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1.  HIV‐free survival at 12–24 months in breastfed infants of HIV‐infected women on antiretroviral treatment 
To provide estimates of HIV‐free survival at 12–24 months in breastfed children by maternal ART (6 months or lifelong) to inform WHO HIV and Infant Feeding guidelines.
Eighteen studies published 2005–2015 were included in a systematic literature review (1295 papers identified, 156 abstracts screened, 55 full texts); papers were analysed by narrative synthesis and meta‐analysis of HIV‐free survival by maternal ART regimen in a random effects model. We also grouped studies by feeding modality. Study quality was assessed using a modified Newcastle–Ottawa Scale (NOS) and GRADE.
The pooled estimates for 12‐month HIV‐free survival were 89.8% (95% confidence interval, CI: 86.5%, 93.2%) for infants of mothers on ART for 6 months post‐natally (six studies) and 91.4% (95% CI 87.5%, 95.4%) for infants of mothers on lifelong ART (three studies). Eighteen‐month HIV‐free survival estimates were 89.0% (95% CI 83.9%, 94.2%) with 6 months ART (five studies) and 96.1% (95% CI 92.8%, 99.0%) with lifelong ART (three studies). Twenty‐four‐month HIV‐free survival for infants whose mothers were on ART to 6 months post‐natally (two studies) was 89.2% (95% CI 79.9%, 98.5%). Heterogeneity was considerable throughout. In four studies, HIV‐free survival in breastfed infants ranged from 87% (95% CI 78%, 92%) to 96% (95% CI 91%, 98%) and in formula‐fed infants from 67% (95% CI 35.5%, 87.9%) to 97.6% (95% CI 93.0%, 98.2%).
Our results highlight the importance of breastfeeding for infant survival and of ART in reducing the risk of mother‐to‐child HIV transmission and support the WHO recommendation to initiate ART for life immediately after HIV diagnosis.
PMCID: PMC5096069  PMID: 27120500
HIV‐free survival; antiretroviral treatment; women; systematic review; survie sans VIH; ART; femmes; revue systématique
2.  The Art of HIV Elimination: Past and Present Science 
Remarkable strides have been made in controlling the HIV epidemic, although not enough to achieve epidemic control. More recently, interest in biomedical HIV control approaches has increased, but substantial challenges with the HIV cascade of care hinder successful implementation. We summarise all available HIV prevention methods and make recommendations on how to address current challenges.
In the early days of the epidemic, behavioural approaches to control the HIV dominated, and the few available evidence-based interventions demonstrated to reduce HIV transmission were applied independently from one another. More recently, it has become clear that combination prevention strategies targeted to high transmission geographies and people at most risk of infections are required to achieve epidemic control. Biomedical strategies such as male medical circumcision and antiretroviral therapy for treatment in HIV-positive individuals and as pre-exposure prophylaxis in HIV-negative individuals provide immense promise for the future of HIV control. In resource-rich settings, the threat of HIV treatment optimism resulting in increased sexual risk taking has been observed and there are concerns that as ART roll-out matures in resource-poor settings and the benefits of ART become clearly visible, behavioural disinhibition may also become a challenge in those settings. Unfortunately, an efficacious vaccine, a strategy which could potentially halt the HIV epidemic, remains elusive.
Combination HIV prevention offers a logical approach to HIV control, although what and how the available options should be combined is contextual. Therefore, knowledge of the local or national drivers of HIV infection is paramount. Problems with the HIV care continuum remain of concern, hindering progress towards the UNAIDS target of 90-90-90 by 2020. Research is needed on combination interventions that address all the steps of the cascade as the steps are not independent of each other. Until these issues are addressed, HIV elimination may remain an unattainable goal.
PMCID: PMC5072486  PMID: 27774350
HIV; Combination HIV prevention; Antiretroviral therapy; Post-exposure prophylaxis; Pre-exposure prophylaxis; HIV vaccines; HIV cascade
3.  Participation Dynamics in Population-Based Longitudinal HIV Surveillance in Rural South Africa 
PLoS ONE  2015;10(4):e0123345.
Population-based HIV surveillance is crucial to inform understanding of the HIV pandemic and evaluate HIV interventions, but little is known about longitudinal participation patterns in such settings. We investigated the dynamics of longitudinal participation patterns in a high HIV prevalence surveillance setting in rural South Africa between 2003 and 2012, taking into account demographic dynamics. At any given survey round, 22,708 to 30,495 persons were eligible. Although the yearly participation rates were relatively modest (26% to 46%), cumulative rates increased substantially with multiple recruitment opportunities: 68% of eligible persons participated at least once, 48% at least twice and 31% at least three times after five survey rounds. We identified two types of study fatigue: at the individual level, contact and consent rates decreased with multiple recruitment opportunities and, at the population level, these rates also decreased over calendar time, independently of multiple recruitment opportunities. Using sequence analysis and hierarchical clustering, we identified three broad individual participation profiles: consenters (20%), switchers (43%) and refusers (37%). Men were over represented among refusers, women among consenters, and temporary non-residents among switchers. The specific subgroup of persons who were systemically not contacted or refusers constitutes a challenge for population-based surveillance and interventions.
PMCID: PMC4395370  PMID: 25875851
4.  The Impact of Gender Norms on Condom Use among HIV-Positive Adults in KwaZulu-Natal, South Africa 
PLoS ONE  2015;10(4):e0122671.
