Combining Latency Reversing Agents to Address the HIV Reservoir
Trial statusNot yet recruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorErasmus Medical Center
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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. .
Disqualifiers
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.
Trial design
Design model
Sequential
Treatments tested in this trial
Pyrimethamine (PYR)
DrugPyrimethamine 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.
Lenalidomide
DrugLenalidomide 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.
Topiramate (drug)
DrugTopiramate 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.
Treatment groups
30 Participants
are divided into 3 treatment groupsGroup A: PYR + LENAExperimental treatment 2 interventions
Group B: PYR + TOPIExperimental treatment 2 interventions
Group C: LENA + TOPIExperimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
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
Time frame
At time points 6 and 24 hours after treatment, compared to baseline2
Phase II primary outcome: Log transformed HIV-DNA
The change in log transformed HIV-DNA within the treatment group. Measured using IPDA and SQuHIVLa
Time frame
At time point 4 weeks compared to baselineSecondary outcomes
1
Phase I & II: Clinical safety and tolerability of the LRA drug combination.
The number and severity of clinical and biochemical adverse events assessed using Common Terminology Criteria for Adverse Events version 6
Time frame
Phase I: 1 week Phase II: 5 weeks2
Phase I: Participant preference on the latency reversing agent (LRA) combinations.
Participant preference for LRA combinations, quantitatively assessed using a pill diary with Likert scales 1-5 (higher scores meaning better outcome)
Time frame
At 0 hours, 24 hours and 7 days3
Phase I: Participant quality of life during combination LRA treatment
To evaluate qualitative patient reported outcomes of quality of life assessed by semi-structured interviews
Time frame
Baseline, and at timepoint 7 days4
Phase I: Plasma HIV-RNA kinetics during interventional treatment
Change in plasma HIV-RNA between and within arms
Time frame
At time points 6 hours, 24 hours and 7 days compared to baselineOther outcomes
1
Inflammatory biomarkers during LRA treatment
Assessment of serum inflammatory biomarkers on LRA treatment
Time frame
At time points 24 hours, 1 week and 4 weeks compared to baseline2
Cellular transcriptomic responses before and after exposure to LRA
Change in host and HIV-related gene expression profile in CD4+ T-cell reservoir cells by RNA sequencing on pathways of immune modulation and off-target effects within and between groups
Time frame
At time points 24 hours, 1 week and 4 weeks compared to baseline3
Viral reservoir myeloid or lymphoid cell origin
Viral envelop myeloid and lymphoid cell tropism by RNA sequencing
Time frame
At baseline and time points 24 hours, 1 week and 4 weeks4
Trained immunity during LRA exposure
Change in transcriptome and epigenetic histone modification in trained monocytes following ex vivo stimulation with several pathogens and ligands of peripheral blood mononuclear cells (PBMC)
Time frame
At time points 24 hours, 1 week and 4 weeks compared to baselineSponsors and contacts
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Source ClinicalTrials.gov
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