Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial.
BACKGROUND
Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.


METHODS
For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086.


RESULTS
1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6-3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8-4·7; hazard ratio [HR] 0·63, 95% CI 0·41-0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90-4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21-0·86] and 0·43 [0·20-0·96]; for positive tests 0·86 [0·37-2·00] and 0·55 [0·26-1·24], respectively).


CONCLUSIONS
Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status.


BACKGROUND
Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).
Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; Clinical Infectious Disease Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa; London School of Hygiene & Tropical Medicine, London, UK. Electronic address: mxrangaka@yahoo.co.uk.
Molebogeng X
MX
Rangaka
Clinical Infectious Disease Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, Imperial College London, London, UK; MRC National Institute for Medical Research, London, UK.
Robert J
RJ
Wilkinson
Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
Andrew
A
Boulle
London School of Hygiene & Tropical Medicine, London, UK.
Judith R
JR
Glynn
London School of Hygiene & Tropical Medicine, London, UK.
Katherine
K
Fielding
Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa; Médecins Sans Frontières, Cape Town, South Africa.
Gilles
G
van Cutsem
Clinical Infectious Disease Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Katalin A
KA
Wilkinson
Clinical Infectious Disease Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Rene
R
Goliath
Provincial Government of the Western Cape, Cape Town, South Africa.
Shaheed
S
Mathee
Médecins Sans Frontières, Cape Town, South Africa.
Eric
E
Goemaere
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Gary
G
Maartens
D017088:AIDS-Related Opportunistic Infections / Q000453:epidemiology / Q000517:prevention & control*; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007538:Isoniazid / Q000627:therapeutic use*; D008297:Male; D010919:Placebos; D013019:South Africa / Q000453:epidemiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000453:epidemiology / Q000517:prevention & control*
D044966:Anti-Retroviral Agents; D000995:Antitubercular Agents; D010919:Placebos; D007538:Isoniazid