South African Medical Research Council Research Articles

Resistance Sniffer: An online tool for prediction of drug resistance patterns of Mycobacterium tuberculosis isolates using next generation sequencing data

The effective control of multidrug resistant tuberculosis (MDR-TB) relies upon the timely diagnosis and correct treatment of all tuberculosis cases. Whole genome sequencing (WGS) has great potential as a method for the rapid diagnosis of drug resistant Mycobacterium tuberculosis (Mtb) isolates. This method overcomes most of the problems that are associated with current phenotypic drug susceptibility testing. However, the application of WGS in the clinical setting has been deterred by data complexities and skill requirements for implementing the technologies as well as clinical interpretation of the next generation sequencing (NGS) data. The proposed diagnostic application was drawn upon recent discoveries of patterns of Mtb clade-specific genetic polymorphisms associated with antibiotic resistance. A catalogue of genetic determinants of resistance to thirteen anti-TB drugs for each phylogenetic clade was created. A computational algorithm for the identification of states of diagnostic polymorphisms was implemented as an online software tool, Resistance Sniffer (http://resistance-sniffer.bi.up.ac.za/), and as a stand-alone software tool to predict drug resistance in Mtb isolates using complete or partial genome datasets in different file formats including raw Illumina fastq read files. The program was validated on sequenced Mtb isolates with data on antibiotic resistance trials available from GMTV database and from the TB Platform of South African Medical Research Council (SAMRC), Pretoria. The program proved to be suitable for probabilistic prediction of drug resistance profiles of individual strains and large sequence data sets.

Infectious morbidity of breastfed, HIV-exposed uninfected infants under conditions of universal antiretroviral therapy in South Africa: a prospective cohort study

Without breastfeeding and maternal antiretroviral therapy (ART), HIV-exposed uninfected (HEU) infants have greater infectious morbidity than HIV-unexposed (HU) infants. We hypothesised that with the introduction of universal maternal ART, breastfed HEU and HU infants would have similar morbidity. We prospectively studied a cohort of HIV-infected pregnant women initiating ART, and a parallel group of HIV-uninfected pregnant women, starting from their first antenatal care visit at the Gugulethu Midwife Obstetrics Unit in Cape Town, South Africa. All pregnant women attending their first antenatal care visit were eligible for enrolment if aged 18 years or older and planning to deliver in Cape Town, without gestational age restrictions. HIV-infected women were participants of the Maternal Child Health ART (MCH-ART) study, and HIV-uninfected women were participants of the HIV-Unexposed Uninfected (HU2) study. All enrolled women were followed up during pregnancy and through delivery. At the early neonatal visit (scheduled for the first week after birth), mother-infant pairs who practiced any breastfeeding in the first 7 days of life were eligible for further postnatal follow-up for at least 12 months post partum. HIV infection was excluded among HEU infants at ages 6 weeks and 12 months by PCR. We evaluated the effect of HIV exposure on two primary outcomes: hospitalisation (all-cause and infection-related admission to hospital) and longitudinal prevalence of child infectious illness (diarrhoea and presumed lower respiratory tract infection [LRTI]). Hospitalisation data were abstracted from routine health records. Crude and adjusted incidence rate ratios (aIRRs; with adjustment for maternal HIV disease severity, timing of ART initiation, breastfeeding, timely vaccination, and birth outcomes [gestational size and age]) for infection-related hospitalisations were calculated from Poisson regression models (with variance corrected for clustering). Prevalence of infant infectious illness was based on maternal self-report for the preceding 2 weeks of each visit, with questions based on Demographic and Health Survey (DHS) questionnaires. Infants who acquired HIV infection during follow-up were excluded from this analysis. MCH-ART is registered on ClinicalTrials.gov, NCT01933477. Pregnant women were recruited between March 20, 2013, and Aug 19, 2015. Mother-infant pairs (HEU, n=459; HU, n=410) were followed up for a median of 12 months until March 24, 2017. Compared with HU infants, HEU infants had more infection-related hospitalisations between the age of 8 days and 3 months (HEU, 34·2 admissions per 100 child-years [24·4-47·9] vs 9·8 per 100 child-years [95% CI 5·1-18·8]; IRR 3·50 [95% CI 1·68-7·30]), but rates were similar at other ages. In infants aged 8 days to 3 months, infection-related hospitalisations for HEU infants with healthier mothers (n=84; ART initiation at <24 weeks' gestation, CD4 count >350 cells per μL, HIV viral load <4·0 log10 copies per mL: 15·88 admissions per 100 child-years [5·12-49·23]) approximated those of HU infants (9·77 per 100 child-years [5·08-18·78]; aIRR 1·28 [0·27-6·05]). HEU infants of mothers with late ART initiation (at ≥24 weeks' gestation) and advanced disease (CD4 count ≤350 cells per μL and HIV viral load ≥4·0 log10 copies per mL; n=44) had the highest admission rate (40·44 per 100 child-years [15·18-107·74]; aIRR 5·01 [1·50-16·71]). In this age group, reduced admissions were seen in HEU infants with optimal breastfeeding (initiated within 1 h of birth and exclusive through age 3 months) and timely vaccination (required doses received within 2 weeks of indicated age; n=90; 9·63 admissions per 100 child-years [2·41-38·49]). Between birth and age 6 months, HEU infants had an almost five times greater prevalence of LRTIs than HU infants (aPR 4·69 [2·40-9·17]), and a three-times greater prevalence of diarrhoeal illness (aPR 2·93 [1·70-5·07]). After age 6 months, these associations were ameliorated. Despite ART in pregnancy, breastfed HEU infants versus breastfed HU infants had transiently increased infectious morbidity risks in early infancy. However, differences were driven by factors potentially amenable to intervention, including delayed diagnosis and ART initiation in HIV-positive mothers, and suboptimal breastfeeding and vaccination of their infants. US National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, Fogarty Foundation and the Office of AIDS Research.

