title: 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US Centers for Disease Control and Prevention and US Agency for International Development.
authors.affiliation: Botswana-USA Partnership (BOTUSA), Gaborone and Francistown, Botswana. tts0@cdc.gov
authors.forename: Taraz
authors.initials: T
authors.lastname: Samandari
authors.forename: Tefera B
authors.initials: TB
authors.lastname: Agizew
authors.forename: Samba
authors.initials: S
authors.lastname: Nyirenda
authors.forename: Zegabriel
authors.initials: Z
authors.lastname: Tedla
authors.forename: Thabisa
authors.initials: T
authors.lastname: Sibanda
authors.forename: Nong
authors.initials: N
authors.lastname: Shang
authors.forename: Barudi
authors.initials: B
authors.lastname: Mosimaneotsile
authors.forename: Oaitse I
authors.initials: OI
authors.lastname: Motsamai
authors.forename: Lorna
authors.initials: L
authors.lastname: Bozeman
authors.forename: Margarett K
authors.initials: MK
authors.lastname: Davis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Talbot
authors.forename: Themba L
authors.initials: TL
authors.lastname: Moeti
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Moffat
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kilmarx
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Castro
authors.forename: Charles D
authors.initials: CD
authors.lastname: Wells
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001902:Botswana; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D012882:Skin Tests; D013997:Time Factors; D016896:Treatment Outcome; D014376:Tuberculosis / Q000150:complications / Q000175:diagnosis / Q000517:prevention & control*
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid