Evaluation of the national clinical sentinel surveillance system for sexually transmitted infections in South Africa: Analysis of provincial and district-level data

Background. Globally, >1 million new cases of curable sexually transmitted infections (STIs) are estimated to occur daily, an alarming rate that has prevailed for over a decade. Modelled STI prevalence estimates for South Africa (SA) are among the highest globally. Robust STI surveillance systems have implications for policy and planning, antimicrobial stewardship and prevention strategies, and are critical in stemming the tide of STIs. Objectives. To evaluate the STI clinical sentinel surveillance system (STI CSSS) in SA, to describe the population incidence of four designated STI syndromes in males and females ≥15 years, and to provide recommendations for strengthening the STI CSSS. Methods. This was a retrospective analysis of the STI CSSS in SA. Distribution of the primary healthcare facilities designated as STI CSSS sites was described, taking into account provincial population distribution and headcount coverage of STI CSSS facilities. Reporting compliance was evaluated to determine completion of data reporting. Further analysis was undertaken for those provinces that had good reporting compliance over a 12-month period. Population-level and demographic STI syndrome incidence were estimated from CSSS data using case reports of male urethritis syndrome (MUS) as a proxy for data extrapolation. Results. Reporting compliance exceeded 70% for seven of the nine provinces. STI syndromes with the highest incidence were MUS and vaginal discharge syndrome (VDS). The 20 - 24 years age group had the highest STI incidence, at least double the incidence estimated in the other two age groups. Overall STI incidence in females was higher than among males in all provinces, except Limpopo and Western Cape. The 15 - 19 years age group had the most prominent gender disparity, with the national STI incidence in females 70% higher than in males. District-level analysis revealed high regional STI incidence even in provinces with lower overall incidence. Conclusion. The STI CSSS is pivotal to epidemiological monitoring and proactive management of STIs, especially in view of the high HIV prevalence in SA. CSSS processes and facility selection should be reviewed and revised to be representative and responsive to the current STI needs of the country, with biennial analysis and reporting to support evidence-based policy development and targeted implementation

An intervention to optimise the delivery of integrated tuberculosis and HIV services at primary care clinics: Results of the MERGE cluster randomised trial

Kielmann, Karina - ORCID 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Objectives: To evaluate the effect of an intervention to optimize TB/HIV integration on patient outcomes.Methods: Cluster randomised control trial at 18 primary care clinics in South Africa. The intervention was placement of a nurse (TB/HIV integration officer) to facilitate provision of integrated TB/HIV services, and a lay health worker (TB screening officer) to facilitate TB screening for 24 months. Primary outcomes were i) incidence of hospitalisation/death among individuals newly diagnosed with HIV, ii) incidence of hospitalisation/ death among individuals newly diagnosed with TB and iii) proportion of HIV-positive individuals newly diagnosed with TB who were retained in HIV care 12 months after enrolment.Results: Of 3328 individuals enrolled, 3024 were in the HIV cohort, 731 in TB cohort and 427 in TB-HIV cohort. For the HIV cohort, the hospitalisation/death rate was 12.5 per 100 person-years (py) (182/1459py) in the intervention arm vs. 10.4/100py (147/1408 py) in the control arms respectively (Relative Risk (RR) 1.17 [95% CI 0.92–1.49]).For the TB cohort, hospitalisation/ death rate was 17.1/100 py (67/ 392py) vs. 11.1 /100py (32/ 289py) in intervention and control arms respectively (RR 1.37 [95% CI 0.78–2.43]). For the TB-HIV cohort, retention in care at 12 months was 63.0% (213/338) and 55.9% (143/256) in intervention and control arms (RR 1.11 [95% 0.89–1.38]).Conclusions: The intervention as implemented failed to improve patient outcomes beyond levels at control clinics. Effective strategies are needed to achieve better TB/HIV service integration and improve TB and HIV outcomes in primary care clinics.Trial registration: South African Register of Clinical Trials (registration number DOH-27-1011-3846).This study was supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of [Cooperative agreement 5U2GPS000811]. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of CDC.https://doi.org/10.1016/j.cct.2018.07.01372pubpu

