Studying Topiramate for Re-Activating the HIV-1 Reservoir

Overview

Even with current HIV treatments, HIV is still a lifelong disease because it hides in some long-lasting cells in the body. One of the strategies to find a cure for HIV works by finding the virus in these cells, making it visible, and then getting rid of it. This is called the 'shock and kill' approach. So far, the drugs tested can find the virus, but they don't get rid of it completely. That's why there need to be new drugs that can do this more effectively. The Erasmus MC HIV Eradication Group (EHEG) has been testing new drugs in the lab and found a drug called topiramate can wake up the virus without harming the cells. The aim of this study is to test topiramate in people living with HIV. Most of the people that participate in HIV cure studies are men, even though most people living with HIV around the world are women. Previous research has shown that men and women might respond differently to these treatments. So, in this study, topiramate will be investigated in both men and women. This could help us find a cure that works for everyone.

Despite antiretroviral therapy (ART), an infection with the human immunodeficiency virus 1 (HIV-1) is still a lifelong disease because of the latent HIV reservoir. This reservoir consists of a pool of long-lived cells harbouring an integrated copy of the HIV provirus in its genome. One approach to curing HIV centres on reversing viral latency, combined with the subsequent elimination of the virus from this reservoir specifically, all while safeguarding other cells through the use of ART. This approach is colloquially known as 'shock and kill'. The limited number of latency reversing agents (LRAs) that have been studied were effective at reactivating the latent reservoir, but do not result in significant reservoir reduction (Debrabander, 2023). Investigating novel LRAs is, therefore, necessary to identify more potent ways of HIV reactivation, with the ultimate goal of reservoir depletion i.e. a functional HIV cure. The Erasmus MC HIV Eradication group has set up a translational trial platform, where successfully study the effects of novel LRAs from bench to bedside. One example is the discovery of small molecule inhibitors of BAF, which reverse HIV-1 latency, to a clinical trial investigating pyrimethamine in people living with HIV (PLWH) (Stoszko, 2016; Prins, 2023). A new promising drug target that was identified in EHEG is the glutamate receptor, ionotropic kainate 5 (GRIK5); a host factor involved in HIV latency (Roling, 2021). The registered drug topiramate was identified as a potential GRIK5 inhibitor. Further ex vivo testing confirmed HIV latency reversal of topiramate at therapeutic levels without inducing cytotoxic effects. This opens new opportunities for HIV cure research. A further knowledge gap to be explored is the influence of sex in HIV latency reversal. Typically, either by design or recruitment, male participants have been vastly overrepresented in HIV cure research (Barr, 2020). This is despite previous research showing significant difference in HIV latency reversal in women (Rao, 2022), and the importance of sex in pharmacodynamics being increasingly recognised (Gandhi, 2004; Mauvais-Jarvis, 2021). As the majority of PLWH worldwide are women and their numbers are expected to grow, studies on any potential cure strategy that provide an evidence base for their use in women increase clinical impact (UNAIDS, 2023). Therefore, the aim of this study is to examine the effect and safety of topiramate as an LRA in both men and women.