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1.  Individual, family, and neighborhood factors distinguish resilient from non-resilient maltreated children: A cumulative stressors model 
Child abuse & neglect  2007;31(3):231-253.
Objective
Children who are physically maltreated are at risk of a range of adverse outcomes in childhood and adulthood, but some children who are maltreated manage to function well despite their history of adversity. Which individual, family, and neighborhood characteristics distinguish resilient from non-resilient maltreated children? Do children’s individual strengths promote resilience even when children are exposed to multiple family and neighborhood stressors (cumulative stressors model)?
Methods
Data were from the Environmental Risk Longitudinal Study which describes a nationally-representative sample of 1,116 twin pairs and their families. Families were home-visited when the twins were 5 and 7 years old, and teachers provided information about children’s behavior at school. Interviewers rated the likelihood that children had been maltreated based on mothers’ reports of harm to the child and child welfare involvement with the family. Results: Resilient children were those who engaged in normative levels of antisocial behavior despite having been maltreated. Boys (but not girls) who had above-average intelligence and whose parents had relatively few symptoms of antisocial personality were more likely to be resilient versus non-resilient to maltreatment. Children whose parents had substance use problems and who lived in relatively high crime neighborhoods that were low on social cohesion and informal social control were less likely to be resilient versus non-resilient to maltreatment. Consistent with a cumulative stressors model of children’s adaptation, individual strengths distinguished resilient from non-resilient children under conditions of low, but not high, family and neighborhood stress.
Conclusion
These findings suggest that for children residing in multi-problem families, personal resources may not be sufficient to promote their adaptive functioning.
doi:10.1016/j.chiabu.2006.03.011
PMCID: PMC1978062  PMID: 17395260
Resilient maltreated children; Non-resilient maltreated children; Cumulative stressors model
2.  Mental Health and Resilience in HIV/AIDS-Affected Children: A Review of the Literature and Recommendations for Future Research 
Background
To date, research on mental health in HIV-affected children (children who have an HIV-positive caregiver or live with the virus themselves) has focused on risk factors associated with the disease. However, simultaneous identification of factors that contribute to resilience in the face of risks is also needed. A greater understanding of modifiable protective processes that contribute to resilience in the mental health of children affected by HIV can inform the design of interventions that bolster naturally-occurring supports and contribute to early prevention or better management of risks.
Methods
We reviewed the recent literature on mental health and resilience in children and adolescents affected by HIV/AIDS. Literature searches of PsycInfo and PubMed were conducted during July-December 2011 consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Qualitative and quantitative studies were included for review if primary research questions pertained to mental health and coping or protective processes in children and families affected by HIV/AIDS. All studies subject to full review were evaluated for quality using a modified Systematic Assessment of Quality in Observational Research (SAQOR) rating system.
Results
171 unique studies were returned from online searches of the literature and bibliography mining. Of these, 29 were evaluated as pertaining directly to mental health and resilience in families and children living with HIV/AIDS. Eight studies presented qualitative analyses. Ten quantitative studies examined individual resources contributing to child resilience and four quantitative studies looked at family-level resources. Ten studies also investigated community-level interactions. Four presented findings from resilience-focused interventions.
Conclusions
There is a clear need for rigorous research on mental health and resilience in HIV-affected children and adolescents. The evidence base would greatly benefit from more standardized and robust approaches to thinking about resilience from an ecological perspective inclusive of resources at multiple levels and their interactions.
doi:10.1111/j.1469-7610.2012.02613.x
PMCID: PMC3656822  PMID: 22943414
HIV/AIDS; Children; Families; Resilience; Mental Health
3.  Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding—The Kisumu Breastfeeding Study, Kenya: A Clinical Trial 
PLoS Medicine  2011;8(3):e1001015.
Timothy Thomas and colleagues report the results of the Kisumu breastfeeding study (Kenya), a single-arm trial that assessed the feasibility and safety of a triple-antiretroviral regimen to suppress maternal HIV load in late pregnancy.
Background
Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention.
Methods and Findings
HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34–36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load.
Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm3 were 8.4% (95% confidence interval [CI] 5.8%–12.0%) and 4.1% (1.8%–8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%–7.8%) and 8.7% (6.1%–12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%–19.4%).
Conclusions
This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.
Trial registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about half a million children become infected with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS). Nearly all these newly infected children live in resource-limited countries and most acquire HIV from their mother, so-called mother-to-child transmission (MTCT). Without intervention, 25%–50% of babies born to HIV-positive mothers become infected with HIV during pregnancy, delivery, or breastfeeding. This infection rate can be reduced by treating mother and child with antiretroviral (ARV) drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to her baby soon after birth nearly halves the risk of MTCT. Further reductions in risk can be achieved by giving mother and baby three ARVs—an NNRTI and two nucleoside reverse transcriptase inhibitors (NRTIs such as zidovudine and lamivudine)—during pregnancy and perinatally (around the time of birth).
Why Was This Study Done?
Breastfeeding is crucial for child survival in poor countries but it is also responsible for up to half of MTCT. Consequently, many researchers are investigating how various ARV regimens given to mothers and/or their infants during the first few months of life as well as during pregnancy and perinatally affect MTCT. In this single-arm trial, the researchers assess the feasibility and safety of using a triple-ARV regimen to suppress the maternal HIV load (amount of virus in the blood) from late pregnancy though 6 months of breastfeeding among HIV-positive women in Kisumu, Kenya, and ask whether this approach achieves a lower HIV transmission rate than other ARV regimens that have been tested in resource-limited settings. In a single-arm trial, all the participants are given the same treatment. By contrast, in a “randomized controlled” trial, half the participants chosen at random are given the treatment under investigation and the rest are given a control treatment. A randomized controlled trial provides a better comparison of treatments than a single-arm trial but is more costly.
What Did the Researchers Do and Find?
In the Kisumu Breastfeeding Study (KiBS), HIV-infected pregnant women took a triple-ARV regimen containing zidovudine and lamivudine and either nevirapine or the protease inhibitor nelfinavir from 34–36 weeks of pregnancy to 6 months after delivery. They were advised to breastfeed their babies (who received single-dose nevirapine at birth), and to wean them rapidly just before 6 months. The researchers then used Kaplan-Meier statistical methods to estimate HIV transmission and death rates among 487 live-born infants from delivery to 24 months. The cumulative HIV transmission rate rose from 2.5% at birth to 7.0% at 24 months. The cumulative HIV transmission or death rate at 24 months was 15.7%; no infant deaths were attributed to ARVs. At 24 months, 3.0% of babies born to mothers with a low viral load were HIV positive compared to 8.7% of babies born to mothers with a high viral load, a statistically significant difference. Similarly, at 24 months, 8.4% of babies born to mothers with low baseline CD4 cell counts (CD4 cells are immune system cells that are killed by HIV; CD4 cell counts indicate the level of HIV-inflicted immune system damage) were HIV positive compared to 4.1% of babies born to mothers with high baseline CD4 cell counts, although this difference did not achieve statistical significance.
What Do These Findings Mean?
Although these findings are limited by the single-arm design, they support the idea that giving breastfeeding women a triple-ARV regimen from late pregnancy to 6 months is a safe, feasible way to reduce MTCT in resource-limited settings. The HIV transmission rates in this study are comparable to those recorded in similar trials in other resource-limited settings and are lower than MTCT rates observed previously in Kisumu in a study in which no ARVs were used. Importantly, the KiBS mothers took most of the ARVs they were prescribed and most stopped breastfeeding by 6 months as advised. The intense follow-up employed in KiBS may be partly responsible for this good adherence to the trial protocol and thus this study's findings may not be generalizable to all resource-limited settings. Nevertheless, they suggest that a simple triple-ARV regimen given to HIV-positive pregnant women regardless of their baseline CD4 cell count can reduce MTCT during pregnancy and breastfeeding in resource-limited setting.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001015.
The accompanying PLoS Medicine Research article by Zeh and colleagues describes the emergence of resistance to ARVs in KiBS
Information on HIV and AIDS is available from the US National Institute of Allergy and Infectious Diseases
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV http://www.who.int/hiv/topics/mtct/en/index.html (in several languages)
doi:10.1371/journal.pmed.1001015
PMCID: PMC3066129  PMID: 21468300
4.  Young Children's Probability of Dying Before and After Their Mother's Death: A Rural South African Population-Based Surveillance Study 
PLoS Medicine  2013;10(3):e1001409.
Brian Houle and colleagues examine the temporal relationship between mother and child death by using 15 years of data (1994–2008) from household surveys conducted in the Agincourt sub-district of South Africa.
Background
There is evidence that a young child's risk of dying increases following the mother's death, but little is known about the risk when the mother becomes very ill prior to her death. We hypothesized that children would be more likely to die during the period several months before their mother's death, as well as for several months after her death. Therefore we investigated the relationship between young children's likelihood of dying and the timing of their mother's death and, in particular, the existence of a critical period of increased risk.
Methods and Findings
Data from a health and socio-demographic surveillance system in rural South Africa were collected on children 0–5 y of age from 1 January 1994 to 31 December 2008. Discrete time survival analysis was used to estimate children's probability of dying before and after their mother's death, accounting for moderators. 1,244 children (3% of sample) died from 1994 to 2008. The probability of child death began to rise 6–11 mo prior to the mother's death and increased markedly during the 2 mo immediately before the month of her death (odds ratio [OR] 7.1 [95% CI 3.9–12.7]), in the month of her death (OR 12.6 [6.2–25.3]), and during the 2 mo following her death (OR 7.0 [3.2–15.6]). This increase in the probability of dying was more pronounced for children whose mothers died of AIDS or tuberculosis compared to other causes of death, but the pattern remained for causes unrelated to AIDS/tuberculosis. Infants aged 0–6 mo at the time of their mother's death were nine times more likely to die than children aged 2–5 y. The limitations of the study included the lack of knowledge about precisely when a very ill mother will die, a lack of information about child nutrition and care, and the diagnosis of AIDS deaths by verbal autopsy rather than serostatus.
