March 1, 2011
A little light from CROI 2011 has shone into the dark corners of HIV research in aging women. Two oral presentations featured HIV-related studies that compared pre-menopausal to post-menopausal women. One study looked at the expression of CCR5 -- the primary CD4 binding receptor for HIV -- in the vaginal tract. The other study assessed levels of a drug widely used in antiretroviral regimens (and in experimental pre-exposure prophylaxis).
Much of the biology of older women as it relates to HIV infection remains undiscovered. However, it is understood that lower levels of estrogen production after menopause affect a variety of factors -- thickness of the vaginal mucosa, vaginal secretion production and drug metabolism, for starters. Meanwhile, it is estimated that, by 2014, half of all people living with HIV in the U.S. will be over 50. Because changes in the vagina could affect susceptibility to HIV infection for women (whose primary route of infection is heterosexual sex), this topic will only continue to grow in importance.
Amie Meditz, M.D., presented a comparison of CCR5+ CD4 cells in the cervixes of HIV-uninfected pre- and post-menopausal women (oral abstract 33). It is known that new infections are increasing in women over 50 in the U.S. and also that elevated expression of CCR5 on CD4 cells correlates with increased susceptibility to HIV infection. What Meditz showed is that post-menopausal women have significantly greater expression of CCR5 on activated CD4 cells in the cervix than do pre-menopausal women.
In the same session, Kristine Patterson, M.D., presented data on the metabolism of tenofovir (TDF, Viread) in post-menopausal women compared to pre-menopausal women (oral abstract 32). She and her colleagues looked at the level of tenofovir in the blood and cervicovaginal fluids after the initial dose of an antiretroviral regimen that included tenofovir with emtricitabine (FTC, Emtriva), as well as the steady-state level of drug exposure after four weeks on the regimen. The pre-menopausal women were studied first, followed at a later date by the post-menopausal part of the study.
After the first dose, drug exposure was similar in the blood for pre- and post-menopausal women, but higher in the cervicovaginal fluids of post-menopausal women. After four weeks, post-menopausal women had higher levels of tenofovir in both the blood and the cervicovaginal fluids. This difference was significant.
The lack of investigation into the hormonal milieu of women with HIV infection was highlighted in this presentation when the investigator acknowledged that the team only looked at drug levels in pre-menopausal women during the first phase of their menstrual cycles. Patterson admitted that the study did not include the second phase because the researchers did not expect there to be a difference. Only later, after discovering the impact of reduced estrogen in the post-menopausal women, did they realize that it would also be important to look at drug levels in pre-menopausal women during the second (lower-estrogen) phase of their menstrual cycle.
There were only six post-menopausal women in the study, compared to 12 pre-menopausal women (though they were mostly women of color -- thank you for the diversity, Patterson et al!), which may have accounted for the variability of drug levels seen in post-menopausal women. However, the significantly increased levels of overall drug exposure in post-menopausal women warrants further study. This is particularly important given the reality that older women are inherently more susceptible to bone loss, the fact that more older women will be living with HIV in the coming years, the association of tenofovir with bone loss and the fact that tenofovir is about as widely used these days as an antiretroviral gets.
The significance of the findings was highlighted when an audience member asked the presenter if she felt the increased drug levels presented a cause for concern about bone loss in post-menopausal women with HIV who are on tenofovir. Patterson's reply was simple and clear: "It's a huge consideration."
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