Multitype violence exposures and adolescent antiretroviral nonadherence in South Africa

Objectives: HIV-positive adolescents have low-ART adherence, with consequent increased risks of mortality, morbidity, and viral resistance. Despite high rates of violence against children in the Africa region, no known studies have tested impacts on HIV-positive adolescents. We examine associations of ART adherence with adolescent violence victimization by caregivers, teachers, peers, community members, and healthcare providers. Design and methods: HIV-positive adolescents were interviewed (n = 1060), and clinic biomarker data collected. We sampled all 10–19-year olds ever ART-initiated within 53 clinics in 180 South African communities (90.1% reached). Analyses examined associations between nonadherence and nine violence types using sequential multivariate logistic regressions. Interactive and additive effects were tested with regression and marginal effects. Results: Past-week self-reported ART nonadherence was 36%. Nonadherence correlated strongly with virologic failure (OR 2.3, CI 1.4–3.8) and symptomatic pulmonary tuberculosis (OR 1.49, CI 1.18–2.05). Four violence types were independently associated with nonadherence: physical abuse by caregivers (OR 1.5, CI 1.1–2.1); witnessing domestic violence (OR 1.8, CI 1.22–2.66); teacher violence (OR 1.51, CI 1.16–1.96,) and verbal victimization by healthcare staff (OR 2.15, CI 1.59–2.93). Past-week nonadherence rose from 25% with no violence to 73.5% with four types of violence exposure. Conclusion: Violence exposures at home, school, and clinic are major and cumulating risks for adolescent antiretroviral nonadherence. Prevention, mitigation, and protection services may be essential for the health and survival of HIV-positive adolescents.</p

Comparative models of biological and social pathways to predict child growth through age 2 years from birth cohorts in Brazil, India, the Philippines, and South Africa

Background: Early growth faltering accounts for one-third of child deaths, and adversely impacts the health and human capital of surviving children. Social as well as biological factors contribute to growth faltering, but their relative strength and interrelations in different contexts have not been fully described. Objective: The aim of this study was to use structural equation modelling to explore social and biological multidetermination of child height at age 2 y in longitudinal data from 4 birth cohort studies in low- and middle-income countries. Methods: We analyzed data from 13,824 participants in birth cohort studies in Brazil, India, the Philippines, and South Africa. We used exploratory structural equation models, with height-for-age at 24 mo as the outcome to derive factors, and path analysis to estimate relations among a wide set of social and biological variables common to the 4 sites. Results: The prevalence of stunting at 24 mo ranged from 14.0% in Brazil to 67.7% in the Philippines. Maternal height and birthweight were strongly predictive of height-for-age at 24 mo in all 4 sites (all P values <0.001). Three social-environmental factors, which we characterized as “child circumstances,” “family socioeconomic status,” and “community facilities,” were identified in all sites. Each social-environmental factor was also strongly predictive of height-for-age at 24 mo (all P values <0.001), with some relations partly mediated through birthweight. The biological pathways accounted for 59% of the total explained variance and the social-environmental pathways accounted for 41%. The resulting path coefficients were broadly similar across the 4 sites. Conclusions: Early child growth faltering is determined by both biological and social factors. Maternal height, itself a marker of intergenerational deprivation, strongly influences child height at 2 y, including indirect effects through birthweight and social factors. However, concurrent social factors, many of which are modifiable, directly and indirectly contribute to child growth. This study highlights opportunities for interventions that address both biological and social determinants over the long and short term

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Objectives: No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods: In a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results: Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL. Conclusions: We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL. HIV Medicin

Genome-Wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia

Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer

Can social protection improve sustainable development goals for adolescent health?

Background The first policy action outlined in the Sustainable Development Goals (SDGs) is the implementation of national social protection systems. This study assesses whether social protection provision can impact 17 indicators of five key health-related SDG goals amongst adolescents in South Africa. Methods We conducted a longitudinal survey of adolescents (10-18 years) between 2009 and 2012. Census areas were randomly selected in two urban and two rural health districts in two South African provinces, including all homes with a resident adolescent. Household receipt of social protection in the form of ‘cash’ (economic provision) and ‘care’ (psychosocial support) social protection, and health-related indicators within five SDG goals were assessed. Gender-disaggregated analyses included multivariate logistic regression, testing for interactions between social protection and socio-demographic covariates, and marginal effects models. Findings Social protection was associated with significant adolescent risk reductions in 12 of 17 gender-disaggregated SDG indicators, spanning SDG 2 (hunger); SDG 3 (AIDS, tuberculosis, mental health and substance abuse); SDG 4 (educational access); SDG 5 (sexual exploitation, sexual and reproductive health); and SDG 16 (violence perpetration). For six of 17 indicators, combined cash plus care showed enhanced risk reduction effects. Two interactions showed that effects of care varied by poverty level for boys’ hunger and girls’ school dropout. For tuberculosis, and for boys’ sexual exploitation and girls’ mental health and violence perpetration, no effects were found and more targeted or creative means will be needed to reach adolescents on these challenging burdens. Interpretation National social protection systems are not a panacea, but findings suggest that they have multiple and synergistic positive associations with adolescent health outcomes. Such systems may help us rise to the challenges of health and sustainable development.</p

