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Smoking and Drinking Alcohol Linked to Lower Efavirenz Levels
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49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 12-15, 2009, San Francisco
Mark Mascolini
People who rapidly metabolize efavirenz because of their genetic makeup risk even lower efavirenz levels if they smoke tobacco or drink alcohol, according to results of a 37-person analysis [1]. The findings rest on scrutiny of small subgroups and should be confirmed in larger populations.
Earlier research showed that people with a GG genotype at position 516 of the CYP2B6 gene metabolize efavirenz faster (and thus have lower efavirenz concentrations) than people with the GT genotype or the TT genotype [2]. The new study involved 18 people with substance-related disorders and 19 without such disorders who enrolled in a multicenter trial of therapeutic drug monitoring and drug interactions in Rochester, New York; the Bronx, New York; Cleveland, Ohio; and Miami, Florida. People with and without substance-related disorders did not differ significantly in proportion of males, age, CD4 count, viral load, or presence of antibodies to HCV.
The investigators rated 19 people extensive efavirenz metabolizers because of a GG genotype, 13 intermediate metabolizers with a GT genotype, and 5 slow metabolizers with a TT genotype. The researchers also evaluated the impact of single-nucleotide polymorphisms (genetic shifts) in genes that encode the drug-metabolizing enzymes ABCB1 and CYP3A5.
Tobacco and alcohol users with a CYP2B6 516 GG genotype had lower CD4 counts and higher viral loads than people who did not smoke or drink. CD4 count averaged 571 among nonsmokers and 346 among smokers, while respective viral loads averaged 1.96 and 2.68 log (about 100 and 500 copies). CD4 count averaged 449 in people with a GG genotype who did not use alcohol and 417 in GG alcohol users, while respective viral loads averaged 2.13 and 3.08 log (about 100 and 1000 copies).
In an analysis adjusted for age, race, gender, and body mass index, CYP2B6 genotype correlated significantly with efavirenz trough concentrations (P = 0.036). Among extensive (GG) metabolizers, tobacco and alcohol use correlated with significantly lower median efavirenz troughs, measured as micrograms/milliliter (and interquartile range):
· Tobacco yes vs no: 1.761 (1.307 to 2.134) vs 2.295 (1.880 to 4.010), P = 0.043
· Alcohol yes vs no: 1.413 (0.659 to 1.876) vs 2.247 (1.761 to 2.482), P = 0.021
Use of marijuana, cocaine, and opioids did not correlate with efavirenz troughs in this analysis. Neither ABCB1 genotype nor CYP3A5 genotype correlated with efavirenz troughs.
The investigators suggest that the mechanisms underlying the association between efavirenz troughs and tobacco and alcohol "may include combined pharmacogenomic and behavioral components." They propose that "clinicians should consider these pharmacologic findings when developing antiretroviral regimens for HIV+ patients with substance-related disorders."
References
1. Ma Q, Venuto C, Brazeau D, et al. Effects of CYP2B6 single nucleotide polymorphisms (SNPs) and substance abuse on efavirenz pharmacokinetics. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-228.
2. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18:2391-2400.
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