The importation and establishment of community transmission of SARSCoV- 2 during the first eight weeks of the South African COVID-19 epidemic

BACKGROUND : We describe the epidemiology of COVID-19 in South Africa following importation and during implementation of stringent lockdown measures. METHODS : Using national surveillance data including demographics, laboratory test data, clinical presentation, risk exposures (travel history, contacts and occupation) and outcomes of persons undergoing COVID-19 testing or hospitalised with COVID-19 at sentinel surveillance sites, we generated and interpreted descriptive statistics, epidemic curves, and initial reproductive numbers (Rt). FINDINGS : From 4 March to 30 April 2020, 271,670 SARS-CoV-2 PCR tests were performed (462 tests/100,000 persons). Of these, 7,892 (2.9%) persons tested positive (median age 37 years (interquartile range 28 49 years), 4,568 (58%) male, cumulative incidence of 13.4 cases/100,000 persons). Hospitalization records were found for 1,271 patients (692 females (54%)) of whom 186 (14.6%) died. Amongst 2,819 cases with data, 489/ 2819 (17.3%) travelled internationally within 14 days prior to diagnosis, mostly during March 2020 (466 (95%)). Cases diagnosed in April compared with March were younger (median age, 37 vs. 40 years), less likely female (38% vs. 53%) and resident in a more populous province (98% vs. 91%). The national initial Rt was 2.08 (95% confidence interval (CI): 1.71 2.51). INTERPRETATION : The first eight weeks following COVID-19 importation were characterised by early predominance of imported cases and relatively low mortality and transmission rates. Despite stringent lockdown measures, the second month following importation was characterised by community transmission and increasing disease burden in more populous provinces.The South African governmenthttps://www.journals.elsevier.com/eclinicalmedicineam2022School of Health Systems and Public Health (SHSPH

Epidemiology of SARS-CoV-2 infection and SARS-CoV-2 positive hospital admissions among children in South Africa

INTRODUCTION : We describe epidemiology and outcomes of confirmed SARS-CoV-2 infection and positive admissions among children <18 years in South Africa, an upper-middle income setting with high inequality. METHODS : Laboratory and hospital COVID-19 surveillance data, 28 January - 19 September 2020 was used. Testing rates were calculated as number of tested for SARS-CoV-2 divided by population at risk; test positivity rates were calculated as positive tests divided by total number of tests. In-hospital case fatality ratio (CFR) was calculated based on hospitalized positive admissions with outcome data who died in-hospital and whose death was judged SARS-CoV-2 related by attending physician. FINDINGS : 315 570 children aged <18 years were tested for SARS-CoV-2; representing 8.9% of all 3 548 738 tests and 1.6% of all children in the country. Of children tested, 46 137 (14.6%) were positive. Children made up 2.9% (n = 2007) of all SARS-CoV-2 positive admissions to sentinel hospitals. Among children, 47 died (2.6% case-fatality). In-hospital deaths were associated with male sex [adjusted odds ratio (aOR) 2.18 (95% confidence intervals [CI] 1.08–4.40)] vs female; age <1 year [aOR 4.11 (95% CI 1.08–15.54)], age 10–14 years [aOR 4.20 (95% CI1.07–16.44)], age 15–17 years [aOR 4.86 (95% 1.28–18.51)] vs age 1–4 years; admission to a public hospital [aOR 5.07(95% 2.01–12.76)] vs private hospital and ≥1 underlying conditions [aOR 12.09 (95% CI 4.19–34.89)] vs none. CONCLUSIONS : Children with underlying conditions were at greater risk of severe SARS-CoV-2 outcomes. Children > 10 years, those in certain provinces and those with underlying conditions should be considered for increased testing and vaccination.SUPPORTING INFORMATION : TABLE S1: Description of SARS-CoV-2 rRT-PCR positive children <18 years in South Africa, 1 March 2020–19 September 2020 (N = 45 609). TABLE S2: Description of SARS-CoV-2 rRT-PCR positive hospital admissions among children <18 years in South Africa by province, 1 March 2020–19 September 2020 (N = 2007). TABLE S3: Distribution of non-missing variables among children with complete follow up and included in multivariable model (N = 1817). TABLE S4: Factors associated with in-hospital death among SARS-CoV-2 rRT-PCR positive admissions in children <18 years, South Africa, 1 March 2020–19 September 2020. FIGURE S1: Number of SARS-CoV-2 rRT-PCR tests*, percent positive tests and associated- hospital admissions among children <18 years by province and epidemiology week, South Africa, 1 March 2020–19 September 2020.National Department of Health, Republic of South Africahttp://wileyonlinelibrary.com/journal/irvhj2022School of Health Systems and Public Health (SHSPH

