Early Metabolic Effects of Antiretroviral Drugs in Healthy volUnteers: a Phase 2 Randomized Study

Study Description:

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral (ARV) drugs that are currently among first-line therapies to treat and prevent HIV. Several observational trials have shown that one side effect of this class of ARVs is involuntary weight gain. How these drugs cause weight gain is incompletely understood. In addition, one of these marketed drugs (bictegravir) is coformulated in combination with the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir alafenamide (TAF), which may also independently contribute to weight gain, including when it is compared against the related prodrug tenofovir disoproxil fumarate (TDF). To better understand the effects of INSTIs and TAF on metabolism, healthy volunteer participants will be randomized 1:1:1:1 to one of four arms: the INSTI dolutegravir (DTG), TAF, DTG plus TAF, or TDF. Participants will undergo an initial screening evaluation, a 2-week treatment-free lead-in period, and then a 4-week open-label treatment phase during which they will take the assigned study drug(s). During the study, participants will be assessed for changes in metabolic pathways, metabolites, and gene expression using a multi-omic approach. They will undergo serial research sample collection, including adipose tissue biopsy and microbiome sampling, both prior to initiation and after 4 weeks of the study drug(s).

Objectives:

Primary Objective:

To characterize the change in plasma metabolite profile that 4 weeks of each treatment may induce in the absence of HIV infection.

Secondary Objectives:

• To characterize the change in plasma proteomics and lipidomics that 4 weeks of each treatment may induce in the absence of HIV infection.
• To characterize the change in peripheral blood mononuclear cell (PBMC) transcriptomics and cell populations that 4 weeks of each treatment may induce in the absence of HIV infection.
• To characterize the changes in adipose tissue via RNA sequencing, metabolomics, and proteomics that 4 weeks of each treatment may induce in the absence of HIV infection.
• To determine if baseline (prior to study agent administration) demographics (eg, age, sex, or weight) or laboratory characteristics (eg, free thyroxine [T4], thyroid-stimulating hormone [TSH], cortisol, or other hormones) are associated with multi-omic changes induced by each treatment.
• To compare the multi-omic changes induced by DTG and/or TAF versus TDF in the absence of HIV infection.

Exploratory Objectives:

• To determine if there is a correlation between pharmacokinetic (PK) measurements of TAF, DTG, or TDF and multi-omic changes.
• Evaluation of microbiota in vaginal, oral, and rectal mucosa, including potential reactivation of human endogenous retroviruses (HERVs) at start and the end of each treatment.

Endpoints:

Primary Endpoint:

Change in plasma metabolites from ARV initiation to the end of the 4-week period of ARV therapy with each treatment.

Secondary Endpoints:

• Comprehensive multi-omic profile changes in plasma, PBMCs, and adipose tissue from ARV initiation to the end of the 4-week treatment period with each treatment, encompassing transcriptomic changes, metabolomic alterations, lipidomic shifts, and proteomic variations.
• Relationship between demographic data or baseline laboratory values and multi-omic profile changes in plasma, PBMC, and adipose tissue.
• Multi-omic comparisons between DTG and/or TAF versus TDF.

Exploratory Endpoints:

• Relationship between PK parameters for TAF, DTG, and TDF and multi-omic profile changes in plasma, PBMC, and adipose tissue.
• Potential changes in microbiome composition and HERV reactivation after treatment periods.

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Aged 18 to 55 years.
• Able to provide informed consent.
• Willing to allow samples and data to be stored and shared for future research.
• Agrees to use a barrier method of contraception or abstain from sexual activity starting at screening though the end of study participation.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Current infection with HIV or hepatitis A, B, or C.
• Body mass index (BMI) <18.5 kg/m^2 or >30.0 kg/m^2.
• Weight change >5% in the past 6 months.
• History of or current cardiovascular disease such as congestive heart failure, heart block, or clinically relevant abnormal ECG as determined by investigators.
• History of or current liver disease or alanine transaminase serum level >2x upper limit of normal.
• History of or current kidney disease or renal insufficiency, or estimated creatinine clearance <=80 mL/min (Modification of Diet in Renal Disease equation).
• Current cancer or history of cancer within 5 years of screening, with the exception of squamous cell carcinoma or basal cell carcinoma that is localized and does not require systemic therapy.
• History of bariatric surgery.
• Diabetes mellitus as defined by a prior diagnosis or a hemoglobin A1c of >6.4 percent on screening labs.
• Fasting serum glucose >126 mg/dL.
• History of or current hypo- or hyper-thyroid or abnormal TSH, except minor deviations deemed to be of no clinical significance by the investigator.
• History of or current asthma or chronic obstructive pulmonary disease.
• Psychological conditions by self-report, such as (but not limited to) clinical depression, bipolar disorders, which would be incompatible with safe and successful participation in this study.
• Pregnancy or within 1 year post-partum.
• Breastfeeding.
• Blood pressure >140/90 mm Hg or current antihypertensive therapy.
• Hemoglobin that is either 10 percent below the lower limit or 10 percent above the upper limit of the normal range for the Clinical Center Laboratory (acceptable ranges: females 10.08-17.27 g/dL, males 12.33-19.25 g/dL).
• History of illicit drug, opioid, or alcohol abuse within the last 5 years; current use of illicit drugs or opioids (by history) or excessive alcohol (CAGE assessment score >=2).
• Current use of the following prescription or over-the-counter medications and supplements:

• Carbamazepine
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Primidone
• Rifabutin
• Rifampin
• Rifapentine
• St. John's wort (Hypericum perforatum)
• Cation-containing antacids or laxatives
• Sucralfate
• Buffered medications
• Oral calcium, iron, magnesium, or zinc supplements, including multivitamins containing these polyvalent cations
• Dalfampridine
• Metformin
• Dofetilide
• Thyroid medications
• Corticosteroids
• Weight loss medications, including prescription drugs (eg, semaglutide and tirzepatide) and over-the-counter diet pills
• Use of TAF, TDF, and/or FTC for the purpose of HIV PrEP or in a research study within the past 6 months.
• Any history of exposure to cabotegravir or lenacapavir (eg, as HIV PrEP or as a participant in a research study for these drug).
• Current use of prescrtiption or nonprescriptive medications that may have interactions with study drugs or confound the study measurements as determined by the investigators.
• History of adverse or allergic reactions to the study drugs.
• Daily caffeine intake >500 mg (about 4 cups of coffee).
• Current smoker or user of tobacco products.
• A change in the participant s diet and/or exercise regimen in the past 3 months or during the timeframe of the study period that, in the opinion of the investigator, would compromise the integrity of the data.
• High-risk sexual activity as determined by the investigators, and/or inability or unwillingness to use barrier contraception during the protocol.
• Any other condition, medication, or dietary pattern that, in the opinion of the investigators, increases risk to the participant, prevents the participant from complying with study procedures, prevents the participant from completing the study, or interferes with the interpretation of study results.