Critical to preventing the spread of HIV is promoting condom use among HIV-positive individuals. Previous studies suggest that gender norms (social and cultural constructions of the ways that women and men are expected to behave) may be an important determinant of condom use. However, the relationship has not been evaluated among HIV-positive women and men in South Africa. We examined gender norms and condom use at last sex among 550 partnerships reported by 530 sexually-active HIV-positive women (372) and men (158) who had sought care, but not yet initiated antiretroviral therapy in a high HIV-prevalence rural setting in KwaZulu-Natal, South Africa between January 2009 and March 2011. Participants enrolled in the cohort study completed a baseline questionnaire that detailed their socio-demographic characteristics, socio-economic circumstances, religion, HIV testing history and disclosure of HIV status, stigma, social capital, gender norms and self-efficacy. Gender norms did not statistically differ between women and men (p = 0.18). Overall, condoms were used at last sex in 58% of partnerships. Although participants disclosed their HIV status in 66% of the partnerships, 60% did not have knowledge of their partner’s HIV status. In multivariable logistic regression, run separately for each sex, women younger than 26 years with more equitable gender norms were significantly more likely to have used a condom at last sex than those of the same age group with inequitable gender norms (OR = 8.88, 95% CI 2.95–26.75); the association between condom use and gender norms among women aged 26+ years and men of all ages was not statistically significant. Strategies to address gender inequity should be integrated into positive prevention interventions, particularly for younger women, and supported by efforts at a societal level to decrease gender inequality.
PMCID: PMC4390283  PMID: 25853870
5.  Time and money: the true costs of health care utilization for patients receiving ‘free’ HIV/TB care and treatment in rural KwaZulu-Natal 
HIV and TB services are provided free-of-charge in many sub-Saharan African countries, but patients still incur costs.
Patient-exit interviews were conducted with a representative sample of 200 HIV-infected patients not yet on ART (pre-ART), 300 ART patients, and 300 TB patients receiving public sector care in rural South Africa. For each group, we calculated health expenditures across different spending categories, time spent traveling to and utilizing services, and how patients financed their spending. Associations between patient group and costs were assessed in multivariate regression models.
Total monthly health expenditures (1 USD = 7.3 South African Rand, ZAR) were: ZAR 171 (95% CI 134, 207) for pre-ART, ZAR 164 (95% CI 141, 187) for ART, and ZAR 122 (95% CI 105, 140) for TB patients (p=0.01). Total monthly time costs (in hours) were: 3.4 (95% CI 3.3, 3.5) for pre-ART, 5.0 (95% CI 4.7, 5.3) for ART and 3.2 (95% CI 2.9, 3.4) for TB patients (p<0.01). Though overall patient costs were similar across groups, pre-ART patients spent on average ZAR 29.2 more on traditional healers and ZAR 25.9 more on chemists and private doctors than ART patients, while ART patients spent ZAR 34.0 more than pre-ART patients on transport to clinics (p<0.05 for all results). 31% of pre-ART, 39% of ART and 41% of TB patients borrowed money or sold assets to finance health costs.
Patients receiving nominally free care for HIV/TB face large private costs, commonly leading to financial distress. Subsidized transport, fewer clinic visits, and drug pickup points closer to home could reduce costs for ART patients, potentially improving retention and adherence. Large expenditure on alternative care among pre-ART patients suggests that transitioning patients to ART earlier, as under HIV treatment-as-prevention policies, may not substantially increase patients’ financial burden.
PMCID: PMC4748708  PMID: 26371611
Borrowing; selling assets; financial distress; healthcare costs; HIV; TB; out-of-pocket; health expenditure; time use; South Africa; ART; pre-ART; retention; costs
6.  Decline in early life mortality in a high HIV prevalence rural area of South Africa: evidence of HIV prevention or treatment impact? 
AIDS (London, England)  2010;24(4):593-602.
We present early life mortality rates in a largely rural population with high antenatal HIV prevalence, and investigate temporal and spatial associations with a prevention of mother-to-child transmission (PMTCT) programme, an HIV treatment programme, and maternal HIV.
A retrospective cohort analysis.
All births from January 2000 to January 2007 to women in the Africa Centre demographic surveillance were included. Under-two child mortality rates (U2MR) computed as deaths per 1000 live-births per year; factors associated with mortality risk assessed with Weibull regression. Availability of PMTCT (single-dose nevirapine; sdNVP) and antiretroviral therapy (ART) in a programme included in multivariable analysis.
Eight hundred and forty-eight (6.2%) of 13 583 children under 2 years died. Deaths in under twos declined by 49% between 2001 and 2006, from 86.3 to 44.1 deaths per thousand live-births. Mortality was independently associated with birth season (adjusted hazard ratio 1.16, 95% confidence interval 1.02–1.33), maternal education (1.21, 1.02–1.43), maternal HIV (4.34, 3.11–6.04) and ART availability (0.46, 0.33–0.65). Children born at home (unlikely to have received sdNVP) had a 35% higher risk of dying than children born in a facility where sdNVP was available (1.35, 1.04–1.74). For 2005 births the availability of PMTCT and ART in public health programmes would have explained 8 and 31% of the decline in U2MR since 2000.
These findings confirm the importance of maternal survival, and highlight the importance of the PMTCT and especially maternal HIV treatment with direct benefits of improved survival of their young children.
PMCID: PMC4239477  PMID: 20071975
Africa; ART; HIV; mortality; PMTCT; rural
7.  Mortality risk and associated factors in HIV‐exposed, uninfected children 
With increasing maternal antiretroviral treatment (ART), the number of children newly infected with HIV has declined. However, the possible increased mortality in the large number of HIV‐exposed, uninfected (HEU) children may be of concern. We quantified mortality risks among HEU children and reviewed associated factors.
