When to Start Antiretroviral Therapy in HIV-Infected Patients with Tuberculosis?

The optimal time to initiate antiretroviral therapy (ART) in patients coinfected with HIV and tuberculosis (TB) has not yet been defined. When potent ART first became available, the conservative wisdom was to complete TB treatment before starting ART, but, increasingly, the evidence points toward concomitant therapy. At last year's Conference on Retroviruses and Opportunistic Infections (Abstract 36a), investigators presented results from the SAPiT trial showing that HIV/TB-coinfected patients have a much better chance of survival if ART is initiated during TB treatment rather than afterward (JW AIDS Clin Care Mar 9 2009). Now, those results have been published.

A total of 642 HIV-infected adults in South Africa who had smear-positive TB and a CD4 count <500 cells/mm³ were randomized 1:1:1 to three treatment groups:

• Early integrated therapy: Patients started ART within 4 weeks after starting TB treatment.

• Late integrated therapy: Patients started ART within 4 weeks after completing the intensive phase of TB treatment.

• Sequential therapy: Patients did not begin ART until they had completed all TB treatment (2 months of intensive therapy, followed by 4 months of continuation therapy).

All study participants received the same antiretroviral regimen — once-daily ddI + 3TC + efavirenz.

During a planned interim analysis (median follow-up, 12 months), mortality rates were found to be 56% lower in the two integrated-therapy groups combined than in the sequential-therapy group (5.4 vs. 12.1 per 100 person-years). Not surprisingly, baseline CD4-cell counts predicted mortality in both groups, but across CD4-cell–count strata, mortality was consistently lower with integrated therapy than with sequential therapy. Immune reconstitution inflammatory syndrome (IRIS) was diagnosed in 12.4% of the integrated-therapy groups combined versus 3.8% of the sequential-therapy group. This difference was statistically significant, but, importantly, ART discontinuation was not required in any of the patients who developed IRIS, and none of the deaths in the study were considered attributable to IRIS.

Based on these results, the Data and Safety Monitoring Board recommended that all patients in the sequential-therapy group begin ART as soon as possible. The comparison between the two integrated-therapy groups is ongoing, leaving open the question of just how early ART should be initiated relative to TB treatment.