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Trough Levels of Four Key Antiretroviral
Higher in Women Than General Population
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1st International Workshop on HIV and Women, January 10-11, 2011, Washington, DC
Mark Mascolini
Minimum concentrations (Cmin) of four much-used antiretrovirals were generally higher in Canadian women than in a mostly male comparison population [1]. But maximum concentrations (Cmax), which often signal a higher side effect risk, were lower in women than in the control population.
Mona Loutfy and the PK in Women Study Team noted that earlier work often found higher antiretroviral side effect rates in women than in men. Side effects can reflect higher drug concentrations in women. But much research comparing antiretroviral levels in women and men involves older drugs tested in small groups.
To gather current data on pharmacokinetics in women, these investigators planned a 14-site study enrolling women over 18 years old who had a confirmed viral load below 50 copies on their first antiretroviral regimen. As part of their first combination, women were taking a single protease inhibitor (PI), which could be boosted by ritonavir, or a single nonnucleoside; they could not be taking both a PI and a nonnucleoside.
Study participants gave timed blood samples weekly for 3 weeks, enabling the investigators to determine a median Cmin and a median Cmax for each woman. The investigators calculated ratios for these median values versus published population mean Cmin and Cmax levels for each drug of interest. Population values consist primarily of drug levels measured in men, although some women contribute to population means. The drugs analyzed were unboosted atazanavir, boosted atazanavir, boosted lopinavir, efavirenz, and nevirapine--all given at standard doses.
The analysis included 79 women enrolled between February 2007 and November 2008. Median age stood at 41 (interquartile range [IQR] 36 to 48), median years since HIV diagnosis at 7 (IQR 3 to 11), and median months since antiretroviral therapy began at 21 (IQR 8 to 45). Most study participants (56%) were black, 34% were white, and 10% were in other ethnic groups. Median current CD4 count was 484 (IQR 380 to 620), and everyone had a viral load below 50 copies.
For all antiretrovirals together, the ratio of women's Cmin to the population Cmin was 1.22, meaning the women studied had a 22% higher overall Cmin than the control population (P < 0.01). In contrast, the overall women/control Cmax ratio was 0.83 (P = 0.01), meaning overall peak antiretroviral levels were about 15% lower in women. Median atazanavir and efavirenz Cmins in these women were marginally lower than control population values, while median lopinavir and nevirapine Cmins were higher. Cmaxs for all antiretrovirals studied were lower in women than in the control population:
Cmin
-- Atazanavir (n = 8): median ratio 0.95
-- Atazanavir/ritonavir (n = 17): median ratio 0.95
-- Lopinavir/ritonavir (n = 19): median ratio 1.23 (P = 0.07)
-- Efavirenz (n = 16): median ratio 0.95
-- Nevirapine (n = 19): median ratio 1.62 (P < 0.01)
Cmax
-- Atazanavir (n = 8): median ratio 0.64 (P = 0.08)
-- Atazanavir/ritonavir (n = 17): median ratio 0.66 (P < 0.001)
-- Lopinavir/ritonavir (n = 19): median ratio 0.89
-- Efavirenz (n = 16): median ratio 0.79
-- Nevirapine (n = 19): median ratio 0.96
Median coefficient of variation for antiretrovirals indicated the highest intrapatient variation in Cmin and Cmax for unboosted atazanavir (Cmin 52.3, Cmax 55.0). Median coefficients of variation were lower for the other drugs, indicating less intrapatient variability in Cmin and Cmax: atazanavir/ritonavir (26.1, 42.7), lopinavir/ritonavir (31.5, 14.1), efavirenz (17.7, 15.5), nevirapine (17.5, 15.7).
None of four variables assessed correlated with Cmin or Cmax ratios: age, race, current CD4 count, or weight.
The investigators noted that their analysis is limited by lack of a male control group permitting a real-time comparison of antiretroviral concentrations in women and men. They cautioned that study inclusion criteria selected to ensure homogeneity of the study population could have limited their ability to detect differences and associations. And they cautioned that the requirement of a substantial time commitment could have resulted in selection bias favoring women with more time to give to such a study.
Loutfy and colleagues believe their results suggest that pharmacokinetics of these antiretrovirals may contribute to better viral suppression in women than in men. But they proposed that antiretroviral level monitoring may still be considered in women when antiretroviral side effects suggest high drug concentrations.
Reference
1. Loutfy M, la Porte C, Walmsley S, et al. Antiretroviral pharmacokinetics in HIV-positive women with full virologic suppression on current regimens. 1st International Workshop on HIV and Women. January 10-11, 2011. Washington, DC. Abstract O_22.
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