By Liz Highleyman

A drug interaction between rifampicin-based therapy for tuberculosis (TB) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune) may lead to an elevated risk of HIV treatment failure, according to data presented Sunday, August 3, in advance of the XVII International AIDS Conference in Mexico City, and published in the August 6 Journal of the American Medical Association.

It is known that rifapicim reduced plasma concentrations of nevirapine and the other NNRTI commonly used for first-line therapy, efavirenz (Sustiva; Stocrin). Therefore, Andrew Boulle of the University of Cape Town and colleagues conducted a study to assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based anti-TB therapy.

The investigators prospectively analyzed clinical data from a community-based South African antiretroviral treatment program in South Africa. Patients starting antiretroviral therapy, with or without concurrent anti-TB therapy, received standard doses of either efavirenz or nevirapine. Individuals who developed TB while taking nevirapine either switched to efavirenz or continued taking nevirapine.

The analysis included antiretroviral treatment-naive HIV positive adults enrolled between May 2001 and June 2006. A total of 2035 patients (including 1074 with TB) started efavirenz and 1935 (including 209 with TB) started nevirapine.

Participants were followed through the end of 2006; more than half (n = 1074) also had TB. The outcomes assessed were detectable HIV viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; and time to confirmed virological failure (defined as 2 consecutive values of 5000 copies/mL or more); time to death; and time to treatment-limiting toxicity.

Results

There were no differences in time to death or substitution of either efavirenz or nevirapine due to toxicity in patients with and without concurrent TB.

Patients starting nevirapine with concurrent TB were about twice as likely as those without to have elevated viral load, most notably at 6 months (16.3% vs 8.3%, respectively; adjusted odds ratio [OR] 2.1).

In the time-to-event analysis of confirmed virological failure, patients starting nevirapine with concurrent TB developed virological failure sooner (adjusted hazard ratio [HR] 2.2).

There were no differences between patients starting efavirenz with or without concurrent TB (adjusted OR 1.1).

There was no difference in time to virological rebound in patients without TB and those who developed TB during follow-up while taking nevirapine (adjusted

HR 1.0) or efavirenz (adjusted HR 0.8).

Based on these findings, the study authors concluded, "In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies."

In their discussion, the researchers suggested that these differences, present in patients who start nevirapine-based therapy when they already had TB, but not in those who developed TB after they were on an established nevirapine-based regimen could potentially be due to "a drug interaction mediated by rifampicin during the lead-in dosing phase of nevirapine."

"Given the continued reliance on nevirapine-containing [antiretroviral therapy] regimens in Africa, together with the important role tuberculosis services play as an entry point for ART, further prospective studies exploring this outcome are warranted," they wrote. "One of the most striking aspects of our study was the demonstration that 40 percent of patients starting ART in recent years have concurrent tuberculosis, underscoring the public health importance of improving affordable treatment options for patients infected with HIV and tuberculosis in this setting."

8/05/08

Sources

A Boulle, G Van Cutsem, K Cohen, and others. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. Journal of the American Medical Association 300(5): 530-539. August 6, 2008.

Journal of the American Medical Association. HIV treatment widely-used in developing countries may be less effective when used with anti-TB therapy. Media release. July 30, 2008.