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

Official title

Early Metabolic Effects of Antiretroviral Drugs in Healthy Volunteers: A Phase 2 Randomized Study

Overview

Background: People with HIV take drugs to keep the amount of virus in their body low. One type of these drugs, called integrase strand transfer inhibitors (INSTIs), can cause weight gain over time. Weight gain can cause diabetes, heart disease, and other serious issues. Researchers want to understand how INSTIs cause weight changes. Objective: To characterize the change in plasma metabolite profile that 4 weeks of each treatment may induce in the absence of HIV infection Eligibility: Healthy people aged 18 to 55. Design: Participants will be screened in the outpatient clinic. They will have a physical exam and blood tests. They will have a nutritional assessment and tests of their heart function. Participants will be randomized to one of four oral treatments: Tenofovir Disoproxil Fumarate TDF/Viread, Tenovovir Alafenamide TAF/Vemlidy, Dolutegravir DTG/Tivicay, or both TAF and DTG taken together for 4 weeks. Participants will have a Day 0 visit for the Lead-In Baseline visit for an exam and blood tests and continuous glucose monitor placement. Participants will return in 2wks or Day 14/Wk 2 for a DEXA (dual-energy X-ray absorptiometry). DEXA is a kind of X-ray that measures body fat and bone density. Optional adiopse (fat) tissue biopsy in the abdomen, and optional microbiome specimen collections. Continuous glucose monitor changed. Oral once a day dose medication will be started with education. Participants will return in 2wks or Day 28/Wk 4 for exam, labs, and continuous glucose monitor changed. Participants will return in 2wks or Day 42/Wk 6 for final exam, labs, repeat DEXA scan, repeat adipose tissue biopsy, and microbiome specimen collections.

Detailed description

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.

Interventions

• Drug Dolutegravir (DTG) AND Tenofovir alafenamide (TAF)
  50mg dolutegravir (DTG) one tablet AND 25mg tenofovir alafenamide (TAF) one tablet together, orally once daily for 4 wks (Day 14 to Day 42)
• Drug Tenofovir Disoproxil Fumarate
  300mg tenofovir disoproxil fumarate (TDF) one tablet orally once daily for 4 wks (Day 14 to Day 42)
• Drug Dolutegravir
  50mg dolutegravir (DTG) one tablet orally once daily for 4 wks (Day 14 to Day 42)
• Drug Tenofovir alafenamide
  25mg tenofovir alafenamide (TAF) one tablet orally once a day for 4 wks (Day 14 to Day 42)

Primary outcome measures

• Change in plasma metabolites from ARV initiation to the end of the 4 week period of ARV therapy with each treatment [Time frame: Day 14/Wk2 to Day 42/Wk6 of ARV therapy for each of 4 drug regimen.]

Secondary outcome measures (4)

• Encompassing transcriptomic changes, metabolic alterations, lipidomic shifts, and proteomic variations. [Time frame: Throughout study - Baseline to Day 42/Wk 6]
• 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 of four treatments [Time frame: Throughout study - Baseline to Day 42/Wk 6]
• Relationship between demographic data or baseline laboratory values and multi-omic profile changes in plasma, PBMC, and adipose tissue. [Time frame: Throughout study - Baseline to Day 42/Wk 6]
• Multi-omic comparisons between DTG and/or TAF versus TDF. [Time frame: Throughout study - Baseline to Day 42/Wk 6]

Eligibility criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• National Institutes of Health Clinical Center — Bethesda

Publications

• Squires K, Kityo C, Hodder S, Johnson M, Voronin E, Hagins D, Avihingsanon A, Koenig E, Jiang S, White K, Cheng A, Szwarcberg J, Cao H. Integrase inhibitor versus protease inhibitor based regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study. Lancet HIV. 2016 Sep;3(9):e410-e420. doi: 10.1016/S2352-3018(16)30016-9. Epub 2016 May 27. PMID 27562742
• Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, Kulagin V, Givens N, de Oliveira CF, Brennan C; FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015 Apr;2(4):e127-36. doi: 10.1016/S2352-3018(15)00027-2. Epub 2015 Ma PMID 26424673
• Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, Kuritzkes DR, Sagar M, Brown TT, Cohn SE, McComsey GA, Aweeka F, Fichtenbaum CJ, Presti RM, Koletar SL, Haas DW, Patterson KB, Benson CA, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS; ACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment PMID 25285539

Identifiers

NCT: NCT05652478 · 10000906 · 000906-I

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