Infectious Disease Advisor: What is the focus of current clinical trials when it comes to the biologic differences (ie, sex hormones) between men and women?
Dr Karris: HIV researchers are very interested in better understanding the impact of sex hormones on HIV prevention. Women appear more vulnerable to sexually transmitted infections (STIs) and HIV infection at certain times of their menstrual phase; this is a concept termed the “window of vulnerability.”39 The hypothesis is that as the body is getting ready for implantation of a fertilized egg, it utilizes hormones to lower the immune responses in the female reproductive tract. In doing so, women may inadvertently be placed at higher risk for the acquisition of HIV infection and other STIs. There is some concern that the use of long-term contraception, particularly medroxyprogesterone acetate (Depo-Provera®), may also put women at increased risk for HIV, with recent data suggesting use increases the proportion of activated T cells at the cervix, but the exact mechanisms are not yet completely described.40,41
Another potential future area of research includes a better understanding of how biologic differences between men and women may or may not affect HIV cure efforts.
Infectious Disease Advisor: Dr Gianella, what is the current status of HIV cure and eradication in women?
Dr Gianella: Poverty, gender, and sex-related inequalities are important barriers when considering HIV cure and eradication. However, biologic differences between men and women might be equally relevant for HIV cure. HIV cure is a hot topic and most cure-related research and early-stage clinical trials are conducted in higher-income countries. Many compounds that are tested as part of HIV cure trials are very early in development with an unclear safety profile and no direct benefit.
Therefore, there is some reluctance to include any women of reproductive potential in early-phase trials because of the risks associated with reproductive toxicity and unintended pregnancies despite rigorous contraceptive requirements.2 Failure to enroll women in early-phase cure trials creates critical knowledge gaps and missed opportunities to learn about basic biological responses and how they might differ between genders.
In fact, there is plenty of evidence suggesting that sex/gender might play an important role in HIV persistence. For example, one French study investigated HIV DNA levels in more than 500 HIV-infected individuals receiving suppressive ART and observed that women are more likely to achieve lower HIV DNA levels compared with men.42 Similarly, the distribution of the reservoir across the body might be different between men and women. The association between the amounts of HIV in blood and in the female genital tract is unknown, especially in relation to menstrual cycling. Sex differences in the HIV reservoir distribution between gut, lymph nodes, and other tissues are under investigation.2 For instance, one recent study found a high proportion of cells harboring HIV DNA in adipose tissue.43 Since men and women have well-documented differences in fat content and distribution, adipose tissue might be playing a different role as an HIV reservoir in women than in men. Sex hormones can also affect the blood-brain barrier, and there is concern that HIV reservoirs might be different in the brains of women compared with men.2
There are some interesting data that were presented in 2015 at the International AIDS Society meeting by Jonathan Karn and colleagues. His group showed that estrogen is a potent inhibitor of HIV transcription in vitro and this might be important for the design of HIV cure interventions.44 In fact, most of the current clinical trials are focused on kicking the virus out of the cells in order to unmask it from latency and target it for elimination (so-called “kick-and-kill” strategies).45 Since estrogen is a potent inhibitor of HIV transcription, such “kick-and-kill” strategies might work differently between men and women and might be highly dependent on circulating estrogen levels. These new data raise concern that interventions designed for men might not work equally well for women. These differences must be addressed to permit the design of effective HIV-eradication strategies across the entire spectrum of genders.