South African Medical Research Council Research Articles

Duration of Effectiveness of Vaccines Against SARS-CoV-2 Infection and COVID-19 Disease: Results of a Systematic Review and Meta-Regression

Background: Knowing whether and to what extent COVID-19 vaccine effectiveness wanes is critical to informing vaccine policy, such as the need for and timing of booster doses. Methods: We performed a systematic review from June 17 to October 27, 2021, using a structured search strategy of multiple databases. Studies with vaccine efficacy or effectiveness (VE) estimates for any WHO Emergency-Use-Listed COVID-19 vaccine at discrete time intervals after full vaccination and meeting pre-defined screening criteria underwent full-text review and risk of bias assessment. Random effects meta-regression was used to estimate the average change in VE from one to six months after full vaccination. Findings: Of 9,261 studies screened, 217 underwent full text review, and 14 were included in analyses. Vaccines evaluated were Pfizer/BioNTech-Comirnaty (n=11), Moderna-mRNA-1273 (n=8), Janssen-Ad26.COV2.S (n=3), and AstraZeneca-Vaxzevria (n=2). On average, VE against SARS-CoV-2 infection decreased between 1 and 6 months after full vaccination by 18·5 percentage points (95% CI 8·4-33·4, p=0·0006) among persons of all ages and 19·9 percentage points (95% CI 9·2-36·7, p=0·0007) among older persons; for symptomatic COVID-19 disease, VE decreased by 25·4 (95% CI 13·7-42·5) and 32·0 percentage points (95% CI 11·0-69·0), respectively; and for severe COVID-19 disease, VE decreased by 8·0 (95% CI 3·6-15·2) and 9·7 percentage points (95% CI 5·9-14·7), respectively. The majority of VE estimates against severe disease remained over 70% for all time points. Interpretation: COVID-19 vaccine efficacy or effectiveness against COVID-19 severe disease remained high (>70%) in most studies in the six months after full vaccination, although it did decrease some (on average, 8-10 percentage points) between one and six months after full vaccination. In contrast, VE against SARS-CoV-2 infection and symptomatic COVID-19 disease decreased approximately 20-30 percentage points during the six months after vaccination. The decrease in VE is likely due, at least in part, to waning immunity, although we cannot rule out the effect of bias. Continued follow-up of VE beyond six months is critical for updating COVID-19 vaccine policy. . Funding Information: Coalition for Epidemic Preparedness Innovations (CEPI)Declaration of Interests: MMH reports research grants from World Health Organization (WHO, Coalition for Epidemic Preparedness Innovations (CEPI), Asian Development Bank (ADB), Bill & Melinda Gates Foundation (BMGF), and Pfizer (all paid to the institution). RA reports a contract from the United States Centers for Disease Control and Prevention, a grant from the Chile Ministry of Science, and consulting fees from Mayo Clinic and Chile Ministry of Health. YG reports research grants from the United States-Israel Binational Science Foundation (BSF) and Israel Science Foundation. MJG reports research grants from South African Medical Research Council and BMGF (all paid to the institution) and participation on a data safety monitoring board for a study on the effectiveness of COVID-19 vaccination against SARS-CoV-2-associated hospitalization and death. AH reports research grants from United States-Israel BSF. KLO serves as the Secretariat for the WHO Strategic Advisory Group of Experts on Immunization. MDK reports research grants from WHO, CEPI, ADB, and Pfizer (all paid to the institution) and consultancy fees from Merck. All other authors have nothing to declare.

The Geography of Emergency Department-Based HIV Testing in South Africa: Can Patients Link to Care?

Background: Emergency Departments (EDs) can serve as clinical sites for identification of new HIV infections and their entry into care. We examined if HIV-positive patients who present to EDs in South Africa are able to successfully link to care. Methods: We conducted a one-year longitudinal prospective cohort study in four hospitals across the Eastern Cape, South Africa between July 2016 and July 2018. All adult, non-critical patients presenting to the ED were systematically approached, asked about their HIV status, and, if unknown, offered a point-of-care (POC) HIV test. All HIV-positive patients were further consented to participate in a follow-up study to assess subsequent linkage to care and distance from “home” to ED. Linkage to care was defined as self-reported linkage (telephonic) or evidence of repeated CD4/viral load testing in the National Health Laboratory System (NHLS) at either 6- or 12-months post index ED visit. Findings: A total of 983 patients consented to participate in the study. In the 12 months following their ED visit, 34∙1% of patients demonstrated linkage to care (335/983), 23∙8% did not link to care (234/983), and 42∙1% (414/983) were lost to follow-up. Though not statistically significant, a higher percentage of young men and those presenting with a trauma-related complaint did not link to care. A considerable proportion of patients (105/454, 23∙2%,) resided 50 or more km from their index ED sites, though there was not a significant difference in linkage to care rate between those who lived closer or further from the ED. Interpretation: Innovative implementation strategies are required to overcome patient-level factors and structural barriers within the health system to improve HIV care linkage to care for both known HIV-positive and newly diagnosed HIV-positive ED patients. Strategies should consider the use of facilitated linkage using case management approaches and same day ART initiation, amongst others. Funding Information: This research was supported by the South African Medical Research Council, the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Johns Hopkins Center for Global Health. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Declaration of Interests: The authors have nothing to disclose. Ethics Approval Statement: The study was approved by the Johns Hopkins University School of Medicine Institutional Review Board (IRB00105801), the Human Research Ethics Committees (HREC) of University of Cape Town (Ref 856/2015), and the Walter Sisulu University HREC (Ref 069/15). Written consent was obtained from all participants for the collection of demographic data and POC HIV testing.

