Browsing by Author "Kumarasamy N"

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Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial.
(2016-Mar-19) Hosseinipour MC; Bisson GP; Miyahara S; Sun X; Moses A; Riviere C; Kirui FK; Badal-Faesen S; Lagat D; Nyirenda M; Naidoo K; Hakim J; Mugyenyi P; Henostroza G; Leger PD; Lama JR; Mohapi L; Alave J; Mave V; Veloso VG; Pillay S; Kumarasamy N; Bao J; Hogg E; Jones L; Zolopa A; Kumwenda J; Gupta A
BACKGROUND: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. METHODS: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080. FINDINGS: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. INTERPRETATION: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. FUNDING: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.
Establishing shared definitions of virological failure and discontinuation for long-acting injectable cabotegravir and rilpivirine therapy (the CONSENSUS-LAI Study): an international survey and Delphi process.
(2025-Sep) Orkin C; Paterson A; Elias A; Smuk M; Ring K; Volny-Anne A; Calmy A; Hazra A; Geretti AM; Radix A; Titanji BK; Spire B; Del Rio C; Foster C; Moore CB; Cortes CP; Mussini C; Kuritzkes DR; Tan DHS; Martinez E; Wit FWNM; Cresswell F; Venter WDF; Levy I; Zucker J; Molina JM; Hoy J; Arribas J; Llibre JM; Currier J; Rockstroh J; Sutinen J; Gebo K; Waters L; Gisslen M; O'Reilly M; Boffito M; Thompson M; Parczewski M; John M; Gandhi M; Kumarasamy N; Paton N; Mackie N; Cahn P; Elion R; Noe S; Walmsley S; Collins S; Cole-Haley S; Apea V; Short WR; Gilleece Y; Paparini S
BACKGROUND: Definitions of virological failure and treatment discontinuation for long-acting injectable (LAI) cabotegravir and rilpivirine antiretroviral therapy are inconsistent in clinical practice and observational studies, which complicates interpretation and implementation of findings. The CONSENSUS-LAI study aimed to establish consistent definitions of virological failure and treatment discontinuation to enhance evidence transferability and support optimal clinical outcomes. METHODS: The study had two phases. Phase 1 was an international online survey exploring existing definitions of virological and treatment discontinuation, conducted between April 25 and July 1, 2024. Eligible participants were health-care professionals working in infectious disease or sexual health services who had provided care to at least ten people living with HIV in the past 6 months, had prescribed LAI cabotegravir and rilpivirine in clinical trials or clinical practice, and were able to give informed consent. Participants were recruited via social media and mailing lists of medical specialist societies. Phase 2 was a Delphi process, in which a panel of experts, selected to ensure representation from all six WHO regions, scored leading definitions from phase 1 on a 9-point Likert scale. The proposed definitions were scored according to four validity criteria: clarity, usability in the expert's setting, appropriateness across clinical purposes, and applicability across relevant population groups. Revisions were suggested in iterative rounds until consensus was reached. Consensus was predefined as at least 75% of experts agreeing or strongly agreeing (scores 7-9) with the validity criteria. FINDINGS: 386 LAI cabotegravir and rilpivirine prescribers across 28 countries completed the survey, revealing 15 definitions for virological failure on LAI cabotegravir and rilpivirine and nine for treatment discontinuation. 52 experts participated in the Delphi process. Consensus agreement on both definitions was reached after two rounds for all validity criteria. For virological failure, the consensus definition was as follows: (a) viral load 200 copies or more per mL or more on two occasions 2-4 weeks apart, or (b) a single viral load of more than 1000 copies per mL, and/or (c) emergent resistance, in the context of timely injections and prior suppression of less than 200 copies per mL, OR (d) unable to suppress viral load to less than 200 copies per mL on continuous therapy. For treatment discontinuation the consensus definition was as follows: people on LAI cabotegravir and rilpivirine who have missed two consecutive injections and have not taken oral bridging in the interim, irrespective of reason for discontinuation. INTERPRETATION: The consensus definitions provide a foundation for aligning practice and evaluating patient outcomes. Further validation of the viral load threshold for virological failure and the optimal viral load retesting window is required. FUNDING: ViiV Healthcare.
Global Trends in CD4 Count Measurement and Distribution at First Antiretroviral Treatment Initiation.
