Cellular Pharmacology and Platelet Effects of Abacavir and Lamivudine Anabolites

HIV-1-infection Clinical Trial

Official title:

Cellular Pharmacology and Platelet Effects of Abacavir and Lamivudine Anabolites

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04301661
• Other study ID #: 18-2749
• Status: Completed
• Start date: March 6, 2020
• Est. completion date: December 17, 2021

Study information

• Verified date: January 2023
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study will evaluate the intracellular pharmacokinetics and platelet effects of abacavir (ABC), lamivudine (3TC), tenofovir alafenamide (TAF), and emtricitabine (FTC) in persons living with HIV that are receiving these medications as part of standard HIV care.

Participants remaining on ABC/3TC- or TAF/FTC-containing therapy will be on study for 4 weeks, and will have two visits: a screening visit and one short PK visit consisting of a single blood draw at week 4.

Participants switching from their ABC/3TC-containing therapy will be on study for 3 weeks, and will have nine visits: a screening visit and 8 short PK visits consisting of a single blood draw at Day 0, 1, 3, 7, 10, 14, 18, and 21.

Description:

Abacavir and lamivudine are recommended antiretroviral medications used in the treatment of human immunodeficiency virus (HIV) infection in the United States and globally. Both agents are nucleos(t)ide reverse transcriptase inhibitors (NRTIs), which exert their antiviral activity following entry into target cells and phosphorylation by intracellular kinases to their active anabolites, carbovir-triphosphate (CBV-TP) and lamivudine-triphosphate (3TC-TP). There is limited knowledge regarding the pharmacokinetic (PK) disposition of abacavir and lamivudine anabolites in red blood cells (RBCs), neutrophils, and platelets. Abacavir has also been linked with prothrombotic activity and an increased risk of cardiovascular events in patients on this therapy, central theories of which point towards interference with purinergic signaling due to its structural similarity to endogenous adenosine and guanosine. These findings have not been replicated with other NRTI medications, such as tenofovir. This pilot study will characterize the pharmacokinetics (PK) of these medications in different cell types of persons living with HIV (PLWH) on these therapies as part of clinical care, and will examine endogenous nucleotide levels and metabolic profiles through the use of metabolomics in platelets specifically to better understand what changes might be happening within this cell type with the use of these medications.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: December 17, 2021
• Est. primary completion date: December 17, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

ABC/3TC Cohort:

• On abacavir 600 mg/lamivudine 300 mg-containing regimen as part of their ART for at least 6 months prior to entry

• HIV-1 RNA <200 copies/mL at screening and within the previous 6 months

TAF/FTC Cohort:

• On tenofovir alafenamide 25 mg/emtricitabine 200 mg-containing regimen as part of standard care for at least 6 months prior to entry

• HIV-1 RNA <200 copies/mL at screening and within the previous 6 months

Switch Cohort:

• Switching from an abacavir/lamivudine-containing regimen (to any other ART regimen not containing ABC/3TC) as part of standard care as recommended by their HIV provider

Exclusion Criteria:

• eGFR <50 mL/min/1.73 m2

• Platelet count <100,000 cells/mm3

• Current or previous use (within 30 days) of anticoagulant or antiplatelet medications (e.g., aspirin, P2Y12 inhibitors, vitamin K antagonists, anti-Xa inhibitors, thrombin inhibitors, etc.)

• History of cardiovascular event(s) (e.g., myocardial infarction, cerebrovascular accident (stroke), peripheral arterial thrombosis, etc.), platelet or bleeding disorders

• Pregnant or planning pregnancy

• Any uncontrolled medical, social, or mental-health issue(s) that, in the opinion of the investigators, could interfere with study participation or the study outcomes

• Inability to comply with directly observed dosing (i.e., lack of availability or ability to use video streaming technology)

Related Conditions & MeSH terms

• HIV-1-infection

Intervention

Other:
• Blood collection
Blood will be collected from participants at defined time points during the study to measure drug levels and assess platelet activity.

Drug:
• Abacavir/lamivudine
Participants who are already taking abacavir/lamivudine as part of standard HIV care will continue taking their therapy.
• Tenofovir alafenamide/emtricitabine
Participants who are already taking tenofovir alafenamide/emtricitabine as part of standard HIV care will continue taking their therapy.
• Switch
Participants who are planning to switch from abacavir/lamivudine as part of standard HIV care will change therapy to per the discretion of their HIV provider.

Locations

Country	Name	City	State
United States	University of Colorado Hospital	Aurora	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
University of Colorado, Denver

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intracellular concentrations of endogenous nucleotides measured in platelets from patients on abacavir- or tenofovir-containing therapy.		(Week 4 in ABC/3TC and TAF/FTC Cohorts; Days 0 and 21 in Switch Cohort)
Other	Intracellular endogenous metabolites measured in platelets from patients on abacavir- or tenofovir-containing therapy.		(Week 4 in ABC/3TC and TAF/FTC Cohorts; Days 0 and 21 in Switch Cohort)
Primary	Intracellular steady-state concentrations of abacavir and lamivudine anabolites in RBCs (also measured in DBS), PBMCs, platelets, and neutrophils.	Based on drug concentrations measured at week 4	(Week 4 in ABC/3TC and TAF/FTC Cohorts)
Primary	Intracellular half-lives of abacavir and lamivudine anabolites in RBCs (also measured in DBS), PBMCs, platelets, and neutrophils.	Based on decline in drug concentrations between days 0 and 21.	(Days 0, 1, 3, 7, 10, 14, 18, 21 in Switch Cohort)