Tobacco and marijuana may reduce levels of atazanavir (Reyataz) in the body, whilst tobacco and alcohol may lower efavirenz (Sustiva or Stocrin) levels in individuals who carry specific genetic variations, according to two posters presented last week at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.
Atazanavir
American researchers looked at the link between what they called 'substance related disorders' and atazanavir levels, HIV viral load and CD4 cell count.
The study included 67 people with HIV in four cities (the Bronx; Rochester, NY; Cleveland; and Miami) who had been on stable atazanavir-containing antiretroviral regimens for more than two years. A majority (60%) were men, the mean age was 46 years, 25% were coinfected with hepatitis C and the average CD4 count was about 450 cells/mm3.
Approximately half of the participants were classified as having substance use disorders. About half reported using tobacco, slightly more than one-quarter used alcohol, nearly 20% used marijuana and opiates, and 10% used cocaine. (Another section of the poster reported higher use rates, including 91% for tobacco, 41% for alcohol and 38% for marijuana.) A considerable proportion- about 40% - used multiple substances.
The researchers found that atazanavir trough levels (the lowest level between doses) were significantly reduced in people who used tobacco or marijuana. In fact, half of tobacco users and more than one-third of marijuana users had trough levels below the effective therapeutic range.
Differences in atazanavir trough concentrations between substance users and non-users were not statistically significant for people who used cocaine or opiates, and levels were about the same for individuals who drank alcohol and those who abstained.
Despite the observed differences in atazanavir levels, however, the researchers noticed no significant direct effects of substance use on HIV viral load or CD4 cell count.
"Although substance-related disorders had no significant direct effects on treatment outcomes, the relatively low CD4 counts and high viral loads among patients with tobacco and marijuana use suggest drug-substance interactions might contribute to inter-individual variability in patients' response to atazanavir-containing regimens," the researchers concluded.
They suggested that these interactions might occur because these substances speed up processing of atazanavir by the CYP3A enzyme in the liver.
Efavirenz
In a second analysis, the same research team looked at the relationship between substance use and efavirenz pharmacokinetics. In particular, they wanted to determine the effect of a particular genetic variation (single nucleotide polymorphism) in the gene encoding CYP2B6, a liver enzyme that plays a role in efavirenz metabolism.
This study included 37 people in the four-city cohort taking efavirenz-containing regimens, of whom 17 were classified as having substance-related disorders. Based on their CYP2B6 genotype, participants were classified as being extensive (genotype GG), intermediate (genotype GT), or slow (genotype TT) efavirenz metabolisers.
The researchers noted significantly lower efavirenz trough concentrations amongst tobacco and alcohol users in the extensive metaboliser group, along with lower CD4 cell counts and higher viral loads. Marijuana, opiates and cocaine, however, were not associated with significant differences in efavirenz concentrations. Furthermore, the researchers said substance use had no direct effect on antiviral response.
"The mechanisms that underlie these observations may include combined pharmacogenomic and behavioural components", the researchers suggested, adding that clinicians should consider these pharmacological findings when constructing antiretroviral regimens for patients with substance-related disorders.
A limitation of these studies is that the investigators did not specifically look at adherence, which may be influenced by substance use. They also did not report the amount of substances used. The first report did not distinguish between boosted and unboosted atazanavir, which has a major impact on drug concentrations. The second did not explore whether liver damage due to heavy drinking might play a role in altered drug processing.
Ma Q et al. Tobacco and marijuana uses significantly decrease atazanavir (ATV) trough concentrations in HIV-infected individuals . 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-231, 2009.
Ma Q et al. Effects of CYP2B6 single nucleotide polymorphisms (SNPs) and substance abuse on efavirenz (EFV) pharmacokinetics. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-228, 2009.