, cluster sampling design. A nationally representative sample of 10 178 infants aged 4–8 weeks was recruited from 565 clinics. Data collection included caregiver interviews, record reviews and infant dried blood spots to identify HIV-exposed infants (HEI) and HIV-infected infants. During analysis, self-reported antiretroviral (ARV) use was categorised: 1a: triple ARV treatment; 1b: azidothymidine >10 weeks; 2a: azidothymidine ≤10 weeks; 2b: incomplete ARV prophylaxis; 3a: no antenatal ARV and 3b: missing ARV information. Findings were adjusted for non-response, survey design and weighted for live-birth distributions.
Results
Nationally, 32% of live infants were HEI; early mother-to-child transmission (MTCT) was 3.5% (95% CI 2.9% to 4.1%). In total 29.4% HEI were born to mothers on triple ARV treatment (category 1a) 55.6% on prophylaxis (1b, 2a, 2b), 9.5% received no antenatal ARV (3a) and 5.5% had missing ARV information (3b). Controlling for other factors groups, 1b and 2a had similar MTCT to 1a (Ref; adjusted OR (AOR) for 1b, 0.98, 0.52 to 1.83; and 2a, 1.31, 0.69 to 2.48). MTCT was higher in group 2b (AOR 3.68, 1.69 to 7.97). Within group 3a, early MTCT was highest among breastfeeding mothers 11.50% (4.67% to 18.33%) for exclusive breast feeding, 11.90% (7.45% to 16.35%) for mixed breast feeding, and 3.45% (0.53% to 6.35%) for no breast feeding). Antiretroviral therapy or >10 weeks prophylaxis negated this difference (MTCT 3.94%, 1.98% to 5.90%; 2.07%, 0.55% to 3.60% and 2.11%, 1.28% to 2.95%, respectively).
Conclusions
SA, a high-HIV-prevalence middle income country achieved <5% MTCT by 4–8 weeks post partum. The long-term impact on PMTCT on HIV-free survival needs urgent assessment.
doi:10.1136/jech-2014-204535
PMCID: PMC4345523  PMID: 25371480
CHILD HEALTH; HIV; PERINATAL EPIDEMIOLOGY; PUBLIC HEALTH; SURVEILLANCE
20.  Population–level effectiveness of PMTCT Option A on early mother–to–child (MTCT) transmission of HIV in South Africa: implications for eliminating MTCT 
Journal of Global Health  null;6(2):020405.
Background
Eliminating mother–to–child transmission of HIV (EMTCT), defined as ≤50 infant HIV infections per 100 000 live births, is a global priority. Since 2011 policies to prevent mother–to–child transmission of HIV (PMTCT) shifted from maternal antiretroviral (ARV) treatment or prophylaxis contingent on CD4 cell count to lifelong maternal ARV treatment (cART). We sought to measure progress with early (4–8 weeks postpartum) MTCT prevention and elimination, 2011–2013, at national and sub–national levels in South Africa, a high antenatal HIV prevalence setting ( ≈ 29%), where early MTCT was 3.5% in 2010.
Methods
Two surveys were conducted (August 2011–March 2012 and October 2012–May 2013), in 580 health facilities, randomly selected after two–stage probability proportional to size sampling of facilities (the primary sampling unit), to provide valid national and sub–national–(provincial)–level estimates. Data collectors interviewed caregivers of eligible infants, reviewed patient–held charts, and collected infant dried blood spots (iDBS). Confirmed positive HIV enzyme immunoassay (EIA) and positive total HIV nucleic acid polymerase chain reaction (PCR) indicated infant HIV exposure or infection, respectively. Weighted survey analysis was conducted for each survey and for the pooled data.
Findings
National data from 10 106 and 9120 participants were analyzed (2011–12 and 2012–13 surveys respectively). Infant HIV exposure was 32.2% (95% confidence interval (CI) 30.7–33.6%), in 2011–12 and 33.1% (95% CI 31.8–34.4%), provincial range of 22.1–43.6% in 2012–13. MTCT was 2.7% (95% CI 2.1%–3.2%) in 2011–12 and 2.6% (95% CI 2.0–3.2%), provincial range of 1.9–5.4% in 2012–13. HIV–infected ARV–exposed mothers had significantly lower unadjusted early MTCT (2.0% [2011–12: 1.6–2.5%; 2012–13:1.5–2.6%]) compared to HIV–infected ARV–naive mothers [10.2% in 2011–12 (6.5–13.8%); 9.2% in 2012–13 (5.6–12.7%)]. Pooled analyses demonstrated significantly lower early MTCT among exclusive breastfeeding (EBF) mothers receiving >10 weeks ARV prophylaxis or cART compared with EBF and no ARVs: (2.2% [95% CI 1.25–3.09%] vs 12.2% [95% CI 4.7–19.6%], respectively); among HIV–infected ARV–exposed mothers, 24.9% (95% CI 23.5–26.3%) initiated cART during or before the first trimester, and their early MTCT was 1.2% (95% CI 0.6–1.7%). Extrapolating these data, assuming 32% EIA positivity and 2.6% or 1.2% MTCT, 832 and 384 infants per 100 000 live births were HIV infected, respectively.
