Publications by authors named "Graeme Meintjes"

267 Publications

Virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line in adults failing a tenofovir-based first-line regimen: a prospective cohort study.

AIDS 2021 May 10. Epub 2021 May 10.

Médecins Sans Frontières South Africa Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa University of Cape Town, Cape Town, South Africa University of Liverpool, Department of Pharmacology, Liverpool, United Kingdom Division of Public Health Medicine, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa University of Stellenbosch, Division of Medical Virology, Cape Town, South Africa Department of Medicine, University of Cape Town, Cape Town, South Africa Department of Infectious Disease, Imperial College London, London, UK.

Objective: Recycling tenofovir and lamivudine/emtricitabine (XTC) with dolutegravir would provide a more tolerable, affordable, and scalable second-line regimen than dolutegravir with an optimized nucleoside reverse transcriptase inhibitor (NRTI) backbone. We evaluated efficacy of tenofovir/lamivudine/dolutegravir (TLD) in patients failing first-line tenofovir/XTC/efavirenz or nevirapine.

Design: Single arm, prospective, interventional study.

Setting: Two primary care clinics in Khayelitsha, South Africa.

Participants: 60 adult patients with two viral loads (VL)>1000 copies/mL.

Intervention: Participants were switched to TLD with additional dolutegravir (50 mg) for two weeks to overcome efavirenz induction.

Primary Outcome: Proportion achieving VL<50 copies/mL at week 24 using the FDA snapshot algorithm.

Results: Baseline median CD4 count was 248 cells/mm3, VL 10580 copies/mL and 48/54 (89%) had resistance (Stanford score ≥15) to one or both of tenofovir and XTC. No participants were lost to follow-up. At week 24, 51/60 (85%, 95% CI 73-93%) were virologically suppressed, six had VL 50-100 copies/mL, one VL 100-1000 copies/mL, one no VL in window, and one switched due to tenofovir-related adverse event. No integrase mutations were detected in the one participant meeting criteria for resistance testing. Virological suppression was achieved by 29/35 (83%, 95% CI 66-93%) with resistance to tenofovir and XTC, 11/13 (85%, 95% CI 55-98%) with resistance to XTC, and 6/6 (100%, 95% CI 54-100%) with resistance to neither.

Conclusion: A high proportion of adults switching to second-line TLD achieved virologic suppression despite substantial baseline NRTI resistance and most not suppressed had low-level viraemia (≤100 copies/mL). This suggests recycling tenofovir and XTC with dolutegravir could provide an effective second-line option.
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http://dx.doi.org/10.1097/QAD.0000000000002936DOI Listing
May 2021

Plasma pharmacokinetics of high dose oral versus intravenous rifampicin in patients with tuberculous meningitis: a randomized controlled trial.

Antimicrob Agents Chemother 2021 May 10. Epub 2021 May 10.

Wellcome Centre for Infectious Diseases Research in Africa, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, 7925, South Africa.

Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis.We performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR).Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm (IQR 66 - 253). Rifampicin geometric mean AUC was 42.9 μg·h/mL (95% CI, 24.5 - 75.0) for standard dose; 295.2 μg·h/mL (95% CI, 189.9 - 458.8) for high dose oral; and 206.5 μg·h/mL (95% CI, 154.6 - 275.8) for intravenous administration. Rifampicin AUC GMR was 1.44 (90% CI, 0.84 - 2.21) and C GMR was 0.89 (90% CI, 0.63 - 1.23) for high dose oral with respect to intravenous dosing.Plasma rifampicin AUC was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.
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http://dx.doi.org/10.1128/AAC.00140-21DOI Listing
May 2021

Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial.

Wellcome Open Res 2021 11;6. Epub 2021 Jan 11.

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Dolutegravir, a second-generation integrase strand transfer inhibitor (InSTI), is replacing efavirenz as first-line antiretroviral therapy (ART) in low middle-income countries (LMICs). Tuberculosis remains the leading cause of HIV-related morbidity and mortality in LMICs. Rifampicin is a key agent in the treatment of tuberculosis but induces genes involved in dolutegravir metabolism and efflux. The resulting drug-drug interaction (DDI) reduces the exposure of dolutegravir. However, this can be overcome by supplying a supplemental dose of 50 mg dolutegravir 12 hours after the standard daily dose, which is difficult to implement in LMICs. Four lines of evidence suggest that the supplemental dose may not be necessary: 1) a phase 2 study showed 10 mg of dolutegravir as effective as 50 mg; 2) the prolonged dissociative half-life of dolutegravir after binding to its receptor; 3) a DDI study reported dolutegravir trough concentrations were maintained above its minimum effective concentration when using 50 mg dolutegravir with rifampicin; and 4) virologic outcomes were similar between standard and double dose of raltegravir (a first-generation InSTI) in participants with HIV-associated tuberculosis treated with rifampicin. We hypothesise that virologic outcomes with standard dose dolutegravir-based ART will be acceptable in patients on rifampicin-based antituberculosis therapy. Here we outline the protocol for a phase 2, non-comparative, randomised, double-blind, placebo-controlled trial of standard versus double dose dolutegravir among adults living with HIV (ART naïve or first-line interrupted) on rifampicin-based antituberculosis therapy. A total of 108 participants will be enrolled from Khayelitsha in Cape Town, South Africa. Follow up will occur over 48 weeks. The primary objective is to assess proportion virological suppression at 24 weeks between groups analysed by modified intention to treat. Participant safety and the emergence of antiretroviral resistance mutations among those with virologic failure will be assessed throughout. ns: clinicaltrials.gov NCT03851588 (22/02/2019), SANCTR DOH-27-072020-8159 (03/07/2020).
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http://dx.doi.org/10.12688/wellcomeopenres.16473.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063551PMC
January 2021

