6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial

Summary

Background

In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy.

Methods

In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per μL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281.

Findings

Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33–0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09–0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38–1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26–0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups.

Interpretation

In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive.

Funding

US Centers for Disease Control and Prevention and US Agency for International Development.

Introduction

Tuberculosis is one of the most common causes of morbidity and mortality in people with HIV infection worldwide.¹ Isoniazid preventive therapy significantly reduces tuberculosis in these patients who have a positive tuberculin skin test but not in those with a negative test.² In 1999, WHO recommended a 6-month course of isoniazid for people with HIV infection and a positive skin test, and extended this recommendation to patients living in areas where tuberculin skin testing was not feasible if the prevalence of latent tuberculosis infection was more than 30%.³ In response to rapidly increasing rates of tuberculosis in people with HIV infection, the government of Botswana initiated a national isoniazid preventive treatment programme that, consistent with these WHO recommendations, did not require tuberculin skin testing.⁴

Antiretroviral therapy profoundly reduces incidence of tuberculosis in people with HIV infection and with continued use risk of tuberculosis progressively declines.⁵ Two retrospective analyses6, 7 concluded that the benefit of combining isoniazid and antiretroviral therapy was additive. Shortly after beginning the national rollout of isoniazid preventive treatment, Botswana's Government began a nationwide programme to provide free antiretroviral therapy.⁸

Although a 6-month course of isoniazid prevented tuberculosis in people with HIV infection in two trials in sub-Saharan Africa,9, 10 this benefit was lost within 6–18 months of completion of prophylaxis in these cohorts.11, 12 Whether the short-lived response was due to reinfection with Mycobacterium tuberculosis or to inadequate treatment of latent infection is unclear. Other studies in Africa reported that 69–77% of tuberculosis recurrences were caused by reinfection with new strains13, 14 and that 42–79% of cases were clustered.15, 16, 17, 18 Such reports emphasised the need to establish whether continuous treatment beyond 6 months is beneficial for people with HIV infection in tuberculosis-endemic countries. We aimed to assess such extended treatment in a large population of people with HIV infection in Botswana using the proxy of 36 months' isoniazid compared with 6 months of isoniazid plus 30 months' placebo. We also aimed to estimate the effect of antiretroviral therapy and tuberculin skin test status on tuberculosis prevention, and frequency of adverse effects and isoniazid resistance.