Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
Condition: HIV Infections; Acquired Immunodeficiency Syndrome; Tuberculosis
MeSH terms: Infections; HIV Infections; Acquired Immunodeficiency Syndrome; Tuberculosis; Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 3

Summary: 
      Tuberculosis (TB) is the most common opportunistic infection among HIV infected persons
      living in developing countries. Directly observed treatment, short-course (DOTS) is the
      internationally recommended strategy for the treatment of TB. However, the efficacy of DOTS
      for the treatment of HIV-associated TB is not well studied. This study aims to compare the
      efficacy of thrice weekly DOTS in HIV-infected versus HIV-negative patients with TB.
    

Detailed description: 
      Several reports have suggested that the initial response to antituberculosis chemotherapy is
      comparable among HIV-positive and negative populations. These series generally demonstrate
      that among "surviving" Patients, the bacteriological, clinical, and radiographic responses
      are similar between the two groups. However, there are consistent indications of higher rates
      of early (first month) deaths from tuberculosis as well as excessive deaths from other causes
      during the course of treatment in the above noted series. These deaths appear related to the
      advanced stage of tuberculosis at diagnosis as well as the debilitating and underlying
      diseased from which the patients suffer and not primarily the drug regimens with which they
      are treated. However, several of the reports from Africa suggested increased early mortality
      in those who received the less-potent traditional isoniazid, thiacetazone, and streptomycin
      regimens than the modern short-course regimens featuring isoniazid, rifampin, and
      pyrazinamide. Excess mortality was seen also among a subset of patients with AIDS and
      tuberculosis in Uganda receiving a thiacetazone regimen in comparison to those receiving a
      rifampin regimen: there was both excess mortality and higher rates of drug reactions
      sequestered among those patients who had elevated levels of neopterin and other markers of
      cellular immune activation.

      Furthermore, several series have shown a modestly greater risk for relapse or recurrence post
      treatment for persons with AIDS that seems related to the duration of therapy. Perriens and
      colleagues in a study from Zaire compared the outcome of HIV-positive patients treated with
      6-month regimen (2-HRZE daily followed by 10-HR twice weekly) and a 12-month regimen (2-HRZE
      daily followed by 10-HR twice weekly). Relapse rates were significantly higher among those
      receiving the 6-months regimen (9%) than 12 months of treatment (1.9%) (p < 0.01). Pulido and
      colleagues in Spain observed in a non-randomize series that, among patients with AIDS and
      tuberculosis, 10 of 40 (24%) patients who received less than 9-months or more did so.
      Multivariate analysis identified duration of therapy as a major element in the disparate
      relapse rates, with a relative hazard of 9.2 for the shorter-duration therapy. Most recently,
      a multicenter national trial in the United States compared 6-month and 9-month of treatment
      for HIV-infected adults with pansusceptible tuberculosis. Relapse rates were 3.9%, two
      patients, for the 6-month regimen, and 2%, one patient, for the 9-month regimen; because of
      the limited number, there was no statistically significant difference.

      Several other studies contrasted relapse or cure rates among HIV infected and uninfected
      persons treated simultaneously with identical 6-month regimens. They universally showed
      somewhat worse outcomes among those with HIV infection.

      Hawkens and colleagues described and increased risk of recurrent tuberculosis in a group of
      patients from Kenya. This report documented that 10 of 58 (17%) HIV Positive patients
      available for follow-up had recurrence, contrasted with 1 of 138 HIV negative patients,
      34-fold apparent relative risk. However, 7 of the 10 who experienced recurrence had major
      cutaneous drug reactions, interrupting therapy and confounding the issue. But, Elliott in
      Zambia noted a marked disparity in relapse rates without the confusing association between
      relapses and drug reactions: HIV-positive patients relapsed at a rate 22-100 patient years of
      observation versus 6/100 patient years among HIV-negatives. A recent Johns Hopkins study in
      Haiti found lower cure rates (69% vs. 79%) and slightly higher relapse rates (5.4% vs. 2.8%,
      p = 0.36) among HIV-infected individuals receiving a 6-month regimen.
    

Intervention name(s): INH, Rifampicin, Ethambutol and Pyrazinamide; INH, Rifampicin, Ethambutol and Pyrazinamide
Intervention type(s): Drug; Drug
Intervention description(s): Directly Observed Treatment Short-course; Thrice weekly (INH 600 mg, Rifampicin 450 mg [600 mg if more than 59 kg], Ethambutol 1200 mg, Pyrazinamide 1500 mg); Directly Observed Treatment Short-course; Thrice weekly (INH 600 mg, Rifampicin 450 mg [600 mg if more than 59 kg], Ethambutol 1200 mg, Pyrazinamide 1500 mg)
Other intervention name(s): Category I DOTS; Category I DOTS
Intervention MeSH terms: Rifampin; Pyrazinamide; Ethambutol
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV infection; Acquired immunodeficiency syndrome; Tuberculosis