Three studies compare gender differences in use of antiretrovirals
Polly Clayden, HIV i-Base
The 3rd International Workshop on Clinical Pharmacology of HIV Therapy included three interesting studies comparing gender differences in aspects of antiretroviral use.
Dr Angela Kashuba from the University of North Carolina presented results from an investigation to evaluate whether PIs and NNRTIs concentrate differently in the male and the female genital tracts.
Preceding the main PK meeting in a small round table organised by the Forum for Collaborative HIV Research focusing on ‘Sanctuary sites and viral reservoirs’, Dr Kashuba gave an excellent overview of research to date into antiretroviral penetration into the genital tract. A report will be produced from this meeting, which we will review in a future issue of HTB.
Dr Kashuba summarised genital tract penetration as having potential clinical significance concerning mother to child transmission, post exposure prophylaxis (PEP), sexual transmission and antiretroviral durability.
Multiple CVL and plasma samples were obtained from 5 HIV-positive women on separate days. Prior to [C12h] and 3-4 hours post [C3-4h] morning doses, plasma and CVL samples were taken. The drugs measured were indinavir (IDV), amprenavir (APV), ritonavir (RTV), lopinavir (LPV), nevirapine (NVP), and delavirdine (DLV). The investigators had previously published a report on antiretroviral genital tract penetration and the results were compared to these data.
Median female genital tract to blood plasma ratios were 1.45 for IDV, 0.03 for RTV, 0.05 for LPV, 0.8 for NVP, and O.5 for DLV. The ranking for penetration in the female genital tract was therefore – IDV>NVP>APV>DLV>LPV>=RTV. This compared to male data in which seminal plasma to blood plasma ratios were 0.4-2.0 for IDV, 0.2 for APV, <0.05 for RTV, 0.07 for LPV, and 0.6-1.0 for NVP, the ranking being IDV>NVP>APV>LPV>RTV. [Note: the ranking of drugs was the same for both sexes and the ratio differences may reflect the differences in protein (and therefore protein binding of drug) in the different fluids – semen is more proteinaceous so carries more of these protein bound drugs.]
Despite physiological genital tract differences and differences between the ratios of antiretroviral penetration between genders, it is interesting to observe no great differences between the ranking of the antiretroviral ratios of penetration. Dr Kashuba cited various challenges to measuring drug concentrations in the genital tract including, small volume of samples, limited sensitivity of the assays, limitations of single random time points. What to measure – extracellular vs intracellular? And protein binding considerations, but this issue deserves further exploration.
A poster from Dr David Burger’s group at UMC Nijmegen reported results from a study looking at gender differences in plasma levels of lopinavir. This group had recently published data demonstrating that female HIV-1 infected patients have a higher risk for toxic indinavir levels than males. Through their therapeutic drug monitoring service they observed a similar pattern for lopinavir and so this study was to evaluate a possible correlation.
The study was performed using their clinic database of lopinavir samples from 130 patients (20 female, 110 male), receiving a lopinavir dose of 400mg q12h and a timeframe between intake and sampling of 4-12 hours. Gender and body weight were recorded.
The investigators concluded that “As a result, female HIV-1 infected patients may be at higher risk for developing lopinavir related toxicity.”
In addition, a poster from Dr M Regazzi and colleagues analysed the PK profile of nevirapine in a cohort of 11 male and 11 female HIV-1 infected patients . They reported higher levels in women than men, which may be attributable to body weight. The authors suggested that this might account for higher incidence of nevirapine-induced rash observed in men than in women.
The Forum for Collaborative HIV Research website is at:
A meeting report of the Third International Workshop on Clinical Pharmacology of HIV Therapy, and details of next year’s workshop are at:
The major determinant of sex differences in response to antiretrovirals is likely to remain body size. “One size fits all” dosing may make women more likely to respond and also to suffer more toxicities with therapy.
Other differences require more women participating in trials and planned analyses of these by subject sex.
All from the programme and abstracts for the 3rd International Workshop on Clinical Pharmacology of HIV Therapy 11-13 April, Washington DC
- Kashuba ADM, Min S, Corbett AH et al. Comparison of protease inhibitor and non-nucleoside reverse transcriptase concentrations in the male and female genital tract. Abs 5.3
- Burger D, Muller RJ, van de Leur MR et al. Lopinavir plasma levels are significantly higher in female than in male HIV-1 infected patients. Abs 6.5
- Regazzi MB, Villani P and Seminari E et al. Analysis of potential gender difference in nevirapine disposition in HIV-infected patients.