CYP1A1Genotype Modifies the Impact of Smoking on Effectiveness of HAART Among Women

Abstract

We have recently shown that cigarette smoking is associated with lesser responses to potent antiretroviral therapies. Certain Cytochrome P-450 enzymes activate compounds derived from tobacco smoke into toxic forms that may promote HIV-1 gene expression through promotion of DNAadduct formation by the oxidation of chemical constituents of cigarette smoke, such as polyaromatic hydrocarbons and dioxins. To explore the association between environmental and genetic factors to viral replication in women who smoke and receive highly active anti-retroviral therapy (HAART), we assessed the impact of polymorphisms in a panel of four Cytochrome P-450 genes (CYP1A1, CYP2A6, CYP2D6, and CYP2E1) and two Glutathione S-transferase genes (GSTM1 and GSST1) in 924 participants of the Women's Interagency HIV Study (WIHS). Our findings showed that GSTM1 and GSST1 deletions were not associated with HAART effectiveness. By contrast, homozygosity for the CYP1A1-m1 polymorphism, was associated with impaired viral response to treatment among smokers (relative hazard (RH) = 0.54; 95% confidence interval = 0.31-0.94) after adjustment for pretreament viral load, CD4 count, age, hepatitis C infecDavid N. Feldman is with the

The Unique Challenges Facing HIV-Positive Patients Who Smoke Cigarettes: HIV Viremia, Art Adherence, Engagement in HIV care, and Concurrent Substance Use

“…In the current sample, smokers were more likely than non-smokers to have a detectable viral load. This finding expands upon previous research suggesting that smokers experience virologic failure sooner than non-smokers [20]. …”

“…This biological pathway is supported by previous studies that have found that smokers had poorer viral and immunologic response to antiretroviral therapy, a greater risk of virologic rebound, and more frequent immunologic failure compared to non-smokers [19]. More recently, Feldman and colleagues [20] found that the adverse effects of smoking on medication response remained even after controlling for adherence. Thus, it is plausible that smoking may contribute to a biological vulnerability that increases susceptibility to co-morbid medical conditions and dampens the therapeutic effect of HIV medications, independent of the relationship with adherence.…”

Impact of HIV infection and smoking on lung immunity and related disorders

“…Notwithstanding the counteracting immunosuppressive effect of HIV/smoking on the efficacy of therapy, other possible causes of smoking-related interference with HAART include 1) smoking is a surrogate marker of a noncompliant disposition [81,82]; 2) higher frequencies of side-effects in smokers, including neuropsychiatric symptoms associated with efavirenz-based HAART regimens [83]; 3) negative effects of smoking-related activation of cytochrome P450 enzymes, such as the CPY1A1-m1 variant, which promote oxidative conversion of smoke-derived toxicants to DNA adducts, causing activation of genes that support HIV replication [70,84]; 4) altered pharmacokinetics of antiretroviral agents, possibly related to smoking-mediated induction of CYP3A4 and aryl-hydrocarbon-hydroxylases [85,86], which metabolise many protease and non-nucleoside reverse transcriptase inhibitors [87,88]; and 5) smoking-induced mitochondrial oxidative stress [89], which may exacerbate the adverse effects of antiretroviral drugs that induce mitochondrial toxicity, such as drugs from the nucleoside reverse transcriptase inhibitor class [90].…”

Short Communication: Expression of Transporters and Metabolizing Enzymes in the Female Lower Genital Tract: Implications for Microbicide Research

“…For example, CYP1A1 is not directly involved in the inactivation of antiretrovirals, however, the CYP1A1 genotype was reported to impact the treatment outcome of highly active antiretroviral therapy (HAART) among female smokers. 30 The genotype with higher activity is associated with impaired HAART effectiveness. Since this enzyme could convert smoke-derived compounds to DNA-damaging agents that promote HIV-1 gene expression and replication, the proposed explanation is that higher CYP1A1 activity contributes to a higher concentration of DNA-damaging agents in HIV-infected tissues.…”

“…Since this enzyme could convert smoke-derived compounds to DNA-damaging agents that promote HIV-1 gene expression and replication, the proposed explanation is that higher CYP1A1 activity contributes to a higher concentration of DNA-damaging agents in HIV-infected tissues. 30 Whether the cervicovaginal CYP1A1 could impact the microbicide efficacy among female smokers would be an interesting topic for future research.…”