Effectiveness and cardiac safety of bedaquiline-based therapy for drug-resistant tuberculosis: a prospective cohort study.

Clin Infect Dis 2021 Apr 21. Epub 2021 Apr 21.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant TB (RR-TB) but prolongs the QT-interval and carries a black-box warning by the U.S. Food and Drug Administration. The World Health Organization recommends that all patients with RR-TB receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published.

Methods: We conducted an observational cohort study of RR-TB patients from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, including electrocardiograms (ECGs) performed in triplicate at four time points during bedaquiline therapy. Participants were followed until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT-prolongation, defined as any QTcF>500 ms or an absolute change from baseline (△ QTcF) >60 ms.

Results: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant (XDR) TB. Most participants (97%) received concurrent clofazimine. 74% of participants were cured or successfully completed treatment, and outcomes did not differ by HIV status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase of 23.7 (SD 22.7) ms from baseline to month 6. Four participants experienced a QTcF>500 ms and 19 experienced a △QTcF>60 ms. Older age was independently associated with QT-prolongation. QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir-ritonavir.

Conclusions: Severe QT-prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close QT-monitoring may be advisable in older patients.
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http://dx.doi.org/10.1093/cid/ciab335DOI Listing
April 2021

Functional and Activation Profiles of Mucosal-Associated Invariant T Cells in Patients With Tuberculosis and HIV in a High Endemic Setting.

Front Immunol 2021 22;12:648216. Epub 2021 Mar 22.

Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ. We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC, = 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB, = 36), (iii) individuals with HIV infection (HIV, = 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB, = 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK) () were analyzed using flow cytometry. MAIT cells were defined as CD3 CD161 Vα7.2 T cells. Circulating MAIT cell frequencies were depleted in individuals with HIV infection ( = 0.009). MAIT cells showed reduced CD107a expression in aTB ( = 0.006), and reduced IFNγ expression in aTB ( < 0.001) and in HIV-TB ( < 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV ( < 0.001), aTB ( = 0.019), and HIV-TB ( = 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB ( = 0.009) and HIV-TB ( = 0.002) after stimulation with BCG-GFP and HK-. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a ( = 0.020) and IFNγ ( = 0.010) expression. Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.
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http://dx.doi.org/10.3389/fimmu.2021.648216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019701PMC
March 2021

TBDBT: A TB DataBase Template for collection of harmonized TB clinical research data in REDCap, facilitating data standardisation for inter-study comparison and meta-analyses.

PLoS One 2021 26;16(3):e0249165. Epub 2021 Mar 26.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

Clinical tuberculosis research, both within research groups and across research ecosystems, is often undertaken in isolation using bespoke data collection platforms and applying differing data conventions. This failure to harmonise clinical phenotype data or apply standardised data collection and storage standards in turn limits the opportunity to undertake meta-analyses using data generated across multiple research projects for the same research domain. We have developed the Tuberculosis DataBase Template (TBDBT), a template for the well-supported, free and commonly deployed clinical databasing platform, REDCap. This template can be used to set up a new tuberculosis research database with a built-in set of standardised data conventions, to ensure standardised data capture across research projects and programs. A modular design enables researchers to implement only the modules of the database template that are appropriate for their particular study. The template includes core modules for informed consent data, participant demographics, clinical symptoms and presentation, diagnostic imaging and laboratory tests. Optional modules have been designed for visit scheduling and calendar functionality, clinical trial randomisation, study logistics and operations, and pharmacokinetic data. Additional fields can be added as needed. This REDCap template can facilitate collection of high-quality data for tuberculosis research, providing a tool to ensure better data harmonisation, analysis and meta-analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249165PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996972PMC
March 2021

Vaccine Efficacy of ALVAC-HIV and Bivalent Subtype C gp120-MF59 in Adults.

