The South African Medical Research Council's Guidelines on Ethics for Medical Research - implications for HIV preventive vaccine trials with children

Children are at risk of HIV infection, stand to benefit from the development of HIV preventive vaccines,  and  therefore should be enrolled in trials of HIV vaccines in order to generate relevant safety, immunogenicity and efficacy data. In South Africa, the national vaccine initiative is considering the future conduct of trials  involving  children; this requires an analysis of the current ethical framework, including elements that facilitate or constrain the conduct of such trials. In this article, we examine the Medical Research Council   (MRC)'s Guidelines on Ethics for Medical Research: General Principles (Book 1), and their provis ons on  research involving children. We argue that this set of influential guidelines includes provisions on research with  children that are conceptually problematic and may prohibit critical research with healthy (but at-risk) child participants, including trials of HIVpreventive vaccines. We recommend that Book 1 provisions should be redrafted to reflect a balance between protecting children from research-related risks and testing interventions critical to their health

Missing HIV prevention opportunities in South African children – A 7-year review

CITATION: Feucht, U. D., Meyer, A., & Kruger, M. 2014. Missing HIV prevention opportunities in South African children – A 7-year review. BMC Public Health, 14:1265, doi:10.1186/1471-2458-14-1265.The original publication is available at http://bmcpublichealth.biomedcentral.comBackground: The prevention of mother-to-child transmission (PMTCT) program in South Africa is now successful in ensuring HIV-free survival for most HIV-exposed children, but gaps in PMTCT coverage remain. The study objective was to identify missed opportunities for prevention of mother-to-child transmission of HIV using the four PMTCT stages outlined in National Guidelines. Methods: This descriptive study enrolled HIV-exposed children who were below the age of 7 years and therefore born during the South African PMTCT era. The study site was in Gauteng, South Africa and enrolment was from June 2009 to May 2010. The clinical history was obtained through a structured caregiver interview and review of medical records and included socio-demographic data, medical history, HIV interventions, infant feeding information and HIV results. The study group was divided into the “single dose nevirapine” (“sdNVP”) and “dual-therapy” (nevirapine & zidovudine) groups due to PMTCT program change in February 2008, with subsequent comparison between the groups regarding PMTCT steps during the preconception stage, antenatal care, labor and delivery and postpartum care. Results: Two-hundred-and-one HIV-exposed children were enrolled: 137 (68%) children were HIV infected and 64 (32%) were HIV uninfected. All children were born between 2002 and 2009, with 78 (39%) in the “sdNVP” and 123 (61%) in the “dual-therapy” groups. The results demonstrate significant improvements in antenatal HIV testing and PMTCT enrolment, known maternal HIV diagnosis at delivery, mother-infant antiretroviral interventions, infant HIV-diagnosis and cotrimoxazole prophylaxis. Missed opportunities without improvement include pre-conceptual HIV-services and family planning, tuberculosis screening, HIV disclosure, psychosocial support and postnatal care. Not receiving consistent infant feeding messaging was the only PMTCT component that worsened over time. Conclusions: Multiple missed opportunities for optimal PMTCT were identified, which collectively increase children’s risk of HIV acquisition. Although HIV-testing and antiretroviral interventions improved, all PMTCT components need to be optimized to reach the goal of total pediatric HIV elimination.http://bmcpublichealth.biomedcentral.com/articles/10.1186/1471-2458-14-1265Publisher's versio

Children’s ability to consent to medical management in South Africa

BACKGROUND : The South African Children's Act No. 38 of 2005 requires paediatric medical consent from 12 years of age. OBJECTIVE : To determine children's ability to provide informed consent for medical treatment. METHODS : Assessment used hypothetical treatment storyboards and structured interviews for assessment of 100 children (aged 10 - 17 years), and 25 adult controls, using a standardised scoring tool to test understanding, ability to deliberate treatment choices, and provide rational reasons. Statistical analysis involved multivariate analyses of variance (MANOVAs) and analysis of variance (ANOVA). RESULTS : The female:male ratios for children and adults were 1:0.92 and 1:0.98, respectively. Children⩾12 years were competent with regard to treatment choices (p<0.001), while 10-year-olds could deliberate reasonable outcomes, similar to adults (p<0.001). However, only children 12 years and older could provide rational reasons, where abstract concepts were not involved, whereas children who were⩾14 years old were able to provide rational reasons involving abstract concepts. The actual understanding of choices, compared with adults, was only observed in children older than 14 years (p<0.001). Gender was not a statistically significant denominator. CONCLUSION : Children of 12 years and older are competent to make medical decisions, but the understanding of medical treatment choices under the age of 14 years is not clear.http://www.sajch.org.za/index.php/SAJCHhj2020Family Medicin

