Tuberculosis incidence after 36 months' isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis.

OBJECTIVE

Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit.

DESIGN

A 36-month double-blind placebo controlled trial (1 : 1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011.

METHODS

One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months.

RESULTS

In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period.

CONCLUSION

The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings.