BMJ 1998;317:625-629 ( 5 September )

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Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials

David Wilkinson, specialist scientist, ^a S B Squire, senior lecturer, ^b Paul Garner, senior lecturer. ^c

^a Centre for Epidemiological Research in Southern Africa, Medical Research Council, PO Box 187, Mtubatuba 3935, South Africa, ^b Tropical Medicine Division, Liverpool School of Tropical Medicine, Liverpool L3 5QA, ^c International Health Division, Liverpool School of Tropical Medicine

Correspondence to: Dr Wilkinson wilkinsd{at}mrc.ac.za

Objective: To determine whether preventive treatment for tuberculosis in adults infected with HIV reduces the frequency of tuberculosis and overall mortality.
Design: Systematic review and data synthesis of randomised placebo controlled trials.
Main outcome measures: Active tuberculosis, mortality, and adverse drug reaction requiring cessation of the study regimen. Outcomes stratified by status of purified protein derivative skin test.
Results: Four trials comprising 4055 adults from Haiti, Kenya, the United States, and Uganda were included. All compared isoniazid (6-12 months) with placebo, and one trial also compared multidrug treatment for 3 months with placebo. Mean follow up was 15-33 months. Overall, frequency of tuberculosis (relative risk 0.57, 95% confidence interval 0.41 to 0.79) was reduced in those receiving preventive treatment compared with placebo: mortality was not significantly reduced (0.93, 0.83 to 1.05). In subjects positive for purified protein derivative receiving preventive treatment, the risk of tuberculosis was reduced substantially (0.32, 0.19 to 0.51) and the risk of death was reduced moderately (0.73, 0.57 to 0.95) compared with those taking placebo. In adults negative for purified protein derivative receiving preventive treatment, the risk of tuberculosis (0.82, 0.50 to 1.36) and the risk of death (1.02, 0.89 to 1.17) were not reduced significantly. Adverse drug reactions were more frequent, but not significantly so, in patients receiving drug compared with placebo (1.45, 0.98 to 2.14).
Conclusions: Preventive treatment given for 3-12 months protects against tuberculosis in adults infected with HIV, at least in the short to medium term. Protection is greatest in subjects positive for purified protein derivative, in whom death is also less frequent. Long term benefits remain to be shown.

Key messages One third of the world's population is infected with Mycobacterium tuberculosis People infected with HIV are at much increased risk of developing active tuberculosis Short term preventive drug treatment given to people infected with HIV reduces the occurrence of active tuberculosis The benefit is greatest in people with latent infection, as shown by a positive skin test for tuberculosis, and this group also exhibits a survival benefit

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