Effects of Minimum Unit Pricing for Alcohol in South Africa Across Different Drinker Groups and Wealth Quintiles: A Modelling Study

Background: Previous research in high income countries has found Minimum Unit Pricing (MUP) for alcohol to be an effective policy for reducing alcohol-related harm. However, these results may not translate well to South Africa, notable for high levels of abstinence, binge drinking, unrecorded alcohol and alcohol-related injury and infectious disease. Methods: We built an epidemiological policy appraisal model using secondary data to estimate the effects of MUP across sex, drinker groups and wealth quintiles. Stakeholder interviews and workshops informed model development and ensured policy relevance. Model outcomes include individual consumption, individual spend, tax revenue, retail revenue and group health harms (HIV, intentional injury, road injury, liver cirrhosis and breast cancer). Findings: We estimate that a MUP of R10 per standard drink (15ml of pure alcohol) would lead to an immediate reduction in consumption of 5.5%. The absolute reduction in standard drinks per drinker per year is greatest for heavy drinkers, followed by moderate drinkers and then binge drinkers (-97.76, -25.48, -17.16).A R10 MUP generates 23,149 lives saved and 1,009,477 cases averted across the five health harms over 20 years. Poorer drinkers would see greater impacts from the policy (consumption: -7.9% in poorest, -3.7% in richest quintile). The bottom three wealth quintiles accrue 76% of the deaths averted and 74% of the cases averted. Interpretation: Our model estimates minimum pricing would reduce alcohol consumption in South Africa, improving health outcomes whilst raising retail and tax revenue. Consumption and harm reductions would be greater in poorer compared to richer groups. Funding Statement: This work was supported by the Wellcome Trust Doctoral Training Centre in Public Health Economics and Decision Science [108903/Z/19/Z] and the University of Sheffield. Also the South African Medical Research Council. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: Ethical approval for engaging with stakeholders was granted by the South African Medical Research Council (Protocol ID: EC005-4/2019) and the School of Health and Related Research at the University of Sheffield, UK (Reference Number: 023357). All data for the model came from secondary sources and was managed according to an approved information governance plan.

Weight Change Among Women Using Intramuscular Depot Medroxyprogesterone Acetate, a Copper Intrauterine Device, or a Levonorgestrel Implant for Contraception: Findings from a Randomised, Multicentre, Open-Label Trial

Background: There is limited evidence on the impact of the use of progestin-only hormonal contraception (POC) on weight change. We conducted a secondary analysis of prospective weight change among women enrolled in the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial. Methods: The ECHO trial was conducted at 12 sites in eSwatini, Kenya, South Africa and Zambia. HIV negative, women aged 16-35 years, desiring contraception, were randomized (1:1:1) to either 3-monthly intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implant or copper intrauterine device (IUD). Follow-up was up to 18 months. Weight (kgs) was measured at baseline and study exit. Analysis was performed as intention to treat (ITT) and time on continuous contraceptive use. Findings: 7829 women were randomly assigned to DMPA-IM (n=2609), copper IUD (n=2607) or LNG implant (n=2613). The ITT population included 7014 women 2293 DMPA-IM group, 2372 copper IUD group and 2349 LNG group) who were not lost to follow-up, pregnant on study, or missing weight data. The mean weight increased in all groups but was significantly different in magnitude: 3.5kg (SD=6.3), 2.4kg (SD=5.9) and 1.5kg (SD=5.7) in the DMPA-IM, LNG implant and copper IUD groups, respectively. Comparative differences between groups were (2.02 kg 95% CI, 1.68,2.36, p<0.001 ) for DMPA-IM versus copper IUD, 0.87kg (0.53,1.20 p<0.001) for LNG implant compared to copper IUD and 1.16kg (0.82, 1.50, p<0.001) for DMPA-IM compared with LNG implant. Results for continuous contraceptive use were similar. Interpretation: We found differences in weight gain between POC users compared to the non-hormonal copper IUD group over 12-18 months of use. Women using POCs should be counselled about this potential side effect when choosing a contraceptive method. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT02550067. Funding Statement: Bill & Melinda Gates Foundation, US Agency for International Development (USAID) and the President’s Emergency Plan for AIDS Relief, Swedish International Development Cooperation Agency, South African Medical Research Council, and UNFPA. Declaration of Interests: None to declare Ethics Approval Statement: Ethics review committees at each study site, FHI 360, and the World Health Organization (WHO) approved the study protocol. Women provided written informed consent in a language of their choice prior to the conduct of any study related procedures.

Looking back, moving forward: 50 years of South African Medical Research Council alcohol-related publications.