N Engl J Med 2021 03;384(12):1089-1100

From the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (G.E.G., Z.M., N. Grunenberg, Y.H., D.G., B.P., J.J.K., J.H., C.B., S.R., S.T., M.J., M. Sikhosana, M. Andrasik, J.G.K., M.J.M., P.B.G., H.J., L.C.), Seattle; the Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand (G.E.G., F.L., E.L., B.M., T.P., S.T.), the National Institute for Communicable Diseases, National Health Laboratory Service (A.P.), and Aurum Institute (C.I., M. Sebe, W.B., P.S., T.A., G. Kobane), Johannesburg, Desmond Tutu HIV Centre (L.-G.B., S.K., C.N.N., M. Atujuna), the Department of Medicine, Wellcome Centre for Infectious Diseases Research in Africa, and Institute of Infectious Disease and Molecular Medicine (G.M., A.M.W.), and the Division of Clinical Pharmacology, Department of Medicine (L.W.), University of Cape Town, Cape Town, Setshaba Research Centre, Soshanguve (M.M., K.S.M.), Mecru Clinical Research Unit, Sefako Mkgatho Health Sciences University, Ga-Rankuwa (M.N., M.P.M.), Nelson Mandela Academic Clinical Research Unit and Department of Internal Medicine and Pharmacology, Walter Sisulu University, Mthatha (T.D., P.M.), the School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria (S.T.), the South African Medical Research Council (G.E.G., D.K., N.S., V.N., G. Kistnasami, Z.G.) and the Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal (N.N., N. Garrett), Durban, and Qhakaza Mbokodo Research Clinic, Ladysmith (P.K., P.B.M.) - all in South Africa; the Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (M. Allen), and GlaxoSmithKline Vaccines, Rockville (N.K.-T.) - both in Maryland; the Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta (D.B.); GSK Vaccines, Cambridge, MA (S.W.B.); Sanofi Pasteur, Swiftwater, PA (S.P., C.D.G.); GlaxoSmithKline, Siena, Italy (S.P.); GlaxoSmithKline, Wavre (M.K.), and GlaxoSmithKline, Rixensart (O.V.D.M.) - both in Belgium; and the Graduate Group in Biostatistics and the Center for Computational Biology, University of California, Berkeley (N.S.H.).

Background: A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa.

Methods: In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months.

Results: In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84).

Conclusions: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).
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http://dx.doi.org/10.1056/NEJMoa2031499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888373PMC
March 2021

Raltegravir in patients with tuberculosis.

Lancet Infect Dis 2021 Mar 2. Epub 2021 Mar 2.

Department of Medicine, Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa.

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http://dx.doi.org/10.1016/S1473-3099(20)30937-3DOI Listing
March 2021

Diagnostic Accuracy of the INSHI Consensus Case Definition for the Diagnosis of Paradoxical Tuberculosis-IRIS.

J Acquir Immune Defic Syndr 2021 04;86(5):587-592

Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.

Background: The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test.

Setting: Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa.

Methods: Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions.

Results: Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms; night sweats; INSHI major criteria 1, 2, and 4; maximum C-reactive protein >90 mg/L; maximum heart rate >120/min; maximum temperature >37.7°C; and preantiretroviral therapy CD4 count <50 cells/µL. The model estimated a TB-IRIS incidence of 43% and had optimal goodness of fit (χ2 = 337, P = 1.0). The INSHI case definition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minor INSHI criteria with objectives measures (C-reactive protein elevation, fever, and/or tachycardia) resulted in a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of 0.88.

Conclusion: The INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the case definition by replacing INSHI minor criteria with objective variables improved sensitivity without loss of specificity.
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http://dx.doi.org/10.1097/QAI.0000000000002606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938911PMC
April 2021

Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.

Open Forum Infect Dis 2020 Nov 16;7(11):ofaa489. Epub 2020 Oct 16.

Institute of Infection and Immunity, St George's University of London, London, United Kingdom.

Background: is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%-10% of patients with HIV/acquired immune deficiency syndrome and profound CD4 T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans.

Methods: We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen).

Results: Six loci upstream of the colony-stimulating factor 1 () gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at  < 10 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42-0.66;  =5.96 × 10). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against in HIV-infected patients and healthy, ethnically matched controls.

Conclusions: This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis.
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http://dx.doi.org/10.1093/ofid/ofaa489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686661PMC
November 2020

Cost-effectiveness of a novel lipoarabinomannan test for tuberculosis in patients with HIV.

Clin Infect Dis 2020 Nov 17. Epub 2020 Nov 17.

Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, MA, USA.

Background: A novel urine lipoarabinomannan assay (FujiLAM) has higher sensitivity and higher cost than the first-generation AlereLAM assay. We evaluated the cost-effectiveness of FujiLAM for tuberculosis testing among hospitalized people with HIV irrespective of symptoms.