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BackgroundThe WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.MethodsIn this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.FindingsWe identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively.InterpretationC-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications.FundingWorld Health Organization

Development and validation of quantitative PCR assays for HIV-associated cryptococcal meningitis in sub-Saharan Africa: a diagnostic accuracy study

Background: HIV-associated cryptococcal meningitis is the second leading cause of AIDS-related deaths, with a 10-week mortality rate of 25–30%. Fungal load assessed by colony-forming unit (CFU) counts is used as a prognostic marker and to monitor response to treatment in research studies. PCR-based assessment of fungal load could be quicker and less labour-intensive. We sought to design, optimise, and validate quantitative PCR (qPCR) assays for the detection, identification, and quantification of Cryptococcus infections in patients with cryptococcal meningitis in sub-Saharan Africa. Methods: We developed and validated species-specific qPCR assays based on DNA amplification of QSP1 (QSP1A specific to Cryptococcus neoformans, QSP1B/C specific to Cryptococcus deneoformans, and QSP1D specific to Cryptococcus gattii species) and a pan-Cryptococcus assay based on a multicopy 28S rRNA gene. This was a longitudinal study that validated the designed assays on cerebrospinal fluid (CSF) of 209 patients with cryptococcal meningitis at baseline (day 0) and during anti-fungal therapy (day 7 and day 14), from the AMBITION-cm trial in Botswana and Malawi (2018–21). Eligible patients were aged 18 years or older and presenting with a first case of cryptococcal meningitis. Findings: When compared with quantitative cryptococcal culture as the reference, the sensitivity of the 28S rRNA was 98·2% (95% CI 95·1–99·5) and of the QSP1 assay was 90·4% (85·2–94·0) in CSF at day 0. Quantification of the fungal load with QSP1 and 28S rRNA qPCR correlated with quantitative cryptococcal culture (R2=0·73 and R2=0·78, respectively). Both Botswana and Malawi had a predominant C neoformans prevalence of 67% (95% CI 55–75) and 68% (57–73), respectively, and lower C gattii rates of 21% (14–31) and 8% (4–14), respectively. We identified ten patients that, after 14 days of treatment, harboured viable but non-culturable yeasts based on QSP1 RNA detection (without any positive CFU in CSF culture). Interpretation: QSP1 and 28S rRNA assays are useful in identifying Cryptococcus species. qPCR results correlate well with baseline quantitative cryptococcal culture and show a similar decline in fungal load during induction therapy. These assays could be a faster alternative to quantitative cryptococcal culture to determine fungal load clearance. The clinical implications of the possible detection of viable but non-culturable cells in CSF during induction therapy remain unclear. Funding: European and Developing Countries Clinical Trials Partnership; Swedish International Development Cooperation Agency; Wellcome Trust/UK Medical Research Council/UKAID Joint Global Health Trials; and UK National Institute for Health Research

