Background Missing or undiagnosed patients with tuberculosis (TB) or coronavirus disease 2019 (CO... more Background Missing or undiagnosed patients with tuberculosis (TB) or coronavirus disease 2019 (COVID-19) are of concern. Identifying both infections in patients with no diagnosis prior to death contributes to understanding the burden of disease. To confirm reports of global reduction in TB incidence, a 2012 autopsy study of adults dying at home of natural causes in a high-TB-burden setting was repeated, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assessments after the first COVID-19 surge in South Africa. Methods Adult decedents who died at home with insufficient information to determine cause of death, no recent hospitalization, and no current antemortem TB or COVID-19 diagnosis were identified between March 2019 and October 2020 with a 4-month halt during lockdown. A standardized verbal autopsy followed by minimally invasive needle autopsy (MIA) was performed. Biopsies were taken for histopathology from liver, bilateral brain and lung; bronchoalveolar la...
Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 a... more Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa’s response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA—a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing an...
BackgroundData on risk factors for COVID-19-associated hospitalisation and mortality in high HIV ... more BackgroundData on risk factors for COVID-19-associated hospitalisation and mortality in high HIV prevalence settings are limited.MethodsUsing existing syndromic surveillance programs for influenza-like-illness and severe respiratory illness at sentinel sites in South Africa, we identified factors associated with COVID-19 hospitalisation and mortality.ResultsFrom April 2020 through March 2022, SARS-CoV-2 was detected in 24.0% (660/2746) of outpatient and 32.5% (2282/7025) of inpatient cases. Factors associated with COVID-19-associated hospitalisation included: older age (25-44 [adjusted odds ratio (aOR) 1.8, 95% confidence interval (CI) 1.1-2.9], 45-64 [aOR 6.8, 95%CI 4.2-11.0] and ≥65 years [aOR 26.6, 95%CI 14.4-49.1] vs 15-24 years); black race (aOR 3.3, 95%CI 2.2-5.0); obesity (aOR 2.3, 95%CI 1.4-3.9); asthma (aOR 3.5, 95%CI 1.4-8.9); diabetes mellitus (aOR 5.3, 95%CI 3.1-9.3); HIV with CD4 ≥200/mm3 (aOR 1.5, 95%CI 1.1-2.2) and CD4<200/mm3 (aOR 10.5, 95%CI 5.1-21.6) or tubercul...
IntroductionData on the economic burden of RSV-associated illness will inform decisions on the pr... more IntroductionData on the economic burden of RSV-associated illness will inform decisions on the programmatic implementation of maternal vaccines and monoclonal antibodies. We estimated these costs in fine age bands to allow more accurate cost-effectiveness models to account for limited duration of protection conferred by short or long acting interventions.MethodsWe conducted a costing study at sentinel sites across South Africa to estimate out-of-pocket and indirect costs for RSV-associated mild and severe illness. We collected facility-specific costs for staffing, equipment, services, diagnostic tests and treatment. Using case-based data we calculated a patient day equivalent (PDE) for RSV-associated hospitalisations or clinic visits; the PDE was multiplied by the number of days of care to provide a case-cost to the healthcare system. We estimated the costs in 3-month age intervals in children aged <1 years and as a single group for children aged 1-4 years. We then applied our da...
BackgroundVaccines and monoclonal antibodies to protect the very young infant against respiratory... more BackgroundVaccines and monoclonal antibodies to protect the very young infant against respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost effectiveness analyses.MethodsWe combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged <5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the <1-year age group, by 3-month intervals until 2 years and then 12 monthly intervals to <5 years for medically and non-medically attended illness.ResultsWe estimated a mean annual total (medically and non-medically attended) of 264,112 (95% Confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) ...
BackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cas... more BackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cases, an etiological agent is not identified. We describe the use of a multi-pathogen platform, TaqMan array card (TAC) real-time PCR, for the detection of pathogens in patients hospitalized with severe respiratory illness (SRI).MethodsWe conducted prospective hospital-based surveillance for SRI among patients at two sentinel sites in South Africa between January and December 2017. Patients were included in this study if a blood specimen and at least one respiratory specimen (naso- and oro-pharyngeal (NP/OP) swabs and/or sputum) were available for testing. We tested respiratory specimens for 21 respiratory pathogens and blood samples for nine bacteria using TAC. Pathogen detection was compared by age group and HIV status using the chi-squared test.ResultsDuring 2017, 956 patients were enrolled in SRI surveillance, and of these, 637 (67%) patients were included in this study (637 blood, 487...