Methods: We used a microsimulation model to project clinical and economic outcomes of three testing strategies: 1) sputum Xpert MTB/RIF (Xpert); 2) sputum Xpert plus urine AlereLAM (Xpert+AlereLAM); 3) sputum Xpert plus urine FujiLAM (Xpert+FujiLAM). The modelled cohort matched that of a two-country clinical trial. We applied diagnostic yields from a retrospective study (yields for Xpert/Xpert+AlereLAM/Xpert+FujiLAM among those with CD4<200/µL: 33%/62%/70%; among those with CD4≥200/µL: 33%/35%/47%). Costs of Xpert/AlereLAM/FujiLAM were USD15/3/6 (South Africa) and USD25/3/6 (Malawi). Xpert+FujiLAM was considered cost-effective if its incremental cost-effectiveness ratio (USD/year-of-life saved) was <$940 (South Africa) and <$750 (Malawi). We varied key parameters in sensitivity analysis and performed a budget impact analysis of implementing FujiLAM countrywide.

Results: Compared with Xpert+AlereLAM, Xpert+FujiLAM increased life expectancy by 0.2 years for those tested in South Africa and Malawi. Xpert+FujiLAM was cost-effective in both countries. Xpert+FujiLAM for all patients remained cost-effective compared with sequential testing and CD4-stratified testing strategies. FujiLAM use added 3.5% (South Africa) and 4.7% (Malawi) to five-year healthcare costs of tested patients, primarily reflecting ongoing HIV treatment costs among survivors.

Conclusions: FujiLAM with Xpert for tuberculosis testing in hospitalized people with HIV is likely to increase life expectancy and be cost-effective at the currently anticipated price in South Africa and Malawi. Additional studies should evaluate FujiLAM in clinical practice settings.
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http://dx.doi.org/10.1093/cid/ciaa1698DOI Listing
November 2020

Correlation between Blood and CSF Compartment Cytokines and Chemokines in Subjects with Cryptococcal Meningitis.

Mediators Inflamm 2020 29;2020:8818044. Epub 2020 Oct 29.

Department of Medicine, University of Minnesota, 55455 Minneapolis, MN, USA.

Background: Though peripheral blood is a crucial sample to study immunology, it is unclear whether the immune environment in the peripheral vasculature correlates with that at the end-organ site of infection. Using cryptococcal meningitis as a model, we investigated the correlation between serum and cerebrospinal fluid biomarkers over time.

Methods: We analyzed the cerebrospinal fluid and serum of 160 subjects presenting with first episode cryptococcal meningitis for soluble cytokines and chemokines measured by Luminex assay. Specimens were collected at meningitis diagnosis, 1-week, and 2-week post cryptococcal diagnosis. We compared paired samples by Spearman's correlation and the value was set at <0.01.

Results: Of the 21 analytes tested at baseline, there was no correlation detected between nearly all analytes. A weak negative correlation was found between serum and cerebrospinal fluid levels of interferon-gamma (Rho = -0.214; = .007) and interleukin-4 (Rho = -0.232; = .003). There was no correlation at 1-week post cryptococcal diagnosis. However, at 2-week post cryptococcal diagnosis, there was a weak positive correlation of granulocyte-macrophage colony-stimulating factor levels (Rho = 0.25; = .007) in serum and cerebrospinal fluid. No cytokine or chemokine showed consistent correlation overtime.

Conclusion: Based on our analysis of 21 biomarkers, serum and cerebrospinal fluid immune responses do not correlate. There appears to be a distinct immune environment in terms of soluble biomarkers in the vasculature versus end-organ site of infection. While this is a model of HIV-related cryptococcal meningitis, we postulate that assuming the blood compartment is representative of the immune function at the end-organ site of infection may not be appropriate.
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http://dx.doi.org/10.1155/2020/8818044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644322PMC
October 2020

The utility of high-flow nasal oxygen for severe COVID-19 pneumonia in a resource-constrained setting: A multi-centre prospective observational study.

EClinicalMedicine 2020 Nov 6;28:100570. Epub 2020 Oct 6.

Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.

Background: The utility of heated and humidified high-flow nasal oxygen (HFNO) for severe COVID-19-related hypoxaemic respiratory failure (HRF), particularly in settings with limited access to intensive care unit (ICU) resources, remains unclear, and predictors of outcome have been poorly studied.

Methods: We included consecutive patients with COVID-19-related HRF treated with HFNO at two tertiary hospitals in Cape Town, South Africa. The primary outcome was the proportion of patients who were successfully weaned from HFNO, whilst failure comprised intubation or death on HFNO.