Development and validation of quantitative PCR assays for HIV-associated cryptococcal meningitis in sub-Saharan Africa: a diagnostic accuracy study

Background: HIV-associated cryptococcal meningitis is the second leading cause of AIDS-related deaths, with a 10-week mortality rate of 25–30%. Fungal load assessed by colony-forming unit (CFU) counts is used as a prognostic marker and to monitor response to treatment in research studies. PCR-based assessment of fungal load could be quicker and less labour-intensive. We sought to design, optimise, and validate quantitative PCR (qPCR) assays for the detection, identification, and quantification of Cryptococcus infections in patients with cryptococcal meningitis in sub-Saharan Africa. Methods: We developed and validated species-specific qPCR assays based on DNA amplification of QSP1 (QSP1A specific to Cryptococcus neoformans, QSP1B/C specific to Cryptococcus deneoformans, and QSP1D specific to Cryptococcus gattii species) and a pan-Cryptococcus assay based on a multicopy 28S rRNA gene. This was a longitudinal study that validated the designed assays on cerebrospinal fluid (CSF) of 209 patients with cryptococcal meningitis at baseline (day 0) and during anti-fungal therapy (day 7 and day 14), from the AMBITION-cm trial in Botswana and Malawi (2018–21). Eligible patients were aged 18 years or older and presenting with a first case of cryptococcal meningitis. Findings: When compared with quantitative cryptococcal culture as the reference, the sensitivity of the 28S rRNA was 98·2% (95% CI 95·1–99·5) and of the QSP1 assay was 90·4% (85·2–94·0) in CSF at day 0. Quantification of the fungal load with QSP1 and 28S rRNA qPCR correlated with quantitative cryptococcal culture (R2=0·73 and R2=0·78, respectively). Both Botswana and Malawi had a predominant C neoformans prevalence of 67% (95% CI 55–75) and 68% (57–73), respectively, and lower C gattii rates of 21% (14–31) and 8% (4–14), respectively. We identified ten patients that, after 14 days of treatment, harboured viable but non-culturable yeasts based on QSP1 RNA detection (without any positive CFU in CSF culture). Interpretation: QSP1 and 28S rRNA assays are useful in identifying Cryptococcus species. qPCR results correlate well with baseline quantitative cryptococcal culture and show a similar decline in fungal load during induction therapy. These assays could be a faster alternative to quantitative cryptococcal culture to determine fungal load clearance. The clinical implications of the possible detection of viable but non-culturable cells in CSF during induction therapy remain unclear

A cluster randomised trial to evaluate the effect of optimising TB/HIV integration on patient level outcomes: the "merge" trial protocol.

INTRODUCTION: We describe the design of the MERGE trial, a cluster randomised trial, to evaluate the effect of an intervention to optimise TB/HIV service integration on mortality, morbidity and retention in care among newly-diagnosed HIV-positive patients and newly-diagnosed TB patients. DESIGN: Eighteen primary care clinics were randomised to either intervention or standard of care arms. The intervention comprised activities designed to optimise TB and HIV service integration and supported by two new staff cadres-a TB/HIV integration officer and a TB screening officer-for 24 months. A process evaluation to understand how the intervention was perceived and implemented at the clinics was conducted as part of the trial. Newly-diagnosed HIV-positive patients and newly-diagnosed TB patients were enrolled into the study and followed up through telephonic interviews and case note abstractions at six monthly intervals for up to 18 months in order to measure outcomes. The primary outcomes were incidence of hospitalisations or death among newly diagnosed TB patients, incidence of hospitalisation or death among newly diagnosed HIV-positive patients and retention in care among HIV-positive TB patients. Secondary outcomes of the study included measures of cost-effectiveness. DISCUSSION: Methodological challenges of the trial such as implementation of a complex multi-faceted health systems intervention, the measurement of integration at baseline and at the end of the study and an evolving standard of care with respect to TB and HIV are discussed. The trial will contribute to understanding whether TB/HIV service integration affects patient outcomes