Brian Hoyle

March 16, 2011

March 16, 2011 (Boston, Massachusetts) — The latest findings from the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial add to the weight of evidence supporting the commencement of integrated antituberculosis and antiretroviral therapy (ART) as soon as possible for patients coinfected with tuberculosis (TB) and HIV. The findings were reported here at the 18th Conference on Retroviruses and Opportunistic Infections.

SAPIT is proceeding after the discontinuation of an ethically contentious treatment group in which patients with low CD4 counts were randomly assigned to receive potentially beneficial treatment or to have treatment withheld.

"In southern Africa, without question, TB is the single biggest challenge we face in ART. HIV and TB are intertwined. We have previously reported that beginning ART during TB treatment reduced death by 55%, compared with ART initiation upon TB treatment completion. This trial attempted to answer the question: When is the best time to initiate ART during TB treatment?" Salim Abdool Karim, MBChB, PhD, director of the Centre for the AIDS Program of Research in South Africa, Durban, said in an interview with Medscape Medical News.

The SAPIT researchers conducted an open-label randomized controlled trial of 642 South African HIV-positive patients with TB (confirmed by a positive sputum acid-fast bacilli smear test). The patients were randomly assigned to receive early ART (n = 214), which was started within 4 weeks of the initiation of TB therapy, or late ART (n = 215), in which ART was started in the 4 weeks after the completion of TB treatment (which typically took 6 weeks). Primary outcomes were AIDS, death, immune reconstitution inflammatory syndrome (IRIS), and drug switching.

At baseline, both treatment groups displayed similar median CD4+ cell counts and RNA viral loads. The incidence rate of AIDS or death in the early group was 6.9 per 100 person-years and in the late group was 7.8 per 100 person-years, producing an incidence rate ratio (IRR) of 0.89 (95% confidence interval [CI], 0.44 to 1.79;= .73).

The 72 patients who had a baseline CD4+ count below 50 cells/mm3 displayed incidence rates of AIDS or death of 8.5 per 100 person-years in the early group, in striking contrast to 26.3 per 100 person-years in the late group (IRR, 0.32; 95% CI, 0.07 to 1.13; P = .06). This is a 68% reduction in AIDS-related mortality with early ART initiation, Dr. Karim reported.

Tempering this finding in the early group was the 5-fold elevation in IRIS incidence rates: 46.8 in the early group and 9.9 in the late group (IRR, 4.71; P = .01). In addition, adverse events in 3 of the patients in the early group necessitated a switch to other ART drugs.

In the 357 patients with a baseline CD4+ count of 50 cells/mm3 or higher, the AIDS/death incidence rates were not appreciably different, at 6.6 and 4.4 per 100 person-years in the early and late groups, respectively (IRR, 1.51; P = .34), Dr. Karim reported. However, patients in the early group had a 2-fold higher incidence rate of IRIS (15.8 vs 7.2 per 100 person-years; IRR, 2.18; P = .02) and a substantially higher rate of adverse-event-prompted drug switches (7 in the early group vs 1 in the late group; P = .04).

"In the early-treatment arm, the dramatic savings in terms of life and AIDS-defining illnesses overshadowed the elevations of IRIS and drug switches. Therefore, we conclude that there was no evidence against the integration of anti-TB and antiretroviral therapy. In fact, our findings strongly support a universal call to integrate anti-TB and ART, and indicate that those who are severely immunosuppressed should start ART as soon as possible; in those with a CD4 count above 50 cells/mm3, the clinician can make their own judgment about whether they can manage IRIS and drug switching," Dr. Karim told Medscape Medical News.

Whether a CD4 count of 50 cells/mm3 is a true cut-off and whether patients coinfected with HIV/TB who have marginally higher counts could benefit from early ART are unclear and should be studied, according to Dr. Karim.

"There is clear evidence that starting ART immediately in TB patients with a CD4+ count below 50 cells/mm3 is associated with reduced mortality," Kevin De Cock, MD, director of global health, Centers for Disease Control and Prevention, in Atlanta, Georgia, told Medscape Medical News.

"These are important findings, although further analyses are [needed]. For example, is 50 cells/mm3 the best cut-off? A practical question will be how to exploit these findings in the absence of access to CD4+ cell counts, a common situation facing TB patients in Africa," Dr. De Cock said.

The authors and Dr. De Cock have disclosed no relevant financial relationships.

18th Conference on Retroviruses and Opportunistic Infections (CROI): Abstract 39LB. Presented February 28, 2011.

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