Findings: The median (IQR) arterial oxygen partial pressure to fraction inspired oxygen ratio (PO2/FiO) was 68 (54-92) in 293 enroled patients. Of these, 137/293 (47%) of patients [PO2/FiO 76 (63-93)] were successfully weaned from HFNO. The median duration of HFNO was 6 (3-9) in those successfully treated versus 2 (1-5) days in those who failed (<0.001). A higher ratio of oxygen saturation/FiO2 to respiratory rate within 6 h (ROX-6 score) after HFNO commencement was associated with HFNO success (ROX-6; AHR 0.43, 0.31-0.60), as was use of steroids (AHR 0.35, 95%CI 0.19-0.64). A ROX-6 score of ≥3.7 was 80% predictive of successful weaning whilst ROX-6 ≤ 2.2 was 74% predictive of failure. In total, 139 patents (52%) survived to hospital discharge, whilst mortality amongst HFNO failures with outcomes was 129/140 (92%).

Interpretation: In a resource-constrained setting, HFNO for severe COVID-19 HRF is feasible and more almost half of those who receive it can be successfully weaned without the need for mechanical ventilation.
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http://dx.doi.org/10.1016/j.eclinm.2020.100570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536126PMC
November 2020

Risk factors for COVID-19 death in a population cohort study from the Western Cape Province, South Africa.

Clin Infect Dis 2020 Aug 29. Epub 2020 Aug 29.

Health Programmes Directorate, Western Cape Government: Health.

Background: Risk factors for COVID-19 death in sub-Saharan Africa and the effects of HIV and tuberculosis on COVID-19 outcomes are unknown.

Methods: We conducted a population cohort study using linked data from adults attending public sector health facilities in the Western Cape, South Africa. We used Cox-proportional hazards models adjusted for age, sex, location and comorbidities to examine the association between HIV, tuberculosis and COVID-19 death from 1 March-9 June 2020 among (i) public sector "active patients" (≥1 visit in the 3 years before March 2020), (ii) laboratory-diagnosed COVID-19 cases and (iii) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19 comparing HIV positive vs. negative adults using modelled population estimates.

Results: Among 3,460,932 patients (16% HIV positive), 22,308 were diagnosed with COVID-19, of whom 625 died. COVID-19 death was associated with male sex, increasing age, diabetes, hypertension and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR] 2.14; 95% confidence interval [CI] 1.70-2.70), with similar risks across strata of viral load and immunosuppression. Current and previous tuberculosis were associated with COVID-19 death (aHR [95%CI] 2.70 [1.81-4.04] and 1.51 [1.18-1.93] respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95%CI 1.96-2.86); population attributable fraction 8.5% (95%CI 6.1-11.1).

Conclusion: While our findings may over-estimate HIV- and tuberculosis-associated COVID-19 mortality risks due to residual confounding, both HIV and current tuberculosis were independently associated with increased COVID-19 mortality. The associations between age, sex and other comorbidities and COVID-19 mortality were similar to other settings.
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http://dx.doi.org/10.1093/cid/ciaa1198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499501PMC
August 2020

Case report: Emergence of dolutegravir resistance in a patient on second-line antiretroviral therapy.

South Afr J HIV Med 2020 2;21(1):1062. Epub 2020 Jul 2.

Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Introduction: The integrase strand transfer inhibitor dolutegravir (DTG) has a high genetic barrier to resistance. Only rare cases of resistance to DTG have been reported when it is used as a component of antiretroviral therapy regimens in treatment-experienced patients unless there was prior use of a first-generation integrase inhibitor.

Patient Presentation: A 38-year-old woman diagnosed with tuberculosis was switched to a second-line antiretroviral regimen of zidovudine, lamivudine and dolutegravir 50 mg 12-hourly together with rifampicin-based TB treatment. Based on treatment history and a previous resistance test there was resistance to lamivudine but full susceptibility to zidovudine. The patient did not suppress her viral load on this regimen and later admitted to only taking dolutegravir 50 mg in the morning because of insomnia.

Management And Outcome: A second resistance test was performed which showed intermediate level of resistance to dolutegravir. Her regimen was changed to tenofovir, emtricitabine and ritonavir-boosted atazanavir with rifabutin replacing rifampicin for the remainder of her TB treatment. She achieved viral suppression on this regimen.

Conclusion: To our knowledge this is the first case report from South Africa of emergent dolutegravir resistance in a treatment-experienced, integrase inhibitor-naïve patient. Factors that may have contributed to resistance emergence in this patient were that there was only one fully active nucleoside reverse transcriptase inhibitor in the regimen and lower exposure to dolutegravir because of the reduced dosing frequency while on rifampicin.
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http://dx.doi.org/10.4102/sajhivmed.v21i1.1062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433307PMC
July 2020

Clofazimine pharmacokinetics in patients with TB: dosing implications.

J Antimicrob Chemother 2020 11;75(11):3269-3277

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.

Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.

Patients And Methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.

Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.

Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
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http://dx.doi.org/10.1093/jac/dkaa310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566350PMC
November 2020

Elevated N-terminal prohormone of brain natriuretic peptide among persons living with HIV in a South African peri-urban township.