Missing HIV prevention opportunities in South African children - a 7-year review

BACKGROUND : The prevention of mother-to-child transmission (PMTCT) program in South Africa is now successful in ensuring HIV-free survival for most HIV-exposed children, but gaps in PMTCT coverage remain. The study objective was to identify missed opportunities for prevention of mother-to-child transmission of HIV using the four PMTCT stages outlined in National Guidelines. METHODS : This descriptive study enrolled HIV-exposed children who were below the age of 7 years and therefore born during the South African PMTCT era. The study site was in Gauteng, South Africa and enrolment was from June 2009 to May 2010. The clinical history was obtained through a structured caregiver interview and review of medical records and included socio-demographic data, medical history, HIV interventions, infant feeding information and HIV results. The study group was divided into the “single dose nevirapine” (“sdNVP”) and “dual-therapy” (nevirapine & zidovudine) groups due to PMTCT program change in February 2008, with subsequent comparison between the groups regarding PMTCT steps during the preconception stage, antenatal care, labor and delivery and postpartum care. RESULTS :: Two-hundred-and-one HIV-exposed children were enrolled: 137 (68%) children were HIV infected and 64 (32%) were HIV uninfected. All children were born between 2002 and 2009, with 78 (39%) in the “sdNVP” and 123 (61%) in the “dual-therapy” groups. The results demonstrate significant improvements in antenatal HIV testing and PMTCT enrolment, known maternal HIV diagnosis at delivery, mother-infant antiretroviral interventions, infant HIV-diagnosis and cotrimoxazole prophylaxis. Missed opportunities without improvement include pre-conceptual HIV-services and family planning, tuberculosis screening, HIV disclosure, psychosocial support and postnatal care. Not receiving consistent infant feeding messaging was the only PMTCT component that worsened over time. CONCLUSIONS : Multiple missed opportunities for optimal PMTCT were identified, which collectively increase children’s risk of HIV acquisition. Although HIV-testing and antiretroviral interventions improved, all PMTCT components need to be optimized to reach the goal of total pediatric HIV elimination.http://www.biomedcentral.com/bmcpublichealthhb201

Aerobic Exercise Training Prevents the Onset of Endothelial Dysfunction via Increased Nitric Oxide Bioavailability and Reduced Reactive Oxygen Species in an Experimental Model of Menopause

ObjectivePrevious studies have shown that estrogen deficiency, arising in postmenopause, promotes endothelial dysfunction. This study evaluated the effects of aerobic exercise training on endothelial dependent vasodilation of aorta in ovariectomized rats, specifically investigating the role of nitric oxide (NO) and reactive oxygen species (ROS).MethodsFemale Wistar rats ovariectomized (OVX - n= 20) or with intact ovary (SHAM - n= 20) remained sedentary (OVX and SHAM) or performed aerobic exercise training on a treadmill 5 times a week for a period of 8 weeks (OVX-TRA and SHAM-TRA). in the thoracic aorta the endothelium-dependent and - independent vasodilation was assessed by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. Certain aortic rings were incubated with L-NAME to assess the NO modulation on the ACh-induced vasodilation. the fluorescence to dihydroethidium in aortic slices and plasma nitrite/nitrate concentrations were measured to evaluate ROS and NO bioavailability, respectively.ResultsACh-induced vasodilation was reduced in OVX rats as compared SHAM (Rmax: SHAM: 86 +/-3.3 vs. OVX: 57+/-3.0%, p<0.01). Training prevented this response in OVX-TRA (Rmax: OVX-TRA: 88+/-2.0%, p<0.01), while did not change it in SHAM-TRA (Rmax: SHAM-TRA: 80+/-2.2%, p<0.01). the L-NAME incubation abolished the differences in ACh-induced relaxation among groups. SNP-induced vasodilation was not different among groups. OVX reduced nitrite/nitrate plasma concentrations and increased ROS in aortic slices, training as effective to restore these parameters to the SHAM levels.ConclusionsExercise training, even in estrogen deficiency conditions, is able to improve endothelial dependent vasodilation in rat aorta via enhanced NO bioavailability and reduced ROS levels.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Biosci, São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Dept Physiol & Biophys, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, São Paulo, BrazilFAPESP: 2012/17709-0FAPESP: 2010/50048-1Web of Scienc

False-positive HIV DNA PCR testing of infants : implications in a changing epidemic