Incidence of Herpes Simplex Virus Type 2 Infection Among African Women Using Depot Medroxyprogesterone Acetate, a Copper Intrauterine Device, or a Levonorgestrel Implant for Contraception: A Nested Randomized Trial

Background: Globally, women have higher herpes simplex type 2 (HSV-2) prevalence than men; data from observational studies suggest a possible association of HSV-2 acquisition with use of certain contraceptive methods, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM). Methods: Within a randomized trial of the effect of three contraceptive methods – DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant – on HIV acquisition, we assessed HSV-2 acquisition. We followed women who were HSV-2 and HIV seronegative, aged 16-35 years, and seeking effective contraception for 12-18 months at 12 sites in Eswatini, Kenya, South Africa, and Zambia from 2015-2018. HSV-2 serologic testing was done at enrollment and final study visits according to a standardized algorithm. Intention–to-treat analysis using Poisson regression with robust standard errors compared HSV-2 incidence by contraceptive method. Findings: At baseline, 4062 randomized women were HSV-2 seronegative, of whom 3898 (96.0%) had a conclusive HSV-2 result at their final study visit. Of these, 614 (15.8%) acquired HSV-2, at an incidence of 12.4/100 person-years (p-y): 10.9/100 p-y among women assigned DMPA-IM, 13.7/100 p-y the copper IUD, and 12.7/100 p-y the LNG implant. Incidence rate ratios (IRR) for HSV-2 acquisition were 0.80 (95% confidence interval [CI] 0.65-0.97) for DMPA-IM compared with copper IUD, 0.86 (95% CI 0.71-1.05) for DMPA-IM compared with LNG implant, and 1.08 (95% CI 0.89-1.30) for copper IUD compared with LNG implant. HSV-2 acquisition risk was significantly increased among women who also acquired HIV during follow-up (IRR 3.55, 95% CI 2.78-4.48). Interpretation: In a randomized trial, DMPA-IM was not associated with increased risk of HSV-2 acquisition. HSV-2 incidence was >10% per year, emphasizing the need for development of novel HSV-2 prevention strategies for African women. Clinical Trial Registration Details: ClinicalTrials.gov number NCT02550067. Funding Information: The ECHO Trial was made possible by the combined generous support of the Bill & Melinda Gates Foundation, the American people through the United States Agency for International Development and the President’s Emergency Plan for AIDS Relief, the Swedish International Development Cooperation Agency as part of the EDCTP2 programme supported by the European Union, the South African Medical Research Council, and the United Nations Population Fund. Contraceptive supplies were donated by the Government of South Africa and United States Agency for International Development. Additional funding for testing for herpes simplex type 2 infection was provided in part by the US Centers for Disease Control and Prevention (U48 DP 005013 SIP 14-023) and the University of Washington/Fred Hutch Center for AIDS Research (US National Institutes of Health P30 AI057757). Declaration of Interests: None. Ethics Approval Statement: Ethics review committees at each study site approved the study protocol. All participants provided written informed consent, which included counseling about randomization, each study contraceptive method, and their rights as research participants.

Accuracy and Effect of Rapid Line Probe Assay Testing for First- and Second-Line Tuberculosis in a High-Volume Programmatic Laboratory

Background: Rapid drug susceptibility testing (DST) is crucial to confirm eligibility for new tuberculosis (TB) regimens. Genotype MTBDRsl is a World Health Organization (WHO)-endorsed assay yet performance data on smear-negative sputum are scarce and programmatic adoption limited. Methods: Sputa from Xpert MTB/RIF-rifampicin resistant patients (n=951) were programmatically tested by Genotype MTBDRplus and Genotype MTBDRsl (both v2). Phenotypic DST was the reference standard for MTBDRsl. Discrepant results underwent Sanger sequencing. Findings: 89% (849/951) of sputa were culture-positive [56% (476/849) smear-negative]. MTBDRplus had non-actionable results (control and/or TB-detection bands absent or invalid; precluding resistance reporting) in 3% (11/373) and 19% (92/476; p=0.001) of smear-positives and -negatives, respectively. Of Xpert rifampicin-resistant specimens, 23% (172/746) were MTBDRplus isoniazid-susceptible. 85% (22/26) Xpert rifampicin-resistant, MTBDRplus rifampicin-susceptible specimens resolved in favour of Xpert by sequencing. MTBDRsl had at least one non-actionable result for 10% (35/342) and 40% (171/427; p=0.001) of smear-positives and -negatives, respectively. MTBDRsl sensitivity in smear-negatives was 84% (95% CI 67-93) for fluoroquinolones, 81% (54-95) for second-line injectables, and 57% (28-82) for resistance to both. Specificities were 93% (89-98), 88% (81-93), and 97% (91-99), respectively. Days to second-line susceptibility reporting with the advent of rapid direct testing improved vs. prior standard-of-care [6 (5-7) vs. 37 (35-46); p<0.001]. Interpretation: MTBDRplus is unsuitable for Xpert-detected rifampicin-resistance confirmation and isoniazid are likely still useful in many Xpert rifampicin-resistant patients. MTBDRsl is accurate for ruling-in second-line resistance, however, non-actionable result rates are unacceptably high (4/10 smear-negatives failed, which is not reflected in sensitivity estimates). Better second-line DSTs are needed. Funding Information: The work was funded by Stellenbosch University Faculty of Health Sciences, the National Research Foundation and Harry Crossley. RMW acknowledges funding from the South African Medical Research Council. GT acknowledges funding from the EDCTP2 programme supported by the European Union (grant SF1401, OPTIMAL DIAGNOSIS) and the National Institute of Allergy and Infection Diseases of the National Institutes of Health (U01AI152087). Declaration of Interests: All authors reported no conflict of interest. Ethics Approval Statement: This study was done in accordance with relevant guidelines and regulations, approved by the Health Research Ethics Committee of Stellenbosch University (N16/04/045) and the Western Cape Province Department of Health (2016RP18 637). Permission was granted to access anonymised residual specimens collected as part of routine diagnostic practice and informed consent waived.

