Articles
Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial

https://doi.org/10.1016/S1473-3099(13)70187-7Get rights and content

Summary

Background

Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil.

Methods

We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov, number NCT00107887.

Results

Of 17 413 patients in the cohort, 12 816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1·31 per 100 person-years) compared with 254 (1·10 per 100 person-years) in the intervention period (unadjusted hazard ratio [HR] 0·87; 95% CI 0·69–1·10). Rates of tuberculosis incidence or death were 3·64 and 3·04 per 100 person-years, respectively (0·76; 95% CI 0·66–0·87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0·73 (95% CI 0·54–0·99) and for tuberculosis or death was 0·69 (0·57–0·83).

Interpretation

Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere.

Funding

Bill & Melinda Gates Foundation and the National Institutes of Health.

Introduction

Isoniazid preventive therapy has long been recognised as an effective intervention for reducing the risk of tuberculosis at the individual and population level.1 Studies in people with HIV infection show that preventive therapy reduces tuberculosis rates, particularly in those with positive tuberculin skin tests.2 Evidence from observational studies in Brazil and South Africa have shown substantial reductions in tuberculosis risk in patients with HIV who received both isoniazid and antiretroviral therapy.3, 4 Although use of isoniazid preventive therapy has been recommended by WHO since 1998,5 uptake of this intervention in countries with high burdens of HIV and tuberculosis has been extremely poor.6 Brazil has a moderate tuberculosis rate (38 per 100 000 in 2011),6 and in Rio de Janeiro, a city where 10% of cases are co-infected with HIV, the prevalence was 95·3 per 100 000 in 2009. Tuberculosis continues to be a leading cause of illness and death in people with HIV infection.7 We sought to determine the effect of an intervention to increase use of isoniazid preventive therapy, and to assess the subsequent effect on rates of tuberculosis and death in HIV-infected individuals in Brazil, where antiretroviral therapy has been freely available through the public sector since 1996.

Section snippets

Study design and participants

The design of the Tuberculosis/HIV in Rio de Janeiro (THRio) study has been previously described.8 It was a stepped-wedge, cluster randomised trial in which 29 of the 51 clinics providing antiretroviral therapy in Rio de Janeiro (representing 57% of all HIV-infected patients in the region) were randomly assigned to the date when a training intervention would be introduced. Clinics ranged in size from 121 to 1749 patients, and were chosen because they were under the administrative control of the

Results

The initial THRio cohort consisted of 17 413 patients with HIV, 11 629 who had visited study clinics before the trial started and 5784 who entered clinical care between Sept 1, 2005, and Aug 31, 2009 (figure). 4597 (26%) patients were excluded from the analysis for the following reasons: diagnosis of tuberculosis before the study start date plus 60 days (n=3566), had isoniazid preventive therapy before the study plus 60 days (n=920), or died within 60 days of study start (n=111). After these

Discussion

The THRio intervention of training clinicians to screen for tuberculosis, to do tuberculin skin testing, and to offer isoniazid preventive therapy had a modest effect on tuberculosis incidence (13% reduction) and a larger and statistically significant effect on tuberculosis or death (24% reduction). After adjustment for important covariates such as age, sex, CD4 count, and receipt of antiretroviral therapy, during the intervention there was a 27% reduction in tuberculosis and a 31% reduction in

References (29)

  • T Samandari et al.

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

    Lancet

    (2011)
  • GW Comstock et al.

    Isoniazid prophylaxis among Alaskan Eskimos: a final report of the bethel isoniazid studies

    Am Rev Respir Dis

    (1979)
  • C Akolo et al.

    Treatment of latent tuberculosis infection in HIV infected persons

    Cochrane Database Syst Rev

    (2010)
  • JE Golub et al.

    The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil

    AIDS

    (2007)
  • JE Golub et al.

    Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort

    AIDS

    (2009)
  • Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings. WHO guidelines 2011. Department of HIV/AIDS. Stop TB Department

    (2011)
  • Global tuberculosis report 2012

    (2012)
  • Secretaria de Vigilância em Saúde

  • LH Moulton et al.

    Statistical design of THRio: a phased implementation clinic-randomized study of a tuberculosis preventive therapy intervention

    Clin Trials

    (2007)
  • MB Conde et al.

    III Brazilian Thoracic Association Guidelines on tuberculosis

    J Bras Pneumol

    (2009)
  • GM Raab et al.

    Balance in cluster randomized trials

    Stat Med

    (2001)
  • LH Moulton

    Covariate-based constrained randomization of group-randomized trials

    Clin Trials

    (2004)
  • RJ Hayes et al.

    Cluster randomized trials

    (2009)
  • Brasil. Ministério da Saúde. Sistema de informação de agravos de notificação

  • Cited by (0)

    View full text