Alcohol is one of the highest risk factors for death and disability in South Africa (SA).Objective. To explore the trajectory of empirical research on alcohol in SA between 1969 and 2019, with an emphasis on South African Medical Research Council (SAMRC) authored publications.Methods. We reviewed published research (Pubmed and Africa-Wide Information) using systematic methods, clear inclusion and exclusion criteria, and defined search terms. The search was not limited by language. Data synthesis was carried out by the first and last authors.Results. A total of 867 journal articles met the inclusion criteria, with 243 (28.0%) authored or co-authored by SAMRC researchers. For the latter group, three-quarters had an SAMRC researcher as first or last author. Over three-quarters (78.6%) of the SAMRC author positions ('first', 'last' or 'other, counting researchers from a unit only once, but counting authors across different units on a single publication) were from intramural units. Over half the articles authored by SAMRC researchers focused on non-communicable diseases (55.9%), 23.8% focused on communicable diseases, and 10% on crime, violence or injury. Few articles focused on alcohol and tuberculosis (TB), alcohol and cancer, or alcohol policy. Over three-quarters (76.9%) were epidemiological in nature, and 65.3% were cross-sectional studies. There were 17 reviews (7 systematic) and 11 randomised controlled trials (RCTs). There was an increase in the annual number of publications over the 50-year period for both SAMRC and non-SAMRC researchers. Over time, there has been a trend towards publishing on alcohol research in journals published outside SA, but the SAMJ still remains a popular journal choice.Conclusion. The SAMRC has contributed substantially to the growing field of alcohol research in SA, but gaps in areas such as alcohol policy evaluation, alcohol and its association with TB and cancer, and interventional research, are evident.

The role of the South African Medical Research Council in reducing lead exposure and preventing lead poisoning in South Africa.

Even at low levels in blood, lead has been associated with reduced IQ scores, behavioural problems, learning impediments, aggression and violent behaviour. Since the 1980s, the South African Medical Research Council (SAMRC) has been investigating the sources of exposure to lead in South Africa (SA), the groups at highest risk of lead poisoning and a selection of the myriad associated health and social consequences. SAMRC research evidence contributed to the phasng out of leaded petrol, restrictions on lead in paint and other interventions. Subsequently, childhood blood lead levels in SA declined significantly. More recent studies have revealed elevated risks of lead exposure in subsistence fishing and mining communities, users of arms and ammunition, those ingesting certain traditional medicines, and users of certain ceramicware and artisanal cooking pots. Lead-related cognitive damage costs the SA economy ~USD17.7 (ZAR261.3) billion annually, justifying further SAMRC investment in lead exposure research in the country.

Gathering the evidence and identifying opportunities for future research in climate, heat and health in South Africa: The role of the South African Medical Research Council.

A changing climate is likely to have widespread and varying impacts on ecosystems and human health. South Africa (SA) is particularly vulnerable to the impacts of climate change, given the projected increases in temperature, and changes in the amount and patterns of rainfall. Moreover, SA's vulnerability is exacerbated by extreme inequality and poverty. To prepare for the impacts of climate change and to ensure timeous adaptation, a perspective is given on essential heat and health research in the country.Objectives. To gather studies conducted by the South African Medical Research Council (SAMRC)'s Environment and Health Research Unit (EHRU) to illustrate the range of possible research key areas in the climate, heat and health domain and to present future research priorities.Methods. Studies conducted by the SAMRC's EHRU were gathered and used to illustrate the range of possible research key areas in the climate, heat and health domain. Using national and international published and grey literature, and tapping into institutional research experiences, an overview of research findings to date and future research priorities were developed.Results. Heat and health-related research has focussed on key settings, for example, schools, homes and outdoor work places, and vulnerable groups such as infants and children, the elderly and people with pre-existing diseases. The need to address basic needs and services provision was emphasised as an important priority.Conclusions. High and low temperatures in SA are already associated with mortality annually; these impacts are likely to increase with a changing climate. Critical cross-sectoral research will aid in understanding and preparing for temperature extremes in SA.

First social impact bond for the SAMRC: A novel financing strategy to address the health and social challenges facing adolescent girls and young women in South Africa.

A social impact bond (SIB) is an innovative financing mechanism to attract investors to social programmes traditionally funded by governments. In this article, in celebration of the 50th anniversary of the South African Medical Research Council (SAMRC), the authors describe the SAMRC's first foray into this new world of financing through a SIB to improve the health and quality of life of adolescent girls and young women (AGYW). The AGYW SIB is in its preparatory phase and is scheduled for implementation in 2020. The authors describe the mechanism, including financial flows and the process of customising the SIB to meet the needs of AGYW, focusing on HIV prevention and treatment and the prevention and management of unintended pregnancies in schoolgoing AGYW. The authors outline an approach to designing the package of interventions, the metrics associated with such a programme and the business model. It is hypothesised that the proposed approach will lead to an improvement in programmatic outcomes, monitoring and evaluation tools and cost-effectiveness, and will develop key learning data for the future use of SIBs in health service delivery.

Burden of disease in South Africa: Protracted transitions driven by social pathologies.