Divergence of Delta and Beta Variants and SARS-CoV-2 Evolved in Advanced HIV Disease into Two Serological Phenotypes

SARS-CoV-2 continues to evolve variants which escape antibody neutralization and have enhanced transmission. One variant may escape immunity elicited by another, and the Delta variant has been reported to escape Beta variant infection elicited immunity. Mapping the serological distance between current and emerging variants will likely guide design of vaccines which can target all variants. Here we mapped neutralization of SARSCoV-2 ancestral and Beta and Delta variant viruses by antibodies elicited by each variant in SARS-CoV-2 convalescent individuals. We also serologically characterized and mapped SARS-CoV-2 which evolved from an ancestral strain in prolonged infection in an immunosuppressed individual due to advanced HIV disease. Beta virus showed moderate (7-fold) and Delta virus slight escape from neutralizing immunity elicited by ancestral virus infection. In contrast, Delta virus had pronounced escape from Beta elicited immunity (12fold), and Beta virus even stronger escape from Delta immunity (34-fold). Evolved virus had 9-fold escape from ancestral immunity, 27-fold escape from Delta immunity, but was effectively neutralized by Beta immunity. We conclude that Beta and Delta variants are serologically distant, further than each is from ancestral virus. An example of SARS-CoV2 evolved during advanced HIV disease immune suppression is serologically close to Beta and far from Delta. These results suggest that SARS-CoV-2 is diverging into distinct serological phenotypes which may become serotypes, and that vaccines tailored to one variant may become vulnerable to infections with another. Funding: This study was supported by the Bill and Melinda Gates award INV-018944 (AS), National Institutes of Health award R01 AI138546 (AS), South African Medical Research Council awards (AS, TdO, PLM) and National Institutes of Health U01 AI151698 (WVV). PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and the NRF (Grant No 9834). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Declaration of Interests: None to declare. Ethics Approval Statement: Nasopharyngeal and oropharyngeal swab samples and plasma samples were obtained from hospitalized adults with PCR-confirmed SARS-CoV-2 infection who were enrolled in a prospective cohort study approved by the Biomedical Research Ethics Committee at the University of KwaZulu–Natal (reference BREC/00001275/2020).

Estimating the Burden of Disease from Alcohol Use in South Africa in 2000, 2006, 2012

Background: Alcohol use was one of the leading contributors to South Africa (SA)’s disease burden in 2000, accounting for 7% of deaths and disability-adjusted life years (DALYs) in the first SA Comparative Risk Assessment (CRA) study. Since then, patterns of alcohol use have changed, as well as the epidemiological evidence pertaining to the role of alcohol as a risk for infectious diseases, most notably HIV/AIDS and tuberculosis (TB). Objectives: To estimate the burden of disease attributable to alcohol use by sex and age group in SA in 2000, 2006 and 2012. Methods: The analysis follows the World Health Organization (WHO)’s CRA methodology. Population attributable fractions (PAFs) were calculated from modelled exposure estimated from a systematic assessment and synthesis of 17 nationally representative surveys and relative risks based on the global review by the International Model of Alcohol Harms and Policies (interMAHP). PAFs were applied to the burden of disease estimates from the revised second SA National Burden of Disease study to calculate the alcohol-attributable burden for deaths and DALYs for 2000, 2006 and 2012. We quantified the uncertainty by observing the posterior distribution of the estimated prevalence of drinkers and mean use among adult drinkers (15+ years old) in a Bayesian model. We assumed no uncertainty in the outcome measures. Results: The alcohol-attributable disease burden decreased from 2000 to 2012 after peaking in 2006, owing to shifts in the disease burden, particularly infectious disease and injuries, and changes in drinking patterns. In 2012, alcohol-attributable harm accounted for an estimated 7.1% (95% uncertainty interval (UI): 6.6 - 7.6) of all deaths and 6.2% (95% UI 5.9 - 6.6) of all DALYs. Attributable deaths were split three ways fairly evenly across major disease categories: infectious diseases (36.4%), non-communicable diseases (32.4%) and injuries (31.2%). Top rankings for alcohol-attributable DALYs for specific causes were: TB (22.6%), HIV/AIDS (16.0%), road traffic injuries (15.9%), interpersonal violence (12.8%), cardiovascular disease (11.1%), cancer and cirrhosis (both 4%). Conclusions: Although reducing overall alcohol use will decrease the burden of disease at a societal level, alcohol harm reduction strategies in SA should prioritise evidence-based interventions to change drinking patterns. Frequent heavy episodic (i.e. binge) drinking accounts for the unusually large share of injuries and infectious diseases in the alcohol-attributable burden of disease profile. Interventions should focus on the distal causes of heavy drinking by focusing on strategies recommended by WHO’s SAFER initiative. Funding: This research and its publication have been funded by the South African Medical Research Council’s Flagships Awards Project (SAMRC-RFA-IFSP-01-2013/SA CRA 2). RM, AC and CDHP acknowledge funding support from SAMRC. Declaration of Interest: Nothing to declare.

