Clinical Trial Update: A5366 - Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation with Histone Deacetylase Inhibitors (the MOXIE trial)

Women bear half the burden of HIV infections worldwide and it is critical that any interventions developed to try to cure HIV are effective in both women and men. However, without studying women specifically, researchers simply cannot be confident new treatments will be as effective in them versus their male counterparts. Therefore, identifying and examining biological differences between men and women living with HIV will assist researchers in discovering new immune responses and provide new approaches to cure research. One important biological difference between women and men is related to the sex hormone estrogen. Recent research has shown that estrogen can directly influence the activity of the HIV virus in cells (Karn et al., International AIDS Society meeting, Vancouver, 2015). The presence of estrogen in women may therefore influence certain strategies being studied to work towards an HIV cure. One therapeutic approach to address this difference is to block the estrogen receptor, to try to increase the activity of other medications targeting the HIV virus. As there is extensive clinical experience using estrogen receptor blocker medications that are safe and effective treatments for breast cancer, researchers were intrigued. With this information in mind, Protocol A5366: Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation with Histone Deacetylase Inhibitors (the MOXIE trial) was developed by a team of ACTG Network researchers led by Protocol Co-Chairs Eileen Scully, MD, PhD, of the Johns Hopkins University Clinical Research Site and Rajesh Gandhi, MD, of Massachusetts General Hospital Clinical Research Site.

“In the field of HIV cure research, many of the proposed treatments are based on stimulating the host immune cells either to induce expression of the HIV virus or to mount an immune response,” said Dr. Scully. “Unlike antiretroviral therapy, which directly targets the virus, cure therapies that target the individual’s immune system may be more heavily influenced by differences among study participants, including sex differences. Since there are so many women living with HIV worldwide, the cure field needs to carefully consider the importance of sex differences when developing new treatments; if we wait too long, we may miss important factors.”

Preliminary data supporting A5366 shows that when researchers try to reactivate or ‘turn on’ the latent reservoir in women living with HIV, the presence of estrogen blocks the expression of virus. This means that a woman (who has circulating estrogen that varies during the monthly cycle) may be more resistant to efforts to try to ‘turn on’ the latent reservoir to flush out the virus than male counterparts.

As Dr. Gandhi explains “Women have higher levels of estrogen, but it is actually found in both women and men. If the results of A5366 are positive, future cure studies may be designed with combinations of estrogen blockade and latency reversal in different populations.”

The A5366 study is using a combination of tamoxifen (which blocks estrogen receptors) and vorinostat to reverse latency. Vorinostat is one of the drugs that tries to ‘wake up’ latent HIV by opening the areas of DNA in the cell that contain the virus. It is one of a class of drugs known as histone deacetylase inhibitors that have been used in HIV clinical trials both in the United States as well as in Europe and Australia. Previously, very few women have been enrolled in those trials, so there is very little data about how these drugs work in women specifically.

A5366 seeks to enroll 30 women across multiple domestic ACTG Network sites. The A5366 team has been working to engage with the community of people living with HIV to open the discussion of how important studies in women are for the field of HIV cure. They believe that one major barrier is that the importance of sex differences and the need to enroll women may not be fully appreciated by both women living with HIV and by the research and clinical trial community.  In addition, having a significant representation of women in decision-making about clinical trials will bring a unique perspective.

“This is the first clinical trial related to HIV cure in the ACTG Network that is exclusively for women. In addition to the study treatments, we are collecting surveys from the women participating in the trial, to understand what about the research is most important to them, and how we can make our studies most relevant for women living with HIV,” said Dr. Scully.

Regardless of the results of A5366, designing and conducting this clinical trial exclusively in women will be an important statement to the research community. It will not only be a testament to the willingness of women to participate in clinical trials, but also to the feasibility of having trials specifically focused on questions relevant to women.

“We hope this important proof of concept trial will mobilize women interested in HIV cure research to learn more about this important area of research.  It is critical that we examine sex differences in the factors that control HIV replication to inform our strategies for a cure,” said Dr. Judith Currier, ACTG Network Chair and Principal Investigator.

There is little doubt that a lack of women participating in HIV clinical trials in the past has left us with many questions about the safety and effectiveness of specific treatments in women. A5366 asks a core scientific question about the influence of estrogen on HIV latency that is relevant to both women and men and underlines the importance of making sure our research reflects the population living with HIV.