Conclusions
Young children in lower income settings are more likely to die not only after their mother's death but also in the months before, when she is seriously ill. Interventions are urgently needed to support families both when the mother becomes very ill and after her death.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over the past few years, there has been enormous international effort to meet the target set by Millennium Development Goal 4—to reduce the under-five child mortality rate by two-thirds from the 1990 level by 2015. There has been some encouraging progress, and according to the latest figures from the World Health Organization, in 2011, just under 7 million children less than five years died, a fall of almost 3 million from a decade ago. However, such efforts must also consider the health of the mother, as it is now also well established that the health of children is intrinsically linked to their mother's health: there is strong evidence from low- and middle-income countries that children's risk of dying increases around the time of their mother's death, particularly relating to the HIV pandemic in Africa.
Why Was This Study Done?
Previous studies examining the timing of a child's death relative to that of their mother have mainly focused on the period after the mother's death. So far, there have been few studies examining the link between a child's death and the period when his/her mother becomes ill and unable to care for and feed her child. In this study from the Agincourt sub-district in northeast South Africa, the researchers investigated the relationship between young children's chance (odds) of dying and the timing of their mother's death, particularly to examine whether there were critical periods of risk for children before their mother's death.
What Did the Researchers Do and Find?
The researchers used the health and socio-demographic surveillance system in the area, which had 15 years (1994–2008) of information from yearly household surveys. The researchers focused on young children (0–6 months, 7–23 months, and 24–59 months) whose mothers had died, and through a statistical model, analysed the changes in the child's chance (odds) of dying from a year before the mother's death through to any time after her death during the study period. The cause of the mother's death was identified from verbal autopsy and categorized as being related to AIDS or tuberculosis (chronic) or other (mostly acute) causes not related to these infections. The researchers took other factors into account in their analysis and compared the odds of dying for children whose mothers died with those whose mothers were alive.
Using these methods, the researchers found that a total of 1,244 children (3% of the total sample) died between 1994 and 2008. Importantly, the researchers found that although the period when children are more likely to die began to increase in the period 6–11 months before their mother's death, there were three distinct periods of a much higher chance (odds) of death: the period 1–2 months before the month in which their mother died (odds ratio 7.1), the month of her death (odds ratio 12.6), and the period 1–2 months following her death (odds ratio 7.0). Furthermore, during the five-month period around the time of their mother's death, children (both boys and girls) aged 0–6 months were about nine times more likely to die than children aged 24–59 months. Finally, children were about 1.5 times more likely to die if their mother died of an AIDS/tuberculosis-related cause.
What Do These Findings Mean?
These finding suggest that in low-income settings, young children are more likely to die in the months before their mother's death, when she is seriously ill, not just in the period after her death. The chance of dying is particularly increased in very young children (0–6 months) and in children whose mother died of HIV/tuberculosis-related causes. Although this study had several limitations, such as limited information on the child's cause of death, this study highlights the urgent need for proactive and coordinated community-based interventions to support families, especially vulnerable children, when a mother becomes seriously ill, in addition to the period following her death.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001409.
The Countdown to 2015 initiative has the latest country information on progress in reducing maternal, neonatal, and child deaths
The World Health Organization has more information on Millennium Development Goal 4
The Joint United Nations Joint Programme on HIV/AIDS has information about the number of deaths from HIV-related causes
MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt) has more information on the research platform that made this study possible
doi:10.1371/journal.pmed.1001409
PMCID: PMC3608552  PMID: 23555200
5.  HIV, Gender, Race, Sexual Orientation, and Sex Work: A Qualitative Study of Intersectional Stigma Experienced by HIV-Positive Women in Ontario, Canada 
PLoS Medicine  2011;8(11):e1001124.
Mona Loutfy and colleagues used focus groups to examine experiences of stigma and coping strategies among HIV-positive women in Ontario, Canada.
Background
HIV infection rates are increasing among marginalized women in Ontario, Canada. HIV-related stigma, a principal factor contributing to the global HIV epidemic, interacts with structural inequities such as racism, sexism, and homophobia. The study objective was to explore experiences of stigma and coping strategies among HIV-positive women in Ontario, Canada.
Methods and Findings
We conducted a community-based qualitative investigation using focus groups to understand experiences of stigma and discrimination and coping methods among HIV-positive women from marginalized communities. We conducted 15 focus groups with HIV-positive women in five cities across Ontario, Canada. Data were analyzed using thematic analysis to enhance understanding of the lived experiences of diverse HIV-positive women. Focus group participants (n = 104; mean age = 38 years; 69% ethnic minority; 23% lesbian/bisexual; 22% transgender) described stigma/discrimination and coping across micro (intra/interpersonal), meso (social/community), and macro (organizational/political) realms. Participants across focus groups attributed experiences of stigma and discrimination to: HIV-related stigma, sexism and gender discrimination, racism, homophobia and transphobia, and involvement in sex work. Coping strategies included resilience (micro), social networks and support groups (meso), and challenging stigma (macro).
Conclusions
HIV-positive women described interdependent and mutually constitutive relationships between marginalized social identities and inequities such as HIV-related stigma, sexism, racism, and homo/transphobia. These overlapping, multilevel forms of stigma and discrimination are representative of an intersectional model of stigma and discrimination. The present findings also suggest that micro, meso, and macro level factors simultaneously present barriers to health and well being—as well as opportunities for coping—in HIV-positive women's lives. Understanding the deleterious effects of stigma and discrimination on HIV risk, mental health, and access to care among HIV-positive women can inform health care provision, stigma reduction interventions, and public health policy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
HIV-related stigma and discrimination—prejudice, negative attitudes, abuse, and maltreatment directed at people living with HIV—is a major factor contributing to the global HIV epidemic. HIV-related stigma, which devalues and stereotypes people living with HIV, increases vulnerability to HIV infection by reducing access to HIV prevention, testing, treatment, and support. At the personal (micro) level, HIV-related stigma can make it hard for people to take tests to determine their HIV status or to tell other people that they are HIV positive. At the social/community (meso) level, it can mean that HIV-positive people are ostracized from their communities. At the organizational/political (macro) level, it can mean that health-care workers treat HIV-positive people differently and that governments are deterred from taking fast, effective action against the HIV epidemic. In addition, HIV-related stigma is negatively associated with well-being among people living with HIV. Thus, among HIV-positive people, those who have experienced HIV-related stigma have higher levels of mental and physical illness.
Why Was This Study Done?
Racism (oppression and inequity founded on ethno-racial differences), sexism and gender discrimination (oppression and inequity based on gender bias in attitudes), and homophobia and transphobia (discrimination, fear, hostility, and violence towards nonheterosexual and transgender people, respectively) can also affect access to HIV services. However, little is known about how these different forms of stigma and discrimination interact (intersect). A better understanding of the effect of intersecting stigmas on people living with HIV could help in the development of stigma reduction interventions and HIV prevention, treatment and care programs, and could help to control global HIV infection rates. In this qualitative study (an analysis of people's attitudes and experiences rather than numerical data), the researchers investigate the intersection of HIV-related stigma, racism, sexism and gender discrimination, homophobia and transphobia among marginalized HIV-positive women in Ontario, Canada. As elsewhere in the world, HIV infection rates are increasing among women in Canada. Nearly 25% of people living with HIV in Canada are women and about a quarter of all new infections are in women. Moreover, there is a disproportionately high infection rate among marginalized women in Canada such as sex workers and lesbian, bisexual, and queer women.
What Did the Researchers Do and Find?
The researchers held 15 focus groups with 104 marginalized HIV-positive women who were recruited by word-of-mouth and through flyers circulated in community agencies serving women of diverse ethno-cultural origins. Each focus group explored topics that included challenges in daily life, medical issues and needs, and issues that were silenced within the participants' communities. The researchers analyzed the data from these focus groups using thematic analysis, an approach that identifies, analyzes, and reports themes in qualitative data. They found that women living with HIV in Ontario experienced multiple types of stigma at different levels. So, for example, women experienced HIV-related stigma at the micro (“If you're HIV-positive, you feel shameful”), meso (“The thing I hate most for people that test positive for HIV is that society ostracizes them”), and macro (“A lot of women are not getting employed because they have to disclose their status”) levels. The women also attributed their experiences of stigma and discrimination to sexism and gender discrimination, racism, homophobia and transphobia, and involvement in sex work at all three levels and described coping strategies at the micro (resilience; “I always live with hope”), meso (participation in social networks), and macro (challenging stigma) levels.
What Do These Findings Mean?
These findings indicate that marginalized HIV-positive women living in Ontario experience overlapping forms of stigma and discrimination and that these forms of stigma operate over micro, meso, and macro levels, as do the coping strategies adopted by the women. Together, these results support an intersectional model of stigma and discrimination that should help to inform discussions about the complexity of stigma and coping strategies. However, because only a small sample of nonrandomly selected women was involved in this study, these findings need to be confirmed in other groups of HIV-positive women. If confirmed, the complex system of interplay of different forms of stigma revealed here should help to inform health-care provision, stigma reduction interventions, and public-health policy, and could, ultimately, help to bring the global HIV epidemic under control.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001124.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment; its publication HIV and stigma deals with HIV-related stigma in the UK
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on women, HIV, and AIDS, on HIV and AIDS stigma and discrimination, and on HIV/AIDS statistics for Canada (in English and Spanish)
The People Living with Stigma Index to address stigma relating to HIV and advocate on key barriers and issues perpetuating stigma; it has recently published Piecing it together for women and girls, the gender dimensions of HIV-related stigma; its website will soon include a selection of individual stories about HIV-related stigma
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001124
PMCID: PMC3222645  PMID: 22131907
6.  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
7.  Causes of Acute Hospitalization in Adolescence: Burden and Spectrum of HIV-Related Morbidity in a Country with an Early-Onset and Severe HIV Epidemic: A Prospective Survey 
PLoS Medicine  2010;7(2):e1000178.
Rashida Ferrand and colleagues show that HIV infection is the commonest cause of hospitalization among adolescents in a high HIV prevalence setting.
