Sex Differences in Pharmacologic Effects of Antiretroviral Drugs

The relationship between a patient’s sex and that individual’s ability to tolerate antiretroviral drugs is increasingly being examined. Several lines of evidence suggest that women are more likely than men to experience adverse effects of antiretroviral drugs.1 Nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), is associated with rash and hepatitis more frequently in women than men.2-6 Protease inhibitor (PI)-associated gastrointestinal intolerance and metabolic disorders are also reported more frequently among women.7-10 Boxwell and colleagues11 reported that 83% of 60 cases of lactic acidosis in HIVinfected patients treated with nucleoside reverse transcriptase inhibitors (nRTIs) involved women, and 85% of the 20 fatal cases were in women. Another study12 examined the relationship between sex and lipodystrophy in 2258 HIV-infected persons on antiretroviral therapy and found that morphologic alterations were twice as likely in women. These observations suggest that adverse effects may be more frequent in women than in men receiving antiretroviral therapy. It has been generally presumed that the efficacy of an antiretroviral drug is comparable in men and women. However, 3 recent studies suggest that this may not always be the case. One study from the United Kingdom13 evaluated the effectiveness of potent antiretroviral therapy in 91 women and 366 men. Virologic suppression was achieved more rapidly in women, and the response was more durable. A second study14 evaluated sex differences in the clinical response to antiretroviral therapy in 497 men and 146 women who were observed for more than 13 months. Disease progression occurred in 11% of men and in 8% of women. Hospital admission for an AIDS-defining illness was required for 17% of the men and 12% of the women. A third study,9 involving 78 women and 616 men, found that the efficacy of antiretroviral therapy in reducing the plasma HIV-1 RNA concentration was similar for men and women; however, the mean increase in the CD4+ cell count was greater in women (116/μL) than in men (84/μL). Although these studies need to be corroborated, the findings suggest that sex may influence the pharmacologic effects of the antiretroviral drugs. Data that indicate increased adverse effects and possibly greater efficacy suggest that women may have better virologic responses to comparable drug doses than do men, or that women may experience higher serum or tissue drug concentrations. Mechanisms proposed to explain sex differences in drug effects have included physiologic differences in factors such as total body weight, fat distribution, protein binding, gastric motility and acid secretions, glomerular filtration rates, and the influence of sex hormones on drug metabolism. More recently, however, there is growing evidence to suggest that the mechanism of sex-related differences in drug effects may occur at the molecular level. Sex-related variations in the expression and activities of drug transporter genes, proteins, and enzymes involved in phase 1 and 2 biotransformation that form the xenobiotic cascade may underlie some of the observed differences between men and women in responding to certain drugs. This report examines how differences in the expression and activities of these important drug-disposing molecules may explain some of the sex-related differences reported in association with the effects of the antiretroviral drugs.