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Civil society leadership in the struggle for AIDS treatment in South Africa and Uganda

Includes abstract.Includes bibliographical references.This thesis is an attempt to theorise and operationalise empirically the notion of ‘civil society leadership’ in Sub-Saharan Africa. ‘AIDS leadership,’ which is associated with the intergovernmental institutions charged with coordinating the global response to HIV/AIDS, is both under-theorised and highly context-specific. In this study I therefore opt for an inclusive framework that draws on a range of approaches, including the literature on ‘leadership’, institutions, social movements and the ‘network’ perspective on civil society mobilisation. This framework is employed in rich and detailed empirical descriptions (‘thick description’) of civil society mobilisation around AIDS, including contentious AIDS activism, in the key case studies of South Africa and Uganda. South Africa and Uganda are widely considered key examples of poor and good leadership (from national political leaders) respectively, while the Treatment Action Campaign (TAC) and The AIDS Support Organisation (TASO) are both seen as highly effective civil society movements. These descriptions emphasise ‘transnational networks of influence’ in which civil society leaders participated (and at times actively constructed) in order to mobilise both symbolic and material resources aimed at exerting influence at the transnational, national and local levels

Social protection:Potential for improving HIV outcomes among adolescents

Introduction Advances in biomedical technologies provide potential for adolescent HIV prevention and HIV‐positive survival. The UNAIDS 90–90–90 treatment targets provide a new roadmap for ending the HIV epidemic, principally through antiretroviral treatment, HIV testing and viral suppression among people with HIV. However, while imperative, HIV treatment and testing will not be sufficient to address the epidemic among adolescents in Southern and Eastern Africa. In particular, use of condoms and adherence to antiretroviral therapy (ART) remain haphazard, with evidence that social and structural deprivation is negatively impacting adolescents’ capacity to protect themselves and others. This paper examines the evidence for and potential of interventions addressing these structural deprivations. Discussion New evidence is emerging around social protection interventions, including cash transfers, parenting support and educational support (“cash, care and classroom”). These interventions have the potential to reduce the social and economic drivers of HIV risk, improve utilization of prevention technologies and improve adherence to ART for adolescent populations in the hyper‐endemic settings of Southern and Eastern Africa. Studies show that the integration of social and economic interventions has high acceptability and reach and that it holds powerful potential for improved HIV, health and development outcomes. Conclusions Social protection is a largely untapped means of reducing HIV‐risk behaviours and increasing uptake of and adherence to biomedical prevention and treatment technologies. There is now sufficient evidence to include social protection programming as a key strategy not only to mitigate the negative impacts of the HIV epidemic among families, but also to contribute to HIV prevention among adolescents and potentially to remove social and economic barriers to accessing treatment. We urge a further research and programming agenda: to actively combine programmes that increase availability of biomedical solutions with social protection policies that can boost their utilization.</p

‘HIV is like a tsotsi. ARVs are your guns’: Associations between HIV-disclosure and adherence to antiretroviral treatment among adolescents in South Africa

Objectives: WHO guidelines recommend disclosure to HIV-positive children by school age in order to improve ART adherence. However, quantitative evidence remains limited for adolescents. This study examines associations between adolescent knowledge of HIV-positive status and ART-adherence in South Africa. Design: Cross sectional study of the largest known community-traced sample of HIV-positive adolescents. N=684 ART-initiated adolescents aged 10-19 (52% female, 79% perinatally-infected) were interviewed. Methods: In a low-resource health district, all adolescents who had ever initiated ART in a stratified sample of 39 health facilities were identified and traced to 150 communities (n=1102, 351 excluded, 27 deceased, 40 (5.5%) refusals). Quantitative interviews used standardised questionnaires and clinic records. Quantitative analyses used multivariate logistic regressions, and qualitative analyses used grounded theory for 18 months of interviews, focus groups and participant observations with 64 adolescents, caregivers and healthcare workers. Results: 36% of adolescents reported past-week ART non-adherence, and 70% of adolescents knew their status. Adherence was associated with fewer opportunistic infection symptoms (OR .55 CI 0.40-0.76). Adolescent knowledge of HIV-positive status was associated with higher adherence, independently of all co-factors (OR 2.18 CI 1.47-3.24). Among perinatally-infected adolescents who knew their status (n=362/540) disclosure prior to age 12 was associated with higher adherence (OR 2.65 CI 1.34-5.22). Qualitative findings suggested that disclosure was undertaken sensitively in clinical and family settings, but that adults lacked awareness about adolescent understandings of HIV status. Conclusion: Early and full disclosure is strongly associated with improved adherence amongst ART-initiated adolescents. Disclosure may be an essential tool in improving adolescent adherence, and reducing mortality and onwards transmission

Logistic regression models showing associations between social protection receipt and SDG indicators among boys (N = 1475).

<p>Logistic regression models showing associations between social protection receipt and SDG indicators among boys (N = 1475).</p