AIM: To examine false-positive HIV DNA polymerase chain reaction (PCR) test results in children, and the potential implications for the paediatric HIV epidemic in sub-Saharan Africa. METHODS: A review was done of records over a 6-year period of children less than 18 months old at an HIV treatment site in South Africa, to evaluate those with an initial ‘false’-positive HIV DNA PCR result, but later proven to be HIV-uninfected with HIV DNA PCR and/or quantitative HIV RNA PCR tests. We calculated the influence of changing HIV transmission rates on predictive values (PV) of HIV DNA PCR tests in a hypothetical population of all HIV-exposed infants over a 1-year period. (Positive PV: proportion of individuals with a positive test with disease; negative PV: proportion of individuals with negative test and no disease). ReSULTS: Of 718 children, 40 with an initial positive HIV DNA PCR test were subsequently proven to be HIV-uninfected, resulting in a positive PV of 94.4%. Most (75%) uninfected children had PMTCT interventions and were asymptomatic or mildly symptomatic (77.5%). Calculations using a test specificity of 99.4%, as reported previously, show a decrease in positive PV using a single-test strategy from 98.6% at 30% HIV transmission rate, to 94.8% at 10% transmission, to 62.5% at 1% transmission. Reduction in test specificity further decreases positive PV at low transmission rates. CONCLUSION: Decreasing mother-to-child HIV transmission rates reduce the positive predictive value of a single HIV DNA PCR test result, necessitating adaptations to diagnostic algorithms to avoid misdiagnosis and inappropriate treatment, especially with early initiation of antiretroviral therapy in asymptomatic infants.http://www.samj.org.z

Research ethics capacity building in Sub-Saharan Africa: a review of NIH Fogarty-funded programs 2000–2012

The last fifteen years have witnessed a significant increase in investment in research ethics capacity development throughout the world. We examine nine research ethics training programs that are focused on Sub-Saharan Africa and supported by the US National Institutes of Health. We collected data from grants awards' documents and annual reports supplemented by questionnaires completed by the training program directors. Together, these programs provided long-term training in research ethics to 275 African professionals, strengthened research ethics committees in 19 countries in Sub-Saharan Africa, and created research ethics curricula at many institutions and bioethics centers within Africa. Trainees' leadership resulted in new national systems and policies on research ethics, human tissue storage and export, and methods of monitoring compliance with research ethics guidelines. Training programs adapted to challenges that arose due to varied trainees' background knowledge in ethics, duration of time available for training, spoken and written English language skills, administrative obstacles, and the need to sustain post-training research ethics activities. Our report showcases the development of awareness of research ethics and building/strengthening of basic research ethics infrastructure in Sub-Saharan Africa. Nevertheless, the increasing amount and complexity of health research being conducted in Sub-Saharan Africa suggests the need for continued investment in research ethics capacity development in this region. This paper is part of a collection of papers analyzing the Fogarty International Center's International Research Ethics Education and Curriculum Development program

Growth in HIV-infected children on long-term antiretroviral therapy

OBEJECTIVES : To describe growth in HIV‐infected children on long‐term antiretroviral therapy (ART) and to assess social, clinical, immunological and virological factors associated with suboptimal growth. METHODS : This observational cohort study included all HIV‐infected children at an urban ART site in South Africa who were younger than 5 years at ART initiation and with more than 5 years of follow‐up. Growth was assessed using weight‐for‐age Z‐scores (WAZ), height‐for‐age Z‐scores (HAZ) and body mass index (BMI)‐forage Z‐scores (BAZ). Children were stratified according to pre‐treatment anthropometry and age. Univariate and mixed linear analysis was used to determine associations between independent variables and weight and height outcomes. RESULTS : Majority of the 159 children presented with advanced clinical disease (90%) and immunosuppression (89%). Pre‐treatment underweight, stunting and wasting occurred commonly (WAZ<‐2= 50%, HAZ<‐2= 73%, BAZ<‐2= 19%). Weight and BMI improvement occurred during the initial 12 months, while height improved during the entire 5‐year period. Height at study exit was significantly worse for children with growth impairment at ART initiation (p<0.001), whilst infants (<1 year) demonstrated superior improvement in terms of BMI (p=0.04). Tuberculosis was an independent risk factor for suboptimal weight (p=0.01) and height (p=0.02) improvement. Weight gain was additionally hindered by lack of electricity (p=0.04). Immune reconstitution and virological suppression were not associated with being underweight or stunted at study end point. CONCLUSIONS : Malnutrition was a major clinical concern for this cohort of HIV‐infected children. Early ART initiation, tuberculosis co‐infection management and nutritional interventions are crucial to ensure optimal growth in HIV‐infected children.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1365-31562017-05-31hb2016Paediatrics and Child Healt