Antiretroviral pharmacokinetics in women with undetectable viral load

Although some studies have shown higher antiretroviral concentrations in women versus men, data are limited.

Mona Loufty presented findings from a Canadian study to look at whether or not non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) drug levels are significantly higher in women compared to a largely male historical population. This analysis also examined whether or not there was an association between weight and drug concentrations.

This was a cross-sectional study conducted at 14 sites across Canada. Women, 18 years and above, on their first antiretroviral regimen, receiving current agents at standard doses (atazanavir, atazanavir/r, lopinavir/r, efavirenz or nevirapine- containing regimens), with an undetectable viral load <50 copies/mL were included.

Timed blood samples for Cmin and Cmax occurred weekly for three weeks. Demographic and clinical data were also collected.

Each individuals median Cmin and Cmax were used to calculate the ratio to the published populations mean values for the antiretroviral.

Data from 79 women were included in the analysis. They were a median age of 41 (IQR 36-48) years, had been receiving HAART for a median of 21 (IQR 8-45) months and had a median CD4 cell count of 484 (IQR 380-620) cells/mm3.

Median antiretroviral Cmin and Cmax ratios to population mean were 1.22 (p<0.01) and 0.83 (p=0.01) respectively. With 32.2% and 8.9% with values %>1.5 population mean. See table 1 for Cmax and Cmin ratios by antiretroviral.

In linear regression models, including age, ethnicity, CD4 and weight, the investigators found no variables correlated with Cmin or Cmax ratios. They noted that both ratios were highly variable within and between women in this cohort.

They also noted that the study was limited having no real time male control group, inclusion criteria that resulted in limited range in the covariates and possible selection bias due to the commitment required for participation.

They suggested that these pharmacokinetics may result in better viral suppression in women and that women with side effects may benefit from drug level monitoring if drug concentrations may be the culprit.

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Table 1: Cmax and Cmin ratios by antiretroviral
ARVs N	Ratio of Cmin to population mean	Ratio of Cmax to population mean
%>1.5 pop. mean	Median	p-value	%>1.5 pop. mean	Median	p-value
Atazanavir N=8	25.0	0.95	0.72	0	0.64	0.08
Atazanavir/r N=17	17.6	0.95	0.85	0	0.66	<0.001
Lopinavir/r N=19	31.6	1.23	0.07	0	0.89	0.44
Efavirenz N=16	37.5	0.95	0.37	25	0.79	0.63
Nevirapine N=19	52.6	1.62	<0.01	15.8	0.96	0.47

As Angela Kashuba discussed in her overview, it seems sex/gender based differences in PK are often subtle and may disappear with weight adjustment.

Although these differences may have a small impact at population level, for some individuals they could be significant and TDM may be useful here. However, nuanced drug dosing is challenging (and not feasible in settings with limited resources).

Loutfy M et al. Antiretroviral pharmacokinetics in HIV-positive women with full virological suppression on current regimens. 1st International Workshop on HIV and Women. 10-11 January 2011, Washington. Oral abstract O_22.