Prognostic value of NT-pro-BNP for myocardial recovery in peripartum cardiomyopathy

Abstract Background Peripartum cardiomyopathy (PPCM) is an important cause of pregnancy-associated heart failure and occurs in women towards the end of pregnancy or within the first five months post-partum. Though PPCM is mostly associated with left ventricular (LV) recovery, many affected women develop chronic heart failure with persistently reduced LV ejection fraction (LVEF). Despite recent advances in the treatment of PPCM, clinical predictors of myocardial recovery remain sparse. Purpose N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is the only clinically established biomarker with diagnostic value in PPCM. However, its prognostic value for LV recovery in PPCM remains uncertain. We aimed to establish whether NT-pro-BNP could serve as a predictor of LV recovery in PPCM, and if so, which levels would help with such risk stratification. Methods Women with PPCM seen at the Cardiomyopathy Clinic at Groote Schuur Hospital were recruited between 2012 and 2018. Clinical details and echocardiographic features were recorded at baseline and follow-up, and NT-pro-BNP was measured at baseline. LV recovery was defined as an LVEF of ≥50% at 12-month follow-up. Results This cohort of 42 women with PPCM had a mean age of 29.3±5.8 years and median parity of 2 (IQR 1–4). Almost half (45.2%) presented with a NYHA functional class III/IV. The median systolic and diastolic blood pressures were 117mmHg (IQR 105–133) and 75mmHg (IQR 68–85) respectively. The median heart was 94bpm (IQR 74–103). At diagnosis, mean LVEF was 31.1±8.4% and LV end-diastolic dimension (EDD) of 59mm (IQR 53–64), which improved to LVEF 44.5%±14.5 (p=0.001) and LVEDD 53.6mm (p=0.007) at 1 year. Median NT-pro-BNP at presentation was 915.8pg/mL (IQR 613.6–2422.5). Patients presenting with sinus tachycardia (heart rate &amp;gt;100 bpm) had significantly higher NT-pro-BNP values (1815 vs. 728pg/mL, p=0.009) at the time of diagnosis. At presentation, NT-pro-BNP tended to correlate with LVEDD (R 0.33, p=0.04) and was inversely correlated with LVEF (R −0.39, p=0.01). Whereas initial LVEDD and LVEF did not predict LV recovery at 1 year, NT-pro-BNP at the time of diagnosis had prognostic significance. Patients without LV recovery had a significantly higher NT-pro-BNP at diagnosis (1694.1pg/mL vs. 613.1pg/mL, p=0.02). As shown in Figure 1, NT-pro-BNP of &amp;gt;900pg/mL was associated with lower probability of LV recovery (OR 0.19 [95% CI 0.05–0.73], p=0.018). Conclusion We show, for the first time, that NT-pro-BNP has a prognostic value for LV recovery in PPCM. NT-pro-BNP may be useful in the risk stratification in PPCM and may be used to recommend more intensive follow-up of patients who have a NT-pro-BNP &amp;gt;900pg/mL at diagnosis. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the South African Medical Research Council and National Research Foundation of South Africa.

Exploring the Use of Oral Pre-exposure Prophylaxis (PrEP) Among Women from Durban, South Africa as Part of the HIV Prevention Package in a Clinical Trial

HIV endpoint-driven clinical trials in Africa enroll women who are at heightened risk of acquiring HIV. In 2017, the South African Medical Research Council recommended the provision of oral pre-exposure prophylaxis (PrEP) in HIV prevention trials, at which time the Evidence for Contraceptive Options and HIV Outcomes trial was ongoing and began to provide PrEP on-site at some trial sites. We interviewed 132 women who initiated PrEP on-site at the Durban, South Africa trial site to explore PrEP use, and conducted phone-based interviews 4–6 months post-trial exit to explore post-trial PrEP access. PrEP uptake was high (42.6%). Among women initiating PrEP on-site, 87.9% felt at risk of acquiring HIV. Most women (> 90%) heard of PrEP for the first time from study staff and three-quarters who initiated PrEP on-site continued at trial-exit. PrEP use declined post-trial exit with more than 50% of women discontinuing PrEP, and barriers relating to access emerged.

Prevalence of Readily Detected Amyloid Blood Clots in ‘Unclotted’ COVID-19 Plasma

The rapid detection of COVID-19 uses genotypic testing for the presence of SARS-Cov-2 virus in nasopharyngeal swabs, but it can have a poor sensitivity. A rapid, host-based physiological test that indicated whether the individual was infected or not would be highly desirable. Coagulaopathies are a common accompaniment to COVID-19, especially micro-clots within the lungs. We show here that microclots can be detected in the native plasma of COVID-19 patient, without the addition of any clotting agent, and in particular that such clots are amyloid in nature as judged by a standard fluorogenic stain. This provides a rapid and convenient test with 100% sensitivity (PFunding: Medical Research Council of South Africa (MRC) (Self-Initiated Research Program: A0X331) supported this collaboration. DBK funding Novo Nordisk Foundation (grant NNF10CC1016517).Declaration of Interests: The authors declare that they have no competing interests.Ethics Approval Statement: Ethical approval for blood collection and analysis of the patients with COVID-19, T2DM and healthy individuals, was given by the Health Research Ethics Committee (HREC) of Stellenbosch University (reference number: 9521). This laboratory study was carried out in strict adherence to the International Declaration of Helsinki, South African Guidelines for Good Clinical Practice and the South African Medical Research Council (SAMRC), Ethical Guidelines for research. Oral consent was obtained from all participants prior to any sample collection.

