Combining Latency Reversing Agents to Address the HIV Reservoir

NCT07384624 | Not Yet Recruiting Phase 1 DMC

• 2 other identifiers: 2026-525211-14-00.2026-525211-14-00
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 4

Brief Summary

The PLUTO trial aims to contribute to the worldwide search for a functional cure of HIV. One the strategies ("shock and kill' strategy) aims to reverse the HIV-reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells. Participants of the trial are adults with HIV with undetectable viral load that are able to give informed consent to participate in the trial, in total 30 patients will be recruited. The investigational medical compounds in this trial are topiramate, lenalidomide and pyrimethamine, which will be combined. These are all licensed drugs for other conditions. The study consists of two phases. In phase I participants will receive a single dose of the IMPs, as combination therapy. Sampling will be performed before, during and after medical treatment to evaluate latency reversal and safety endpoints. In phase II, participants will receive the combination of IMPs which is the most potent and within safety limits selected from phase I during a four-week treatment. Sampling will take place on a weekly basis to assess latency reversal, reservoir reduction and safety. Participants will be recruited from the Erasmus MC, Amsterdam university Medical Center, Radboud University Medical Center and the University Medical Center Utrecht.

Conditions

HIV (Human Immunodeficiency Virus); HIV -1 Infection

Keywords

HIV; HIV reservoir; Latency Reversing Agent; HIV cure; Topiramate; Pyrimethamine; Lenalidomide

Outcome Measures

Primary Outcomes (2)

• Phase I primary outcome: Fold change in cell-associated HIV-RNA

  The fold change in cell-associated HIV-RNA within and between the study arms

  At time points 6 and 24 hours after treatment, compared to baseline

• Phase II primary outcome: Log transformed HIV-DNA

  The change in log transformed HIV-DNA within the treatment group. Measured using IPDA and SQuHIVLa

  At time point 4 weeks compared to baseline

Secondary Outcomes (19)

• Phase I & II: Clinical safety and tolerability of the LRA drug combination.

  Phase I: 1 week Phase II: 5 weeks

• Phase I: Participant preference on the latency reversing agent (LRA) combinations.

  At 0 hours, 24 hours and 7 days

• Phase I: Participant quality of life during combination LRA treatment

  Baseline, and at timepoint 7 days

• Phase I: Plasma HIV-RNA kinetics during interventional treatment

  At time points 6 hours, 24 hours and 7 days compared to baseline

• Phase I: Change of the functionality of immune cells

  At 7 days, compared to baseline

Other Outcomes (6)

• Inflammatory biomarkers during LRA treatment

  At time points 24 hours, 1 week and 4 weeks compared to baseline

• Cellular transcriptomic responses before and after exposure to LRA

  At time points 24 hours, 1 week and 4 weeks compared to baseline

• Viral reservoir myeloid or lymphoid cell origin

  At baseline and time points 24 hours, 1 week and 4 weeks

Study Arms (3)

PYR + LENA

EXPERIMENTAL

Pyrimethamine 200mg oral administration + Lenalidomide 25mg oral administration

Drug: Pyrimethamine (PYR); Drug: Lenalidomide

PYR + TOPI

EXPERIMENTAL

Pyrimethamine 200mg oral administration + Topiramate 400mg oral administration

Drug: Pyrimethamine (PYR); Drug: Topiramate (drug)

LENA + TOPI

EXPERIMENTAL

Lenalidomide 25mg oral administration + Topiramate 400 mg oral administration

Drug: Lenalidomide; Drug: Topiramate (drug)

Interventions

Pyrimethamine (PYR) DRUG

Pyrimethamine is a registered antiprotozoal agent, which is used for treating toxoplasmosis and malaria. As a latency reversing agent it exerts its effect by targeting the BAF chromatin remodeling complex involved in maintaining a transcriptional repression.

