Jennifer M Ross1, Anani Badje2, Molebogeng X Rangaka3, A Sarah Walker3, Adrienne E Shapiro4, Katherine K Thomas5, Xavier Anglaret2, Serge Eholie6, Delphine Gabillard2, Andrew Boulle7, Gary Maartens8, Robert J Wilkinson9, Nathan Ford10, Jonathan E Golub11, Brian G Williams12, Ruanne V Barnabas4. 1. Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA. Electronic address: jross3@uw.edu. 2. University of Bordeaux, Bordeaux, France. 3. MRC Clinical Trials Unit, University College London, London, UK. 4. Department of Global Health, University of Washington, Seattle, WA, USA; Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA. 5. Department of Global Health, University of Washington, Seattle, WA, USA. 6. University Félix Houphouet-Boigny, Abidjan, Côte d'Ivoire. 7. Wellcome Centre for Infectious Disease Research in Africa, University of Cape Town, Cape Town, South Africa; Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa; School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 8. Wellcome Centre for Infectious Disease Research in Africa, University of Cape Town, Cape Town, South Africa; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 9. Wellcome Centre for Infectious Disease Research in Africa, University of Cape Town, Cape Town, South Africa; The Francis Crick Institute, London, UK; Department of Infectious Diseases, Imperial College London, London, UK. 10. Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa. 11. School of Medicine, Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD, USA. 12. South African Centre for Epidemiological Modelling and Analysis, Stellenbosch, South Africa.
Abstract
BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.
BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.
Authors: Susan Swindells; Ritesh Ramchandani; Amita Gupta; Constance A Benson; Jorge Leon-Cruz; Noluthando Mwelase; Marc A Jean Juste; Javier R Lama; Javier Valencia; Ayotunde Omoz-Oarhe; Khuanchai Supparatpinyo; Gaerolwe Masheto; Lerato Mohapi; Rodrigo O da Silva Escada; Sajeeda Mawlana; Peter Banda; Patrice Severe; James Hakim; Cecilia Kanyama; Deborah Langat; Laura Moran; Janet Andersen; Courtney V Fletcher; Eric Nuermberger; Richard E Chaisson Journal: N Engl J Med Date: 2019-03-14 Impact factor: 91.245
Authors: Alessandro Liberati; Douglas G Altman; Jennifer Tetzlaff; Cynthia Mulrow; Peter C Gøtzsche; John P A Ioannidis; Mike Clarke; P J Devereaux; Jos Kleijnen; David Moher Journal: BMJ Date: 2009-07-21
Authors: Jonathan E Golub; Paul Pronyk; Lerato Mohapi; Nkeko Thsabangu; Mosa Moshabela; Helen Struthers; Glenda E Gray; James A McIntyre; Richard E Chaisson; Neil A Martinson Journal: AIDS Date: 2009-03-13 Impact factor: 4.177
Authors: Andrew Anglemyer; George W Rutherford; Philippa J Easterbrook; Tara Horvath; Marco Vitória; Michael Jan; Meg C Doherty Journal: AIDS Date: 2014-03 Impact factor: 4.177
Authors: Molebogeng X Rangaka; Robert J Wilkinson; Andrew Boulle; Judith R Glynn; Katherine Fielding; Gilles van Cutsem; Katalin A Wilkinson; Rene Goliath; Shaheed Mathee; Eric Goemaere; Gary Maartens Journal: Lancet Date: 2014-05-13 Impact factor: 79.321
Authors: Mercedes Yanes-Lane; Edgar Ortiz-Brizuela; Jonathon R Campbell; Andrea Benedetti; Gavin Churchyard; Olivia Oxlade; Dick Menzies Journal: PLoS Med Date: 2021-09-14 Impact factor: 11.613
Authors: Mulugeta Russom; Henok G Woldu; Araia Berhane; Daniel Y B Jeannetot; Bruno H Stricker; Katia Verhamme Journal: Infect Dis Ther Date: 2022-01-29
Authors: Elijah Kakande; Canice Christian; Laura B Balzer; Asiphas Owaraganise; Joshua R Nugent; William DiIeso; Derek Rast; Jane Kabami; Jason Johnson Peretz; Carol S Camlin; Starley B Shade; Elvin H Geng; Dalsone Kwarisiima; Moses R Kamya; Diane V Havlir; Gabriel Chamie Journal: Lancet HIV Date: 2022-07-28 Impact factor: 16.070
Authors: Neil A Martinson; Limakatso Lebina; Emily L Webb; Andrew Ratsela; Ebrahim Varavia; Anthony Kinghorn; Sanjay G Lala; Jonathan E Golub; Zama Bosch; Kegaugetswe P Motsomi; Peter MacPherson Journal: Clin Infect Dis Date: 2022-09-14 Impact factor: 20.999