For several decades, researchers from the South African Medical Research Council have made invaluable contributions towards improving the health of the population through the analysis and interpretation of cause of death data. This article reflects the mortality trends in pre-and post-apartheid South Africa (SA), and describes efforts to improve vital statistics, innovations to fill data gaps, and studies to estimate the burden of disease after adjusting for data deficiencies. The profound impact of HIV/AIDS, particularly among black African children and young adults, is striking, within a protracted epidemiological transition and the current reversals of multiple epidemics. Over the next 20 years, it will be important to sustain and enhance the country's capacity to collect, analyse and utilise cause of death data. SA needs to support development in the region, harnessing new data platforms and approaches such as including verbal autopsy tools in the official system and improving data linkage.

Tuberculosis research in South Africa over the past 30 years: From bench to bedside

The South African Medical Research Council Centre for Tuberculosis Research has a rich history of high-impact research that has influenced our understating of this hyper-epidemic which is further exacerbated by the emergence and spread of drug-resistant forms of the disease. This review aims to summarise the past 30 years of research conducted in the Centre which has influenced the way that tuberculosis (TB) is diagnosed and treated. The review includes the development of new technologies for rapid screening of people with probable TB and the repurposing of human diagnostics for wildlife conservation.

Reducing homicide through policy interventions: The case of gun control

Injuries impose a fourth major disease burden on the South African population, which is driven in particular by the high incidence of interpersonal violence. There was a significant decline in mortality from interpersonal violence between 1997 and 2012, and research conducted by South African Medical Research Council (SAMRC) researchers has ascribed much of this decline to a decrease in firearm homicide. In the present brief review, we summarise South African research on fatal and non-fatal firearm injuries, with a particular focus on research conducted by SAMRC intra- and extramural units between 1969 and 2019. More recent data suggest a lapse in firearm control that has led to an increase in homicide and that the fluctuating homicide rate is being influenced by adherence to firearm control policies.

Mycobacterium Tuberculosis Blood Stream Infection Prevalence, Diagnosis, and Mortality Hazard in HIV-Positive Adults: A Systematic Review and Meta-Analysis of Individual Patient Data

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis blood stream infection (MTB-BSI) is incompletely understood. We hypothesised that MTB-BSI prevalence has been underestimated, that MTB-BSI independently predicts death, and sputum Xpert has suboptimal diagnostic yield for MTB-BSI. Methods: We conducted a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood-culture (TBBC), including HIV-positive adults aged ≥13-years with suspected tuberculosis. Predicted probabilities of MTB-BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum (Xpert or culture if Xpert unavailable) and urinelipoarabinomannan for MTB-BSI were obtained by two-level random-effect meta-analysis, mortality hazard of MTB-BSI by mixed-effect Cox proportional-hazard modelling, and effect of treatment delay with propensity-score analysis. Findings 5751 patients met inclusion criteria. Predicted probability of MTB-BSI was 45% (95%CI 38-52%) for danger-sign positive tuberculosis inpatients with cohort median CD4 count of 76 cells/μL. Diagnostic yield of sputum was 77% (95%CI 63–87%), rising to 89% (95%CI 80-94%) when combined with urinelipoarabinomannan testing. MTB-BSI increased hazard of death before 30-days (aHR2·5, 95%CI 2·1–3·1). In a propensity-score matched cohort (n=630), mortality increased with treatment delay >4 days in MTB-BSI (OR 3·2, 95%CI 1·1–10·3). Interpretation: In critically-ill adults with HIV-tuberculosis, MTB-BSI is a very frequent manifestation of tuberculosis and strongly predicts mortality. Better diagnostic yield in patients with MTB-BSI can be achieved by parallel use of sputum-Xpert and urine-LAM. Treatment delay may increase mortality hazard. Funding Statement: This study was supported by Wellcome fellowships 109105z/15/a, 105165/Z14/A. Charlotte Schutz was funded by the South African Medical Research Council under the National Health Scholars Programme. Moshi, Tanzania research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a program funded by the US National Institutes of Health (NIH) (U01 AI062563). John A. Crump receives support from US NIH R01AI121378. Elizabeth L. Corbett is supported by a Wellcome trust senior fellowship in clinical science (WT200901). Gary Maartens was supported in part by National Research Fund incentive funding (UID: 85810). Susan E. Dorman was supported by contract #HHSN2722000900050C and grant K24AI104830 (to SED), both from the US National Institutes of Health. Douglas Wilson was supported by BMS Secure the Future. Graeme Meintjes was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014). Declaration of Interests: David Alland is on the Scientific Advisory Board of Specific Technologies and receives a portion of the licensing income paid by Cepheid to Rutgers University for sales of the Xpert Ultra assay. Neil Martinson has received institutional grants for collection of specimens for Roche and Becton Dickinson, and from Pfizer for assessing incident pneumonia. All other authors declare no competing interests. Ethics Approval Statement: PROSPERO registration: CRD42016050022.

