R01AI157756

A Novel Reverse Transcriptase Chain Termination (RESTRICT) Assay for Near-Patient, Objective Monitoring of Long-Term PreP Adherence - Abstract

Oral pre-exposure prophylaxis (PreP), composed of tenofovir disoproxil fumarate and emtricitabine, is effective for preventing HIV acquisition. However, PreP efficacy is highly dependent on drug adherence. In several trials and implementation studies, PreP clients have difficulties maintaining adequate adherence and persistence, and monitoring their PreP use is challenging. PreP providers have relied on self-reported adherence, which is often inaccurate and unreliable. The lack of an objective PreP adherence monitoring tool has led to inefficient counseling and poor supportive care.

To address these issues, we completed a randomized pharmacokinetic study to determine drug levels during controlled directly-observed PreP. Longer-term metabolites, such as tenofovir-diphosphate (TFV-DP) (with a ~17-day half-life), provide a more accurate picture of long-term PreP adherence. We recently developed a novel enzymatic assay that semi-quantitatively measures the concentration of TFV-DP by measuring inhibition of reverse transcriptase, which is the cellular target of oral PreP drugs.

In this proposal, our primary objectives are optimizing the reverse transcriptase chain termination (RESTRICT) assay to measure drug concentrations of PreP clients, to establish validation for Clinical Laboratory Improvement Amendments (CLIA) criteria when implemented in a near-patient clinical lab, and to evaluate the feasibility and acceptability of using the RESTRICT assay for drug level measurement among PreP clients and providers.

We will test our central hypotheses with three specific aims:
(1) To calibrate and optimize the RESTRICT assay for measuring long-term TFV-DP drug concentrations, compared to gold-standard liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement;
(2) To validate the RESTRICT assay for meeting established CLIA criteria to enable clinical reporting of an objective near-patient measure for monitoring long-term TFV-DP drug concentrations;
(3) To evaluate the feasibility and acceptability of near-patient TFV-DP testing among PreP clients and providers at a major PreP clinic in Seattle.

Our proposed study will be the first to validate a rapid, near-patient long-term objective measure of oral PreP adherence. This study will also provide crucial data on the feasibility and acceptability of a novel approach for improving PreP delivery and monitoring to prevent HIV transmission. The results of this study will develop a new tool that may help improve PreP delivery in the US and worldwide.

University Of Washington

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Seattle, Washington 981951016 United States

Single Zip Code

Improving Patient Adherence to Treatment and Prevention Regimens to Promote Health (R01 Clinical Trial Optional) (PA-18-722)

Amendment Since initial award the total obligations have increased 399% from $767,819 to $3,828,468.