A trial in which adults from four continents took standard-dose efavirenz with or without the anti-TB drug rifampin (rifampicin) found a trend toward higher efavirenz minimum concentrations (Cmin) with than without rifampin. The result does not support the US labeling recommendation to raise the dose of efavirenz from 600 to 800 mg daily in people taking rifampin and weighing 50 kg or more.
Rifampin induces CYP 450 enzymes involved in efavirenz metabolism and so may lower efavirenz concentrations in people taking the drugs simultaneously. Lower efavirenz levels could impair the antiviral activity of this much-prescribed nonnucleoside.
AIDS Clinical Trials Group (ACTG) study A5221, the STRIDE Study, enrolled 780 HIV-positive antiretroviral-naive adults who had confirmed or probable tuberculosis and randomized them to start antiretroviral therapy (ART) within 2 weeks of starting anti-TB therapy or to delay ART until 8 to 12 weeks after anti-TB treatment began.
This drug-interaction analysis included STRIDE participants who had one or more efavirenz Cmin levels measured during the trial. There were 505 participants who had efavirenz Cmin measured while taking rifampin and 362 who had Cmin measured while not taking rifampin.
Median weight of study participants stood at 52.8 kg (interquartile range [IQR] 48.0 to 59.5), median body mass index at 19.4 kg/m(2) (IQR 17.5 to 21.6), and median age at 34 years (IQR 29 to 41). Almost two thirds (63%) of people in this analysis were men, 74% were black, and 20% were Hispanic. Participants lived in sub-Saharan Africa (70%), Brazil or Peru (25%), Haiti (3%), or Thailand or the United States (1%).
Median efavirenz Cmin when people were taking rifampin was 1.96 µg/mL, compared with 1.80 µg/mL without rifampin, a nearly significant difference (P = 0.067). Among black study participants, Cmin values were significantly higher with than without rifampin (2.08 versus 1.75 µg/mL, P = 0.005).
People weighing 60 kg or more had a significantly lower median Cmin with than without rifampin (1.68 versus 2.02 µg/mL, P 0.021). But the lower efavirenz Cmin in these people did not result in a worse virologic response. In fact, at study week 48 a higher proportion of people weighing 60 kg or more had a viral load below 400 copies than people weighing less (81.9% versus 73.8%, P = 0.023).
The paradoxically higher efavirenz Cmin in black participants taking rifampin could mean rifampin given with isoniazid and other anti-TB drugs may lower efavirenz clearance—particularly in people with certain genetic profiles—and thus raise efavirenz concentrations.
The ACTG team concludes that their findings “do not support weight-based dose increase of efavirenz during rifampin-based tuberculosis treatment.”
Source: Anne F. Luetkemeyer, Susan L. Rosenkranz, Darlene Lu, Florence Marzan, Prudence Ive, Evelyn Hogg, Susan Swindells, Constance A. Benson, Beatriz Grinsztejn, Ian M. Sanne, Diane V. Havlir, Francesca Aweeka, for the Adult AIDS Clinical Trials Group A5221 Study Team. Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study. Clinical Infectious Diseases. 2013; 57: 586-593.
Source: IAS