Background: All people with HIV who screen negative for active tuberculosis (TB) should receive i... more Background: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach.Setting: Primary care clinics in Matlosana, South Africa.Design: This was a mixed-methods implementation study.Methods: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers.Results: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qua...
Southern African Journal of Infectious Diseases, 2019
Setting: Klerksdorp-Tshepong Hospital Complex MDR-TB Unit, North-West Province, South Africa.Back... more Setting: Klerksdorp-Tshepong Hospital Complex MDR-TB Unit, North-West Province, South Africa.Background: To determine the time to sputum culture conversion (TTSCC) and factors predictive of TTSCC in patients with multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in the North-West Province.Methods: A retrospective cohort study, abstracting patient demographic and clinical data, laboratory results, dates of sputum testing and sputum culture conversion results, from medical records of 526 MDR-TB and 47 XDR-TB patients started on TB treatment between 01 January 2012 and 31 December 2014. Predictors of TTSCC were determined by Cox proportional hazards regression.Results: The median age was 38 years (interquartile range 31–47) with 64% being male. Overall, 79% (449) were Human Immunodeficiency Virus (HIV)-infected. The median TTSCC was 56.5 days and 162.5 days for MDR-TB and XDR-TB patients, respectively. In the multivariate analysis, age [haz...
Background: Tuberculosis (TB) is a leading infectious cause of death globally. Current treatment ... more Background: Tuberculosis (TB) is a leading infectious cause of death globally. Current treatment for drug-susceptible (DS-TB) and rifampicin-resistant (RR-TB) infections is lengthy and toxic. Methods: The STAND trial was a partially-randomised, open-label, non-inferiority phase 3 study. Patients ≥18 years with smear positive sputum were eligible. HIV-positive patients with CD4+ counts <100 cells/mm3 were excluded. DS-TB participants were randomised 1:1:1:1 to receive: 200mg pretomanid (P) daily, 400mg moxifloxacin (M) and 1500mg pyrazinamide (Z) for either 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) in combination for 6 months as control. The primary outcome was treatment failure or relapse 12 months after randomisation. The non-inferiority margin for between-group differences was 12 percent. RR-TB participants were allocated to 6Pa200MZ. Recruitment was paused in September 2015 and did not resume. Findings: In total 43 of 56 (76.8%), 46 of 61 (75.4%), 38 of 57 (66.7%), and 52 of 60 (86.7%) DS-TB participants were favourable on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ, and control respectively. The difference in favourable response between control and 6Pa200MZ was 9.9% [95%CI -4.1 to 23.9%]. Ten of 11 (90.9%) RR-TB participants were favourable. Grade 3 or higher adverse events affected 22 of 67 (32.8%) 6Pa200MZ participants, 21 of 71 (29.6%) on 4Pa200MZ, 25 of 65 (38.5%) on 4Pa100MZ, and 19 of 68 (27.9%) on control. Serious adverse events affected 19 of 203 (9.4%) experimental DS-TB participants, 3 of 68 (4.4%) on control, and 3 of 13 (23.1%) RR-TB cases. Ten of 203 (5%) participants on the experimental arms and 2 of 68 (3%) participants on the control arm died, with 2 deaths on the 4MPa200Z arm and one death on the 4MPa100Z arm attributed to hepatotoxicity. Interpretation: The experimental DS-TB treatment did not achieve non-inferiority in this underpowered trial. The role of Pa200MZ in tuberculosis treatment needs to be investigated further. Trial Registration: (Clinicaltrials.gov identifier NCT02342886) Funding Statement: Sponsored by TB Alliance with financial support from the U.K. Department for International Development, Bill and Melinda Gates Foundation, U.S. Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Federal Ministry for Education and Research of Germany. Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the national and local ethics committees for the sites participating in the trial.