Background
Survival to older childhood with untreated, vertically acquired HIV infection, which was previously considered extremely unusual, is increasingly well described. However, the overall impact on adolescent health in settings with high HIV seroprevalence has not previously been investigated.
Methods and Findings
Adolescents (aged 10–18 y) systematically recruited from acute admissions to the two public hospitals in Harare, Zimbabwe, answered a questionnaire and underwent standard investigations including HIV testing, with consent. Pre-set case-definitions defined cause of admission and underlying chronic conditions. Participation was 94%. 139 (46%) of 301 participants were HIV-positive (median age of diagnosis 12 y: interquartile range [IQR] 11–14 y), median CD4 count = 151; IQR 57–328 cells/µl), but only four (1.3%) were herpes simplex virus-2 (HSV-2) positive. Age (median 13 y: IQR 11–16 y) and sex (57% male) did not differ by HIV status, but HIV-infected participants were significantly more likely to be stunted (z-score<−2: 52% versus 23%, p<0.001), have pubertal delay (15% versus 2%, p<0.001), and be maternal orphans or have an HIV-infected mother (73% versus 17%, p<0.001). 69% of HIV-positive and 19% of HIV-negative admissions were for infections, most commonly tuberculosis and pneumonia. 84 (28%) participants had underlying heart, lung, or other chronic diseases. Case fatality rates were significantly higher for HIV-related admissions (22% versus 7%, p<0.001), and significantly associated with advanced HIV, pubertal immaturity, and chronic conditions.
Conclusion
HIV is the commonest cause of adolescent hospitalisation in Harare, mainly due to adult-spectrum opportunistic infections plus a high burden of chronic complications of paediatric HIV/AIDS. Low HSV-2 prevalence and high maternal orphanhood rates provide further evidence of long-term survival following mother-to-child transmission. Better recognition of this growing phenomenon is needed to promote earlier HIV diagnosis and care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV) that causes AIDS. HIV destroys the cells in the immune system that normally provide protection against disease-causing organisms. Consequently, people infected with HIV are susceptible to so-called opportunistic infections, including tuberculosis and pneumonia. HIV is most commonly spread through unprotected sex with an infected partner but another major route of transmission is mother-to-child (vertical transmission) during pregnancy or delivery or during breast feeding. Mother-to-child transmission can be prevented by giving antiviral drugs to HIV-positive mothers during their pregnancy and to their newborn children. But, although most mothers in developed countries have access to this intervention, fewer than half of HIV-positive mothers in low- and middle-income countries receive this treatment and, every year, nearly half a million children become infected with HIV.
Why Was This Study Done?
It is generally thought that HIV infections in infants progress rapidly and that half of the children who acquire HIV from their mothers will die before their second birthday if not treated with antiretroviral drugs. However, as the AIDS epidemic matures, more children are surviving to adolescence with untreated, vertically acquired HIV infection in sub-Saharan Africa, the region where most children with HIV/AIDS live. Little is known about the burden of HIV infection and its contribution to illness and death in adolescents in sub-Saharan Africa but this information is needed to help health care providers prepare for this new aspect of the AIDS epidemic. In this study, the researchers examine the causes of acute hospital admissions (admissions for conditions with a sudden onset and usually a short course) among adolescents in Zimbabwe, a country where the HIV epidemic started early and where one in seven adults is HIV-positive and more than 17,000 children are infected with HIV every year, mainly through vertical transmission.
What Did the Researchers Do and Find?
The researchers recruited 301 10–18-year olds who were admitted to each of the two public hospitals in Harare (Zimbabwe) for acute illnesses between September 2007 and April 2008. Each patient completed a questionnaire about themselves and their health and underwent standard investigations, including HIV testing. Nearly half the participants were HIV positive; about a quarter of these HIV-positive individuals only found out about their status during the study. HIV-positive participants were more likely to be stunted, to have pubertal delay, and to be maternal orphans or have an HIV-infected mother than HIV-negative participants. 69% of HIV-positive participants were admitted to hospital because of infections, often tuberculosis or pneumonia whereas only 19% of the HIV-negative participants were admitted for infections. More than a quarter of all the participants had underlying heart, lung, or other chronic conditions. Finally, 22% of the HIV-positive participants died while in hospital compared to only 7% of the HIV-negative participants. Factors that increased the risk of death among all the participants were advanced HIV infection, pubertal immaturity, and chronic conditions.
What Do These Findings Mean?
These findings indicate that HIV infection is the commonest cause of acute adolescent admission to hospital in Harare (and probably elsewhere in Zimbabwe). Most of these admissions are due to opportunistic infections similar to those seen in HIV-positive adults and to long-term complications of having HIV/AIDS as an infant such as delayed puberty. Other findings indicate that most of the HIV-positive adolescents who participated in this study were infected via vertical transmission, which supports the idea that long-term survival after vertical infection is possible. Because the AIDS epidemic started early in Zimbabwe, there is likely to be a lag before adolescent survivors of vertical HIV transmission become common elsewhere. Nevertheless, all African countries and other places where HIV infection in adults is common need to recognize that the burden of HIV in their acutely unwell adolescents is likely to increase over the next few years. To deal with this emerging aspect of the AIDS epidemic, measures must be introduced to ensure early diagnosis of HIV in this previously neglected age group so that treatment can be started before HIV-positive adolescents become critically ill.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000178.
This study is further discussed in a PLoS Medicine Perspective by Glenda Gray
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including a list of articles and other sources of information about the primary care of adolescents with HIV
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Zimbabwe, and on children, HIV, and AIDS (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
doi:10.1371/journal.pmed.1000178
PMCID: PMC2814826  PMID: 20126383
8.  Measuring Coverage in MNCH: Population HIV-Free Survival among Children under Two Years of Age in Four African Countries 
PLoS Medicine  2013;10(5):e1001424.
Background
Population-based evaluations of programs for prevention of mother-to-child HIV transmission (PMTCT) are scarce. We measured PMTCT service coverage, regimen use, and HIV-free survival among children ≤24 mo of age in Cameroon, Côte D'Ivoire, South Africa, and Zambia.
Methods and Findings
We randomly sampled households in 26 communities and offered participation if a child had been born to a woman living there during the prior 24 mo. We tested consenting mothers with rapid HIV antibody tests and tested the children of seropositive mothers with HIV DNA PCR or rapid antibody tests. Our primary outcome was 24-mo HIV-free survival, estimated with survival analysis. In an individual-level analysis, we evaluated the effectiveness of various PMTCT regimens. In a community-level analysis, we evaluated the relationship between HIV-free survival and community PMTCT coverage (the proportion of HIV-exposed infants in each community that received any PMTCT intervention during gestation or breastfeeding). We also compared our community coverage results to those of a contemporaneous study conducted in the facilities serving each sampled community. Of 7,985 surveyed children under 2 y of age, 1,014 (12.7%) were HIV-exposed. Of these, 110 (10.9%) were HIV-infected, 851 (83.9%) were HIV-uninfected, and 53 (5.2%) were dead. HIV-free survival at 24 mo of age among all HIV-exposed children was 79.7% (95% CI: 76.4, 82.6) overall, with the following country-level estimates: Cameroon (72.6%; 95% CI: 62.3, 80.5), South Africa (77.7%; 95% CI: 72.5, 82.1), Zambia (83.1%; 95% CI: 78.4, 86.8), and Côte D'Ivoire (84.4%; 95% CI: 70.0, 92.2). In adjusted analyses, the risk of death or HIV infection was non-significantly lower in children whose mothers received a more complex regimen of either two or three antiretroviral drugs compared to those receiving no prophylaxis (adjusted hazard ratio: 0.60; 95% CI: 0.34, 1.06). Risk of death was not different for children whose mothers received a more complex regimen compared to those given single-dose nevirapine (adjusted hazard ratio: 0.88; 95% CI: 0.45, 1.72). Community PMTCT coverage was highest in Cameroon, where 75 of 114 HIV-exposed infants met criteria for coverage (66%; 95% CI: 56, 74), followed by Zambia (219 of 444, 49%; 95% CI: 45, 54), then South Africa (152 of 365, 42%; 95% CI: 37, 47), and then Côte D'Ivoire (3 of 53, 5.7%; 95% CI: 1.2, 16). In a cluster-level analysis, community PMTCT coverage was highly correlated with facility PMTCT coverage (Pearson's r = 0.85), and moderately correlated with 24-mo HIV-free survival (Pearson's r = 0.29). In 14 of 16 instances where both the facility and community samples were large enough for comparison, the facility-based coverage measure exceeded that observed in the community.
Conclusions
HIV-free survival can be estimated with community surveys and should be incorporated into ongoing country monitoring. Facility-based coverage measures correlate with those derived from community sampling, but may overestimate population coverage. The more complex regimens recommended by the World Health Organization seem to have measurable public health benefit at the population level, but power was limited and additional field validation is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
For a pregnant woman who is HIV-positive, the discrepancy across the world in outlook for mother and child is stark. Mother-to-child transmission of HIV during pregnancy is now less than 1% in many high-income settings, but occurs much more often in low-income countries. Three interventions have a major impact on transmission of HIV to the baby: antiretroviral drugs, mode of delivery, and type of infant feeding. The latter two are complex, as the interventions commonly used in high-income countries (cesarean section if the maternal viral load is high; exclusive formula feeding) have their own risks in low-income settings. Minimizing the risks of transmitting HIV through effective drug regimes therefore becomes particularly important. Monitoring progress on reducing the incidence of mother-to-child HIV transmission is essential, but not always easy to achieve.
Why Was This Study Done?
A research group led by Stringer and colleagues recently reported a study from four countries in Africa: Cameroon, Côte D'Ivoire, South Africa, and Zambia. The study showed that even in the health facility setting (e.g., hospitals and clinics), only half of infants whose mothers were HIV-positive received the minimum recommended drug treatment (one dose of nevirapine during labor) to prevent HIV transmission. Across the population of these countries, it is possible that fewer receive antiretroviral drugs, as the study did not include women who did not access health facilities. Therefore, the next stage of the study by this research group, reported here, involved going into the communities around these health facilities to find out how many infants under two years old had been exposed to HIV, whether they had received drugs to prevent transmission, and what proportion were alive and not infected with HIV at two years old.