ESC Heart Fail 2020 10 25;7(5):3246-3251. Epub 2020 Jun 25.

Department of Medicine, University of Cape Town, Cape Town, South Africa.

Aims: Efforts to improve access to antiretroviral therapy (ART) have shifted morbidity and mortality among persons living with HIV (PLWH) from AIDS to non-communicable diseases, such as cardiovascular disease (CVD). However, contemporary data on CVD among PLWH in sub-Saharan Africa in the current ART era are lacking. The aim of this study was to assess the burden of cardiac stress among PLWH in South Africa via measurement of N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

Methods And Results: NT-proBNP was measured at baseline in 224 PLWH enrolled in a sub-study of a tuberculosis vaccine trial in Khayelitsha township near Cape Town, South Africa. Thresholds were applied at the assay's limit of detection (≥137 pg/mL) and a level indicative of symptomatic heart failure in the acute setting (>300 pg/mL). Mean (SD) age of participants was 39 (6) years, 86% were female, and 19% were hypertensive. Mean (SD) duration of HIV diagnosis was 8.3 (3.9) years and CD4 + count was 673 (267) with 79% prescribed ART for a duration of 5.6 (2.7) years. Thirty-one percent of participants had NT-proBNP > 300 pg/mL. Elevated vs. undetectable NT-proBNP level was associated with older age (P = 0.04), no ART (P = 0.03), and higher plasma tumour necrosis factor-α (P = 0.01).

Conclusions: Among South African PLWH largely free of known CVD and on ART with high CD4 + counts and few comorbidities, we observed a high proportion with elevated NT-proBNP levels, suggesting the burden of cardiac stress in this population may be high. This observation underscores the need for more in-depth research, including the current effect of HIV on heart failure risk among a growing ART-treated population in sub-Saharan Africa.
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http://dx.doi.org/10.1002/ehf2.12849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524119PMC
October 2020

Responding to SARS-CoV-2 in South Africa: what can we learn from drug-resistant tuberculosis?

Eur Respir J 2020 07 23;56(1). Epub 2020 Jul 23.

Dept of Medicine and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.

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http://dx.doi.org/10.1183/13993003.01369-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257618PMC
July 2020

Management of intracranial tuberculous mass lesions: how long should we treat for?

Wellcome Open Res 2019 31;4:158. Epub 2019 Oct 31.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, 7925, South Africa.

Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting ( ) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3 International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.
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http://dx.doi.org/10.12688/wellcomeopenres.15501.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996525PMC
October 2019

Diagnostic accuracy of a novel tuberculosis point-of-care urine lipoarabinomannan assay for people living with HIV: A meta-analysis of individual in- and outpatient data.

PLoS Med 2020 05 1;17(5):e1003113. Epub 2020 May 1.

FIND, Geneva, Switzerland.

Background: Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV), yet TB often goes undiagnosed since many patients are not able to produce a sputum specimen, and traditional diagnostics are costly or unavailable. A novel, rapid lateral flow assay, Fujifilm SILVAMP TB LAM (SILVAMP-LAM), detects the presence of TB lipoarabinomannan (LAM) in urine, and is substantially more sensitive for diagnosing TB in PLHIV than an earlier LAM assay (Alere Determine TB LAM lateral flow assay [LF-LAM]). Here, we present an individual participant data meta-analysis of the diagnostic accuracy of SILVAMP-LAM in adult PLHIV, including both published and unpublished data.

Methods And Findings: Adult PLHIV (≥18 years) were assessed in 5 prospective cohort studies in South Africa (3 cohorts), Vietnam, and Ghana, carried out during 2012 to 2017. Of the 1,595 PLHIV who met eligibility criteria, the majority (61%) were inpatients, median age was 37 years (IQR 30-43), 43% had a CD4 count ≤ 100 cells/μl, and 35% were receiving antiretroviral therapy. Most participants (94%) had a positive WHO symptom screen for TB on enrollment, and 45% were diagnosed with microbiologically confirmed TB, using mycobacterial culture or Xpert MTB/RIF testing of sputum, urine, or blood. Previously published data from inpatients were combined with unpublished data from outpatients. Biobanked urine samples were tested, using blinded double reading, with SILVAMP-LAM and LF-LAM. Applying a microbiological reference standard for assessment of sensitivity, the overall sensitivity for TB detection was 70.7% (95% CI 59.0%-80.8%) for SILVAMP-LAM compared to 34.9% (95% CI 19.5%-50.9%) for LF-LAM. Using a composite reference standard (which included patients with both microbiologically confirmed as well as clinically diagnosed TB), SILVAMP-LAM sensitivity was 65.8% (95% CI 55.9%-74.6%), and that of LF-LAM 31.4% (95% CI 19.1%-43.7%). In patients with CD4 count ≤ 100 cells/μl, SILVAMP-LAM sensitivity was 87.1% (95% CI 79.3%-93.6%), compared to 56.0% (95% CI 43.9%-64.9%) for LF-LAM. In patients with CD4 count 101-200 cells/μl, SILVAMP-LAM sensitivity was 62.7% (95% CI 52.4%-71.9%), compared to 25.3% (95% CI 15.8%-34.9%) for LF-LAM. In those with CD4 count > 200 cells/μl, SILVAMP-LAM sensitivity was 43.9% (95% CI 34.3%-53.9%), compared to 10.9% (95% CI 5.2%-18.4%) for LF-LAM. Using a microbiological reference standard, the specificity of SILVAMP-LAM was 90.9% (95% CI 87.2%-93.7%), and that of LF-LAM 95.3% (95% CI 92.2%-97.7%). Limitations of this study include the use of biobanked, rather than fresh urine samples, and testing by skilled laboratory technicians in research laboratories, rather than at the point of care.

