U01AI179561

A clinical trial of three broadly neutralizing antibodies and analytic treatment interruption in early-treated children in Botswana - project summary/abstract

Novel HIV-1 treatment strategies that maintain viral suppression while allowing time off small molecule antiretroviral treatment (ART) are of high priority. An ART-sparing treatment intervention using potent and long-acting broadly neutralizing antibodies (BNABs) may reduce direct ART toxicities during critical periods of growth and development for children with HIV, will ensure adherence, and may have benefits over ART for viral reservoir reduction and post-treatment control. BNABs have been associated with reduction in viral reservoirs, and recent studies support a potential vaccine-like effect that may train immune responses and improve long-term outcomes.

Like early-treated adults, early-treated children may have the best chance to become post-treatment controllers, but further studies are needed -- including studies that utilize an analytic treatment interruption (ATI). We recently completed the TATELO study, a proof-of-concept trial demonstrating that monthly treatment with dual BNABs could maintain viral suppression for 24 weeks without ART in 44% of early-ART treated children. We also showed that specific markers for success were identifiable, and that interruption of standard ART could be safely performed in our study setting.

In the proposed study (TATELO PLUS), we will perform a multi-step interventional clinical trial that advances the field farther. Using a novel step-wise design and an innovative BNAB rotation strategy, we will first determine the safety, pharmacokinetics, dosing, and reservoir impact of long-acting triple BNAB immunotherapy with VRC07-523LS, PGDM1400LS, and PGT121-414LS when added to existing effective ART. In selected participants with favorable markers for success, we will next measure triple-BNAB treatment success following ART discontinuation. Finally, we will test for the maintenance of virologic control during an ATI in an even more highly selected group of participants -- those with extremely low viral reservoir or evidence of HIV integration in non-encoding regions of the genome.

The specific aims of this study are:
(1) To determine the safety, pharmacokinetics, and dosing of up to 24 weeks of concomitant use of triple BNAB immunotherapy when added to ART in 35 early-treated children living with HIV-1 in Botswana.
(2) To determine the safety, maintenance of virologic suppression, and CD4 cell count preservation of 24 weeks of maintenance triple BNAB treatment following the discontinuation of standard ART in selected early-treated children.
(3) To determine the safety, maintenance of virologic suppression, and CD4 cell count preservation of a 24-week ATI among two groups: a) those with markers for the lowest viral reservoir, and b) those with evidence of HIV-1 integration in predominantly non-encoding regions of the genome.

At each study step, we will measure the size and cellular composition of residual viral reservoirs, and the magnitude and quality of antiviral innate and adaptive immune responses. This study will represent a leap forward for combination BNAB treatment in children and will advance the pediatric cure agenda through a carefully conducted ATI.

President And Fellows Of Harvard College

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]

Boston, Massachusetts 021156028 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 239% from $1,799,067 to $6,096,179.