Effect of co-trimoxazole prophylaxis on morbidity and mortality of HIV-exposed, HIV-uninfected infants in South Africa: a randomised controlled, non-inferiority trial

WHO guidelines recommend co-trimoxazole prophylaxis for HIV-exposed, HIV-uninfected infants. These guidelines date back to an era in which HIV testing of infants was impossible and mothers had poor access to antiretroviral treatment. To determine whether this guideline requires revision in the current era of effective prevention of mother-to-child transmission and early infant diagnosis programmes, we aimed to investigate whether receiving no co-trimoxazole prophylaxis is inferior to receiving co-trimoxazole prophylaxis in the resulting incidence of grade 3 or 4 common childhood illnesses or mortality in breastfed HIV-exposed, HIV-uninfected infants. We investigated our aim in a randomised controlled, non-inferiority trial. We enrolled the HIV-negative infants of mothers living with HIV who were actively involved in transmission prevention programmes in two clinics in Durban, South Africa. Infants were included in the study if they were breastfeeding at the screening and enrolment visits, and their mother was planning to breastfeed for at least 6 months; were a singleton birth and had a birthweight of 2 kg or more; had no clinically observed genetic disorders; and had no serious illnesses and had not received antibiotics or traditional medications (such as herbal remedies). Infants were randomly assigned (1:1) to receive co-trimoxazole or no co-trimoxazole. In the co-trimoxazole group, infants received the drug until all exposure to HIV had ceased (ie, 6 weeks after last exposure to breastmilk) and the infant was confirmed to be uninfected with HIV. The drug was administered by mothers in once-daily regimens of 20 mg trimethoprim and 100 mg sulfamethoxazole orally (age <6 months or bodyweight <5 kg), or 40 mg trimethoprim and 200 mg sulfamethoxazole orally (age >6 months or bodyweight >5 kg). Clinical and laboratory staff always remained masked to group assignment, but mothers and study counsellors were not. Infants and their mothers attended study visits at ages 6 weeks (for enrolment and randomisation), 10 weeks, 14 weeks, and then monthly from 4 to 12 months. Our primary outcome was the incidence of grade 3 or 4 common childhood illnesses (pneumonia or diarrhoea) or mortality in breastfed HIV-exposed, HIV-uninfected infants by age 12 months. A non-inferiority bound of 5% was used. The study is registered with the Pan African Clinical Trials Registry, number PACTR201311000621110, and the South African National Clinical Trials Registry, number DOH-27-0614-4728. We screened 1570 mother-child pairs for study enrolment, from whom (78%) eligible infants were enrolled into the study between Oct 16, 2013, and May 23, 2018. Of the infants enrolled, 611 (50%) were randomly assigned to the co-trimoxazole group and 609 (50%) were randomly assigned to the no co-trimoxazole group. One (<1%) infant in the no co-trimoxazole group was excluded from the analysis of the final outcomes for having received traditional medicine (which only became apparent after randomisation); therefore, 611 (50%) infants in the co-trimoxazole group and 608 (50%) infants in the no co-trimoxazole group were included in the final intention-to-treat analysis. 136 (22%) infants in the co-trimoxazole group and 139 (23%) infants in the no co-trimoxazole group did not complete the 12-month study visit, predominantly because of loss to follow-up (93 [15%] infants in the co-trimoxazole group; 90 [15%] infants in the no co-trimoxazole group). The cumulative probability of the composite primary outcome was 0·114 (95% CI 0·076 to 0·147; 49 events) in the co-trimoxazole group versus 0·0795 (0·044 to 0·115; 39 events) in the no co-trimoxazole group. The risk difference (no co-trimoxazole group minus co-trimoxazole group) was -0·0319 (-0·075 to 0·011), meaning that the risk was around 3 percentage points lower in the no co-trimoxazole group on the additive scale. We can conclude that no co-trimoxazole is not inferior to daily co-trimoxazole among breastfed HIV-exposed, HIV-uninfected infants whose mothers are accessing a prevention of mother-to-child transmission programme in an area unaffected by malaria. We therefore believe that WHO should revise the co-trimoxazole guidelines for HIV-exposed, HIV-uninfected infants in areas unaffected by malaria. HIV Prevention Research Unit of the South African Medical Research Council and the Family Larsson-Rosenquist Foundation.

P2427The development of a computational fluid dynamics pipeline for the study of tetralogy of Fallot and coarctation of the aorta in a developing world context

Abstract Background Tetralogy of Fallot (ToF) and coarctation of the aorta (CoA) each constitute approximately 7% of congenital heart disease (CHD) births worldwide. Compared to developed countries, developing countries have a disparate level of access to prompt diagnosis and treatment for these diseases. Computational fluid dynamics (CFD) approaches implemented on routinely available non-invasive imaging data may yield low-cost improvements to the management of these patients. Purpose The purpose of this research is to develop a patient-specific computational pipeline that allows the modelling of blood flow in diseased arteries of patients suffering from ToF and CoA. The project aims to prove the feasible use of broadly available imaging techniques - CT angiograms (CTA) and echocardiographs (echo) - for achieving this in low-to-middle income countries. The capability of the pipeline will be demonstrated through a qualitative study of the effects of different systemic to pulmonary shunt configurations used in the palliative treatment of ToF. In addition, the effects of idealised stent configurations on the blood flow through the aorta of a patient with CoA will be studied. Methods A retrospective search through the hospital database was conducted to select suitable CTA data for a CoA and ToF case. Data for patient A, a five-month-old child with typical CoA, and patient B, a twelve-month-old child with typical ToF who had a central shunt in place, was found. Echo data was obtained for patient A through an investigation protocol which focused on CFD application whereas there was no echo data available for patient B. As a result, idealised volume flow rate data was implemented for patient B. Geometries for patient A and patient B were extracted and volume discretisation was implemented for grid independence testing. The Navier-Stokes governing equations for fluid flow were solved using the open source software, OpenFOAM, for the transient case where inlet volume flow rate was defined for four cardiac cycles. Figure 1 shows key features of the flow in the shunt and pulmonary branches (A), the aortic arch (B), the inlet at the ascending aorta (C) and the descending aorta (D) for the geometry extracted from the data set of patient B. Figure 1. Key flow features of patient B Results and discussion We have implemented CFD models which are able to qualitatively assess the favourable or unfavourable impact of different approaches to ToF and CoA repairs on the characteristics of blood flow in the aorta and pulmonary arteries. An echo investigation protocol has been developed and successfully applied. CTA studies have been shown as feasible sources of geometry data in spite of the restriction on quality by the important requirement for low doses of radiation in paediatric patients. This project represents progress towards an advanced tool that may be broadly implemented in both well-resourced and minimally-resourced hospitals. Acknowledgement/Funding National Research Fund, British Heart Foundation, Newton Fund (UK MRC, South African Medical Research Council), University of Cape Town