Room for Improvement: Results of a Baseline Evaluation of Environmental Cleaning in a Resource-Limited Neonatal Unit

Background: Contamination of the near-patient hospital environment including work surfaces and equipment, contributes to skin colonization and subsequent invasive bacterial infections in hospitalized neonates. In resource-limited settings, cleaning of the neonatal ward environment and equipment is seldom standardized and infrequently audited. Methods: A baseline multimodal assessment of surface and equipment cleaning was performed in a 30-bed high-care neonatal ward in Cape Town, South Africa, October 7–9, 2019. Adequacy of routine cleaning was evaluated using ATP bioluminescence assays, fluorescent ultraviolet (UV) markers, and quantitative bacterial surface cultures. For flat surfaces (eg, tables, incubators, trolleys), a 10×10-cm template was used to standardize the swab inoculum; for small equipment and devices with complex surfaces (eg, humidifiers, suction apparatus, stethoscopes), a standard swabbing protocol was developed for each item. Swabs in liquid transport medium were processed in the laboratory by vortexing for 30 seconds, plating onto blood and MacConkey agars, and incubating at 37°C for 48 hours. Manual counting of bacterial colony forming units was performed, followed by conventional biochemical testing and/or VITEK automated identification. Results: Of 100 swabs (58 from surfaces and 42 from equipment), 11 yielded growth of known neonatal pathogens (Enterobacteriaceae, A. baumannii, P. aeruginosa, S. aureus, S. agalactiae, and enterococci), 36 isolated potential neonatal pathogens (mostly coagulase-negative staphylococci). In addition, 4 grew environmental organisms and 49 showed no growth. The highest aerobic colony counts (ACCs) were obtained from swabs of suction tubing, milk kitchen surfaces, humidifiers, and sinks; the median ACC from swabs with any bacterial growth (n = 51) was 3 (IQR, 1–22). Only 40% of the 100 surface and equipment swabs had ATP values &lt;200 relative light units (RLU) threshold for cleanliness. Median ATP values were 301 (IQ range, 179–732) RLUs for surface swabs versus 230 (IQ range, 78–699) RLUs for equipment swabs (P = .233). Of the 100 fluorescent UV markers placed on near-patient surfaces and high-touch equipment, only 23% had been removed after 2 staff shift changes (24 hours later). Surfaces had a higher proportion of UV marker removal than equipment (19 of 58 [32.8%] vs 4 of 42 [9.5%]; P = .008). Conclusions: Environmental cleaning of this neonatal ward was suboptimal, especially for equipment. Improvement of environmental cleaning practices is an important intervention for neonatal infection prevention in resource-limited settings. Future studies should evaluate the impact of staff training, environmental cleaning tools and repeated audit with feedback, on the adequacy of cleaning in neonatal wards.Funding: Funding: for the laboratory work was provided by The Society for Healthcare Epidemiology of America (SHEA) International Ambassador Alumni Research Award and a South African Medical Research Council Self-initiated Research (SIR) Grant to Angela Dramowski, who is supported by a NIH Fogarty Emerging Global Leader Award K43 TW010682.Disclosures: None

Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial

ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study. This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262. Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common. Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study. USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.

Early-life respiratory syncytial virus lower respiratory tract infection in a South African birth cohort: epidemiology and effect on lung health

SummaryBackgroundRespiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) in children. Early-life RSV LRTI might affect long-term health but there are few data from low-income and middle-income countries. We investigated the epidemiology and effect of early-life RSV LRTI on lung health in a South African birth cohort.MethodsWe conducted the Drakenstein Child Health Study (DCHS), an ongoing birth cohort longitudinal study in the Western Cape province, South Africa. We enrolled pregnant women aged 18 years or older during their second trimester of pregnancy at two public health clinics. We followed up study children from birth to 2 years. The primary outcome of the study was LRTI and RSV LRTI. LRTI and wheezing episodes were identified through active surveillance; respiratory samples were tested for RSV and other pathogens. Wheezing was longitudinally identified by caregiver report and ascertainment at health facilities. Lung function was measured from 6 weeks to 2 years. We analysed the associations between RSV LRTI and subsequent LRTI, wheezing, and lung function using generalised estimating equations and mixed-effects linear regression.FindingsWe enrolled 1137 mothers between March 5, 2012, and March 31, 2015. Among their 1143 infants, accruing 2093 child-years of follow-up, there were 851 cases of LRTI (incidence 0·41 episodes per child-year, 95% CI 0·38–0·43). Admission to hospital owing to LRTI occurred in 169 (20%) cases (incidence 0·08 episodes per child-year, 0·07–0·09), with a case-fatality ratio of 0·5%. RSV was detected in 164 (21%) of 785 LRTI events with a specimen available for qPCR, an incidence of 0·08 episodes per child-year (0·07–0·09); highest at age 0–6 months (0·15 episodes per child-year, 0·12–0·19). Children with a first RSV LRTI were three times as likely to develop recurrent LRTI compared with those with non-RSV LRTI (0·32 [0·22–0·48] vs 0·10 [0·07– 0·16] episodes per child-year; p<0·0001), particularly following hospitalised RSV LRTI. RSV LRTI and hospitalisation for all-cause LRTI were independently associated with recurrent wheezing (adjusted incident rate ratio 1·41, 95% CI 1·25–1·59, for RSV LRTI and 1·48, 1·30–1·68, for hospitalisation). LRTI or recurrent LRTI was associated with impaired lung function, but a similar outcome was observed following RSV LRTI or non-RSV LRTI. All-cause LRTI was associated with an average 3% higher respiratory rate (95% CI 0·01–0·06; p=0·013) and lower compliance (–0·1, −0·18 to 0·02) at 2 years compared with no LRTI. Recurrent LRTI was associated with further increased respiratory rate (0·01, 0·001–0·02), resistance (0·77 hPa s L−1, 0·07–1·47), and lower compliance (–0·6 mL hPa−1, −0·09 to −0·02) with each additional event.InterpretationRSV LRTI was common in young infants and associated with recurrent LRTI, particularly after hospitalised RSV. Hospitalisation for all-cause LRTI, especially for RSV-LRTI, was associated with recurrent wheezing. Impairments in lung function followed LRTI or recurrent episodes, but were not specific to RSV. New preventive strategies for RSV might have an effect on long-term lung health.FundingBill & Melinda Gates Foundation; South African Medical Research Council; National Research Foundation South Africa; National Institutes of Health, Human Heredity and Health in Africa; Wellcome Trust.