PYR + LENA; PYR + TOPI

Lenalidomide DRUG

Lenalidomide is a registered immunomodulatory drug, registered for multipel myeloma, lymphoma's and Kaposi Sarcoma. As an LRA it targets transcription factor IKZF1, a transcriptional repressor.

LENA + TOPI; PYR + LENA

Topiramate (drug) DRUG

Topiramate is a drug registered to for migraine prophylaxis and epilepsy. It binds to GRIK5 at the proviral promotor and inhibits its function. GRIK5 derepresses virus transcription initiation with latency reversal as a result.

LENA + TOPI; PYR + TOPI

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented HIV-1 infection, confirmed by 4th generation ELISA, Western Blot or PCR.
• Age ≥ 18 years old.
• Confirmed HIV1, subtype A, B, C or D.
• Uninterrupted ART therapy for a minimum 6 months. .
• No disclosed missed ART on more than 2 days per month.
• Current blood CD4+T-cell count of ≥200 cells/mm3
• No clinical signs of cellular immunodeficiency or AIDS.
• Pre-ART plasma HIV RNA ≥1000 copies/mL.
• Able to understand provided information and to give informed consent.

You may not qualify if:

• Prior exposure to any of the studied LRAs in the previous 90 days
• HIV-2 (double)infection
• Co-infection with hepatitis B, unless resolved HBV (anti-HBc positive, anti-HBs positive and HBsAg negative) OR HBsAg positive and on continuous HBV-active antiviral therapy for ≥24 weeks prior to dosing, and HBV DNA undetectable or ≤ 200 IU/mL on two measurements (screening and within 4 weeks prior to enrolment), and no history of advanced fibrosis/cirrhosis (stage F2 and higher)
• Co-infection with hepatitis C, measured by the presence of hepatitis C virus RNA in blood.
• Co-medication with clinically significant interactions with LRA
• mRNA vaccine or adjuvant vaccine (e.g. Shingrix) in the previous 8 weeks.
• Megaloblastic anaemia due to folate deficiency and untreated haemolysis of any cause
• Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi's sarcoma treated with ART alone or other indolent malignancies.
• History of suicide attempt 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.
• History of epileptic seizures in the previous year.
• Registered allergies for any of the investigational medical products
• Sexually active participants who do not fit any of the following:
• a) Female subject of childbearing potential willing to comply with pregnancy tests before start and four weeks after end of treatment and willing to use of double contraceptive measures during and until 1 week after administration of study medication. Non-childbearing is defined by one of the following criteria: amenorrhoea for ≥ 1 year, premature ovarian failure, assigned male at birth, or having undergone bilateral salpingo-oophorectomy, or hysterectomy. b) Sexually active male PLWH who have sex with female partners of childbearing potential and willing to abstain from sex or willing to use condom protection during and until 1 week after administration of study medication.

Sponsors & Collaborators

• Erasmus Medical Center: lead

Study Sites (4)

Amsterdam University Medical Center

Amsterdam, Netherlands

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Pyrimethamine; Lenalidomide; Topiramate; Pharmaceutical Preparations

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses

Study Officials

• Casper Rokx, MD PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Casper Rokx, MD PhD

CONTACT

+31681336328; c.rokx@erasmusmc.nl

Daniek Teijema, MD

CONTACT

d.teijema@erasmusmc.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Erasmus MC internist-infectious diseases specialist, principal investigator

Model Details: Proof of concept two-phase sequential randomized controlled trial Phase I consists 3 arms of a single dose combination treatment, with a 7-day follow-up. Phase II consists of a single arm four-week treatment, with a total follow-up duration of five weeks.

Study Record Dates

• First Submitted: January 8, 2026
• First Posted: February 3, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): July 1, 2028
• Last Updated: February 3, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, ANALYTIC CODE
• Time Frame: Data will be available after publication of primary results. Data will kept in storage for 25 years
• Access Criteria: Receiving facility has data privacy protection meeting EU GDPR standards

Locations

NL (4)