TY - JOUR
T1 - Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis
T2 - a systematic review and meta-analysis of individual participant data
AU - Ross, Jennifer M.
AU - Badje, Anani
AU - Rangaka, Molebogeng X.
AU - Walker, A. Sarah
AU - Shapiro, Adrienne E.
AU - Thomas, Katherine K.
AU - Anglaret, Xavier
AU - Eholie, Serge
AU - Gabillard, Delphine
AU - Boulle, Andrew
AU - Maartens, Gary
AU - Wilkinson, Robert J.
AU - Ford, Nathan
AU - Golub, Jonathan E.
AU - Williams, Brian G.
AU - Barnabas, Ruanne V.
N1 - Funding Information:
ASW reports grants from the UK Medical Research Council and the Department for International Development UK; trial drugs donated from Gilead Sciences, Cipla Pharmaceuticals, Merck, and ViiV Healthcare for the REALITY trial; and personal fees from Janssen, outside the submitted work. RJW reports grants from the Wellcome Trust, the European and Developing Countries Clinical Trials Partnership, the National Institutes of Health, Cancer Research UK, UK Research and Innovation, and the Foundation for the National Institutes of Health, during the conduct of the study. All other authors declare no competing interests.
Funding Information:
We thank Diana Louden for assistance with the literature search. We thank Cole Grabow and Joshua Stern for assistance with data management. JMR receives support from the National Institute of Allergy and Infectious Diseases (K01 AI138620). Research reported in this publication was supported by the University of Washington and Fred Hutch Center for AIDS Research, a National Institutes of health (NIH)-funded programme (award number AI027757). ASW is supported by core support from the UK Medical Research Council (MRC) to the MRC Clinical Trials Unit (MC_UU_12023/22) through a concordat with the Department for International Development; and is a National Institutes of Health Research (NIHR) senior investigator. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the UK Department of Health. The Wellcome Centre for Infectious Diseases Research in Africa is supported by core funding from the Wellcome Trust (203135/Z/16/Z). RJW is supported by Francis Crick Institute, which is funded by UK Research and Innovation (FC0010218), Cancer Research UK (FC0010218) and Wellcome (FC0010218); and also receives support from Wellcome (104803, 203135), NIH (U19 AI111276), and South African MRC-Strategic Health Innovation Partnerships.
Funding Information:
We thank Diana Louden for assistance with the literature search. We thank Cole Grabow and Joshua Stern for assistance with data management. JMR receives support from the National Institute of Allergy and Infectious Diseases (K01 AI138620). Research reported in this publication was supported by the University of Washington and Fred Hutch Center for AIDS Research, a National Institutes of health (NIH)-funded programme (award number AI027757). ASW is supported by core support from the UK Medical Research Council (MRC) to the MRC Clinical Trials Unit (MC_UU_12023/22) through a concordat with the Department for International Development; and is a National Institutes of Health Research (NIHR) senior investigator. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the UK Department of Health. The Wellcome Centre for Infectious Diseases Research in Africa is supported by core funding from the Wellcome Trust (203135/Z/16/Z). RJW is supported by Francis Crick Institute, which is funded by UK Research and Innovation (FC0010218), Cancer Research UK (FC0010218) and Wellcome (FC0010218); and also receives support from Wellcome (104803, 203135), NIH (U19 AI111276), and South African MRC-Strategic Health Innovation Partnerships.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S2352-3018(20)30299-X
DO - 10.1016/S2352-3018(20)30299-X
M3 - Article
C2 - 33387480
AN - SCOPUS:85098490267
VL - 8
SP - e8-e15
JO - The Lancet HIV
JF - The Lancet HIV
SN - 2352-3018
IS - 1
ER -