Effect of Tuberculosis Preventive Therapy on HIV Disease Progression and Survival in HIV-Infected Adults

Abstract

Purpose: To determine whether tuberculosis (TB) preventive therapies alter the rate of disease progression to AIDS or death and to identify significant prognostic factors for HIV disease progression to AIDS. Method:In a randomized placebo-controlled trial in Kampala, Uganda, 2,736 purified protein derivative (PPD)-positive and anergic HIV-infected adults were randomly assigned to four and two regimens, respectively. PPD-positive patients were treated with isoniazid (INH) for 6 months (6H; n = 536), INH plus rifampicin for 3 months (3HR; n = 556), INH plus rifampicin plus pyrazinamide for 3 months (3HRZ; n = 462), or placebo for 6 months (n = 464). Anergic participants were treated with 6H (n = 395) or placebo (n = 323).Results: During follow-up, 404 cases progressed to AIDS and 577 deaths occurred. The cumulative incidence of the AIDS progression was greater in the anergic cohort compared to the PPD-positive cohort (p < .0001). Among PPD-positive patients, the relative risk of the AIDS progression with INH alone was 0.95 (95% CI 0.68-1.32); with 3HR it was 0.83 (95% CI 0.59-1.17); and with 3HRZ it was 0.76 (95% CI 0.52-1.08), controlling for significant baseline predictors. Among anergic patients, the relative risk of the AIDS progression was 0.81 (95% CI 0.56-1.15). Survival was greater in the PPD-positive cohort compared to the anergic cohort (p = . 0001). Conclusion:The number of signs or symptoms at baseline and anergic status are associated with increasing morbidity and mortality. Even though the tuberculosis preventive therapies were effective in reducing the incidence of TB for HIV-infected adults, their benefit of delaying HIV disease progression to AIDS was not observed. There is now the promise for greater access to antiretroviral medications. These medications must be properly used to maximize benefit and minimize untoward, adverse effects. Although recommendations have been developed and the availability of new antiretroviral drugs has expanded treatment choices, 7 this does not take into account the technology void in many developing countries. To make informed decisions about when to start treatment, what therapy to start with, and how to monitor the response to treatment, health care practitioners need more details about the natural history of HIV infection. Few studies have addressed disease progression in sub-Saharan Africa, where over 65% of the world's 39.4 million infected adults and children live. 7 In Uganda, the prevalence of HIV infection in adults is estimated at 8% in rural areas and up to 40% in some rural areas and trading centers. 8,9 The cumulative progression to AIDS at 1, 3, and 5 years after seroconversion is 2%, 6%, and 22%, respectively. The median survival time after the onset of AIDS is 9.3 months. 10 Although the recent declines in morbidity and mortality due to HIV/AIDS are attributable to the use of more intensive antiretroviral therapies, 3,4 the availability of antiretroviral drugs is limited in developing countries. Even as the antiretroviral therapy rolls out i...

Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals

“…[37][38][39][40] We excluded an additional study on the basis that it examined outcomes of isoniazid prophylaxis on HIV-positive children. 47 We excluded an RCT of IHZ with placebo control because it did not disaggregate outcomes of TB incidence by treatment group, 48 and another because it evaluated only PPD+ patients. 49 We excluded a study because it focused on the impact of IHZ on recurrent incidence of TB.…”

Treatment of Latent Tuberculosis Infection

“…There is a substantial literature now indicating that little if any reduction in TB incidence is obtained by treating persons with negative TST and no history of TB contact. [136][137][138][139][140][141] The review by Akolo et al reported that individuals with a positive TST had a significant 62% reduction in incident TB, whereas those with a negative TST did not have a significant benefit (RR 0.89, 95% CI 0.64 to 1.24). 135 This is consistent with a review of 11 studies (both HIV negative and HIV positive) by Watkins et al, who reported a positive association between TST reactivity and incidence of TB.…”

“…146 A recent trial of IPT given for 12 months to persons with HIV who were on or beginning ART in Cape Town, South Africa, reported a 37% reduction in hazard of TB; most of the reduction appeared to occur during the active INH treatment period and diminished during later follow-up, and there was no significant mortality benefit. 147 Further, TB preventive therapy does not appear to prevent death among persons with HIV who are TST-negative, [137][138][139]141,142 in contrast to earlier speculation that many such persons might be TB-infected but anergic due to advanced HIV disease.…”

Epidemiology and Challenges to the Elimination of Global Tuberculosis

“…It is a cost-effective strategy that could be utilized in resource-limited settings where latent TB is likely to be INH-susceptible. INH prophylaxis further enhances the probability of reducing TB when taking antiretroviral therapy [72,73]. If included with comprehensive contact investigations in low-income and middle-income countries, the latent TB reservoir that underlies the continued epidemic could be effectively addressed [74].…”