Conclusions
Although we demonstrate sustained national–level PMTCT impact in a high HIV prevalence setting, results are far–removed from EMTCT targets. Reducing maternal HIV prevalence and treating all maternal HIV infection early are critical for further progress.
doi:10.7189/jogh.6.020405
PMCID: PMC5032343  PMID: 27698999
21.  Evaluation of postpartum HIV superinfection and mother-to-child transmission 
AIDS (London, England)  2015;29(12):1567-1573.
Objective
This study examined HIV superinfection (HIV SI) in HIV-infected women postpartum, and its association with mother-to-child transmission (MTCT).
Design
Plasma samples were obtained from HIV-infected women who transmitted HIV to their infants after 6 weeks of age (transmitters, n=91) and HIV-infected women who did not transmit HIV to their infants (non-transmitters, n=91). These women were originally enrolled in a randomized trial for prevention of MTCT of HIV in Malawi (PEPI-Malawi).
Methods
Two HIV genomic regions (p24 and gp41) were analyzed by next generation sequencing (NGS) for HIV SI. HIV SI was established if the follow-up sample contained a new, phylogenetically distinct viral population. HIV SI and transmission risk were examined by multiple logistic regression, adjusted for PEPI study arm, baseline viral load, baseline CD4 cell count, time to resumption of sex, and breastfeeding duration.
Results
Transmitters had lower baseline CD4 cell counts (p=0.001) and higher viral loads (p<0.0001) compared to non-transmitters. There were five cases of SI among transmitters [rate of SI=4.7/100pys person year (pys)] compared to five cases among the non-transmitters (rate of SI=4.4/100pys; p=0.78). HIV SI was not associated with increased risk of post-natal MTCT of HIV after controlling for maternal age, baseline viral load and CD4 cell count (adjusted odds ratio=2.32, p=0.30). Longer breastfeeding duration was independently associated with a lower risk of HIV SI after controlling for study arm and baseline viral load (p=0.05).
Conclusions
There was a significant level of HIV SI in women postpartum, but this was not associated with an increased risk of MTCT via breastfeeding.
doi:10.1097/QAD.0000000000000740
PMCID: PMC4609898  PMID: 26244396
22.  A three-source capture-recapture estimate of the number of new HIV diagnoses in children in France from 2003–2006 with multiple imputation of a variable of heterogeneous catchability 
BMC Infectious Diseases  2012;12:251.
Background
Nearly all HIV infections in children worldwide are acquired through mother-to-child transmission (MTCT) during pregnancy, labour, delivery or breastfeeding. The objective of our study was to estimate the number and rate of new HIV diagnoses in children less than 13 years of age in mainland France from 2003–2006.
Methods
We performed a capture-recapture analysis based on three sources of information: the mandatory HIV case reporting (DOVIH), the French Perinatal Cohort (ANRS-EPF) and a laboratory-based surveillance of HIV (LaboVIH). The missing values of a variable of heterogeneous catchability were estimated through multiple imputation. Log-linear modelling provided estimates of the number of new HIV infections in children, taking into account dependencies between sources and variables of heterogeneous catchability.
Results
The three sources observed 216 new HIV diagnoses after record-linkage. The number of new HIV diagnoses in children was estimated at 387 (95%CI [271–503]) from 2003–2006, among whom 60% were born abroad. The estimated rate of new HIV diagnoses in children in mainland France was 9.1 per million in 2006 and was 38 times higher in children born abroad than in those born in France. The estimated completeness of the three sources combined was 55.8% (95% CI [42.9 – 79.7]) and varied according to the source; the completeness of DOVIH (28.4%) and ANRS-EPF (26.1%) were lower than that of LaboVIH (33.3%).
Conclusion
Our study provided, for the first time, an estimated annual rate of new HIV diagnoses in children under 13 years old in mainland France. A more systematic HIV screening of pregnant women that is repeated during pregnancy among women likely to engage in risky behaviour is needed to optimise the prevention of MTCT. HIV screening for children who migrate from countries with high HIV prevalence to France could be recommended to facilitate early diagnosis and treatment.
doi:10.1186/1471-2334-12-251
PMCID: PMC3526568  PMID: 23050554
23.  Estimating the Timing of Mother-to-Child Transmission of the Human Immunodeficiency Virus Type 1 Using a Viral Molecular Evolution Model 
PLoS ONE  2014;9(4):e90421.
Background
Mother-to-child transmission (MTCT) is responsible for most pediatric HIV-1 infections worldwide. It can occur during pregnancy, labor, or breastfeeding. Numerous studies have used coalescent and molecular clock methods to understand the epidemic history of HIV-1, but the timing of vertical transmission has not been studied using these methods. Taking advantage of the constant accumulation of HIV genetic variation over time and using longitudinally sampled viral sequences, we used a coalescent approach to investigate the timing of MTCT.
