ISONIAZID PREVENTIVE THERAPY FOR TUBERCULOSIS IN HIV-1-INFECTED ADULTS - RESULTS OF A RANDOMIZED CONTROLLED TRIAL

Objectives: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV-1-infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV-1-infected adults. Design and setting: Randomized, double-blin d, placebo-controlled trial in Nairobi, Kenya. Subjects: Six hundred a nd eighty-four HIV-1-infected adults. Main outcome measures: Developme nt of tuberculosis and death. Results: Three hundred and forty-two sub jects received isoniazid and 342 received placebo. The median CD4 lymp hocyte counts at enrolment were 322 and 346 x 10(6)/l in the isoniazid and placebo groups, respectively. The overall median follow-up from e nrolment was 1.83 years (range, 0-3.4 years). The incidence of tubercu losis in the isoniazid group was 4.29 per 100 person-years (PY) of obs ervation [95% confidence interval (CI) 2.78-6.33] and 3.86 per 100 PY of observation (95% CI, 2.45-5.79) in the placebo group, giving an adj usted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49-1. 71). The adjusted rate ratio for tuberculosis for isoniazid versus pla cebo for tuberculin skin test (TST)-positive subjects was 0.60 (95% CI , 0.23-1.60) and for the TST-negative subjects, 1.23 (95% CI, 0.55-2.7 6). The overall adjusted mortality rate ratio for isoniazid versus pla cebo was 1.18 (95% Cl, 0.79-1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST-positive of 0.3 3 (95% CI, 0.09-1.23) and for TST-negative subjects, 1.39 (95% CI, 0.9 0-2.12). Conclusions: Overall there was no statistically significant p rotective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST-positive subjects, where reactivation is like ly to be the more important pathogenetic mechanism, there was some pro tection and some reduction in mortality, although this was not statist ically significant. The small number of individuals in this subgroup m ade the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rap id progression to disease or insufficient duration of isoniazid in sub jects with relatively advanced immunosuppression. The rate of drug res istance observed in subjects who received isoniazid and subsequently d eveloped tuberculosis was low.