R37AI098472

?Hair Lengthening?: Using Hair Levels to Interpret Long-Acting Prep Studies. - Project Summary/ Abstract

Long-acting injectables for antiretroviral therapy (ART) or pre-exposure prophylaxis (PreP) are the most exciting recent advance in HIV medicine. The roll-out of cabotegravir long-acting (CAB LA) PreP will be expanded massively globally with the WHO advising this PreP option in late July 2022.

For any new PreP tool, determining the best way to avert failures is key, especially with CAB LA PreP which can fail with integrase inhibitor mutations, with implications for future management. The trials demonstrating that CAB LA was superior to oral PreP across populations employed single plasma levels of CAB as exposure metrics to adjudicate failures.

However, half of the breakthroughs in the trials were not explained by plasma CAB levels, especially with on-time injections, likely because of limitations of plasma levels. Drugs delivered via injection elute from depot compartments at variable rates over time, making long-term metrics of exposure important.

Our UCSF group has been working on long-acting exposure metrics of antiretrovirals (ARVs) in hair samples (which are easy to collect, store and ship) during the first iteration and first renewal of this R01 grant. We have been highly productive over this R01 to date (publishing 72 papers), demonstrating important uses of hair levels in the fields of HIV treatment, prevention, over the perinatal period, and in low-income countries.

As PreP is revolutionized with the availability (e.g. CAB) and promise (e.g. lenacapavir) of LA agents, drug levels will play a critical role in determining the onset of protection, adjudicating failures, and assessing risks with discontinuation; this renewal seeks to contribute to this important field.

As an exploratory objective, we will also develop an antibody to CAB to create a point-of-care urine assay, as we have with tenofovir. This proposal will leverage three important trials to explore key knowledge gaps that will arise in the next phase of LA PreP.

The Sustainable East Africa Research in Community Health (SEARCH) Sapphire trial is evaluating a number of interventions to prevent and treat HIV, including the provision of CAB LA to 600 at-risk individuals across 10 communities in East Africa (Aim 1).

The Botswana Harvard AIDS Institute Partnership will launch a new study to provide women in the immediate postpartum period CAB LA PreP and follow mothers and their infants for 96 weeks, evaluating incident HIV and resistance, as well as the pharmacokinetics (PK) of CAB and its transfer during breastfeeding (Aim 2).

The Purpose 1 and 2 trials (Gilead) will study lenacapavir LA (a new capsid inhibitor given every 6 months as a subcutaneous injection) for PreP in diverse populations and will incorporate hair collection in their open-label extension phases.

All 3 trials will collect hair and plasma for drug levels, and track robust outcomes, to allow us to 1) investigate hair levels as predictors of failure; 2) determine maternal to infant transfer of CAB; and 3) assess contributors to PK variability to LA PreP in diverse populations.

The overarching goal of this renewal is to develop highly predictive biologic PK measures to optimize LA PreP and to inform public health interventions in prevention.

San Francisco Regents Of The University Of California

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]

San Francisco, California 941102859 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 285% from $820,860 to $3,163,248.