Combining Latency Reversing Agents to Address the HIV Reservoir

Rationale Though combined antiretroviral therapy (ART) has made HIV a clinically manageable chronic illness by preventing viral replication, HIV poses great burdens on PLWH and society to this day. Due to the presence of a stable, latent viral reservoir, the virus rebounds when ART is stopped. Additionally this reservoir fuels inflammation with related comorbidities. Finding therapies to reduce the reservoir are therefore an important research objective. One strategy to shrink or eliminate the latent reservoir aims to reverse the reservoir from latency, leading to increased antigen presentation and trigger immune recognition (the "shock and kill" strategy). Several latency reversal agents (LRA) have been identified. Though single LRA treatment are effective to a limited extent, they have not resulted in significant HIV reservoir reduction. PLUTO, aims to study novel combinations of promising LRAs with different targets to reactivate and reduce the latent viral reservoir by identifying the combination with strongest latency reversal of phase I of our study and assessing latency reversal and reservoir decay after prolonged treatment in phase II of our study.

Objectives

Primary objectives phase I:

• To assess the efficacy of LRA combinations during a one day treatment on HIV reservoir reactivation in people living with HIV.

Primary objectives phase II:

• Efficacy of dual LRA combination treatments on HIV reservoir reduction.

Main trial endpoints

Phase I Primary endpoint:

• Fold change in cell-associated HIV-RNA at time points 6, and 24 hours compared to baseline

Phase II Primary endpoint:

• Log transformed HIV-DNA at T=4w compared to T=0

Trial design Proof of concept two-phase sequential randomized controlled trial. Phase I consists of three arms receiving a single dose combination treatment, with a 7-day follow-up.

Phase II consists of a single arm receiving a four-week treatment with the selected treatment from phase I, and a with a total follow-up duration of five weeks.

Trial population Phase I 30 people with HIV-1 with inclusion criteria: ≥18years of age, plasma HIV-RNA >1000c/mL before ART, current plasma HIV-RNA <50c/ml for at least two measurements on uninterrupted ART and current CD4+T-cells > 200/mm3.

Phase II A minimum of 16 people with HIV-1 with the same inclusion criteria. All participants from phase I are eligible, and may move on to, phase II with additional consent. In case the required number of participants are not reached from phase I, new participants can be recruited following the same selection procedure as in phase I.

Interventions Phase I The investigational drugs are Pyrimethamine, Lenalidomide, and Topiramate. Patients will be randomized 1:1:1 in one of three arms to receive a single dose of LRA combination of two investigational drugs

Phase II Compound combination with highest latency reversing potential, within safety limits and taking patient participant preference into account is the phase II intervention. Dosing is adjusted to achieve steady state concentrations similar to phase I.

Inclusion criteria

• 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. .
• Plasma HIV RNA <≤50 copies/ml prior to inclusion at two consecutive measurements at least three months apart.
• 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.

Exclusion criteria

• 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.

c) Sexually active male PLWH who have sex with postmenopausal female partners and willing to abstain from sex or willing to use condom protection or with a postmenopausal female partner on pre-exposure prophylaxis during and until 1 week after administration of study medication.

d) Male PLWH who have sex with male partners and willing to abstain from sex or willing to use a condom protection during and until 1 week after administration of study medication.

e) Male PLWH who have sex with male partners on preexposure prophylaxis during and until 1 week after administration of study medication.

• Any lab abnormalities at screening as listed below:

• Moderate kidney impairment, defined as eGFR <50 mL/min. In PLWH on dolutegravir- or bictegravir-based ART regimens, cystatin C-based eGFR can be used, since possible drug interference with tubular creatinine excretion which leads to eGFR underestimation.
• Moderate hepatic impairment, defined as bilirubin > 3 x upper limit of normal (ULN) or ALT > 3x ULN
• Inadequate blood counts, defined as: haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), Absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L, international standardized ratio >1.6, activated partial thromboplastin time >40 seconds,