Systematic search of electronic databases (PubMed, Scopus). We included all studies reporting mortality of HEU children to age 60 months and associated factors. Relative risk of mortality between HEU and HIV‐unexposed, uninfected (HUU) children was extracted where relevant. Inverse variance methods were used to adjust for study size. Random‐effects models were fitted to obtain pooled estimates.
A total of 14 studies were included in the meta‐analysis and 13 in the review of associated factors. The pooled cumulative mortality in HEU children was 5.5% (95% CI: 4.0–7.2; I 2 = 94%) at 12 months (11 studies) and 11.0% (95% CI: 7.6–15.0; I 2 = 93%) at 24 months (four studies). The pooled risk ratios for the mortality in HEU children compared to HUU children in the same setting were 1.9 (95% CI: 0.9–3.8; I 2 = 93%) at 12 months (four studies) and 2.4 (95% CI: 1.1–5.1; I 2 = 93%) at 24 months (three studies).
Compared to HUU children, mortality risk in HEU children was about double at both age points, although the association was not statistically significant at 12 months. Interpretation of the pooled estimates is confounded by considerable heterogeneity between studies. Further research is needed to characterise the impact of maternal death and breastfeeding on the survival of HEU infants in the context of maternal ART, where current evidence is limited.
PMCID: PMC5021152  PMID: 27091659
HIV; mortality; infant; child; risk factor; meta‐analysis; VIH; Mortalité; nourrisson; enfant; facteur de risque; méta‐analyse
9.  Uptake of Home-Based HIV Testing, Linkage to Care, and Community Attitudes about ART in Rural KwaZulu-Natal, South Africa: Descriptive Results from the First Phase of the ANRS 12249 TasP Cluster-Randomised Trial 
PLoS Medicine  2016;13(8):e1002107.
The 2015 WHO recommendation of antiretroviral therapy (ART) for all immediately following HIV diagnosis is partially based on the anticipated impact on HIV incidence in the surrounding population. We investigated this approach in a cluster-randomised trial in a high HIV prevalence setting in rural KwaZulu-Natal. We present findings from the first phase of the trial and report on uptake of home-based HIV testing, linkage to care, uptake of ART, and community attitudes about ART.
Methods and Findings
Between 9 March 2012 and 22 May 2014, five clusters in the intervention arm (immediate ART offered to all HIV-positive adults) and five clusters in the control arm (ART offered according to national guidelines, i.e., CD4 count ≤ 350 cells/μl) contributed to the first phase of the trial. Households were visited every 6 mo. Following informed consent and administration of a study questionnaire, each resident adult (≥16 y) was asked for a finger-prick blood sample, which was used to estimate HIV prevalence, and offered a rapid HIV test using a serial HIV testing algorithm. All HIV-positive adults were referred to the trial clinic in their cluster. Those not linked to care 3 mo after identification were contacted by a linkage-to-care team. Study procedures were not blinded.
In all, 12,894 adults were registered as eligible for participation (5,790 in intervention arm; 7,104 in control arm), of whom 9,927 (77.0%) were contacted at least once during household visits. HIV status was ever ascertained for a total of 8,233/9,927 (82.9%), including 2,569 ascertained as HIV-positive (942 tested HIV-positive and 1,627 reported a known HIV-positive status). Of the 1,177 HIV-positive individuals not previously in care and followed for at least 6 mo in the trial, 559 (47.5%) visited their cluster trial clinic within 6 mo. In the intervention arm, 89% (194/218) initiated ART within 3 mo of their first clinic visit. In the control arm, 42.3% (83/196) had a CD4 count ≤ 350 cells/μl at first visit, of whom 92.8% initiated ART within 3 mo. Regarding attitudes about ART, 93% (8,802/9,460) of participants agreed with the statement that they would want to start ART as soon as possible if HIV-positive. Estimated baseline HIV prevalence was 30.5% (2,028/6,656) (95% CI 25.0%, 37.0%). HIV prevalence, uptake of home-based HIV testing, linkage to care within 6 mo, and initiation of ART within 3 mo in those with CD4 count ≤ 350 cells/μl did not differ significantly between the intervention and control clusters. Selection bias related to noncontact could not be entirely excluded.
Home-based HIV testing was well received in this rural population, although men were less easily contactable at home; immediate ART was acceptable, with good viral suppression and retention. However, only about half of HIV-positive people accessed care within 6 mo of being identified, with nearly two-thirds accessing care by 12 mo. The observed delay in linkage to care would limit the individual and public health ART benefits of universal testing and treatment in this population.
Trial registration NCT01509508
Collins Iwuji and colleagues report implementation indicators and early health outcomes from the first phase of a cluster-randomized trial of immediate antiretroviral therapy to all HIV-positive individuals in rural KwaZulu-Natal, South Africa.
Author Summary
Why Was This Study Done?
A study in stable sexual partners in which one partner was HIV-positive and the other partner was HIV-negative (and both partners had disclosed to each other) showed that if the HIV-positive partner was on antiretroviral therapy, there was a 96% reduction in HIV transmission from the HIV-positive partner to the HIV-negative partner.
However, we do not know if antiretroviral therapy prescribed to HIV-positive individuals in the general population—and where individuals might not disclose their HIV status to sexual partners—would have a similar impact on HIV transmission.
It is important to determine whether prescribing antiretroviral therapy to all HIV-positive individuals is more effective at decreasing HIV transmission than starting individuals on antiretroviral therapy only once their HIV has progressed to the point at which local HIV treatment guidelines currently recommend that HIV-positive individuals start treatment.
