Studying Topiramate for Re-Activating the HIV-1 Reservoir (STAR)

A Phase I/II Clinical Trial Investigating the Effect of Topiramate on the Reactivation of the HIV-1 Reservoir in People Living With HIV on Antiretroviral Therapy

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.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV Infections; Hiv; HIV-1-infection; HIV I Infection
• Intervention / Treatment: Drug: Topiramate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Erasmus Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented HIV-1, subtype B or C
• Aged 18 or over
• On ART for a minimum of 2 consecutive years and a maximum of 12 consecutive years
• HIV-1 RNA plasma level <30 copies/mL for at least two consecutive measurements prior to inclusion (viral blips with a detectable HIVRNA 30-200 c/mL preceded and followed by HIV-RNA <30 are allowed)
• CD4+ T cell count ≥200 cells/mm^3 at screening
• Able to understand the information and give informed consent

Exclusion Criteria:

• Any major acute medical condition requiring hospitalisation within the past 4 weeks.
• Presence of an active opportunistic infection that defines Acquired Immunodeficiency Syndrome (AIDS).
• Any medical condition deemed by the investigator to hinder compliance with the study treatment.
• The following laboratory values at the screening phase (available before baseline (T0)): hepatic transaminases (AST or ALT) ≥3 times the upper limit of normal (ULN), serum total bilirubin ≥3 times the ULN, estimated glomerular filtration rate (eGFR) ≤60 mL/min based on CKD-EPI, haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), leucocytes <2.5 x10^9/L, absolute neutrophil count <1000 cells/mm^3, thrombocytes <100 x10^9/L
• Active malignancy during the past year except for basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi Sarcoma treated with ART alone, or other indolent malignancies.
• Participants who are unwilling or unable to use barrier contraception during sexual intercourse during the study.
• History of suicide or suicidal ideation.
• History of ophthalmological medical problems leading to glaucoma or visual field disturbances (e.g. macula oedema). Refraction abnormalities that can be corrected by lenses are acceptable.
• History of any medical condition with a causal relationship with hyperammonemia.
• Participants using phenytoin, carbamazepine, digoxin, lithium, or valproic acid throughout the trial period.
• Any concurrent medicine use associated with hyperammonemia (e.g. valproic acid).
• Participants with active substance abuse.
• Participants who have registered allergies to the investigational medical product.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Men; Sex assigned at birth, male Single dose of 400mg topiramate	Drug: Topiramate; Single dose of 400mg
Experimental: Women; Sex assigned at birth, female Single dose of 400mg topiramate	Drug: Topiramate; Single dose of 400mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of topiramate as measured by cell-associated HIV RNA	To assess the effect of topiramate on HIV reactivation in people living with HIV on ART	24 hours
Number of treatment-related adverse events as assessed by CTCAE v4.0	To evaluate the clinical safety and tolerability of topiramate	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Influence of sex on the primary outcome measures	To evaluate the influence of sex on reactivation potential as measured by cell-associated HIV RNA, and safety and tolerability of topiramate as assessed by CTCAE v4.0	24 hours
The effect of topiramate on the size of the HIV reservoir measured by relevant assays	To assess the effect of topiramate on the size of the HIV reservoir	24 hours

Collaborators and Investigators

• Sponsor: Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: February 12, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Actual): February 28, 2024

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Topiramate; HIV Cure; Latency Reversing Agents; Shock and Kill; Latency Reversal
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Hypoglycemic Agents; Physiological Effects of Drugs; Anticonvulsants; Topiramate
• Other Study ID Numbers: 2024-511532-27-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data will be stored in accordance with the FAIR use principle for potential future studies. If external researchers express interest in this dataset, they are encouraged to reach out to the lead investigator. Provided that sufficient privacy measures are in place, the data may be disseminated under a newly established Data Sharing Agreement.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No