Excess mortality associated with mental illness in people living with HIV in Cape Town, South Africa: a cohort study using linked electronic health records

SummaryBackgroundMental disorders can adversely affect HIV treatment outcomes and survival. Data are scarce on premature deaths in people with mental disorders in HIV-positive populations, particularly in low-income and middle-income countries. In this study, we quantified excess mortality associated with mental disorders in HIV-positive people in South Africa, adjusting for HIV treatment outcomes.MethodsFor this cohort study, we analysed routinely collected data on HIV-positive adults receiving antiretroviral therapy (ART) in Cape Town, South Africa between Jan 1, 2004, to Dec 31, 2017. Data from three ART programmes were linked with routine medical records on mental health treatment from Jan 1, 2010, to Dec 31, 2017, and mortality surveillance data from the South African National Population Register up to Dec 31, 2017. People living with HIV aged 15 years or older who initiated ART at a programme site were eligible for analysis. We followed up patients from ART initiation or Jan 1, 2010, whichever occurred later, to transfer, death, or Dec 31, 2017. Patients were considered as having a history of mental illness if they had ever received psychiatric medication or been hospitalised for a mental disorder. We calculated adjusted hazard ratios (aHRs) with 95% CIs for associations between history of mental illness, mortality, and HIV treatment outcomes (retention in care with viral load suppression [VLS; viral load <1000 copies per mL], retention in care with non-suppressed viral load [NVL; viral load ≥1000 copies per mL], and loss to follow-up [LTFU; >180 days late for a clinic visit at closure of the database]) using Cox proportional hazard regression and multistate models.Results58 664 patients were followed up for a median of 4·3 years (IQR 2·1–6·4), 2927 (5·0%) of whom had a history of mental illness. After adjustment for age, sex, treatment programme, and year of ART initiation, history of mental illness was associated with increased risk of mortality from all causes (aHR 2·98 [95% CI 2·69–3·30]), natural causes (3·00 [2·69–3·36]), and unnatural causes (2·10 [1·27–3·49]), compared with no history of mental illness. Risk of all-cause mortality in people with a history of mental illness remained increased in multivariable analysis adjusted for age, sex, treatment programme, year of ART initiation, CD4 count and WHO clinical stage at ART initiation, retention in HIV care with or without VLS, and LTFU (2·73 [2·46–3·02]). In our multistate model, adjusted for age, sex, year of ART initiation, cumulative time with NVL, and WHO clinical stage and CD4 cell count at ART initiation, rates of excess all-cause mortality in people with history of mental illness were greatest in patients retained in care with VLS (aHR 3·43 [95% CI 2·83–4·15]), followed by patients retained in care with NVL (2·74 [2·32–3·24]), and smallest in those LTFU (2·12 [1·78–2·53]). History of mental illness was also associated with increased risk of HIV viral rebound (transitioning from VLS to NVL; 1·50 [1·32–1·69]) and LTFU in people with VLS (1·19 [1·06–1·34]).InterpretationMental illness was associated with substantial excess mortality in HIV-positive adults in Cape Town. Excess mortality among people with a history of mental illness occurred independently of HIV treatment success. Interventions to reduce excess mortality should address the complex physical and mental health-care needs of people living with HIV and mental illness.FundingNational Institutes of Health, Swiss National Science Foundation, South African Medical Research Council.

A genomics network established to respond rapidly to public health threats in South Africa

In response to the COVID-19 pandemic, we created the Network for Genomic Surveillance in South Africa (NGS-SA) in May, 2020 with grants from the South African Medical Research Council and the South African Department of Science and Innovation. Our goal is to sequence the genome of at least 10 000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) samples to inform the public health response in South Africa. As of July 27, 2020, we have sequenced the genome of 500 isolates, which has provided insights into how and when it was introduced into the country, and information on its early spread through clusters of outbreaks in health-care facilities, workplaces, and other congregate settings.