What Did the Researchers Do and Find?
We designed an experiment to investigate whether antiretroviral therapy can reduce new HIV infections in the general population, and piloted the trial in ten communities in KwaZulu-Natal, South Africa, to check whether starting HIV-positive individuals on antiretroviral therapy directly after diagnosis is feasible and acceptable.
We visited people in their homes, offered HIV rapid tests every six months to all individuals 16 years and older, and referred identified HIV-positive individuals to trial clinics, where they were offered antiretroviral therapy either regardless of their CD4 count (intervention group) or when they were treatment-eligible per current national guidelines (control group).
During the two-year study, we contacted 9,927 (77%) of 12,894 eligible individuals and ascertained the HIV status of 80% of contacted women and 75% of contacted men.
HIV-positive status was ascertained for 1,339 adults who were not previously in care; 1,177 were followed in the trial at least 6 mo after referral, of whom 559 (47.5%) engaged with care within this period.
What Do These Findings Mean?
Our findings show good acceptance of home-based HIV testing in rural South Africa but highlight the challenges in reaching adequate numbers of people to offer HIV tests to, especially among men.
We also found that linkage to care was slower than expected, but amongst those who reached the clinics, uptake of antiretroviral therapy was high, with the majority of individuals achieving good control of the virus.
Our study informs health care professionals, planners, and policy makers about the challenges that need to be addressed to achieve the UNAIDS target of 90% of people living with HIV aware of their HIV diagnosis, 90% on antiretroviral therapy, and 90% achieving good control of the virus, with testing and treatment offered to all.
PMCID: PMC4978506  PMID: 27504637
10.  High-Levels of Acquired Drug Resistance in Adult Patients Failing First-Line Antiretroviral Therapy in a Rural HIV Treatment Programme in KwaZulu-Natal, South Africa 
PLoS ONE  2013;8(8):e72152.
To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa.
Cross-sectional study nested within HIV treatment programme.
Adult (≥18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms.
A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32–53) and median duration of antiretroviral failure was 27 months (IQR 17–40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60–12.49).
There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved.
PMCID: PMC3749184  PMID: 23991055
11.  Exclusive Breastfeeding and Cognition, Executive Function, and Behavioural Disorders in Primary School-Aged Children in Rural South Africa: A Cohort Analysis 
PLoS Medicine  2016;13(6):e1002044.
Exclusive breastfeeding (EBF) is associated with early child health; its longer-term benefits for child development remain inconclusive. We examine the associations between EBF, HIV exposure, and other maternal/child factors and the cognitive and emotional-behavioural development of children aged 7–11 y.
Methods and Findings
The Vertical Transmission Study (VTS) supported EBF in HIV-positive and HIV-negative women; between 2012 and 2014, HIV-negative VTS children (332 HIV exposed, 574 HIV unexposed) were assessed in terms of cognition (Kaufman Assessment Battery for Children Second Edition [KABC-II]), executive function (Developmental Neuropsychological Assessment Second Edition [NEPSY-II]), and emotional-behavioural functioning (parent-reported Child Behaviour Checklist, [CBCL]). We developed population means by combining the VTS sample with 629 same-aged HIV-negative children from the local demographic platform. For each outcome, we split the VTS sample into scores above or at/below each population mean and modelled each outcome using logistic regression analyses, overall and stratified by child sex. There was no demonstrated effect of EBF on overall cognitive functioning. EBF was associated with fewer conduct disorders overall (adjusted odds ratio [aOR] 0.44 [95% CI 0.3–0.7], p ≤ 0.01), and there was weak evidence of better cognition in boys who had been exclusively breastfed for 2–5 mo versus ≤1 mo (Learning subscale aOR 2.07 [95% CI 1.0–4.3], p = 0.05). Other factors associated with better child cognition were higher maternal cognitive ability (aOR 1.43 [95% CI 1.1–1.9], p = 0.02, Sequential; aOR 1.74 [95% CI 1.3–2.4], p < 0.001, Planning subscales) and crèche attendance (aOR 1.96 [95% CI 1.1–3.5], p = 0.02, Sequential subscale). Factors positively associated with executive function were home stimulation (aOR 1.36 [95% CI 1.0–1.8], p = 0.04, Auditory Attention; aOR 1.35 [95% CI 1.0–1.8], p = 0.05, Response Set) and crèche (aOR 1.74 [95% CI 1.0–3.0], p = 0.05, Animal Sorting). Maternal mental health problems and parenting stress were associated with increased emotional-behavioural problems on the total CBCL (aOR 2.44 [95% CI 1.3–4.6], p = 0.01; aOR 7.04 [95% CI 4.2–11.9], p < 0.001, respectively). Maternal HIV status was not associated with any outcomes in the overall cohort. Limitations include the nonrandomised study design and lack of maternal mental health assessment at the child’s birth.
EBF was associated with fewer than average conduct disorders and weakly associated with improved cognitive development in boys. Efforts to improve stimulation at home, reduce maternal stress, and enable crèche attendance are likely to improve executive function and emotional-behavioural development of children.
Bland and colleagues report that exclusive breastfeeding leads to a reduction in conduct disorder incidents in children but does not significantly impact on cognition.
Author Summary
Why Was This Study Done?
The benefits of exclusive breastfeeding (EBF) in early life are well established and include optimal nutrition and protection from infectious diseases.
The longer-term benefits of EBF on child development and behaviour are less clear, and studies in low-income settings have shown conflicting results depending on the design of the study and whether other factors known to influence development, such as HIV exposure, have been taken into account.