What Did the Researchers Do and Find?
The researchers tested all consenting women who had delivered a baby in the last two years in the surrounding communities. If the mother was found to be HIV-positive, then the infant was also tested for HIV. The researchers then calculated how many of the infants would be alive at two years and free of HIV infection.
Most mothers (78%) agreed to testing for themselves and their infants. There were 7,985 children under two years of age in this study, of whom 13% had been born to an HIV-positive mother. Less than half (46%) of the HIV-positive mothers had received any drugs to prevent HIV transmission. Of the children with HIV-positive mothers, 11% were HIV-infected, 84% were not infected with HIV, and 5% had died. Overall, the researchers estimated that around 80% of these children would be alive at two years without HIV infection. This proportion differed non-significantly between the four countries (ranging from 73% to 84%). The researchers found higher rates of infant survival than they had expected and knew that they might have missed some infant deaths (e.g., if households with infant deaths were less likely to take part in the study).
The researchers found that their estimates of the proportion of HIV-positive mothers who received drugs to prevent transmission were fairly similar between their previous study, looking at health facilities, and this study of the surrounding communities. However, in 14 out of 16 comparisons, the estimate from the community was lower than that from the facility.
What Do These Findings Mean?
This study shows that it would be possible to estimate how many infants are surviving free of HIV infection using a study based in the community, and that these estimates may be more accurate than those for studies based in health facilities. There are still a large proportion of HIV-positive mothers who are not receiving drugs to prevent transmission to the baby. The authors suggest that using two or three drugs to prevent HIV may help to reduce transmission.
There are already community surveys conducted in many low-income countries, but they have not included routine infant testing for HIV. It is now essential that organizations providing drugs, money, and infrastructure in this field consider more accurate means of monitoring incidence of HIV transmission from mother to infant, particularly at the community level.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001424.
The World Health Organization has more information on mother-to-child transmission of HIV
The United Nations Children's Fund has more information on the status of national PMTCT responses in the most affected countries
doi:10.1371/journal.pmed.1001424
PMCID: PMC3646218  PMID: 23667341
9.  Promoting Resilience among Parents and Caregivers of Children with Cancer 
Journal of Palliative Medicine  2013;16(6):645-652.
Abstract
Background
Promoting resilience is an aspect of psychosocial care that affects patient and whole-family well-being. There is little consensus about how to define or promote resilience during and after pediatric cancer.
Objectives
The aims of this study were (1) to review the resilience literature in pediatric cancer settings; (2) to qualitatively ascertain caregiver-reported perceptions of resilience; and (3) to develop an integrative model of fixed and mutable factors of resilience among family members of children with cancer, with the goal of enabling better study and promotion of resilience among pediatric cancer families.
Methods
The study entailed qualitative analysis of small group interviews with eighteen bereaved parents and family members of children with cancer treated at Seattle Children's Hospital. Small-group interviews were conducted with members of each bereaved family. Participant statements were coded for thematic analysis. An integrative, comprehensive framework was then developed.
Results
Caregivers' personal appraisals of the cancer experience and their child's legacy shape their definitions of resilience. Described factors of resilience include baseline characteristics (i.e., inherent traits, prior expectations of cancer), processes that evolve over time (i.e., coping strategies, social support, provider interactions), and psychosocial outcomes (i.e., post-traumatic growth and lack of psychological distress). These elements were used to develop a testable model of resilience among family members of children with cancer.
Conclusions
Resilience is a complex construct that may be modifiable. Once validated, the proposed framework will not only serve as a model for clinicians, but may also facilitate the development of interventions aimed at promoting resilience in family members of children with cancer.
doi:10.1089/jpm.2012.0494
PMCID: PMC3719479  PMID: 23646887
10.  Barriers to Provider-Initiated Testing and Counselling for Children in a High HIV Prevalence Setting: A Mixed Methods Study 
PLoS Medicine  2014;11(5):e1001649.
Rashida Ferrand and colleagues combine quantitative and qualitative methods to investigate HIV prevalence among older children receiving primary care in Harare, Zimbabwe, and reasons why providers did not pursue testing.
Please see later in the article for the Editors' Summary
Background
There is a substantial burden of HIV infection among older children in sub-Saharan Africa, the majority of whom are diagnosed after presentation with advanced disease. We investigated the provision and uptake of provider-initiated HIV testing and counselling (PITC) among children in primary health care facilities, and explored health care worker (HCW) perspectives on providing HIV testing to children.
Methods and Findings
Children aged 6 to 15 y attending six primary care clinics in Harare, Zimbabwe, were offered PITC, with guardian consent and child assent. The reasons why testing did not occur in eligible children were recorded, and factors associated with HCWs offering and children/guardians refusing HIV testing were investigated using multivariable logistic regression. Semi-structured interviews were conducted with clinic nurses and counsellors to explore these factors. Among 2,831 eligible children, 2,151 (76%) were offered PITC, of whom 1,534 (54.2%) consented to HIV testing. The main reasons HCWs gave for not offering PITC were the perceived unsuitability of the accompanying guardian to provide consent for HIV testing on behalf of the child and lack of availability of staff or HIV testing kits. Children who were asymptomatic, older, or attending with a male or a younger guardian had significantly lower odds of being offered HIV testing. Male guardians were less likely to consent to their child being tested. 82 (5.3%) children tested HIV-positive, with 95% linking to care. Of the 940 guardians who tested with the child, 186 (19.8%) were HIV-positive.
Conclusions
The HIV prevalence among children tested was high, highlighting the need for PITC. For PITC to be successfully implemented, clear legislation about consent and guardianship needs to be developed, and structural issues addressed. HCWs require training on counselling children and guardians, particularly male guardians, who are less likely to engage with health care services. Increased awareness of the risk of HIV infection in asymptomatic older children is needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over 3 million children globally are estimated to be living with HIV (the virus that causes AIDS). While HIV infection is most commonly spread through unprotected sex with an infected person, most HIV infections among children are the result of mother-to-child HIV transmission during pregnancy, delivery, or breastfeeding. Mother-to-child transmission can be prevented by administering antiretroviral therapy to mothers with HIV during pregnancy, delivery, and breast feeding, and to their newborn babies. According to a report by the Joint United Nations Programme on HIV/AIDS published in 2012, 92% of pregnant women with HIV were living in sub-Saharan Africa and just under 60% were receiving antiretroviral therapy. Consequently, sub-Saharan Africa is the region where most children infected with HIV live.
Why Was This Study Done?
If an opportunity to prevent mother-to-child transmission around the time of birth is missed, diagnosis of HIV infection in a child or adolescent is likely to depend on HIV testing in health care facilities. Health care provider–initiated HIV testing and counselling (PITC) for children is important in areas where HIV infection is common because earlier diagnosis allows children to benefit from care that can prevent the development of advanced HIV disease. Even if a child or adolescent appears to be in good health, access to care and antiretroviral therapy provides a health benefit to the individual over the long term. The administration of HIV testing (and counselling) to children relies not only on health care workers (HCWs) offering HIV testing but also on parents or guardians consenting for a child to be tested. However, more than 30% of children in countries with severe HIV epidemics are AIDS orphans, and economic conditions in these countries cause many adults to migrate for work, leaving children under the care of extended families. This study aimed to investigate the reasons for acceptance and rejection of PITC in primary health care settings in Harare, Zimbabwe. By exploring HCW perspectives on providing HIV testing to children and adolescents, the study also sought to gain insight into factors that could be hindering implementation of testing procedures.
What Did the Researchers Do and Find?
The researchers identified all children aged 6 to 15 years old at six primary care clinics in Harare, who were offered HIV testing as part of routine care between 22 January and 31 May 2013. Study fieldworkers collected data on numbers of child attendances, numbers offered testing, numbers who underwent HIV testing, and reasons why HIV testing did not occur. During the study 2,831 children attending the health clinics were eligible for PITC, and just over half (1,534, 54.2%) underwent HIV testing. Eighty-two children tested HIV-positive, and nearly all of them received counselling, medication, and follow-up care. HCWs offered the test to around 75% of those eligible. The most frequent explanation given by HCWs for a diagnostic test not being offered was that the child was accompanied by a guardian not appropriate for providing consent (401 occasions, 59%); Other reasons given were a lack of available counsellors or test kits and counsellors refusing to conduct the test. The likelihood of being offered the test was lower for children not exhibiting symptoms (such as persistent skin problems), older children, or those attending with a male or a younger guardian. In addition, over 100 guardians or parents provided consent but left before the child could be tested.
The researchers also conducted semi-structured interviews with 12 clinic nurses and counsellors (two from each clinic) to explore challenges to implementation of PITC. The researchers recorded the factors associated with testing not taking place, either when offered to eligible children or when HCWs declined to offer the test. The interviewees identified the frequent absence or unavailability of parents or legal guardians as an obstacle, and showed uncertainty or misconceptions around whether testing of the guardian was mandatory (versus recommended) and whether specifically a parent (if one was living) must provide consent. The interviews also revealed HCW concerns about the availability of adequate counselling and child services, and fears that a child might experience maltreatment if he or she tested positive. HCWs also noted long waiting times and test kits being out of stock as practical hindrances to testing.
What Do These Findings Mean?
Prevalence of HIV was high among the children tested, validating the need for PITC in sub-Saharan health care settings. Although 76% of eligible attendees were offered testing, the authors note that this is likely higher than in routine settings because the researchers were actively recording reasons for not offering testing and counselling, which may have encouraged heath care staff to offer PITC more often than usual. The researchers outline strategies that may improve PITC rates and testing acceptance for Zimbabwe and other sub-Saharan settings. These strategies include developing clear laws and guidance concerning guardianship and proxy consent when testing older children for HIV, training HCWs around these policies, strengthening legislation to address discrimination, and increasing public awareness about HIV infection in older children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001649.