Background Missing or undiagnosed patients with tuberculosis (TB) or coronavirus disease 2019 (CO... more Background Missing or undiagnosed patients with tuberculosis (TB) or coronavirus disease 2019 (COVID-19) are of concern. Identifying both infections in patients with no diagnosis prior to death contributes to understanding the burden of disease. To confirm reports of global reduction in TB incidence, a 2012 autopsy study of adults dying at home of natural causes in a high-TB-burden setting was repeated, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assessments after the first COVID-19 surge in South Africa. Methods Adult decedents who died at home with insufficient information to determine cause of death, no recent hospitalization, and no current antemortem TB or COVID-19 diagnosis were identified between March 2019 and October 2020 with a 4-month halt during lockdown. A standardized verbal autopsy followed by minimally invasive needle autopsy (MIA) was performed. Biopsies were taken for histopathology from liver, bilateral brain and lung; bronchoalveolar la...
Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 a... more Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa’s response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA—a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing an...
BackgroundData on risk factors for COVID-19-associated hospitalisation and mortality in high HIV ... more BackgroundData on risk factors for COVID-19-associated hospitalisation and mortality in high HIV prevalence settings are limited.MethodsUsing existing syndromic surveillance programs for influenza-like-illness and severe respiratory illness at sentinel sites in South Africa, we identified factors associated with COVID-19 hospitalisation and mortality.ResultsFrom April 2020 through March 2022, SARS-CoV-2 was detected in 24.0% (660/2746) of outpatient and 32.5% (2282/7025) of inpatient cases. Factors associated with COVID-19-associated hospitalisation included: older age (25-44 [adjusted odds ratio (aOR) 1.8, 95% confidence interval (CI) 1.1-2.9], 45-64 [aOR 6.8, 95%CI 4.2-11.0] and ≥65 years [aOR 26.6, 95%CI 14.4-49.1] vs 15-24 years); black race (aOR 3.3, 95%CI 2.2-5.0); obesity (aOR 2.3, 95%CI 1.4-3.9); asthma (aOR 3.5, 95%CI 1.4-8.9); diabetes mellitus (aOR 5.3, 95%CI 3.1-9.3); HIV with CD4 ≥200/mm3 (aOR 1.5, 95%CI 1.1-2.2) and CD4<200/mm3 (aOR 10.5, 95%CI 5.1-21.6) or tubercul...
IntroductionData on the economic burden of RSV-associated illness will inform decisions on the pr... more IntroductionData on the economic burden of RSV-associated illness will inform decisions on the programmatic implementation of maternal vaccines and monoclonal antibodies. We estimated these costs in fine age bands to allow more accurate cost-effectiveness models to account for limited duration of protection conferred by short or long acting interventions.MethodsWe conducted a costing study at sentinel sites across South Africa to estimate out-of-pocket and indirect costs for RSV-associated mild and severe illness. We collected facility-specific costs for staffing, equipment, services, diagnostic tests and treatment. Using case-based data we calculated a patient day equivalent (PDE) for RSV-associated hospitalisations or clinic visits; the PDE was multiplied by the number of days of care to provide a case-cost to the healthcare system. We estimated the costs in 3-month age intervals in children aged <1 years and as a single group for children aged 1-4 years. We then applied our da...
BackgroundVaccines and monoclonal antibodies to protect the very young infant against respiratory... more BackgroundVaccines and monoclonal antibodies to protect the very young infant against respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost effectiveness analyses.MethodsWe combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged <5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the <1-year age group, by 3-month intervals until 2 years and then 12 monthly intervals to <5 years for medically and non-medically attended illness.ResultsWe estimated a mean annual total (medically and non-medically attended) of 264,112 (95% Confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) ...
BackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cas... more BackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cases, an etiological agent is not identified. We describe the use of a multi-pathogen platform, TaqMan array card (TAC) real-time PCR, for the detection of pathogens in patients hospitalized with severe respiratory illness (SRI).MethodsWe conducted prospective hospital-based surveillance for SRI among patients at two sentinel sites in South Africa between January and December 2017. Patients were included in this study if a blood specimen and at least one respiratory specimen (naso- and oro-pharyngeal (NP/OP) swabs and/or sputum) were available for testing. We tested respiratory specimens for 21 respiratory pathogens and blood samples for nine bacteria using TAC. Pathogen detection was compared by age group and HIV status using the chi-squared test.ResultsDuring 2017, 956 patients were enrolled in SRI surveillance, and of these, 637 (67%) patients were included in this study (637 blood, 487...