Conclusions: In this study, we found that SILVAMP-LAM identified a substantially higher proportion of TB patients in PLHIV than LF-LAM. The sensitivity of SILVAMP-LAM was highest in patients with CD4 count ≤ 100 cells/μl. Further work is needed to demonstrate accuracy when implemented as a point-of-care test.
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http://dx.doi.org/10.1371/journal.pmed.1003113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194366PMC
May 2020

Ventriculoperitoneal shunt insertion in human immunodeficiency virus infected adults: a systematic review and meta-analysis.

BMC Neurol 2020 Apr 17;20(1):141. Epub 2020 Apr 17.

Division of Neurosurgery, University of Cape Town, H53 Old Main Building, Groote Schuur Hospital, Main Road, Observatory, Cape Town, 7925, South Africa.

Background: Hydrocephalus is a common, life threatening complication of human immunodeficiency virus (HIV)-related central nervous system opportunistic infection which can be treated by insertion of a ventriculoperitoneal shunt (VPS). In HIV-infected patients there is concern that VPS might be associated with unacceptably high mortality. To identify prognostic indicators, we aimed to compare survival and clinical outcome following VPS placement between all studied causes of hydrocephalus in HIV infected patients.

Methods: The following electronic databases were searched: The Cochrane Central Register of Controlled Trials, MEDLINE (PubMed), EMBASE, CINAHL Plus, LILACS, Research Registry, the metaRegister of Controlled Trials, ClinicalTrials.gov, African Journals Online, and the OpenGrey database. We included observational studies of HIV-infected patients treated with VPS which reported of survival or clinical outcome. Data was extracted using standardised proformas. Risk of bias was assessed using validated domain-based tools.

Results: Seven Hunderd twenty-three unique study records were screened. Nine observational studies were included. Three included a total of 75 patients with tuberculous meningitis (TBM) and six included a total of 49 patients with cryptococcal meningitis (CM). All of the CM and two of the TBM studies were of weak quality. One of the TBM studies was of moderate quality. One-month mortality ranged from 62.5-100% for CM and 33.3-61.9% for TBM. These pooled data were of low to very-low quality and was inadequate to support meta-analysis between aetiologies. Pooling of results from two studies with a total of 77 participants indicated that HIV-infected patients with TBM had higher risk of one-month mortality compared with HIV non-infected controls (odds ratio 3.03; 95% confidence-interval 1.13-8.12; p = 0.03).

Conclusions: The evidence base is currently inadequate to inform prognostication in VPS insertion in HIV-infected patients. A population-based prospective cohort study is required to address this, in the first instance.
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http://dx.doi.org/10.1186/s12883-020-01713-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164262PMC
April 2020

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

Lancet Infect Dis 2020 06 13;20(6):742-752. Epub 2020 Mar 13.

Johns Hopkins University Centre for TB Research, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI.

Methods: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022.

Findings: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84).

Interpretation: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients.

Funding: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.
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http://dx.doi.org/10.1016/S1473-3099(19)30695-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254058PMC
June 2020

Time to embrace access programmes for medicines: lessons from the South African flucytosine access programme.

Int J Infect Dis 2020 Jun 29;95:459-461. Epub 2020 Feb 29.

Doctors Without Borders South Africa, Johannesburg, South Africa; Centre for Infectious Disease and Research, University of Cape Town, Cape Town, South Africa.

Background: Cryptococcal meningitis (CM) is estimated to cause 181 000 deaths annually, with the majority occurring in Sub-Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure, quality-assured flucytosine remains unregistered and largely inaccessible throughout Africa.

Methods: The recently established South African flucytosine clinical access programme is an attempt to address the market failure that led to a lack of public sector access to flucytosine for CM, by making the medicine freely available to tertiary hospitals in South Africa.

Results: Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale-up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observations from this experience that may have wider relevance.

