Prolonged Deferral of Antiretroviral Therapy in the SAPIT Trial: Did We Need a Clinical Trial to Tell Us That This Would Increase Mortality?(Issues IN Research) (Clinical Report)
Tuberculosis is the major cause of morbidity and mortality in HIV-infected patients in sub-Saharan Africa. HIV infection is often first diagnosed following a diagnosis of tuberculosis, with many patients needing antiretroviral therapy (ART). Starting ART in HIV-infected patients with tuberculosis (TB) may be associated with complications, including side-effects from co-administration of multiple drugs with many overlapping toxicities, reductions in concentrations of certain antiretroviral drugs following the induction of metabolising enzymes and drug transporters by rifampicin, and paradoxical deterioration due to the immune reconstitution inflammatory syndrome (IRIS). Furthermore, the high pill burden of co-treatment could reduce adherence, resulting in poor treatment outcomes for both diseases. These potential harms must be weighed against the high mortality rates in patients with HIV-associated tuberculosis who do not receive ART, especially those with low CD4 counts. The optimal time to initiate ART in patients with tuberculosis is an important research question, and randomised controlled trials are addressing this issue. Interim results of the South African Starting Antiretroviral Therapy at Three Points in Tuberculosis Therapy (SAPIT) study have been published in the New England Journal of Medicine. (1) The SAPIT investigators are the first group to publish controlled data on when to initiate ART in patients with TB. Patients with sputum smear-positive pulmonary TB and CD4 counts below 500 cells/[micro]l were randomised to start ART in one of three phases of TB treatment: within 4 weeks of starting TB therapy; within 4 weeks after the completion of the intensive phase of TB therapy (2 or 3 months of 4 or 5 anti-TB drugs for patients with new or retreatment TB, respectively); or within 4 weeks after the completion of TB treatment (6 or 8 months for patients with new or retreatment TB, respectively). Recruitment into the latter group (the sequential arm) was stopped prematurely by the Data Safety Monitoring Board (DSMB) when it was found that mortality was significantly higher in this group compared with the groups that started ART during TB therapy. Mortality largely occurred in patients with CD4 counts below 200 cells/[micro]l. The groups starting ART during and after the intensive phase of TB treatment completed enrolment, and results are still pending.