P0769ESTABLISHING AN AFRICAN NETWORK FOR CHRONIC KIDNEY DISEASE EPIDEMIOLOGY: THE CKD-AFRICA COLLABORATION

Abstract Background and Aims Chronic kidney disease (CKD) is a global public health problem, disproportionately affecting individuals of African ancestry. Unfortunately, due to the lack of data in various African countries or the limitations of available data, the true magnitude of CKD on the continent is still unknown. Although there has been an increase in the number of reports on CKD prevalence in recent years, up to now there has been no coordinated effort to provide reliable estimates to adequately support the health service and policy solutions to address the adverse consequences of CKD in Africa. The Chronic Kidney Disease in Africa Collaboration (CKD-AFRICA Collaboration), which is an initiative of the South African Medical Research Council, seeks to address this issue by collating data, at individual participant data (IPD) level, from existing African studies. Thus, the main aims for establishing this platform are, (1) to utilize the available data from all relevant prevalence studies of CKD, to provide an updated and comprehensive synthesis on the burden of CKD in Africa, and (2) to bring together active investigators in the field of CKD epidemiology and prevention, by providing a platform to plan, in a more coordinated way, future observational and interventional studies on CKD across the continent. Method To establish the CKD-AFRICA Collaboration as a continental resource, a stepwise approach was utilized, which included, 1) the identification of data sources through various systematic literature searches and contacting health agencies to access publicly available population-based measurement surveys; 2) establishing a database platform, by inviting active CKD research groups to contribute data on CKD at IPD level; 3) data processing and quality control and 4) piloting the consortium, by using the data from existing studies to determine the prevalence of CKD in the African adult population, by two-stage IPD meta-analysis. Results Through extensive systematic literature searches, 134 potential collaborators were identified. These included studies conducted in general adult populations and high-risk sub-populations, such as those with HIV/AIDS, hypertension and diabetes. Of those identified, 101 principal investigators (PIs) were contacted, via email, to gauge their interest in collaborating in the consortium, as 33 PIs lacked contact information. Of the 101 PIs, 42 responded positively to the call and have agreed to participate in the consortium, spanning 12 African countries, namely Ghana, Kenya, Nigeria, Burundi, Cameroon, Maputo, Sudan, South Africa, Egypt, Uganda, Senegal and Tanzania (Figure 1). To date, the consortium has potential access to 27,346 IPD, with 11,810 IPD already received. Conclusion The strength of this Consortium has far-reaching potential for Africa. Indeed, by harnessing IPD from numerous African studies, important research questions can be explored, and by connecting active CKD researchers, this platform could aid a more coordinated way of developing future observational and interventional studies on CKD in Africa. The research obtained from this collaboration will therefore permit the exploration in understanding the diversity of clinical manifestations of CKD in Africa.

1330-P: Molecular Biomarkers during Gestational Diabetes Mellitus

Background/Aim: Gestational diabetes mellitus (GDM) is associated with short- and long-term complication in both mothers and offspring. Molecular mechanisms are attracting increased interest for their potential as biomarkers for GDM that could lead to improved detection of GDM with positive effects on health outcomes. The aim of this study was to explore the potential of DNA methylation and single nucleotide polymorphisms (SNPs) to serve as molecular biomarkers for GDM in South African women. Methods: Genome-wide DNA methylation using a MethylationEPIC BeadChip Array (n=24) and gene-specific methylation of the adiponectin (ADIPOQ) gene using bisulfite pyrosequencing (n=286) were profiled in the peripheral blood of women with or without GDM. In addition, variants ADIPOQ rs266729 and rs17300539, and methylenetetrahydrofolate reductase (MTHFR) rs1801133 were quantified using quantitative real-time PCR (n=449). Results: Genome-wide methylation analysis identified 1046 differentially methylated CpG sites (associated with 939 genes), of which 148 CpG sites were hypermethylated and 898 CpG sites were hypomethylated (p&amp;lt;0.01). Among the top five CpG sites, one CpG mapped to the calmodulin-binding transcription activator 1 (CAMTA1) gene, which has been shown to regulate insulin production and secretion. Two CpG sites (-3410: p=0.048 and -3400: p=0.004) in the ADIPOQ promoter were hypomethylated during GDM in Human Immunodeficiency Virus (HIV) negative, but not in HIV positive women. Lastly, no association between ADIPOQ and MTHFR polymorphisms and GDM was observed in our population. Discussion: DNA methylation may offer potential as molecular biomarkers for GDM in a South African population. Future longitudinal studies in larger samples that include both HIV negative and positive pregnant women are warranted to explore the candidacy of DNA methylation as molecular biomarkers for GDM. Disclosure S. Dias: None. S. Adam: None. P. Rheeder: None. J. Louw: None. C. Pheiffer: None. Funding National Research Foundation (99391); South African Medical Research Council

Contextualised strategies to increase childhood and adolescent vaccination coverage in South Africa: a mixed-methods study

IntroductionDespite the unparalleled success of immunisation in the control of vaccine preventable diseases, immunisation coverage in South Africa remains suboptimal. While many evidence-based interventions have successfully improved vaccination coverage in...

National expenditure on health research in South Africa: How has the landscape changed in the past decade?

Over the past 18 years, the South African (SA) Ministry of Health has committed to allocate 2% of the national health budget to research, while the National Health Research Policy (2001) proposed that the health research budget should be 2% of total public sector health expenditure. A review was conducted by the National Health Research Committee (NHRC) in 2014 to determine whether these goals had been met, using available data up to 2009/10. Itrevealed that public sector health research funding remained below 2% of the national health budget, supporting the perception of reduced public sector health research funding. To provide an update on the previous review to investigate changes in the health research landscape since 2009/10 and whether goals have been met. Various publicly available sources of information on public and private expenditure on health research in SA were used to investigate health research funding and expenditure. In addition, questionnaires were sent to 35 major national and international funders of health research in SA to obtain data on the level of funding provided and the fields of research funded. Total health research expenditure in SA was ZAR6.9 billion in 2016/17, or 19.2% of gross expenditure on research and development, with 1.7% of the ZAR38.6 billion National Department of Health budget from National Treasury being spent on health research through the South African Medical Research Council (ZAR658 million), corresponding to 0.4% of the consolidated government expenditure on health. However, although the total government plus science council spend on health research in 2016/17 was ZAR1.45 billion, this represents just 0.033% of the gross domestic product (GDP), thus remaining well below the aspirational target of 0.15% of the GDP set by the NHRC in 2014. Based on feedback from the funders, the estimated baseline health research funding in 2016/17 was in excess of ZAR4.1 billion, which is considerably higher than many researchers may realise. Three-quarters of this funding originated from foreign sources, suggesting both strengths and opportunities for health research in SA, but also highlighting increasing dependence on foreign funding. Notably, the majority of funders approached were not able to readily break down expenditure according to disease area. Health research funding has changed significantly since our previous review, although the government's own commitments to it remain unmet. Improved mechanisms to track health research expenditure are urgently required for better alignment of funding priorities and increased co-ordination between science councils in health research funding.