6133Profile of cardiomyopathy patients in Cape Town - pilot phase the IMHOTEP Study

Abstract Background Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in LMIC with limited access to specialised care. Little is known about the clinical profile of cardiomyopathy in Africa. Purpose Delineation of clinical presentation and cardiovascular magnetic resonance (CMR) phenotypes of cardiomyopathy. Method The African Cardiomyopathy and Myocarditis Registry Program (IMHOTEP) is a prospective multi-centre, hospital-based study and aims to investigate the clinical characteristics, aetiology, genetics, management and outcomes of cardiomyopathies in Africans. Results Assessment of the first 99 adult cases showed that dilated cardiomyopathy (DCM; n=67) was commonest, followed by hypertrophic (HCM; n=13), left ventricular noncompaction (LVNC; n=11), restrictive (RCM; n=4) and arrhythmogenic (ARVC; n=4) cardiomyopathies. Idiopathic DCM (22%) and peripartum cardiomyopathy (16%) accounted for the majority (Figure). A family history of cardiomyopathy or SCD was reported in 20% of cases. Mean age of presentation was 37±12 years. Most patients (96%) were symptomatic at presentation. NYHA class III/IV was more frequently seen in DCM (61%), RCM (50%) and LVNC (64%), whereas syncope was more common in ARVC (50%) and HCM (23%). VT and aborted cardiac arrest were reported in 7% and 3%, respectively. Onset of symptoms in the peripartum period was observed in 47% of women. Beta-blockers and ACE-inhibitors were prescribed in 77% and 78%, respectively, however optimal dosing was achieved in ≤14% of patients at a median time of 5.4 months after symptom onset. CMR was performed in 67 (68%) cases (Table) and contributed diagnostically in a third of cases. Late gadolinium enhancement (LGE) was observed in 92%. In DCM, linear mid-wall and subendocardial patterns of LGE were seen in 95% and 8% of patients respectively – a much higher percentage than previously reported in the literature. CMR volumetric and functional assessment DCM, n=38 HCM, n=11 ARVC, n=3 RCM, n=4 LVNC, n=11 LVEF (%) 27±15 78±7 55±5 52±7 32±17 LVEDV/BSA (ml/m2) 150±40 80±17 98±12 59±13 155±52 LV mass/BSA (g/m2) 82±23 102±35 74±3 71±14 88±31 RVEF (%) 34±15 68±10 22±15 49±18 33±15 RVEDV/BSA (ml/m2) 104±37 68±15 189±27 56±8 106±51 All continuous variables presented as mean ± standard deviation. Cardiomyopathy diagnosis (n=99) Conclusion IMHOTEP is the first multi-centre registry for cardiomyopathy in Africa. Preliminary data suggests an earlier age of onset with female predominance compared to other cohorts, and DCM is the predominant form of cardiomyopathy in Africa. Acknowledgement/Funding NEWTON FUND NON-COMMUNICABLE DISEASE - South African Medical Research Council (SAMRC/GSK)

Open-labelled randomised controlled trial of 12 hours versus 24 hours modified Pritchard regimen in the management of eclampsia and pre-eclampsia in Ghana (MOPEP Study): study protocol

IntroductionHypertensive disorders of pregnancy continue to be a major contributor to maternal and perinatal morbidity and mortality. Magnesium sulfate therapy is the standard of care for seizure prophylaxis and treatment...

HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial

SummaryBackgroundObservational and laboratory studies suggest that some hormonal contraceptive methods, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM), might increase women's susceptibility to HIV acquisition. We aimed to compare DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant among African women seeking effective contraception and living in areas of high HIV incidence.MethodsWe did a randomised, multicentre, open-label trial across 12 research sites in eSwatini, Kenya, South Africa, and Zambia. We included HIV-seronegative women aged 16–35 years who were seeking effective contraception, had no medical contraindications to the trial contraceptive methods, agreed to use the assigned method for 18 months, and reported not using injectable, intrauterine, or implantable contraception for the previous 6 months. Participants were randomly assigned (1:1:1) to receive an injection of 150 mg/mL DMPA-IM every 3 months, a copper IUD, or a LNG implant with random block sizes between 15 and 30, stratified by site. Participants were assigned using an online randomisation system, which was accessed for each randomisation by study staff at each site. The primary endpoint was incident HIV infection in the modified intention-to-treat population, including all randomised participants who were HIV negative at enrolment and who contributed at least one HIV test. The primary safety endpoint was any serious adverse event or any adverse event resulting in method discontinuation, until the trial exit visit at 18 months and was assessed in all enrolled and randomly assigned women. This study is registered with ClinicalTrials.gov, number NCT02550067.FindingsBetween Dec 14, 2015, and Sept 12, 2017, 7830 women were enrolled and 7829 were randomly assigned to the DMPA-IM group (n=2609), the copper IUD group (n=2607), or the LNG implant group (n=2613). 7715 (99%) participants were included in the modified intention-to-treat population (2556 in the DMPA-IM group, 2571 in the copper IUD group, and 2588 in the LNG implant group), and women used their assigned method for 9567 (92%) of 10 409 woman-years of follow-up time. 397 HIV infections occurred (incidence 3·81 per 100 woman-years [95% CI 3·45–4·21]): 143 (36%; 4·19 per 100 woman-years [3·54–4·94]) in the DMPA-IM group, 138 (35%: 3·94 per 100 woman-years [3·31–4·66]) in the copper IUD group, and 116 (29%; 3·31 per 100 woman-years [2·74–3·98]) in the LNG implant group. In the modified intention-to-treat analysis, the hazard ratios for HIV acquisition were 1·04 (96% CI 0·82–1·33, p=0·72) for DMPA-IM compared with copper IUD, 1·23 (0·95–1·59, p=0·097) for DMPA-IM compared with LNG implant, and 1·18 (0·91–1·53, p=0·19) for copper IUD compared with LNG implant. 12 women died during the study: six in the DMPA-IM group, five in the copper IUD group, and one in the LNG implant group. Serious adverse events occurred in 49 (2%) of 2609 participants in the DMPA-IM group, 92 (4%) of 2607 participants in the copper IUD group, and 78 (3%) of 2613 participants in the LNG implant group. Adverse events resulting in discontinuation of the randomly assigned method occurred in 109 (4%) women in the DMPA-IM group, 218 (8%) women in the copper IUD group, and 226 (9%) women in the LNG implant group (p<0·0001 for DMPA-IM vs copper IUD and for DMPA-IM vs LNG implant). 255 pregnancies occurred: 61 (24%) in the DMPA-IM group, 116 (45%) in the copper IUD group, and 78 (31%) in the LNG implant group. 181 (71%) pregnancies occurred after discontinuation of randomly assigned method.InterpretationWe did not find a substantial difference in HIV risk among the methods evaluated, and all methods were safe and highly effective. HIV incidence was high in this population of women seeking pregnancy prevention, emphasising the need for integration of HIV prevention within contraceptive services for African women. These results support continued and increased access to these three contraceptive methods.FundingBill & Melinda Gates Foundation, US Agency for International Development and the President's Emergency Plan for AIDS Relief, Swedish International Development Cooperation Agency, South African Medical Research Council, and UN Population Fund. Contraceptive supplies were donated by the Government of South Africa and US Agency for International Development.

Low-dose ritonavir-boosted darunavir once daily versus ritonavir-boosted lopinavir for participants with less than 50 HIV RNA copies per mL (WRHI 052): a randomised, open-label, phase 3, non-inferiority trial

Pilot studies suggest that ritonavir-boosted darunavir could show high efficacy at doses below those currently approved. We investigated whether switch to 400 mg of darunavir boosted with 100 mg ritonavir once daily could show equivalent efficacy to continuation of ritonavir-boosted lopinavir (a protease inhibitor commonly used in low-income and middle-income countries) for individuals with HIV RNA suppression. In the WRHI 052 study, a randomised, parallel-group, open-label, non-inferiority phase 3 trial, adults who were HIV-1 positive were enrolled in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. Eligible participants were 18 years or older, who tolerated ritonavir-boosted lopinavir in combination with two nucleoside analogues (standard of care) for 6 months or more, and had plasma HIV-1 RNA of less than 50 copies per mL within 60 days of enrolment. We randomly assigned participants (1:1), using a computer-generated randomisation plan, to switch to darunavir (400 mg) boosted with ritonavir (100 mg) once daily or remain on ritonavir-boosted lopinavir (800 mg [plus 200 mg ritonavir]), with nucleoside analogues left unchanged. The primary endpoint was the proportion of patients with less than 50 HIV-1 RNA copies per mL at week 48 (US Food and Drug Administration snapshot algorithm; non-inferiority margin -4%). Primary and safety analyses included participants receiving at least one dose of darunavir boosted with ritonavir. This trial is registered with ClinicalTrials.gov, number NCT02671383. Between June 30, 2016, and June 15, 2017, 148 participants were assigned to ritonavir-boosted darunavir 400 mg and 152 continued on their lopinavir-containing regimen. Four (3%) patients in the darunavir group and three (2%) in the lopinavir group discontinued before week 48. At week 48, darunavir was non-inferior to lopinavir for the primary outcome (142 [96%] of 148 participants on darunavir had <50 HIV-1 RNA copies per mL vs 143 [94%] of 152 participants on lopinavir; difference 1·9% [95% CI -3·4 to 7·3]), with a predefined margin of -4%. More participants taking darunavir (30 [20%] participants) had drug-related adverse events than those on lopinavir (eight [5%]), but the adverse events were generally asymptomatic and resolved when switching back to lopinavir. Elevated liver transaminase in three (1%; one symptomatic) darunavir participants led to study withdrawal; all transaminase elevations resolved on restarting lopinavir. Low-dose ritonavir-boosted darunavir might be a safe and efficacious switch option to maintain HIV suppression for patients on lopinavir. However, an adequately powered and designed study in viraemic participants is needed. South African Medical Research Council, United States Agency for International Development, and US National Institute of Allergy and Infectious Diseases.

