Optimal treatment of Codisease due to HIV and tuberculosis.

Tuberculosis remains the most common cause of death from human immunodeficiency virus (HIV) infection in most areas of the developing world, and a broad array of approaches are being studied and implemented to reduce mortality from HIV-associated tuberculosis [1]. Prevention is, of course, paramount, and measures that are of proven or potential benefit include intensified case finding, infection control measures, isoniazid preventive therapy (IPT), initiation of antiretroviral therapy (ART), and immunization with new tuberculosis vaccines, an approach we might call the ‘‘5 i’s’’ of prevention [2, 3]. Early diagnosis is also critical, and has been aided by the recognition of subclinical tuberculosis during HIV infection, the increasing recognition of smear-negative and even culture-negative disease, and the introduction of more rapid and sensitive diagnostic tests [4, 5]. Since current diagnostic tests do not detect all cases of HIV-associated tuberculosis, another emerging concept is the broader use of empiric treatment for active tuberculosis in high-risk subgroups of patients with HIV infection, especially those hospitalized with advanced AIDS [6–8]. Once active tuberculosis is suspected or confirmed, aggressive clinical management is critical to reduce the known enhanced mortality risk of HIV and tuberculosis codisease (often and inappropriately considered ‘‘coinfection,’’ a term that should be reserved for latent tuberculosis infection in the setting of HIV). Optimal treatment of HIV-associated tuberculosis requires treatment with 2 multidrug regimens: typically 6 months of a 4-drug, then 2-drug, regimen to treat tuberculosis, and a lifelong 3-drug ART regimen to reverse the functional immunosuppression that resulted in the development of active tuberculosis and to halt the further acceleration of HIV disease induced by active tuberculosis. Until recently, expert opinion had favored initial treatment for tuberculosis with subsequent initiation of ART 2–6 months later to avoid drug interactions, combined side effects, and the potential for increasing the rate of immune reconstitution inflammatory syndrome (IRIS). Three randomized, controlled trials have now demonstrated the safety and superiority of initiating ART as soon as 2 weeks after the initiation of treatment for active tuberculosis, rather than at intervals .2–6 months later. In the 642subject SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy) study from South Africa, an ART regimen of didanosine, lamivudine, and efavirenz was started early in 2 integrated therapy groups (,4 weeks or 8–12 weeks after initiation of tuberculosis treatment) and delayed until 6 months (after completion of tuberculosis treatment) in the comparison group. Mortality was reduced by 56%, from 12.1/100 person-years to 5.4/100 person-years, in the integrated therapy group (P 5 .003) [9]. Subsequent analysis of data showed that the rate of the composite endpoint of AIDS/death did not differ between the 2 integrated therapy groups, but was lower in the CD4 ,50 cells/uL subgroup with treatment at ,4 weeks versus 8–12 weeks (P 5 .06). The rate of IRIS in the CD4,50 cells/uL group was 47% with treatment at ,4 weeks, compared with 10% with treatment at 8–12 weeks [10]. In the CAMELIA (Cambodian Early Versus Late Introduction of Antiretrovirals) study from Cambodia, 661 HIV-infected subjects with newly diagnosed tuberculosis were randomized to an ART regimen of stavudine, lamivudine, and efavirenz, starting either 2 weeks or 8 weeks after initiation of treatment for tuberculosis. There was a statistically significant 34% reduction in the mortality rate in the 2-week versus the 8-week group, from 13.8/100 person-years to 8.3/100 person-years; rates of IRIS were 3 times higher in the 2-week group [11]. The STRIDE ACTG 5221 trial enrolled codisease patients with CD4,250 cells/uL, and randomized patients to an immediate (,2 weeks) or early (8–12 weeks) 3-drug ART regimen. The composite Received 18 May 2011; accepted 18 May 2011. Potential conflicts of interest: none reported. Correspondence: C. Fordham von Reyn, MD, Infectious Disease and International Health, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756 ([email protected]). The Journal of Infectious Diseases 2011;204:817–9 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected] 0022-1899 (print)/1537-6613 (online)/2011/2046-0002$14.00 DOI: 10.1093/infdis/jir418