Materials and Methods
Six-hundred and twenty-two clonal env sequences from the RNA and DNA viral population were longitudinally sampled from nine HIV-1 infected mother-and-child pairs [range: 277–1034 days]. For each transmission pair, timing of MTCT was determined using a coalescent-based model within a Bayesian statistical framework. Results were compared with available estimates of MTCT timing obtained with the classic biomedical approach based on serial HIV DNA detection by PCR assays.
Results
Four children were infected during pregnancy, whereas the remaining five children were infected at time of delivery. For eight out of nine pairs, results were consistent with the transmission periods assessed by standard PCR-based assay. The discordance in the remaining case was likely confused by co-infection, with simultaneous introduction of multiple maternal viral variants at the time of delivery.
Conclusions
The study provided the opportunity to validate the Bayesian coalescent approach that determines the timing of MTCT of HIV-1. It illustrates the power of population genetics approaches to reliably estimate the timing of transmission events and deepens our knowledge about the dynamics of viral evolution in HIV-infected children, accounting for the complexity of multiple transmission events.
doi:10.1371/journal.pone.0090421
PMCID: PMC3981669  PMID: 24717647
24.  Evaluating the Impact of Zimbabwe’s Prevention of Mother-to-Child HIV Transmission Program: Population-Level Estimates of HIV-Free Infant Survival Pre-Option A 
PLoS ONE  2015;10(8):e0134571.
Objective
We estimated HIV-free infant survival and mother-to-child HIV transmission (MTCT) rates in Zimbabwe, some of the first community-based estimates from a UNAIDS priority country.
Methods
In 2012 we surveyed mother-infant pairs residing in the catchment areas of 157 health facilities randomly selected from 5 of 10 provinces in Zimbabwe. Enrolled infants were born 9–18 months before the survey. We collected questionnaires, blood samples for HIV testing, and verbal autopsies for deceased mothers/infants. Estimates were assessed among i) all HIV-exposed infants, as part of an impact evaluation of Option A of the 2010 WHO guidelines (rolled out in Zimbabwe in 2011), and ii) the subgroup of infants unexposed to Option A. We compared province-level MTCT rates measured among women in the community with MTCT rates measured using program monitoring data from facilities serving those communities.
Findings
Among 8568 women with known HIV serostatus, 1107 (12.9%) were HIV-infected. Among all HIV-exposed infants, HIV-free infant survival was 90.9% (95% confidence interval (CI): 88.7–92.7) and MTCT was 8.8% (95% CI: 6.9–11.1). Sixty-six percent of HIV-exposed infants were still breastfeeding. Among the 762 infants born before Option A was implemented, 90.5% (95% CI: 88.1–92.5) were alive and HIV-uninfected at 9–18 months of age, and 9.1% (95%CI: 7.1–11.7) were HIV-infected. In four provinces, the community-based MTCT rate was higher than the facility-based MTCT rate. In Harare, the community and facility-based rates were 6.0% and 9.1%, respectively.
Conclusion
By 2012 Zimbabwe had made substantial progress towards the elimination of MTCT. Our HIV-free infant survival and MTCT estimates capture HIV transmissions during pregnancy, delivery and breastfeeding regardless of whether or not mothers accessed health services. These estimates also provide a baseline against which to measure the impact of Option A guidelines (and subsequently Option B+).
doi:10.1371/journal.pone.0134571
PMCID: PMC4527770  PMID: 26248197
25.  Comparing competing risk outcomes within principal strata, with application to studies of mother-to-child transmission of HIV 
Statistics in medicine  2012;31(27):3406-3418.
In randomized trials to prevent breast milk transmission of human immunodeficiency virus (HIV) from mother to infant, investigators are often interested in assessing the effect of a treatment or intervention on the cumulative risk of HIV infection by time (age) t in infants who are alive and uninfected at a certain time point τ0 < t. Such comparisons are challenging for two reasons. First, infants are typically randomized at birth (time 0 < τ0) such that comparisons between trial arms among the subset of infants alive and uninfected at τ0 are subject to selection bias. Second, in most mother-to-child transmission (MTCT) trials competing risks are often present, such as death or cessation of breastfeeding prior to HIV infection. In this paper we present methods for assessing the causal effect of a treatment on competing risk outcomes within principal strata. In MTCT trials, the causal effect of interest is that of treatment on the risk of HIV infection by time t > τ0 within the principal stratum of infants who would be alive and uninfected by τ0 regardless of randomization assignment. Large sample non-parametric bounds and a semi-parametric sensitivity analysis model are developed for drawing inference about this causal effect. A simulation study is presented demonstrating that the proposed methods perform well in finite samples. The proposed methods are applied to a large, recent MTCT trial.
doi:10.1002/sim.5583
PMCID: PMC3494821  PMID: 22927321
Causal inference; Infectious diseases; Principal stratification; Sensitivity analysis

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