Increasing Cervical Cancer Incidence in Rural Eastern Cape Province of South Africa, 1998-2012 - A Population-Based Cancer Registry Study

Background: South Africa introduced free cytology-based screening for cervical cancer in 1999. A high cervical cancer incidence has been observed in rural Eastern Cape Province, an area with a high prevalence of Human Immunodeficiency Virus and extensive provision of highly active anti-retroviral therapy. Cervical cancer incidence trends from the population-based Eastern Cape Cancer Registry are further examined by distinct geographic areas; northern and southern. Methods: Cases (topography C53.0-C53.9) for the period 1998-2012 were extracted from a cancer registry database from which basic descriptive statistics and frequencies were analysed for all variables using CanReg4.Trends over time were estimated using a direct standardization method and world standard population as a reference. Screening coverage annualized figures for women 30 years and older by sub-health district were extracted from the District Health Information System. Findings: In the northern area, annual age-standardized incidence rates per 100 000 women increased from 24.0 (95% CI: 21.1-27.0) in 1998-2002 to 39.0 (95% CI: 35.6-42.5) in 2008-2012, with a screening coverage rate of 15% by 2012. In contrast, no increase was observed in incidence in the southern area, with rates of 20.0 (95% CI: 18.5-21.4) in 1998-2002 and 18.8 (95% CI: 16.2-21.4) in 2008-2012, and a higher screening coverage of 41% in 2012. Overall, the percentage distribution of stage at diagnosis showed that 28.5% of cases were diagnosed at disease stages I and II, 35% III and IV, and 36% with missing stage information (2003-2012). In 77% of cases, a histologically verified diagnosis was made, compared with only 12.3% by cytology. Interpretation: The significant increase in the incidence in the northern area does not appear to be directly related to the screening programme but may portend increases associated with the widespread provision of highly active ante-retroviral therapy. Funding Statement: South African Medical Research Council. Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: This study was approved by the South African Medical Research Council.

Psychological, Biological, and Behavioral Predictors of Changes in Eating Attitudes from Age 13 to 17 Y Among Urban, Black South African Adolescents (P18-102-19)

ObjectivesPsychological, biological, and behavioral predictors of change in adolescent eating attitudes have not previously been examined in a South African context. We aimed to characterize patterns and predictors of trends in eating attitudes from age 13 to 17 y in an urban South African cohort. MethodsData come from the Birth to Twenty Plus birth cohort in Soweto-Johannesburg. The 26-item Eating Attitudes Test (EAT-26) was administered at ages 13 and 17 y. Self-esteem, weight control behavior, and body mass index (BMI) were assessed at the same ages. Sex-specific associations of changes in predictors over time with changes in the EAT-26 were modeled using linear regression. ResultsAt age 13 y, EAT-26 (mean ± SD) was 9.92 ± 7.34 with no difference between girls and boys. At age 17 y, EAT-26 was higher, reflecting poorer eating attitudes, among girls (11.14 ± 8.75) than boys (10.06 ± 6.77). From age 13 to 17 y, self-esteem scores improved slightly (0.36 ± 4.95), with no difference by sex, while BMI increased more among girls (2.57 ± 2.34 kg/m2) than boys (1.72 ± 2.21 kg/m2). More girls reported a weight loss attempt at age 17 (32%) than at 13 y (19%), while more boys reported trying to lose weight at age 13 (14%) than at 17 y (9%). Among girls, greater BMI increase from age 13 to age 17 y was associated with higher EAT-26 (β = 0.52 per kg/m2, 95% confidence interval [CI]: 0.09, 0.95), and increased self-esteem score was associated with decreased EAT-26 (β = −0.40, CI: −0.59, −0.22). Similar associations were observed among boys. Compared to those whose weight control behavior did not change, attempted weight loss at age 13 y but not at age 17 y was associated with decreased EAT-26 (β = −3.67, CI: −7.3, −0.03) among girls, while among boys, attempted weight loss at age 17 y but not at age 13 y was associated with increased EAT-26 (β = 7.16, CI: 3.53, 10.8). ConclusionsIn a longitudinal sample of Black South African adolescents, improved self-esteem and decreased BMI were each associated with improved eating attitudes in both boys and girls, while associations of patterns of weight control behavior with eating attitudes differed by sex. Funding SourcesNIH Fogarty International Center, Bill & Melinda Gates Foundation, Wellcome Trust, University of the Witwatersrand, South African Medical Research Council. Supporting Tables, Images and/or Graphs▪▪