There is a dearth of evidence examining the development of HIV-uninfected children born to HIV-infected mothers and whether these children are disadvantaged compared to those born to HIV-uninfected mothers.
What Did the Researchers Do and Find?
This study was established in 2012 to investigate the development (cognitive and emotion-behaviour) of 1,536 HIV-negative children, born to HIV-infected and HIV-uninfected mothers, in rural South Africa, taking into account a range of current and early life factors known to be associated with child development.
Duration of EBF was associated with a reduction in conduct disorders in girls and boys, but there was no association with cognitive development in the overall sample, when allowing for other factors. Maternal intelligence quotient (IQ) was strongly associated with children’s later cognitive development.
Children born to HIV-infected mothers performed as well as the children born to HIV-uninfected mothers.
What Do the Findings Mean?
Promoting, protecting, and supporting EBF may result in fewer conduct disorders, in addition to the established benefits of improved nutrition and reduced morbidity and mortality.
Reducing conduct disorders is important because they may lead to aggressive or disruptive behaviours and are associated with an increase in later criminal behaviour and poor long-term mental health and academic achievement.
PMCID: PMC4915617  PMID: 27328132
12.  MaiMwana women’s groups: a community mobilisation intervention to improve mother and child health and reduce mortality in rural Malawi 
This article presents a detailed description of a community mobilization intervention involving women’s groups in Mchinji District, Malawi. The intervention was implemented between 2005 and 2010.
The intervention aims to build the capacities of communities to take control of the mother and child health issues that affect them. To achieve this it comprises trained local female facilitators establishing groups and using a manual, participatory rural appraisal tools and picture cards to guide them through a community action cycle to identify and implement solutions to mother and child health problems. Significant resource inputs include salaries for facilitators and supervisors, and training, equipment and materials to support their work with groups.
It is hypothesized that the groups will catalyse community collective action to address mother and child health issues and improve the health and reduce the mortality of mothers and children. Their impact, implementation and cost-effectiveness have been rigorously evaluated through a randomized controlled trial design. The results of these evaluations will be reported in 2011.
PMCID: PMC3345770  PMID: 21977831
13.  Breast-feeding and Transmission of HIV-1 
Breast-feeding substantially increases the risk of HIV-1 transmission from mother to child, and although peripartum antiretroviral therapy prophylaxis significantly decreases the risk of mother-to-child transmission around the time of delivery, this approach does not affect breast-feeding transmission. Increased maternal RNA viral load in plasma and breast milk is strongly associated with increased risk of transmission through breast-feeding, as is breast health, and it has been suggested that exclusive breast-feeding could be associated with lower rates of breast-feeding transmission than mixed feeding of both breast- and other milk or feeds. Transmission through breast-feeding can take place at any point during lactation, and the cumulative probability of acquisition of infection increases with duration of breast-feeding. HIV-1 has been detected in breast milk in cell-free and cellular compartments; infant gut mucosal surfaces are the most likely site at which transmission occurs. Innate and acquired immune factors may act most effectively in combination to prevent primary HIV-1 infection by breast milk.
PMCID: PMC3382106  PMID: 14722454
breastfeeding; mother-to-child transmission; postnatal transmission; risk factors; mechanisms
14.  Access to HIV care in the context of universal test and treat: challenges within the ANRS 12249 TasP cluster-randomized trial in rural South Africa 
We aimed to quantify and identify associated factors of linkage to HIV care following home-based HIV counselling and testing (HBHCT) in the ongoing ANRS 12249 treatment-as-prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa.
Individuals ≥16 years were offered HBHCT; those who were identified HIV positive were referred to cluster-based TasP clinics and offered antiretroviral treatment (ART) immediately (five clusters) or according to national guidelines (five clusters). HIV care was also available in the local Department of Health (DoH) clinics. Linkage to HIV care was defined as TasP or DoH clinic attendance within three months of referral among adults not in HIV care at referral. Associated factors were identified using multivariable logistic regression adjusted for trial arm.
Overall, 1323 HIV-positive adults (72.9% women) not in HIV care at referral were included, of whom 36.9% (n=488) linked to care <3 months of referral (similar by sex). In adjusted analyses (n=1222), individuals who had never been in HIV care before referral were significantly less likely to link to care than those who had previously been in care (<33% vs. >42%, p<0.001). Linkage to care was lower in students (adjusted odds-ratio [aOR]=0.47; 95% confidence interval [CI] 0.24–0.92) than in employed adults, in adults who completed secondary school (aOR=0.68; CI 0.49–0.96) or at least some secondary school (aOR=0.59; CI 0.41–0.84) versus ≤ primary school, in those who lived at 1 to 2 km (aOR=0.58; CI 0.44–0.78) or 2–5 km from the nearest TasP clinic (aOR=0.57; CI 0.41–0.77) versus <1 km, and in those who were referred to clinic after ≥2 contacts (aOR=0.75; CI 0.58–0.97) versus those referred at the first contact. Linkage to care was higher in adults who reported knowing an HIV-positive family member (aOR=1.45; CI 1.12–1.86) versus not, and in those who said that they would take ART as soon as possible if they were diagnosed HIV positive (aOR=2.16; CI 1.13–4.10) versus not.
Fewer than 40% of HIV-positive adults not in care at referral were linked to HIV care within three months of HBHCT in the TasP trial. Achieving universal test and treat coverage will require innovative interventions to support linkage to HIV care.