Xpert MTB/RIF Ultra and Xpert MTB/RIF for diagnosis of tuberculosis in an HIV-endemic setting with a high burden of previous tuberculosis: a two-cohort diagnostic accuracy study

Xpert MTB/RIF Ultra (Ultra) is a new test for tuberculosis undergoing global roll-out. We assessed the performance of Ultra compared with Xpert MTB/RIF (Xpert) in an HIV-endemic setting where previous tuberculosis is frequent and current test performance is suboptimal. In this two-cohort diagnostic accuracy study, we used sputum samples from patients in South Africa to evaluate the accuracy of Ultra and Xpert against a single culture reference standard. For the first cohort (cohort A), we recruited adults (aged ≥18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa. We collected three sputum samples from each patient in cohort A, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), decontaminated sediments were, after processing, randomly allocated (1:1) for testing with Ultra or Xpert. For both cohorts we calculated the sensitivity and specificity of Ultra and Xpert and evaluated the effects of different methods of interpreting Ultra trace results. Between Feb 6, 2016, and Feb 2, 2018, we recruited 302 people into cohort A, all of whom provided sputum samples and 239 were included in the head-to-head analyses of Ultra and Xpert. For cohort B, we collected sputum samples from eligible patients who had submitted samples between Dec 6, 2016, and Dec 21, 2017, to give a cohort of 831 samples, of which 352 were eligible for inclusion in analyses and randomly assigned to Ultra (n=173) or Xpert (n=179). In cohort A, Ultra gave more non-actionable results (not positive or negative) than did Xpert (28 [10%] 275 vs 14 [5%] 301; p=0·011). In the head-to-head analysis, in smear-negative patients, sensitivity of Ultra was 80% (95% CI 64-90) and of Xpert was 73% (57-85; p=0·45). Overall, specificity of Ultra was lower than that of Xpert (90% [84-94] vs 99% [95-100]; p=0·001). In cohort B, overall sensitivity was 92% (81-98) for Xpert versus 86% (73-95; p=0·36) for Ultra and overall specificity was 69% (60-77) for Ultra versus 84% (78-91; p=0·005) for Xpert. Ultra specificity estimates improved after reclassification of results with the lowest Ultra-positive semiquantitation category (trace) to negative (15% [8-22]). In cohort A, the positive predictive value (PPV) for Ultra was 78% (67-87) and for Xpert was 96% (87-99; p=0·004); in cohort B, the PPV for Ultra was 50% (43-57) and for Xpert was 70% (61-78; p=0·014). Ultra PPV estimates in previously treated patients were low: at 15% tuberculosis prevalence, half of Ultra-positive patients with presumptive tuberculosis would be culture negative, increasing to approximately 70% in patients with recent previous tuberculosis. In cohort B, 21 (28%) of 76 samples that were Ultra positive were rifampicin indeterminate (all trace) and, like cohort A, most were culture negative (19 [90%] of 21). In a setting with a high burden of previous tuberculosis, Ultra generated more non-actionable results and had diminished specificity compared with Xpert. In patients with recent previous tuberculosis, a quarter of Ultra-positive samples were indeterminate for rifampicin resistance and culture negative, suggesting that additional drug-resistance testing will probably be unsuccessful. Our data have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings. South African Medical Research Council, the EDCTP2 program, and the Faculty of Medicine and Health Sciences, Stellenbosch University.

Ethnic and gender-specific incidence rates for hip fractures in South Africa: A multi-centre study.

Limited data exist on the incidence of hip fractures in South Africa (SA). We report gender and ethnic specific incidence rates of hip fractures in SA. In a multicentre prospective study, conducted in geographically defined municipalities of three provinces in SA, a structured questionnaire was administered to all subjects aged 40years and over, presenting with a new atraumatic hip fracture, from 1 April 2017 to 31 March 2018. Gender and ethnic specific incidence rates (IR) of hip fractures were calculated using population statistics from Statistics SA. Of the 2767 subjects enrolled, 1914 (69·2%) were women and 853 (30·8%) were men. The majority of subjects were from the White population (40·9%) followed by those from the African (26·4%), Coloured (18·7%) and Indian (13·9%) populations. Men with hip fractures were significantly younger than women in the total group (69 [IQR 59-79] versus 77years [IQR 68-84], p<0·001) and in each ethnic group. White subjects were significantly older (p<0·0001) and Africans significantly younger (p<0·0001) than the other ethnic groups. In women, the highest IR was noted in the White population (176·0 per 100,000), followed by that in the Indian (147·7 per 100,000), Coloured (73·2 per 100,000) and African populations (43·6 per 100,000). A similar pattern was seen in men albeit at lower rates, with the highest rate in White men at 76·5 per 100,000. In the total study population and the African population, the IR was higher in men compared to women in subjects under 60years. In the White population, the IR was higher in men compared to women in the 40-44years age group. While in the Coloured and Indian populations the IR was higher in men compared to women in the 40-49years and 45-54years age groups, respectively. There was an increase in the relative risk ratios with age in the total study population, and in all ethnic groups in both women and men. Hip fractures occur in all ethnic groups in South Africa with higher IRs in the White and Indian populations compared to the Coloured and African populations. Consistent with the published literature, the overall hip fracture IR was higher in women than in men, except in the younger age groups, and increased with age. South African Medical Research Council and the University of KwaZulu-Natal Competitive Research Grant.