R01AI162181

An enhanced package of care to reduce mortality in persons with advanced HIV disease - antiretroviral therapy (ART) is recommended for all people living with HIV (PLWH) – regardless of their CD4 cell count – to improve survival and reduce transmission. This “treat-all” approach benefits PLWH overall, but also confers a risk of unmasking immune reconstitution inflammatory syndrome (IRIS) and death, particularly for the 30-40% of people who present with advanced HIV disease (CD4 count <200 cells/μL) worldwide.

In 2017, the World Health Organization (WHO) recommended that persons with advanced HIV disease be screened for opportunistic infections (OIs) and given prophylaxis for tuberculosis (TB) and cryptococcal antigen (CRAG). However, because this screening and prophylaxis package has never been validated in a clinical trial, it is not consistently implemented in sub-Saharan Africa. Compounding the problem, funding for CD4 testing has been reduced by stakeholders as CD4 testing is no longer needed for ART initiation. Consequently, identification of persons with advanced HIV disease via CD4 testing and OI screening and prophylaxis often does not occur in reality. As a result, early mortality after ART initiation remains high.

Subsequent to the release of the initial 2017 WHO recommendations for OI screening and prophylaxis, several novel point-of-care diagnostics and treatments for OIs have emerged: Visitect point-of-care CD4 assay provides a visual result of CD4 count >200 of <200 cells/μL, with a sensitivity of 92% and specificity of 89% in venous blood; semi-quantitative CRAG lateral flow assay (CRAG-SQ LFA) can detect persons with CRAG titers who likely have disseminated infection and are at risk of meningitis/death despite standard of care antifungal therapy; Fujifilm Silvamp TB LAM, a new point-of-care TB urinary test, has 70% sensitivity and 91% specificity; isoniazid (INH) + rifapentine given for one month for latent TB treatment is non-inferior to 9 months of INH.

The objective of this proposal is to improve survival in persons with advanced HIV disease. We will implement a 2x2 factorial, cluster-randomized trial in 24 Ugandan clinics to:

(Aim 1) Determine the survival benefit of a novel point-of-care CD4 test compared with standard flow cytometry CD4 testing in persons with advanced HIV disease; and

(Aim 2) Determine the survival benefit of an enhanced diagnostic OI screening and prophylaxis strategy in persons with advanced HIV disease. The enhanced OI screening and prophylaxis strategy will include point-of-care Fujifilm TB LAM, CRAG-SQ LFA, with enhanced prophylaxis for TB (1 month of INH + rifapentine), and referral of plasma CRAG+ with high titers to hospital. Survival and retention-in-care will be assessed at 6 months.

Lastly, (Aim 3) we will evaluate the cost and cost-effectiveness of the CD4 testing strategies (described in Aim 1) and OI screening and prophylaxis strategies (described in Aim 2). Findings from this trial will have the potential to impact international HIV treatment guidelines on optimal management of persons with advanced HIV disease in order to reduce HIV-related mortality globally.

Regents Of The University Of Minnesota

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]

Minneapolis, Minnesota 554550356 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 380% from $662,335 to $3,179,431.