(2025-Jul-18) de Waal R; Wools-Kaloustian K; Brazier E; Althoff KN; Jaquet A; Duda SN; Kumarasamy N; Savory T; Byakwaga H; Murenzi G; Justice A; Ekouevi DK; Cesar C; Pasayan MKU; Thawani A; Kasozi C; Babakazo P; Karris M; Messou E; Cortes CP; Kunzekwenyika C; Choi JY; Owarwo NC; Niyongabo A; Marconi VC; Ezechi O; Castilho JL; Petoumenos K; Johnson LF; Ford N; Kassanjee R
BACKGROUND: While people with human immunodeficiency virus (PWH) start antiretroviral treatment (ART) regardless of CD4 count, CD4 measurement remains crucial for detecting advanced human immunodeficiency virus (HIV) disease and evaluating ART programs. We explored CD4 measurement (proportion of PWH with a CD4 result available) and prevalence of CD4 <200 cells/µL (hereafter "CD4 <200") at ART initiation within the International epidemiology Databases to Evaluate AIDS (IeDEA) global collaboration. METHODS: We included PWH at participating ART programs who first initiated ART at age 15-80 years during 2005-2019. We described proportions of PWH with a CD4 result (measured within 6 months before to 2 weeks after ART initiation) and, among those with a CD4 result, with CD4 <200, by year of ART initiation and region. RESULTS: We included 1 355 104 PWH from 42 countries in 7 regions; 63% were female. The median (interquartile range) age at ART initiation was 37 (3144) years in males and 32 (26-39) years in females. CD4 measurement initially increased, or remained stable over time until around 2013, but then declined to low levels in some regions (Southern Africa, except South Africa: from 54% to 13%; East Africa: 85% to 31%; Central Africa: 72% to 20%; West Africa: 91% to 53%; and Latin America: 87% to 56%). Prevalence of CD4 <200 declined over time in all regions, but plateaued after 2015 at ≥30%. CONCLUSIONS: CD4 measurement has declined sharply in recent years, especially in sub-Saharan Africa. Among those with a CD4 measurement, the prevalence of CD4 <200 remains concerningly high. Scaling up CD4 testing and securing adequate funding are urgent priorities.
The long-term impact of the COVID-19 pandemic on tuberculosis care and infection control measures in anti-retroviral therapy (ART) clinics in low- and middle-income countries: a multiregional site survey in Asia and Africa.
(2025-Mar-24) Ballif M; Banholzer N; Perrig L; Avihingsanon A; Nsonde DM; Obatsa S; Muula G; Komena E; Uemura H; Lelo P; Otaalo B; Huwa J; Gouéssé P; Kumarasamy N; Brazier E; Michael D; Rafael I; Ramdé R; Somia IKA; Yotebieng M; Diero L; Euvrard J; Ezechi O; Fenner L
BACKGROUND: The COVID-19 pandemic challenged healthcare systems, particularly in settings with high infectious disease burden. We examined the postpandemic long-term impacts of COVID-19 on tuberculosis (TB) services at anti-retroviral therapy (ART) clinics in lower-income countries. METHODS: Using standardised online questionnaires, we conducted a cross-sectional site survey among ART clinics providing TB services in Africa and Asia from July to September 2023 (site-level information and number of TB diagnoses and tests). RESULTS: Of 45 participating ART clinics, 32 (71%) were in Africa and 13 (29%) in Asia. During the COVID-19 pandemic (2020-2022), 43 (96%) clinics reported implementing social distancing or separation measures, 39 (87%) personal protections for staff members and 32 (71%) protections for patients. Infection control measures were in place in 45% of the clinics before the pandemic (until 2019), 23% introduced measures during the pandemic and 15% maintained them after the pandemic (after 2022). Service provision was affected during the pandemic in 33 (73%) clinics, including TB services in 22 (49%) clinics. TB service restrictions were addressed by introducing changes in directly observed therapy provision in 8 (18%) clinics, multimonth TB drug dispensing in 23 (51%), telehealth services in 25 (56%) and differentiated service delivery in 19 (42%). These changes were sustained after the pandemic at 4 (9%), 11 (24%), 17 (38%) and 12 (27%) clinics, respectively. Compared with 2018-2019, the number of TB diagnoses decreased sharply in 2020-2021 and improved after the pandemic. CONCLUSIONS: COVID-19 affected TB care services in ART clinics in Africa and Asia. This was paralleled by a reduction in TB diagnoses, which partly resumed after the pandemic. Infection control measures and alternative modes of service delivery were adopted during the pandemic and only partially maintained. Efforts should be made to sustain the lessons learnt during the COVID-19 pandemic, particularly approaches that reduce the risk of transmission of infectious diseases, including TB, in ART clinics.