PMCID: PMC4891946  PMID: 27258430
HIV/AIDS; home-based HIV counselling and testing; linkage to care; universal test and treat; South Africa
15.  Children Who Acquire HIV Infection Perinatally Are at Higher Risk of Early Death than Those Acquiring Infection through Breastmilk: A Meta-Analysis 
PLoS ONE  2012;7(2):e28510.
Assumptions about survival of HIV-infected children in Africa without antiretroviral therapy need to be updated to inform ongoing UNAIDS modelling of paediatric HIV epidemics among children. Improved estimates of infant survival by timing of HIV-infection (perinatally or postnatally) are thus needed.
Methodology/Principal Findings
A pooled analysis was conducted of individual data of all available intervention cohorts and randomized trials on prevention of HIV mother-to-child transmission in Africa. Studies were right-censored at the time of infant antiretroviral initiation. Overall mortality rate per 1000 child-years of follow-up was calculated by selected maternal and infant characteristics. The Kaplan-Meier method was used to estimate survival curves by child's HIV infection status and timing of HIV infection. Individual data from 12 studies were pooled, with 12,112 children of HIV-infected women. Mortality rates per 1,000 child-years follow-up were 39.3 and 381.6 for HIV-uninfected and infected children respectively. One year after acquisition of HIV infection, an estimated 26% postnatally and 52% perinatally infected children would have died; and 4% uninfected children by age 1 year. Mortality was independently associated with maternal death (adjusted hazard ratio 2.2, 95%CI 1.6–3.0), maternal CD4<350 cells/ml (1.4, 1.1–1.7), postnatal (3.1, 2.1–4.1) or peri-partum HIV-infection (12.4, 10.1–15.3).
These results update previous work and inform future UNAIDS modelling by providing survival estimates for HIV-infected untreated African children by timing of infection. We highlight the urgent need for the prevention of peri-partum and postnatal transmission and timely assessment of HIV infection in infants to initiate antiretroviral care and support for HIV-infected children.
PMCID: PMC3285615  PMID: 22383946
17.  Cumulative Exposure to Cell-Free HIV in Breast Milk, Rather Than Feeding Pattern per se, Identifies Postnatally Infected Infants 
In a nested case-control study, postnatal HIV infection was strongly associated with cumulative HIV RNA breastmilk exposure, even after allowing for maternal CD4 and plasma viral load; cases ingested approximately 15 times more HIV-1 RNA particles than controls.
Background. We quantified the relationship between human immunodeficiency virus (HIV) RNA shedding in breast milk, cumulative RNA exposure, and postnatal transmission, relating timing of infection in the infant to estimated total volume of milk exposure.
Methods. Nested case-control study of 36 infants of HIV-infected mothers. Case patients were infants who acquired HIV infection through breastfeeding from age 6 through 28 weeks, and control subjects were uninfected infants matched on age at obtainment of a breast milk sample. Mothers and infants received peripartum single-dose nevirapine prophylaxis. Feeding data were collected daily; breast milk samples were collected and infant anthropometry was performed at 6 weeks and monthly thereafter. Volume of milk ingested was estimated using infant weight and feeding pattern.
Results. Before HIV acquisition in case patients, feeding pattern (exclusive breastfeeding; median duration, 65 vs 70 days; P = .6) and daily milk intake (mean volume, 638 vs 637 mL; P = .97) did not differ significantly between case patients and control subjects. Case mothers were more likely to shed virus (64% vs 9% always, 22% vs 20.5% intermittently, 14% vs 70.5% never shed; overall, P < .001). Case patients ingested ∼15 times more HIV-1 RNA particles than did control subjects (196.5 vs 13 × 106 copies; P < .001). Allowing for maternal antenatal CD4 cell count and plasma HIV-1 load, child sex and duration of mixed breastfeeding, the association between HIV RNA exposure and infection remained statistically significant (P < .001).
Conclusions. Postnatal acquisition of HIV-1 is more strongly associated with cumulative exposure to cell-free particles in breast milk than with feeding mode. Reducing breast milk viral load through antiretroviral therapy to mother or child can further decrease postnatal transmission in exclusively breastfed infants.
PMCID: PMC3049337  PMID: 21367736
18.  Factors associated with pre-ART loss-to-follow up in adults in rural KwaZulu-Natal, South Africa: a prospective cohort study 
BMC Public Health  2016;16:358.
Timely initiation of antiretroviral treatment (ART) requires sustained engagement in HIV care before treatment eligibility. We assessed loss to follow-up (LTFU) correlates in HIV-positive adults accessing HIV treatment and care, not yet ART-eligible (CD4 >500 cells/mm3).
This was a sub-study of a prospective cohort study (focusing on sexual behaviour) in an area of high HIV prevalence and widespread ART availability in rural KwaZulu-Natal, South Africa. Psychosocial, clinical and demographic data were collected at recruitment from individuals with CD4 >500 cells/mm3. LTFU was defined as not attending clinic within 13 months of last visit or before death. Individuals starting ART were censored at ART initiation. Data were collected between January 2009 and January 2013. Analysis used Competing Risks regression.