This study is further discussed in a PLOS Medicine Perspective by Davies and Kalk
The Joint United Nations Programme on HIV/AIDS publishes an annual report on the global AIDS epidemic, which provides information on progress towards eliminating new HIV infections
The World Health Organization has more information on mother-to-child transmission of HIV
The World Health Organization's website also has information about treatment for children living with HIV
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through NAM/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001649
PMCID: PMC4035250  PMID: 24866209
11.  Resilience, an Evolving Concept: A Review of Literature Relevant to Aboriginal Research 
Pimatisiwin  2008;6(2):7-23.
Resilience has been most frequently defined as positive adaptation despite adversity. Over the past 40 years, resilience research has gone through several stages. From an initial focus on the invulnerable or invincible child, psychologists began to recognize that much of what seems to promote resilience originates outside of the individual. This led to a search for resilience factors at the individual, family, community — and, most recently, cultural — levels. In addition to the effects that community and culture have on resilience in individuals, there is growing interest in resilience as a feature of entire communities and cultural groups. Contemporary researchers have found that resilience factors vary in different risk contexts and this has contributed to the notion that resilience is a process. In order to characterize the resilience process in a particular context, it is necessary to identify and measure the risk involved and, in this regard, perceived discrimination and historical trauma are part of the context in many Aboriginal communities. Researchers also seek to understand how particular protective factors interact with risk factors and with other protective factors to support relative resistance. For this purpose they have developed resilience models of three main types: “compensatory,” “protective,” and “challenge” models. Two additional concepts are resilient reintegration, in which a confrontation with adversity leads individuals to a new level of growth, and the notion endorsed by some Aboriginal educators that resilience is an innate quality that needs only to be properly awakened.
The review suggests five areas for future research with an emphasis on youth: 1) studies to improve understanding of what makes some Aboriginal youth respond positively to risk and adversity and others not; 2) case studies providing empirical confirmation of the theory of resilient reintegration among Aboriginal youth; 3) more comparative studies on the role of culture as a resource for resilience; 4) studies to improve understanding of how Aboriginal youth, especially urban youth, who do not live in self-governed communities with strong cultural continuity can be helped to become, or remain, resilient; and 5) greater involvement of Aboriginal researchers who can bring a nonlinear world view to resilience research.
PMCID: PMC2956753  PMID: 20963184 CAMSID: cams387
12.  “I know it when I see it.” The complexities of measuring resilience among parents of children with cancer 
Purpose
Promoting parent resilience may provide an opportunity to improve family-level survivorship after pediatric cancer; however, measuring resilience is challenging.
Methods
The “Understanding Resilience in Parents of Children with Cancer” was a cross-sectional, mixed-methods study of bereaved and non-bereaved parents. Surveys included the Connor-Davidson Resilience scale, the Kessler-6 psychological distress scale, the Post-Traumatic Growth Inventory, and an open-ended question regarding the on-going impact of cancer. We conducted content analyses of open-ended responses and categorized our impressions as “resilient,” “not resilient,” or “unable to determine.” “Resilience” was determined based on evidence of psychological growth, lack of distress, and parent-reported meaning/purpose. We compared consensus-impressions with instrument scores to examine alignment. Analyses were stratified by bereavement status.
Results
Eighty-four (88%) non-bereaved, and 21 (88%) bereaved parents provided written responses. Among non-bereaved, 53 (63%) were considered resilient, 15 (18%) were not. Among bereaved, 11 (52%) were deemed resilient, 5 (24%) were not. All others suggested a mixed or incomplete picture. Rater-determined “resilient” parents tended to have higher personal resources and lower psychological distress (p=<0.001–0.01). Non-bereaved “resilient” parents also had higher post-traumatic growth (p=0.02). Person-level analyses demonstrated that only 50–62% of parents had all 3 instrument scores aligned with our impressions of resilience.
Conclusions
Despite multiple theories, measuring resilience is challenging. Our clinical impressions of resilience were aligned in 100% of cases; however, instruments measuring potential markers of resilience were aligned in approximately half. Promoting resilience therefore requires understanding of multiple factors, including person-level perspectives, individual resources, processes of adaptation and emotional well-being.
doi:10.1007/s00520-014-2249-5
PMCID: PMC4264630  PMID: 24756554
Cancer; Oncology; Pediatrics; Parents; Resilience; Psychosocial Outcomes
13.  Adolescent Response to Having an HIV-infected Mother 
AIDS care  2013;25(6):10.1080/09540121.2013.769495.
In this study, late adolescents/early adults whose mothers were living with HIV (MLH) were interviewed in order to explore their perceptions of what it had been like for them to grow up under the shadow of their mothers’ illness. Adolescents were asked to describe what the difficult aspects of growing up with an HIV-positive mother were as well as what, if any, were the more rewarding aspects. Interviews were conducted in 2009 - 2010 with a random sample of 40 adolescents being followed in a longitudinal assessment study. All study participants were English or Spanish speaking. Mean age was 18.9 (SD = 1.9) years; 67.5% were Latino; 27.5% African American; and 5% other/multi-racial. Results revealed that growing up with an HIV-positive mother had both challenges as well as rewards. On the challenge side, adolescents mentioned six main issues: (1) disappointment regarding mothers’ missing of childhood activities and events; (2) worry about mothers’ health; (3) worry about the possibility of mothers’ death; (4) increased burden of adult responsibilities/caregiving; (5) feelings of secrecy/stigma associated with HIV/AIDS; and (6) need to self-monitor behavior and communication to avoid maternal stress. On the positive side, adolescents mentioned three main rewarding aspects of growing up with an HIV-positive mother: increased closeness in the mother-child relationship; fostering of positive personality traits (e.g., resilience, gratitude, open-mindedness); and “perks” accorded to HIV-affected families.
doi:10.1080/09540121.2013.769495
PMCID: PMC3832195  PMID: 23414445
HIV+ Mothers; Family Functioning; Chronic Illness; Qualitative Interviews; Longitudinal Study
14.  Resilience to Maternal Depression in Young Adulthood 
Developmental Psychology  2010;46(4):805-814.
Using a prospective longitudinal design this study investigated factors associated with resilience in 20-year old offspring of depressed mothers (n=648). Resilient youth were operationally defined as those whose mothers were depressed, but who themselves had no history of recurrent depression, and currently evidenced adequate academic/work and romantic functioning, no Axis I psychopathology, and no clinically significant internalizing behavior problems. Low levels of perceived maternal psychological control (p=.02), and high child IQ (p<.01) acted as protective factors in the context of maternal depression. Low paternal psychological control (p=.02), high maternal warmth (p<.01), high self esteem (p<.01), and healthy peer social functioning (p<.01) all acted as resource factors predicting high functioning outcomes for young adults, regardless of mother depression status. Notably, high child IQ acted as a protective factor predicting resilient outcomes that persisted from adolescence to adulthood (p<.01), and low maternal psychological control acted as a protective factor predicting resilient outcomes that emerged in early adulthood (p=.03). Interventions focused on these two protective factors might yield the strongest benefits for offspring of depressed mothers as they transition to early adulthood.
doi:10.1037/a0019817
PMCID: PMC3375903  PMID: 20604603
maternal depression; resilience; young adulthood
15.  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
16.  Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Infected Women Receiving Cotrimoxazole Prophylaxis: A Multicenter Randomized Placebo-Controlled Trial 
PLoS Medicine  2014;11(9):e1001735.
Clara Menéndez and colleagues conducted a randomized controlled trial among HIV-positive pregnant women in Kenya, Mozambique, and Tanzania to investigate the safety and efficacy of mefloquine as intermittent preventative therapy for malaria in women receiving cotrimoxazole prophylaxis and long-lasting insecticide treated nets.
Please see later in the article for the Editors' Summary
Background
Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).
Methods and Findings
A total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27–0.82]; p = 0.008), placental malaria (RR, 0.52 [95% CI 0.29–0.90]; p = 0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37–0.95]; p = 0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p = 0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14–3.33]; p = 0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.
Conclusions
An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.
Trial registration
ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, kills about 600,000 people every year. Most of these deaths occur among young children living in sub-Saharan Africa but pregnant women living in Africa are also very vulnerable to malaria. Infection with malaria during pregnancy can cause severe maternal anemia (reduced red blood cell numbers), stillbirths, and pre-term and low-birthweight babies, and is responsible for the deaths of many African women and their babies. To reduce the loss of life from malaria in pregnancy, the World Health Organization (WHO) recommends that pregnant women living in Africa receive the antimalarial drug sulfadoxine-pyrimethamine (SP) at each scheduled antenatal care visit given at least a month apart (intermittent preventive treatment in pregnancy [IPTp]). In addition, WHO advises pregnant women to sleep under insecticide-treated bed nets to protect themselves from the bites of infected mosquitoes and recommends effective case management of pregnant women with malarial illness.
Why Was This Study Done?
Pregnant women living in Africa are often infected with HIV, the virus that causes AIDS. HIV infection increases both the risk and severity of malaria infection during pregnancy, and at least one million pregnancies are complicated by co-infection with malaria and HIV in sub-Saharan Africa every year. WHO recommends that HIV-positive pregnant women take cotrimoxazole (CTX) daily to prevent opportunistic infections (CTX prophylaxis [CTXp]). Unfortunately, both CTX and SP are antifolate drugs and taking two drugs of this type increases a woman's risk of developing a severe skin reaction. Moreover, although CTXp protects children and HIV-infected adults against malaria, it is not known whether CTXp alone protects HIV-infected pregnant women adequately against malaria. Thus, evaluations of alternative drugs for use in IPTp in HIV-positive pregnant women are needed. In this randomized placebo-controlled trial, the researchers study the safety and efficacy of the antimalarial drug mefloquine (MQ) in HIV-infected women receiving CTXp. A randomized, placebo-controlled trial compares outcomes among people chosen through the play of chance to receive either the drug under investigation or a “dummy” (placebo) drug.
What Did the Researchers Do and Find?
