Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy.

 Abdool Karim S, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A, Gengiah T, Nair G, Bamber S, Singh A, Khan M, Pienaar J, El-Sadr W, Friedland G, Abdool Karim Q. N Engl J Med 2010;362:697-706.

The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. In an open-label, randomized, controlled trial in Durban, South Africa, Karim et al assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimetre were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim–sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P = 0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services.

For abstract access click here: 1 [2]

Editors’ note: Despite WHO guidelines encouraging concomitant treatment of TB and HIV, antiretroviral treatment is often deferred because of worries about possible drug interactions between some antiretroviral drugs and the TB drug rifampin, immune reconstitution inflammatory syndrome (IRIS), adherence concerns because of a high pill burden, and programme challenges of coordinating HIV and TB care. The result is that people with active TB infection who are eligible for antiretroviral treatment may die before they get HIV treatment. The SAPIT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial was stopped early by its DSMB (Data Safety Monitoring Board) which recommended that all patients in the sequential-therapy group be started on HIV treatment immediately because of their significantly higher risk of mortality. The results of the other two groups, i.e. those who had started HIV treatment 4 weeks after the start of TB treatment and those who started after 2 months of TB treatment, were combined in this analysis. Whether there are differences between outcomes in these two integrated therapy groups will not be known until the trial ends. In the meantime, the reduced all-cause mortality, improved TB outcomes, and reduced incidence of IRIS found in SAPIT were considered in the development of the new WHO guidelines which recommend that all people with HIV infection who develop active TB should be placed on antiretroviral treatment as soon as possible after their TB treatment has begun. For more information, see [3].

Treatment of latent tuberculosis infection in HIV infected persons.  

Akolo C, Adetifa I, Shepperd S, Volmink J. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000171.

Individuals with human immunodeficiency virus (HIV) infection are at an increased risk of developing active tuberculosis (TB). It is known that treatment of latent TB infection (LTBI), also referred to as TB preventive therapy or chemoprophylaxis, helps to prevent progression to active disease in HIV-negative populations. However, the extent and magnitude of protection (if any) associated with preventive therapy in those infected with HIV should be quantified. This present study is an update of the original review. The objective of the review was to determine the effectiveness of TB preventive therapy in reducing the risk of active tuberculosis and death in HIV-infected persons. This review was updated using the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, AIDSLINE, AIDSTRIALS, AIDSearch, NLM Gateway and AIDSDRUGS (publication date from 01 July 2002 to 04 April 2008). Akolo et al also scanned reference lists of articles and contacted authors and other researchers in the field in an attempt to identify additional studies that may be eligible for inclusion in this review. They included randomized controlled trials in which HIV positive individuals were randomly allocated to TB preventive therapy or placebo, or to alternative TB preventive therapy regimens. Participants could be tuberculin skin test positive or negative, but without active tuberculosis. Three reviewers independently applied the study selection criteria, assessed study quality and extracted data. Effects were assessed using relative risk for dichotomous data and mean differences for continuous data. 12 trials were included with a total of 8578 randomized participants. TB preventive therapy (any anti-TB drug) versus placebo was associated with a lower incidence of active TB (RR 0.68, 95% CI 0.54 to 0.85). This benefit was more pronounced in individuals with a positive tuberculin skin test (RR 0.38, 95% CI 0.25 to 0.57) than in those who had a negative test (RR 0.89, 95% CI 0.64 to 1.24). Efficacy was similar for all regimens (regardless of drug type, frequency or duration of treatment). However, compared to isoniazid (INH) monotherapy, short-course multi-drug regimens were much more likely to require discontinuation of treatment due to adverse effects. Although there was reduction in mortality with isoniazid monotherapy versus placebo among individuals with a positive tuberculin skin test (RR 0.74, 95% CI 0.55 to 1.00) and with isoniazid plus rifampicin versus placebo regardless of tuberculin skin test status (RR 0.69, 95% CI 0.50 to 0.95), overall, there was no evidence that TB preventive therapy versus placebo reduced all-cause mortality (RR 0.94, 95% CI 0.85 to 1.05). The authors conclude that treatment of latent tuberculosis infection reduces the risk of active TB in HIV-positive individuals especially in those with a positive tuberculin skin test. The choice of regimen will depend on factors such as availability, cost, adverse effects, adherence and drug resistance. Future studies should assess these aspects. In addition, trials evaluating the long-term effects of anti-tuberculosis chemoprophylaxis, the optimal duration of TB preventive therapy, the influence of level of immunocompromise on effectiveness and combination of anti-tuberculosis chemoprophylaxis with antiretroviral therapy are needed.

For full text access click here: 1 [4]

Editors’ note: One-third of the world’s population has latent tuberculosis (TB) infection meaning that they are infected but have no symptoms. Once you are infected with TB, you are infected for life. The lifetime risk of progressing to active disease is about 10% but this soars to 30% or more in people with HIV infection who have a 5-10% annual risk of developing active TB. Several trials have shown that HIV-negative people who take isoniazid (INH) daily for 6 to 12 months have a substantially reduced risk of active TB. Daily INH also reduces the risk of active TB in people living with HIV, particularly those whose immune systems are healthy enough, as evidenced by a positive skin test to TB, to benefit from INH’s help. This updated Cochrane review confirms previous findings but calls for more research to find out how long people need to take preventive therapy and the best drug or drugs to take, either before or after antiretroviral treatment has started. Nonetheless, there is no justification to wait. All people with HIV should be assessed for TB, particularly in high TB prevalence settings, and if latently infected with TB they should placed on INH or combination anti-TB drugs. The challenge is to determine whether their TB infection is latent or active.
















Comorbidity [6]
  • [7]