Background: All people with HIV who screen negative for active tuberculosis (TB) should receive i... more Background: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach.Setting: Primary care clinics in Matlosana, South Africa.Design: This was a mixed-methods implementation study.Methods: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers.Results: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qua...
Southern African Journal of Infectious Diseases, 2019
Setting: Klerksdorp-Tshepong Hospital Complex MDR-TB Unit, North-West Province, South Africa.Back... more Setting: Klerksdorp-Tshepong Hospital Complex MDR-TB Unit, North-West Province, South Africa.Background: To determine the time to sputum culture conversion (TTSCC) and factors predictive of TTSCC in patients with multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in the North-West Province.Methods: A retrospective cohort study, abstracting patient demographic and clinical data, laboratory results, dates of sputum testing and sputum culture conversion results, from medical records of 526 MDR-TB and 47 XDR-TB patients started on TB treatment between 01 January 2012 and 31 December 2014. Predictors of TTSCC were determined by Cox proportional hazards regression.Results: The median age was 38 years (interquartile range 31–47) with 64% being male. Overall, 79% (449) were Human Immunodeficiency Virus (HIV)-infected. The median TTSCC was 56.5 days and 162.5 days for MDR-TB and XDR-TB patients, respectively. In the multivariate analysis, age [haz...
Background: Tuberculosis (TB) is a leading infectious cause of death globally. Current treatment ... more Background: Tuberculosis (TB) is a leading infectious cause of death globally. Current treatment for drug-susceptible (DS-TB) and rifampicin-resistant (RR-TB) infections is lengthy and toxic. Methods: The STAND trial was a partially-randomised, open-label, non-inferiority phase 3 study. Patients ≥18 years with smear positive sputum were eligible. HIV-positive patients with CD4+ counts <100 cells/mm3 were excluded. DS-TB participants were randomised 1:1:1:1 to receive: 200mg pretomanid (P) daily, 400mg moxifloxacin (M) and 1500mg pyrazinamide (Z) for either 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) in combination for 6 months as control. The primary outcome was treatment failure or relapse 12 months after randomisation. The non-inferiority margin for between-group differences was 12 percent. RR-TB participants were allocated to 6Pa200MZ. Recruitment was paused in September 2015 and did not resume. Findings: In total 43 of 56 (76.8%), 46 of 61 (75.4%), 38 of 57 (66.7%), and 52 of 60 (86.7%) DS-TB participants were favourable on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ, and control respectively. The difference in favourable response between control and 6Pa200MZ was 9.9% [95%CI -4.1 to 23.9%]. Ten of 11 (90.9%) RR-TB participants were favourable. Grade 3 or higher adverse events affected 22 of 67 (32.8%) 6Pa200MZ participants, 21 of 71 (29.6%) on 4Pa200MZ, 25 of 65 (38.5%) on 4Pa100MZ, and 19 of 68 (27.9%) on control. Serious adverse events affected 19 of 203 (9.4%) experimental DS-TB participants, 3 of 68 (4.4%) on control, and 3 of 13 (23.1%) RR-TB cases. Ten of 203 (5%) participants on the experimental arms and 2 of 68 (3%) participants on the control arm died, with 2 deaths on the 4MPa200Z arm and one death on the 4MPa100Z arm attributed to hepatotoxicity. Interpretation: The experimental DS-TB treatment did not achieve non-inferiority in this underpowered trial. The role of Pa200MZ in tuberculosis treatment needs to be investigated further. Trial Registration: (Clinicaltrials.gov identifier NCT02342886) Funding Statement: Sponsored by TB Alliance with financial support from the U.K. Department for International Development, Bill and Melinda Gates Foundation, U.S. Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Federal Ministry for Education and Research of Germany. Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the national and local ethics committees for the sites participating in the trial.
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Papers by Ebrahim Variava