The researchers allocated 1,071 HIV-infected pregnant women from Kenya, Mozambique, and Tanzania to receive three doses of MQ (IPTp-MQ), given at least one month apart, or three doses of placebo. All the women received CTXp and were given an insecticide-treated bed net. In an intention-to-treat analysis (an analysis that considers the outcomes of all trial participants irrespective of whether they receive their allocated treatment), the prevalence of parasitemia (parasites in the blood) at delivery among women given IPTp-MQ was 3.5% whereas the prevalence among women given the placebo was 6.9%. In other words, compared to placebo, IPTp-MQ was associated with a reduced risk of maternal parasitemia. IPTp-MQ was also associated with a reduced rate of placental malaria (parasites in the placenta) and a reduced incidence of hospital admissions for non-pregnancy related causes. There was no difference in adverse pregnancy outcomes such as stillbirth between the intervention groups but drug tolerability was poorer in the MQ group than in the placebo group. Finally, in an exploratory (unplanned) according-to-protocol analysis (an analysis that only considers outcomes in trial participants who receive their allocated intervention), women in the MQ group had a higher HIV viral load at delivery than women in the control group and were nearly twice as likely to transmit HIV to their child around the time of birth.
What Do These Findings Mean?
These findings suggest that the addition of IPTp-MQ to CTXp and the use of insecticide-treated bed nets can improve malaria prevention and maternal health in HIV-infected pregnant women in Africa. However, the poor tolerability of MQ and the association of MQ treatment with both an increased HIV viral load at delivery and a higher frequency of mother-to-child-transmission of HIV when compared to placebo raise concerns about the use of MQ in IPTp. Because these last two findings came from an exploratory analysis, which is more likely to throw up a chance finding than a pre-planned analysis further studies are needed to confirm these unexpected but potentially important findings. Nevertheless, overall, the findings of this study suggest that MQ should not be recommended for IPTp in HIV-infected pregnant women in Africa and highlight the need to find alternative drugs for malaria prevention in this group of women who are particularly vulnerable to malaria.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001735.
This study is further discussed in a PLOS Medicine Perspective by Richard Steketee.
A related PLOS Medicine Research Article by González et al. compares the efficacy of IPTp-MQ and IPTp-SP in HIV-negative women
Information is available from the World Health Organization on malaria (in several languages) and on malaria in pregnancy; information on IPTp and the current WHO policy recommendation on IPTp with SP are available; the 2013 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention also provides information on malaria; a personal story about malaria in pregnancy is available
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy
MedlinePlus provides links to additional information on malaria (in English and Spanish)
More information about the trial protocol is available
doi:10.1371/journal.pmed.1001735
PMCID: PMC4172537  PMID: 25247995
17.  Two-Year Morbidity–Mortality and Alternatives to Prolonged Breast-Feeding among Children Born to HIV-Infected Mothers in Côte d'Ivoire 
PLoS Medicine  2007;4(1):e17.
Background
Little is known about the long-term safety of infant feeding interventions aimed at reducing breast milk HIV transmission in Africa.
Methods and Findings
In 2001–2005, HIV-infected pregnant women having received in Abidjan, Côte d'Ivoire, a peripartum antiretroviral prophylaxis were presented antenatally with infant feeding interventions: either artificial feeding, or exclusive breast-feeding and then early cessation from 4 mo of age. Nutritional counseling and clinical management were provided for 2 y. Breast-milk substitutes were provided for free. The primary outcome was the occurrence of adverse health outcomes in children, defined as validated morbid events (diarrhea, acute respiratory infections, or malnutrition) or severe events (hospitalization or death). Hazards ratios to compare formula-fed versus short-term breast-fed (reference) children were adjusted for confounders (baseline covariates and pediatric HIV status as a time-dependant covariate). The 18-mo mortality rates were also compared to those observed in the Ditrame historical trial, which was conducted at the same sites in 1995–1998, and in which long-term breast-feeding was practiced in the absence of any specific infant feeding intervention. Of the 557 live-born children, 262 (47%) were breast-fed for a median of 4 mo, whereas 295 were formula-fed. Over the 2-y follow-up period, 37% of the formula-fed and 34% of the short-term breast-fed children remained free from any adverse health outcome (adjusted hazard ratio [HR]: 1.10; 95% confidence interval [CI], 0.87–1.38; p = 0.43). The 2-y probability of presenting with a severe event was the same among formula-fed (14%) and short-term breast-fed children (15%) (adjusted HR, 1.19; 95% CI, 0.75–1.91; p = 0.44). An overall 18-mo probability of survival of 96% was observed among both HIV-uninfected short-term and formula-fed children, which was similar to the 95% probability observed in the long-term breast-fed ones of the Ditrame trial.
Conclusions
The 2-y rates of adverse health outcomes were similar among short-term breast-fed and formula-fed children. Mortality rates did not differ significantly between these two groups and, after adjustment for pediatric HIV status, were similar to those observed among long-term breast-fed children. Given appropriate nutritional counseling and care, access to clean water, and a supply of breast-milk substitutes, these alternatives to prolonged breast-feeding can be safe interventions to prevent mother-to-child transmission of HIV in urban African settings.
Given appropriate nutritional counseling and care, access to clean water, and supply of breast milk substitutes, replacing prolonged breast-feeding with formula-feeding appears to be a safe intervention to prevent mother-to-child transmission of HIV in this setting.
Editors' Summary
Background.
The HIV virus can be transmitted from infected mothers to their babies during pregnancy and birth as well as after birth through breast milk. Mother-to-child transmission in developed countries has been all but eliminated by treatment of mothers with the best available combination of antiretroviral drugs and by asking them to avoid breast-feeding. However, in many developing countries, the best drug treatments are not available to mothers. Moreover, breast-feeding is generally the best nutritional choice for infants, especially in areas where resources such as clean water, formula feed, and provision of healthcare are scarce. And even if formula feed is available, formula-fed babies might be at higher risk of dying from diarrhea and chest infections, which are more common in infants who are not breast-fed. International guidelines say that HIV-positive mothers should avoid all breast-feeding and adopt formula feeding instead if this option is practical and safe for them, which would require that they can afford formula feed and have easy access to clean water. If formula-feeding is not feasible, guidelines recommend that mothers should breast-feed only for the first few months and then stop and switch the baby to solid food. One of these two alternative options should be feasible in most African cities if mothers are given the right support.
Why Was This Study Done?
Several completed and ongoing studies are assessing the relative risks and benefits of the two recommended strategies for different developing country locations, and this is one of them. The study, the “Ditrame Plus” trial by researchers from France and Côte d'Ivoire, was conducted in Abidjan, an urban West African setting. The goal was to compare death rates and rates of certain diseases (such as diarrhea and chest infections) between babies born to HIV-positive mothers that were formula-fed and those that were breast-fed for a short time after birth.
What Did the Researchers Do and Find?
HIV-positive pregnant women were invited to enter the study, and they received short-term drug treatments intended to reduce the risk of HIV transmission to their babies. Women in the trial were then asked to choose one of the two feeding options and offered support and counseling for either one. This support included free formula, transport, and healthcare provision. Babies were followed up to their second birthday, and data were collected on death rates and any serious illnesses. A total of 643 women were enrolled into the study, and safety data were collected for 557 babies, of whom 295 were in the formula group and 262 were in the short-term breast-feeding group. The researchers corrected for HIV infection in the babies and found no evidence that the risk of other negative health outcomes and death rates was any different between the formula-fed babies and short-term breast-fed babies. Looking specifically at individual diseases, the researchers found that the risks for diarrhea and chest infections were slightly higher among formula-fed babies, but this did not translate into a greater risk of death or worse overall health. They also compared the death rates in this study with some historical data from a previous research project done in the same area on children born to HIV-positive mothers who had practiced long-term breast-feeding. The mother-to-child transmission rate of HIV had been much higher in that earlier trial, but looking only at the HIV-negative children, the researchers found no difference in risk for death or serious disease between the formula-fed or short-term breast-fed babies from the Ditrame Plus trial and the long-term breast-fed babies from the earlier trial.
What Do These Findings Mean?
This study shows that if HIV-positive mothers are well supported, either of the two feeding options currently recommended (formula-only feed, or short-term breast-feeding) are likely to be equivalent in terms of the baby's chances for survival and health. However, women in this study were offered a great deal of support and the findings may not necessarily apply to real-life situations in other settings in Africa, or outside the context of a research project. In addition to routine care after birth, access to better drugs to prevent mother-to-child transmission in developing countries remains an important goal.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040017.
Resources from Avert (an AIDS charity) on HIV and infant feeding.
Information from the US Centers for Disease Control on mother-to-child transmission of HIV
Guidelines from the World Health Organization on mother-to-child transmission of HIV
AIDSMap pages on breast-feeding and HIV
HIV Care and PMTCT in Resource-Limited Setting contains monthly bulletins and a database devoted to HIV/AIDS infections and prevention of the mother-to-child transmission of HIV
The Ghent group is a network of researchers and policymakers in the area of prevention of mother-to-child transmission of HIV
doi:10.1371/journal.pmed.0040017
PMCID: PMC1769413  PMID: 17227132
18.  Gene by Environment Interaction and Resilience: Effects of Child Maltreatment and Serotonin, Corticotropin Releasing Hormone, Dopamine, and Oxytocin Genes 
Development and psychopathology  2012;24(2):411-427.
In this investigation, gene-environment interaction effects in predicting resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 595) were examined. A multi-component index of resilient functioning was derived and levels of resilient functioning were identified. Variants in four genes, 5-HTTLPR, CRHR1, DRD4 -521C/T, and OXTR, were investigated. In a series of ANCOVAs, child maltreatment demonstrated a strong negative main effect on children’s resilient functioning, whereas no main effects for any of the genotypes of the respective genes were found. However, gene-environment interactions involving genotypes of each of the respective genes and maltreatment status were obtained. For each respective gene, among children with a specific genotype, the relative advantage in resilient functioning of nonmaltreated compared to maltreated children was stronger than was the case for nonmaltreated and maltreated children with other genotypes of the respective gene. Across the four genes, a composite of the genotypes that more strongly differentiated resilient functioning between nonmaltreated and maltreated children provided further evidence of genetic variations influencing resilient functioning in nonmaltreated children, whereas genetic variation had a negligible effect on promoting resilience among maltreated children. Additional effects were observed for children based on the number of subtypes of maltreatment children experienced, as well as for abuse and neglect subgroups. Finally, maltreated and nonmaltreated children with high levels of resilience differed in their average number of differentiating genotypes. These results suggest that differential resilient outcomes are based on the interaction between genes and developmental experiences.
doi:10.1017/S0954579412000077
PMCID: PMC3684053  PMID: 22559122
19.  The Role of HIV-Related Stigma in Utilization of Skilled Childbirth Services in Rural Kenya: A Prospective Mixed-Methods Study 
PLoS Medicine  2012;9(8):e1001295.
