U01AI157931

A Randomized Controlled Trial of Prophylaxis with Direct-Acting Antivirals for Kidney Transplantation from Hepatitis C Virus-Infected Donor to Uninfected Recipients (PREVENT-HCV)

Due to epidemics of opioid overdose and Hepatitis C Virus (HCV), the availability of kidneys from HCV-viremic (HCV+) donors is increasing. However, there are limited numbers of HCV+ transplant candidates, resulting in 500-1000 HCV+ donor kidneys being discarded each year. A new practice of HCV+ donor to HCV-naïve recipient (HCV D+/R-) kidney transplantation (KT) with direct-acting antivirals (DAAs) has shown early success. However, there is still uncertainty about whether to give DAAs as prophylaxis or as treatment post-transplant ("transmit-and-treat"). Transmit-and-treat cures HCV with 8-12 weeks of DAAs, but complications such as fibrosing cholestatic hepatitis, rejection, CMV, and BK virus have been reported. Prophylaxis seems to prevent these complications, but data is limited. A direct comparison of prophylaxis and transmit-and-treat has not been done. Determining the best strategy would allow for the expansion of HCV D+/R- KT and minimize clinical complications.

We propose PREVENT HCV, a multicenter randomized controlled trial comparing DAA prophylaxis with transmit-and-treat in HCV D+/R- KT. We will perform 120 HCV D+/R- KTs over 2 years at 6 transplant centers. Aim 1 will compare the safety and efficacy of transmit-and-treat (SOF/VEL for 12 weeks starting day 14 post-KT) vs prophylaxis (SOF/VEL for 2 weeks started several hours pre-KT). We will also measure clinical complications of HCV D+/R- KT, such as liver injury, rejection, and infection, with these two strategies. In this trial, the exact timing, size, and genetic composition of the transmitted viral inoculum will be known, providing an unprecedented opportunity to study the earliest events in primary HCV infection.

Leveraging this, Aim 2 will characterize the earliest viral dynamics and phylogenetics of early HCV in the liver and blood, as well as the transmitted virome, identifying emerging viruses, including SARS-CoV-2, some of which have been implicated in rejection. Aim 3 will characterize the innate immune response to primary HCV, measuring cytokines and the transcriptome of innate immune cells. These studies can contribute new knowledge about HCV related to vaccine efforts and a deeper understanding of the virome, generalizable beyond transplantation.

Our multidisciplinary team includes experts in transplant surgery, infectious diseases, nephrology, epidemiology, biostatistics, pathology, virology, and immunology. Our team has experience successfully enrolling and conducting multicenter transplantation trials (U01AI134591, U01AI138897) and will leverage existing infrastructure for operations, data management, analysis, and safety monitoring.

In summary, PREVENT HCV will quantify the clinical risks of HCV D+/R- KT and determine the optimal DAA approach. This could facilitate thousands of additional KTs, contributing to one of the mandates of the White House Executive Order on American Kidney Health. Finally, this trial includes unique mechanistic studies that can generate fundamental insights into the biology of primary HCV relevant to vaccine efforts and knowledge about the transmitted virome and its significance in immunocompromised hosts.

The Johns Hopkins University

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]

Baltimore, Maryland 212051832 United States

Single Zip Code

NIAID Clinical Trial Implementation Cooperative Agreement (U01 Clinical Trial Required) (PAR-21-083)

Amendment Since initial award the total obligations have increased 403% from $1,025,696 to $5,162,956.