Trial of efavirenz with/without rifampin does not support weight-based dosing
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