Janet Turan and colleagues examined the role of the perception of women in rural Kenya of HIV-related stigma during pregnancy on their subsequent utilization of maternity services.
Background
Childbirth with a skilled attendant is crucial for preventing maternal mortality and is an important opportunity for prevention of mother-to-child transmission of HIV. The Maternity in Migori and AIDS Stigma Study (MAMAS Study) is a prospective mixed-methods investigation conducted in a high HIV prevalence area in rural Kenya, in which we examined the role of women's perceptions of HIV-related stigma during pregnancy in their subsequent utilization of maternity services.
Methods and Findings
From 2007–2009, 1,777 pregnant women with unknown HIV status completed an interviewer-administered questionnaire assessing their perceptions of HIV-related stigma before being offered HIV testing during their first antenatal care visit. After the visit, a sub-sample of women was selected for follow-up (all women who tested HIV-positive or were not tested for HIV, and a random sample of HIV-negative women, n = 598); 411 (69%) were located and completed another questionnaire postpartum. Additional qualitative in-depth interviews with community health workers, childbearing women, and family members (n = 48) aided our interpretation of the quantitative findings and highlighted ways in which HIV-related stigma may influence birth decisions. Qualitative data revealed that health facility birth is commonly viewed as most appropriate for women with pregnancy complications, such as HIV. Thus, women delivering at health facilities face the risk of being labeled as HIV-positive in the community. Our quantitative data revealed that women with higher perceptions of HIV-related stigma (specifically those who held negative attitudes about persons living with HIV) at baseline were subsequently less likely to deliver in a health facility with a skilled attendant, even after adjusting for other known predictors of health facility delivery (adjusted odds ratio = 0.44, 95% CI 0.22–0.88).
Conclusions
Our findings point to the urgent need for interventions to reduce HIV-related stigma, not only for improving quality of life among persons living with HIV, but also for better health outcomes among all childbearing women and their families.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Every year, nearly 350,000 women die from pregnancy- or childbirth-related complications. Almost all these “maternal” deaths occur in developing countries. In sub-Saharan Africa, for example, the maternal mortality ratio (the number of maternal deaths per 100,000 live births) is 500 whereas in industrialized countries it is only 12. Most maternal deaths are caused by hemorrhage (severe bleeding after childbirth), post-delivery infections, obstructed (difficult) labor, and blood pressure disorders during pregnancy. All these conditions can be prevented if women have access to adequate reproductive health services and if trained health care workers are present during delivery. Notably, in sub-Saharan Africa, infection with HIV (the virus that causes AIDS) is an increasingly important contributor to maternal mortality. HIV infection causes maternal mortality directly by increasing the occurrence of pregnancy complications and indirectly by increasing the susceptibility of pregnant women to malaria, tuberculosis, and other “opportunistic” infections—HIV-positive individuals are highly susceptible to other infections because HIV destroys the immune system.
Why Was This Study Done?
Although skilled delivery attendants reduce maternal mortality, there are many barriers to their use in developing countries including cost and the need to travel long distances to health facilities. Fears and experiences of HIV-related stigma and discrimination (prejudice, negative attitudes, abuse, and maltreatment directed at people living with HIV) may also be a barrier to the use of skilled childbirth service. Maternity services are prime locations for HIV testing and for the provision of interventions for the prevention of mother-to-child transmission (PMTCT) of HIV, so pregnant women know that they will have to “deal with” the issue of HIV when visiting these services. In this prospective mixed-methods study, the researchers examine the role of pregnant women's perceptions of HIV-related stigma in their subsequent use of maternity services in Nyanza Province, Kenya, a region where 16% women aged 15–49 are HIV-positive and where only 44.2% of mothers give birth in a health facility. A mixed-methods study combines qualitative data—how people feel about an issue—with quantitative data—numerical data about outcomes.
What Did the Researchers Do and Find?
In the Maternity in Migori and AIDS Stigma (MAMAS) study, pregnant women with unknown HIV status living in rural regions of Nyanza Province answered questions about their perceptions of HIV-related stigma before being offered HIV testing during their first antenatal clinic visit. After delivery, the researchers asked the women who tested HIV positive or were not tested for HIV and a sample of HIV-negative women where they had delivered their baby. They also gathered qualitative information about barriers to maternity and HIV service use by interviewing childbearing women, family members, and community health workers. The qualitative data indicate that labor in a health facility is commonly viewed as being most appropriate for women with pregnancy complications such as HIV infection. Thus, women delivering at health facilities risk being labeled as HIV positive, a label that the community associates with promiscuity. The quantitative data indicate that women with more negative attitudes about HIV-positive people (higher perceptions of HIV-related stigma) at baseline were about half as likely to deliver in a health facility with a skilled attendant as women with more positive attitudes about people living with HIV.
What Do These Findings Mean?
These findings suggest that HIV-related stigma is associated with the low rate of delivery by skilled attendants in rural areas of Nyanza Province and possibly in other rural regions of sub-Saharan Africa. Community mobilization efforts aimed at increasing the use of PMTCT services may be partly responsible for the strong perception that delivery in a health facility is most appropriate for women with HIV and other pregnancy complications and may have inadvertently strengthened the perception that women who give birth in such facilities are likely to be HIV positive. The researchers suggest, therefore, that health messages should stress that delivery in a health facility is recommended for all women, not just HIV-positive women or those with pregnancy complications, and that interventions should be introduced to reduce HIV-related stigma. This combined strategy has the potential to increase the use of maternity services by all women and the use of HIV and PMTCT services, thereby reducing some of the most pressing health problems facing women and their children 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.1001295.
The United Nations Children's Fund (UNICEF) provides information on maternal mortality, including the WHO/UNICEF/UNFPA/World Bank 2008 country estimates of maternal mortality; a UNICEF special report tells the stories of seven mothers living with HIV in Lesotho
The World Health Organization provides information on maternal health, including information about Millennium Development Goal 5, which aims to reduce maternal mortality (in several languages); the Millennium Development Goals, which were agreed by world leaders in 2000, are designed to eradicate extreme poverty worldwide by 2015
Immpact is a global research initiative for the evaluation of safe motherhood intervention strategies
Maternal Death: The Avoidable Crisis is a briefing paper published by the independent humanitarian medical aid organization Médecins Sans Frontières (MSF) in March 2012
Information is available from Avert, an international AIDS charity on all aspects of HIV/AIDS, including information on women, HIV and AIDS, on HIV and pregnancy, on HIV and AIDS stigma and discrimination, and on HIV in Kenya (in English and Spanish); Avert also has personal stories from women living with HIV
The Stigma Action Network (SAN) is a collaborative endeavor that aims to comprehensively coordinate efforts to develop and expand program, research, and advocacy strategies for reducing HIV stigma worldwide, including mobilizing stakeholders, delivering program and policy solutions, and maximizing investments in HIV programs and services globally
The People Living with Stigma Index aims to address stigma relating to HIV and advocate on key barriers and issues perpetuating stigma; it has recently published Piecing it together for women and girls, the gender dimensions of HIV-related stigma
The Health Policy Project http://www.healthpolicyproject.com has prepared a review of the academic and programmatic literature on stigma and discrimination as barriers to achievement of global goals for maternal health and the elimination of new child HIV infections (see under Resources)
More information on the MAMAS study is available from the UCSF Center for AIDS Prevention Studies
doi:10.1371/journal.pmed.1001295
PMCID: PMC3424253  PMID: 22927800
20.  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
21.  Predicting Patterns of Long-Term CD4 Reconstitution in HIV-Infected Children Starting Antiretroviral Therapy in Sub-Saharan Africa: A Cohort-Based Modelling Study 
PLoS Medicine  2013;10(10):e1001542.
Using data from the ARROW trial, Joanna Lewis and colleagues investigate the CD4 cell count recovery profiles of children infected with HIV starting antiretroviral therapy in Sub-Saharan Africa.
Please see later in the article for the Editors' Summary
Background
Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
Methods and Findings
CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4–17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization–recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
Conclusions
Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.3 million children under 15 years old are infected with HIV, the virus that causes AIDS. More than 90% of these children live in sub-Saharan Africa, where nearly 600 children become infected with HIV every day, usually acquiring the virus from their mother during pregnancy, birth, or breastfeeding. HIV gradually reduces the numbers of CD4 lymphocytes in the immune system, leaving infected individuals susceptible to other infections. HIV infection can be kept in check but not cured with antiretroviral therapy (ART)—cocktails of drugs that have to be taken every day throughout life. ART reduces the amount of virus in the blood (viral load), which allows the immune system to recover (long-term immune reconstitution). Unfortunately, ART is very expensive, but concerted international efforts over the past decade mean that about a third of children who need ART are now receiving it, including half a million children in sub-Saharan Africa.
Why Was This Study Done?
World Health Organization (WHO) guidelines recommend initiation of ART at age-related CD4 cell count thresholds based on the risk of short-term disease progression. The guidelines recommend that all HIV-positive children under two years old begin ART as soon they receive a diagnosis of HIV infection. For children aged 2–5 years, ART initiation is recommended once the CD4 count drops below 750 cells/µl blood, whereas for older children the threshold for ART initiation is 350 CD4 cells/µl. Because of improved ART coverage, many more HIV-infected children now survive into adulthood than in the past. It is therefore important to know how the timing of ART initiation in childhood affects long-term immune reconstitution. Unfortunately, although several studies have examined the effect of ART on immune reconstitution in adults, the results of these studies cannot be extrapolated to children because of age-related differences in immune reconstitution. In this cohort-based modelling study, the researchers investigate long-term CD4 recovery in a cohort (group) of HIV-infected children initiating ART in Uganda and Zimbabwe, and present statistical models that predict patterns of long-term CD4 status based on age and CD4 count at ART initiation.