Conclusions: The South African flucytosine access programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.
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http://dx.doi.org/10.1016/j.ijid.2020.02.057DOI Listing
June 2020

Seizures in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Predictors and Outcomes.

Open Forum Infect Dis 2019 Nov 5;6(11):ofz478. Epub 2019 Nov 5.

University of Minnesota, Minneapolis, Minnesota, USA.

Background: Seizures commonly occur in patients with cryptococcal meningitis, yet risk factors and outcomes related to seizures are not well described.

Methods: We performed post hoc analyses on participants prospectively enrolled in 3 separate human immunodeficiency virus (HIV)-associated cryptococcal meningitis clinical trials during 2010-2017. Documentation of seizures at presentation or during hospitalization and antiseizure medication receipt identified participants with seizures. We summarized participant characteristics by seizure status via Kruskal-Wallis and χ  tests. Cox proportional hazards models analyzed the relationship between seizures and mortality. We compared mean quantitative neurocognitive performance Z (QNPZ-8) scores, and individual domain z-scores, at 3-months using independent tests.

Results: Among 821 HIV-infected cryptococcal meningitis participants, 28% (231 of 821) experienced seizures: 15.5% (127 of 821) experienced seizures at presentation, and 12.7% (104 of 821) experienced incident seizures. Participants with seizures at presentation had a significantly lower Glasgow coma scale ([GCS] <15; < .001), CD4 count (<50 cells/mcL; = .02), and higher cerebrospinal fluid (CSF) opening pressure (>25 cm HO; = .004) when compared with participants who never experienced seizures. Cerebrospinal fluid fungal burden was higher among those with seizures at presentation (125 000 colony-forming units [CFU]/mL CSF) and with seizures during follow-up (92 000 CFU/mL) compared with those who never experienced seizures (36 000 CFU/mL, < .001). Seizures were associated with increased 10-week mortality (adjusted hazard ratio = 1.45; 95% confidence interval, 1.11-1.89). Participants with seizures had lower neurocognitive function at 3 months (QNPZ-8 = -1.87) compared with those without seizures (QNPZ-8 = -1.36; < .001).

Conclusions: Seizures were common in this HIV-associated cryptococcal meningitis cohort and were associated with decreased survival and neurocognitive function.
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http://dx.doi.org/10.1093/ofid/ofz478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001112PMC
November 2019

Loss to follow-up from antiretroviral therapy clinics: A systematic review and meta-analysis of published studies in South Africa from 2011 to 2015.

South Afr J HIV Med 2019 18;20(1):984. Epub 2019 Dec 18.

Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Background: South Africa has the largest antiretroviral therapy (ART) programme in the world. To optimise programme outcomes, it is critical that patients are retained in care and that retention is accurately measured.

Objectives: To identify all studies published in South Africa from 2011 to 2015 that used loss to follow-up (LTFU) as an indicator or outcome to describe the variation in definitions and to estimate the proportion of patients lost to care across studies.

Method: All studies published between 01 January 2011 and October 2015 that included loss to follow-up or default from ART care in a South African cohort were included by use of a broad search strategy across multiple databases. To be included, the cohort had to include any patient ART data, including follow-up time, from 01 January 2010. Two authors, working independently, extracted data and assessed risk of bias from all manuscripts. Meta-analysis was performed for studies stratified by the same loss to follow-up definition.

Results: Forty-eight adult, 15 paediatric and 4 pregnant cohorts were included. Median cohort size was 3737; follow-up time ranged from 9 weeks to 5 years. Meta-analysis did not reveal an important difference in LTFU estimates in adult cohorts at 1 year between loss to follow-up defined as 3 months (11.0%, = 4; 95% CI 10.7% - 11.2%) compared with 6 months (12.0%, = 4; 95% CI 11.8% - 12.2%). Only two cohorts reported reliable LTFU estimates at 5 years: this was 25.1% (95% CI 24.8% - 25.4%).

Conclusion: South Africa should standardise a LTFU definition. This would aid in monitoring and evaluation of ART programmes, with the broader goal of improving patient outcomes.
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http://dx.doi.org/10.4102/sajhivmed.v20i1.984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956684PMC
December 2019

"SILVAMP TB LAM" Rapid Urine Tuberculosis Test Predicts Mortality in Patients Hospitalized With Human Immunodeficiency Virus in South Africa.

Clin Infect Dis 2020 11;71(8):1973-1976

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa.

Reducing diagnostic delay is key toward decreasing tuberculosis-associated deaths in people living with human immunodeficiency virus. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.
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http://dx.doi.org/10.1093/cid/ciaa024DOI Listing
November 2020

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

Clin Infect Dis 2020 10;71(7):e45-e49

Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN, USA.

Background: In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks.

Methods: We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days.

Results: Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001).

Conclusions: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.
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http://dx.doi.org/10.1093/cid/ciaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755087PMC
October 2020