Two hundred forty-seven individuals (212 females) were recruited (median follow-up 2.13 years, total follow-up 520.15 person-years). 86 remained in pre-ART care (34.8 %), 94 were LTFU (38.1 %), 58 initiated ART (23.5 %), 7 died (2.8 %), 2 transferred out (0.8 %). The LTFU rate was 18.07 per 100 person-years (95 % CI 14.76–21.12). LTFU before a competing event was 13.5 % at one and 34.4 % at three years. Lower LTFU rates were significantly associated with age (>37 versus ≤37 years: adjusted sub-Hazard ratio (aSHR) 0.51, 95 % CI 0.30–0.87), openness with family/friends (a little versus not at all, aSHR 0.81, 95 % CI 0.45–1.43; a lot versus not at all, aSHR 1.57, 95 % CI 0.94–2.62), children (0 versus 4+, aSHR 0.68, 95 % CI 0.24–1.87; 1 versus 4+, aSHR 2.05 95 % CI 1.14–3.69, 2 versus 4+; aSHR 1.71, 95 % CI 0.94–3.09; 3 versus 4a, aSHR 1.14, 95 % CI 0.57–2.30), previous CD4 counts (1 versus 0, aSHR 0.81, 95 % CI 0.45–1.43; 2+ versus 0, aSHR 0.43, 95 % CI 0.25–0.73), and most recent partner HIV status (not known versus HIV-positive, aSHR 0.77, 95 % CI 0.50–1.19; HIV-negative versus HIV-positive, aSHR 2.40, 95 % CI 1.18–4.88). The interaction between openness with family/friends and HIV partner disclosure was close to significance (p = 0.06). Those who had neither disclosed to partners nor were open with family/friends had lowest LTFU rates.
Strategies to retain younger people in pre-ART care are required. How openness with others, partner HIV status and disclosure, and children relate to LTFU needs further exploration.
PMCID: PMC4847371  PMID: 27117271
HIV; Pre-ART; Loss-to-follow up; South Africa; Psychosocial
19.  Preventing postnatal transmission of HIV-1 through breast-feeding: modifying infant feeding practices 
Approaches to reduce or prevent the risk of postnatal transmission through breastfeeding include the avoidance of all BF and the use of exclusive replacement feeds (RF) or exclusive breastfeeding for a limited duration with early and rapid cessation of BF around 4–6 months of age. The efficacy and safety of the latter approach has not been established and studies are in progress to provide further information. In addition, inactivation of HIV in breastmilk would allow breastfeeding to continue while reducing the risk of postnatal transmission of HIV, and may be usefully applied in certain circumstances, such as for premature infants or while a mother recovers from mastitits. In this review, experience from clinical trials or studies additional to their main objective of assessing rates and risk factors for MTCT, is discussed. This may inform policy, programming and training options, and be especially valuable in the absence of conclusive data of the efficacy of the interventions to be applied during the breastfeeding period.
PMCID: PMC2475579  PMID: 14722453
Acquired Immunodeficiency Syndrome; prevention & control; transmission; Breast Feeding; adverse effects; Disease Transmission; Vertical; prevention & control; Female; Humans; Infant; Milk; Human; virology; Pregnancy; Safety
21.  Adjusting HIV prevalence estimates for non-participation: an application to demographic surveillance 
HIV testing is a cornerstone of efforts to combat the HIV epidemic, and testing conducted as part of surveillance provides invaluable data on the spread of infection and the effectiveness of campaigns to reduce the transmission of HIV. However, participation in HIV testing can be low, and if respondents systematically select not to be tested because they know or suspect they are HIV positive (and fear disclosure), standard approaches to deal with missing data will fail to remove selection bias. We implemented Heckman-type selection models, which can be used to adjust for missing data that are not missing at random, and established the extent of selection bias in a population-based HIV survey in an HIV hyperendemic community in rural South Africa.
We used data from a population-based HIV survey carried out in 2009 in rural KwaZulu-Natal, South Africa. In this survey, 5565 women (35%) and 2567 men (27%) provided blood for an HIV test. We accounted for missing data using interviewer identity as a selection variable which predicted consent to HIV testing but was unlikely to be independently associated with HIV status. Our approach involved using this selection variable to examine the HIV status of residents who would ordinarily refuse to test, except that they were allocated a persuasive interviewer. Our copula model allows for flexibility when modelling the dependence structure between HIV survey participation and HIV status.
For women, our selection model generated an HIV prevalence estimate of 33% (95% CI 27–40) for all people eligible to consent to HIV testing in the survey. This estimate is higher than the estimate of 24% generated when only information from respondents who participated in testing is used in the analysis, and the estimate of 27% when imputation analysis is used to predict missing data on HIV status. For men, we found an HIV prevalence of 25% (95% CI 15–35) using the selection model, compared to 16% among those who participated in testing, and 18% estimated with imputation. We provide new confidence intervals that correct for the fact that the relationship between testing and HIV status is unknown and requires estimation.
We confirm the feasibility and value of adopting selection models to account for missing data in population-based HIV surveys and surveillance systems. Elements of survey design, such as interviewer identity, present the opportunity to adopt this approach in routine applications. Where non-participation is high, true confidence intervals are much wider than those generated by standard approaches to dealing with missing data suggest.
PMCID: PMC4662682  PMID: 26613900
HIV prevalence; non-participation; missing data; selection bias; Heckman-type selection models; demographic surveillance
22.  Pregnancy is associated with elevation of liver enzymes in HIV-positive women on antiretroviral therapy 
AIDS (London, England)  2015;29(7):801-809.
To assess whether pregnancy is associated with an increased risk of liver enzyme elevation (LEE) and severe LEE in HIV-positive women on antiretroviral therapy (ART).
Two observational studies; the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC).
Combined data from UK CHIC and NSHPC were used to identify factors associated with LEE (grade 1-4) and severe LEE (grade 3-4). Women starting ART in 2000-2012 were included irrespective of pregnancy status. Cox proportional hazards were used to assess fixed and time-dependent covariates including pregnancy status, CD4 count, drug regimen and hepatitis B/C (HBV/HCV) co-infection.