What Did the Researchers Do and Find?
To investigate long-term CD4 reconstitution in children, the researchers used CD4 counts collected during the ARROW trial, a study designed to investigate monitoring strategies during first-line ART in 1,206 HIV-positive children. In three-quarters of the children, CD4 reconstitution following ART initiation was asymptotic—CD4 counts increased rapidly immediately after ART initiation, then slowed before eventually reaching a constant level of about 80% of the CD4 count expected in an uninfected child of the same age. Using a nonlinear mixed-effects statistical model that fitted this pattern of immune reconstitution, the researchers predicted CD4 trajectories for children starting ART at different ages and with different CD4 counts. Higher long-term counts were predicted for children starting ART earlier and with higher CD4 counts. Thus, to achieve a CD4 count greater than 700 cells/µl at age 20 years, CD4 counts of at least 96 cells/µl, 130 cells/µl, and 557 cells/µl are needed for children aged two, five, and 12 years, respectively, when they initiate ART. Qualitatively distinct reconstitution patterns were seen in the remaining children in the study.
What Do These Findings Mean?
These findings suggest that young HIV-positive, ART-naïve children can achieve high CD4 counts in later life, provided ART is initiated as recommended in the current WHO guidelines. However, the recommended CD4 count thresholds for ART initiation are unlikely to maximize immune reconstitution in treatment-naïve children over ten years old. Rather, these findings suggest that ART initiation should be considered in these older children when their CD4 count is still high—even though they have a low risk of immediate disease progression—in order to achieve higher long-term CD4 levels. The omission of viral load measurements in the researchers' model may limit the accuracy of these findings. Moreover, although the predictions made by the model apply to children who will go on to experience asymptotic recovery, they are less relevant to those with different recovery profiles, who cannot currently be accurately identified. Further exploration of the immunological mechanisms underlying the CD4 recovery profiles described here should improve our understanding of the factors that determine the response of HIV-positive children to ART and provide information to guide the management of HIV infections in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001542.
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 HIV and AIDS in Africa and on HIV infection in children (in English and Spanish)
The UNAIDS World AIDS Day Report 2012 provides up-to-date information about the AIDS epidemic and efforts to halt it; the UNAIDS's 2013 Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children by 2015
The World Health Organization provides information about universal access to AIDS treatment (in several languages); its 2010 guidelines for ART in infants and children can be downloaded
Information about the ARROW trial is available
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, through Nam/aidsmap, and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001542
PMCID: PMC3812080  PMID: 24204216
22.  Developing population interventions with migrant women for maternal-child health: a focused ethnography 
BMC Public Health  2013;13:471.
Background
Literature describing effective population interventions related to the pregnancy, birth, and post-birth care of international migrants, as defined by them, is scant. Hence, we sought to determine: 1) what processes are used by migrant women to respond to maternal-child health and psychosocial concerns during the early months and years after birth; 2) which of these enhance or impede their resiliency; and 3) which population interventions they suggest best respond to these concerns.
Methods
Sixteen international migrant women living in Montreal or Toronto who had been identified in a previous study as having a high psychosocial-risk profile and subsequently classified as vulnerable or resilient based on indicators of mental health were recruited. Focused ethnography including in-depth interviews and participant observations were conducted. Data were analyzed thematically and as an integrated whole.
Results
Migrant women drew on a wide range of coping strategies and resources to respond to maternal-child health and psychosocial concerns. Resilient and vulnerable mothers differed in their use of certain coping strategies. Social inclusion was identified as an overarching factor for enhancing resiliency by all study participants. Social processes and corresponding facilitators relating to social inclusion were identified by participants, with more social processes identified by the vulnerable group. Several interventions related to services were described which varied in type and quality; these were generally found to be effective. Participants identified several categories of interventions which they had used or would have liked to use and recommended improvements for and creation of some programs. The social determinants of health categories within which their suggestions fell included: income and social status, social support network, education, personal health practices and coping skills, healthy child development, and health services. Within each of these, the most common suggestions were related to creating supportive environments and building healthy public policy.
Conclusions
A wealth of data was provided by participants on factors and processes related to the maternal-child health care of international migrants and associated population interventions. Our results offer a challenge to key stakeholders to improve existing interventions and create new ones based on the experiences and views of international migrant women themselves.
doi:10.1186/1471-2458-13-471
PMCID: PMC3733625  PMID: 23672838
Immigrants; Women; Health services; Qualitative research; Childbirth
23.  Personality, adrenal steroid hormones, and resilience in maltreated children: A multi-level perspective 
Development and psychopathology  2007;19(3):787-809.
In this multi-level investigation, resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 677) was examined in relation to the regulation of two stress-responsive adrenal steroid hormones, cortisol and dehydroepiandosterone (DHEA), as well as the personality constructs of ego resiliency and ego control. Maltreatment status was not related to differences in average levels of morning or afternoon cortisol or DHEA. However, lower morning cortisol was related to higher resilient functioning, but only in nonmaltreated children. In contrast, among physically abused children, high morning cortisol was related to higher resilient functioning. Morning and afternoon DHEA was negatively related to resilient functioning. Although diurnal change in cortisol was not related to resilience, for DHEA, maltreated children with high resilience showed an atypical rise in DHEA from morning to afternoon. Morning and afternoon cortisol/DHEA ratios were positively related to resilient functioning, but did not interact with maltreatment status. Ego resiliency and ego control strongly differentiated maltreated and nonmaltreated children, and the personality variables were substantially predictive of resilience. When considered together, demonstrated effects of personality, cortisol, and DHEA maintained independent contributions in predicting resilience among high-risk youth.
doi:10.1017/S0954579407000399
PMCID: PMC3409470  PMID: 17705903
24.  Physical Health of Mothers with HIV/AIDS and the Mental Health of Their Children 
A longitudinal study was conducted on the psychological well-being of 81 young children (mean age = 8.8 years) living with mothers with AIDS or HIV-infected mothers with symptomatic disease. The relationship between mothers’ physical health and children’s psychological well-being was investigated. The children were assessed at seven time points over approximately 6 years. Individual growth models were estimated for children’s depression, anxiety, and aggressiveness in relation to: mothers’ viral load (medical records) and physical functioning, number of HIV-related physical symptoms, and medical visits due to illness (self-report). Results showed significant linear declines in children’s depression, anxiety, and aggressiveness over time. Lower levels of physical functioning and more physical symptoms among mothers were associated with higher levels of children’s depression, anxiety, and aggressiveness at baseline. Lower levels of physical functioning and more physical symptoms among mothers were associated with initially high but more rapidly decreasing levels of depression among children. However, mothers who began the study in better health appear to have changed in health more quickly than mothers who began the study in poorer health. Thus, stability in mothers’ health appears to be associated with a more rapid improvement in children’s mental health over time. Our findings suggest that the measures representing observable levels of, and changes in, mothers’ health that are most likely to be directly experienced by themselves and their children are the measures that are most predictive of changes in children’s mental health over time.
PMCID: PMC2276144  PMID: 17041275
HIV/AIDS; mother health/child psychological well-being
25.  HIV: prevention of mother-to-child transmission  
Clinical Evidence  2011;2011:0909.
Introduction
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
Results
We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breastfeeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15% to 30% during pregnancy and labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads, advanced HIV disease, or both.Without antiretroviral treatment (ART), 15% to 35% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the complications associated with life-long treatment, including adverse effects of antiretroviral drugs, difficulties of adherence across the developmental trajectory of childhood and adolescence, and the development of resistance.From a paediatric perspective, successful prevention of MTCT and HIV-free survival for infants remain the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, to the baby immediately after birth, or to the mother and baby reduce the risk of intrauterine and intrapartum MTCT of HIV-1 and when given to the infant after birth and to the mother or infant during breastfeeding reduce the risk of postpartum MTCT of HIV-1.
Reductions in MTCT are possible using multidrug ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1% to 2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. There is evidence that short courses of antiretroviral drugs have confirmed efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.The development of viral resistance in mothers and infants after single-dose nevirapine and other short-course regimens that include single-dose nevirapine is of concern. An additional short-course of antiretrovirals with a different regimen during labour and early postpartum, and the use of HAART, may decrease the risk of viral resistance in mothers, and in infants who become HIV-infected despite prophylaxis.World Health Organization guidelines recommend starting prophylaxis with antiretroviral drugs from as early as 14 weeks' gestation, or as soon as possible if women present late in pregnancy, in labour, or at delivery.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin seems no more effective than immunoglobulin without HIV antibody at reducing HIV-1 MTCT risk.
Vaginal microbicides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that supplementation with vitamin A reduces the risk of HIV-1 MTCT, and there is concern that postnatal vitamin A supplementation for mother and infant may be associated with increased risk of mortality.
We don't know whether micronutrients are effective in prevention of MTCT of HIV as we found no RCT evidence on this outcome.
Avoidance of breastfeeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breastfeeding-related HIV transmission needs to be balanced against the multiple benefits that breastfeeding offers. In resource-poor countries, breastfeeding is strongly associated with reduced infant morbidity and improved child survival. Exclusive breastfeeding during the first 6 months may reduce the risk of HIV transmission compared with mixed feeding, while retaining most of its associated benefits.In a population where prolonged breastfeeding is usual, early, abrupt weaning may not reduce MTCT or HIV-free survival at 2 years compared with prolonged breastfeeding, and may be associated with a higher rate of infant mortality for those infants diagnosed as HIV-infected at <4 months of age. Antiretrovirals given to the mother or the infant during breastfeeding can reduce the risk of HIV transmission in the postpartum period. World Health Organization guidelines recommend that HIV-positive mothers should exclusively breastfeed for the first 6 months, after which time appropriate complementary foods can be introduced. Breastfeeding should be continued for the first 12 months of the infant's life, and stopped only when an adequate diet without breast milk can be provided. Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
PMCID: PMC3217724  PMID: 21477392

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