One-quarter (25.7%, 982/3815) of women were pregnant during follow-up; 14.2% (n=541) when starting ART. The rate of LEE was 14.5/100 person-years (PY) in and 6.0/100 PY outside of pregnancy. The rate of severe LEE was 3.9/100 PY in and 0.6/100 PY outside of pregnancy. The risk of LEE and severe LEE was increased during pregnancy (LEE: aHR 1.66 [1.31-2.09]; severe LEE: aHR 3.57 [2.30-5.54]), including in secondary analyses excluding 541 women pregnant when starting ART. Other factors associated with LEE and severe LEE included lower CD4 count (<250 cells/mm3), HBV/HCV co-infection and calendar year.
Although few women developed severe LEE, this study provides further evidence that pregnancy is associated with increased risk of LEE and severe LEE, reinforcing the need for regular monitoring of liver biomarkers during pregnancy.
PMCID: PMC4439178  PMID: 25710412
HIV; Highly Active Antiretroviral Therapy; Toxicity; Pregnancy; Women
23.  The risk of viral rebound in the year after delivery in women remaining on antiretroviral therapy 
AIDS (London, England)  2015;29(17):2269-2278.
The objective of this study is to assess the risk of viral rebound in postpartum women on suppressive combination antiretroviral therapy (cART).
Using data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC), women with HIV-RNA 50 copies/ml or less at delivery in 2006–2011, who started life-long cART during pregnancy (n = 321) or conceived on cART (n = 618), were matched by age, duration on cART and time period, with at least one control (non-postpartum). The cumulative probability of viral rebound (HIV-RNA >200 copies/ml) was assessed by Kaplan–Meier analysis; adjusted hazard ratios (aHRs) for the 0–3 and 3–12 months postdelivery (cases)/pseudo-delivery (controls) were calculated in Cox proportional hazards models.
In postpartum women who conceived on cART, 5.9% [95% confidence interval (95% CI) 4.0–7.7] experienced viral rebound by 3 months, and 2.2% (1.4–3.0%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during the first 3 months [aHR 2.63 (1.58–4.39)] but not during the 3–12 months postdelivery/pseudo-delivery. In postpartum women who started cART during pregnancy, 27% (22–32%) experienced viral rebound by 3 months, and 3.0% (1.6–4.4%) of their controls. The risk of viral rebound was higher in postpartum women than in controls during both postdelivery/pseudo-delivery periods [<3 months: aHR 6.63 (3.58–12.29); 3–12 months: aHR 4.05 (2.03–8.09)].
In women on suppressive cART, the risk of viral rebound is increased following delivery, especially in the first 3 months, which may be related to reduced adherence, indicating the need for additional adherence support for postpartum women.
PMCID: PMC4631122  PMID: 26544700
adherence; HAART; HIV; postpartum women; pregnant women; viral load
24.  Understanding Family Migration in Rural South Africa: Exploring Children’s Inclusion in the Destination Households of Migrant Parents 
Population, space and place  2015;21(4):310-321.
Despite the removal of restrictions on movement and increasing female participation in migration, only a minority of migrant parents in South Africa include their children in their destination household. Quantitative analyses of the circumstances in which children accompany a migrant parent have been limited by the lack of available data that document family arrangements from the perspective of more than one household. This paper uses data about members of rural households in a demographic surveillance population in KwaZulu-Natal and a linked sample survey of adult migrants to examine factors associated with children’s inclusion in the destination household of migrant parents, analyse the timing and sequence of children’s moves to parental destination households, and describe the composition of parental origin and destination households. The findings confirm that in contemporary South Africa, only a small percentage (14%) of migrants’ children who are members of the parental origin household are also members of the parental destination household. Membership of the parental destination household is associated with parental characteristics and the child’s age, but not measures of socio-economic status, and children most commonly migrate several years after their migrant parent. Children included in the destination household of migrant fathers frequently live in small households, which also include their mother, whereas children included in the destination household of migrant mothers live in larger households. This study contributes to understanding the contexts of children’s inclusion in parental destination households in South Africa and demonstrates the potential of data collected in migrants’ origin and destination households.
PMCID: PMC4430824  PMID: 25983667
children; migrant parents; family migration; destination household; South Africa
25.  An Approach to Measuring Dispersed Families with a Particular Focus on Children ‘Left Behind’ by Migrant Parents: Findings from Rural South Africa 
Population, space and place  2015;21(4):322-334.
There is growing policy and academic interest in the conditions, experiences, and well-being of migrant families stretched across origin and destination households. In South Africa, the dispersal of children and migrant parents across multiple households is a commonplace childhood experience. However, in common with the broader international context, quantitative analyses of the social and residential connections between children and migrant parents in South Africa have been limited by the lack of available data that document family arrangements from the perspective of more than one household. This paper describes a new data collection effort in the origin and destination households of migrants from rural KwaZulu-Natal and explains the methodology for using this data to examine multiple household contexts for children and parents. In order to illustrate the contribution that this form of data collection effort could make to family migration studies, the paper also presents results on the living arrangements of children ‘left behind’ by migrant parents; a potentially vulnerable group whose arrangements are challenging to examine with existing data sources. The empirical results show the majority (75%) of left behind children have previously migrated and a significant proportion of migrants’ children (25%) were not living in their parent’s origin or destination household. The findings highlight the need for careful measurement of the circumstances of left behind children and demonstrate the contribution of linked data for providing insights into the residential arrangements of migrants’ children.
PMCID: PMC4430828  PMID: 25983668
left behind children; migrant parents; dispersed families; migration measurement issues; South Africa

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