Related Announcements

PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required)
PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
NOT-HL-19-690 - NHLBI Limitations on Clinical Trial Applications Submitted to the NIH Parent (R01 Clinical Trial Required) Funding Opportunity Announcement (FOA)

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

Purpose

The purpose of this Notice of Special Interest (NOSI) is to stimulate research focused on elucidating the impact of HIV pre-exposure prophylaxis (PrEP) on heart, lung, blood, and sleep (HLBS) conditions. Projects ranging from basic mechanistic studies to implementation investigations, including clinical studies and NIH-defined clinical trials fitting the definition of mechanistic clinical trials/BESH research, may be considered responsive to the Notice.

Background

The landscape of HIV management changed significantly with the demonstration (via multiple NIH-funded clinical trials) that specific antiretroviral therapies used in the treatment of HIV could also be employed in uninfected, at-risk individuals prior to HIV exposure to prevent infection. This strategy is known as pre-exposure prophylaxis (PrEP). It is sufficiently effective that the World Health Organization began recommending PrEP to at-risk individuals in 2015 as part of its guidelines for prevention of HIV. The CDC estimated that in 2015, 1.1 million Americans had an indication for PrEP (see https://pubmed.ncbi.nlm.nih.gov/29941379/ for details), and PrEP is a key feature of the 10-year Ending the HIV Epidemic initiative announced in 2019.

Though the benefits of PrEP for reducing transmission of HIV are well established, the long-term effects of these drugs on the manifestations of HLBS conditions in individuals who are at-risk but not infected with HIV are relatively unstudied. Use of these agents chronically by individuals who do not have HIV (and thus are not at direct risk for the HLBS sequelae of HIV infection itself) may uncover unexpected effects, positive or negative. This NOSI is intended to stimulate research into identifying these potentially unexpected effects, so that the efficacy and impact of PrEP can be maximized by enhancing unforeseen positive effects on HLBS conditions and by minimizing potential unforeseen negative effects.

Research Objectives and Examples

This NOSI is intended to stimulate studies of the effects of PrEP on HLBS function/disease at all levels. Specific examples of the kinds of questions/studies appropriate for this NOSI are presented by broad category below and include, but are not limited to, the following:

Interests Across the Research Spectrum

• Studies that involve secondary analyses of existing data – preclinical, translational, clinical, epidemiologic, etc. – to help define the spectrum of potential effects of PrEP on HLBS function more quickly
• Studies that incorporate examination of any age-dependent and/or sex-dependent effects of PrEP on heart, lung, blood, and sleep function
• Studies that specifically investigate the effects of intrinsic drivers of health disparities – race/ethnicity-based drivers, gender-based drivers, gender identity-based drivers, etc. – and their interactions with PrEP effects on HLBS function/disease
• Studies specifically incorporating questions of maternal health and the effects of PrEP on HLBS function/disease

Molecular/Cellular Examples

• Studies elucidating the effects of PrEP use on progenitor cell populations in the heart, lungs, or bone marrow/hematopoietic tissues and the mechanisms that underlie those effects
• Studies examining the mechanistic basis for how PrEP use may impact tissue repair or regeneration in HLBS diseases
• Proposed studies examining molecular-level and cellular-level effects of PrEP that may predispose to or protect from HLBS diseases with long term use of PrEP – e.g., how subclinical inhibition of normal mitochondrial function by PrEP agents may predispose to development of myocardial dysfunction, or how similar cellular effects of PrEP may protect against vascular remodeling in pulmonary hypertension
• Investigations into PrEP agents’ potential to decrease systemic inflammatory markers, decrease circulating monocyte activation, and improve vascular inflammation and endothelial dysfunction among individuals using PrEP compared to those not

Translational/Clinical Examples

• Investigations into how PrEP agents may impact specific screening/diagnostic tests – e.g., HIV detection in the national supply of donated blood – and how any negative impacts may be mitigated (could also fit under the Epidemiology category below)
• Studies focused on understanding how PrEP use may impact heart, lung, or bone marrow transplantation, either in terms of transplant recipients who are PrEP users or in terms of PrEP use as a potential variable in use of donor organs
• Investigations into the long term cardio-metabolic implications of PrEP
• Evaluation of the subclinical effects of PrEP agents on structural heart disease including heart failure with preserved ejection function (HFpEF), heart failure with reduced ejection function (HFrEF), and cardiomyopathies; structural lung disease including COPD and pulmonary hypertension

Epidemiologic/Implementation/”Big Data” & Informatics Examples

• Studies proposing to examine how PrEP use may be related to other risk or health-promoting behaviors and practices with respect to HLBS diseases
• Studies that examine baseline HLBS comorbidities and how the development and progression of these comorbidities interact with PrEP use
• Pharmacogenomics of PrEP agents and comparative efficacy and safety of the agents for implementing personalized precision strategy for instituting PrEP using data science tools exploring EHR or other existing data bases.
• Studies seeking to use existing cohorts and data resources (including real-world data such as EHR-based data resources) to systematically untangle the complex relationship between HIV infection status, PrEP use, traditional risk factors, chronic inflammation, immune activation, and markers and manifestations of HLBS health and disease

Types of studies that would NOT be considered responsive to this NOSI include, but are not limited to:

• Studies of PrEP uptake and adherence that do not include HLBS endpoints as the primary focus
• Studies focusing on ART agents that are not used in PrEP regimens
• Studies of ART agents used in PrEP regimens but that are not representative of a preventive use pattern (e.g., focusing on an HIV treatment paradigm or post-exposure prophylaxis paradigm)

Application and Submission Information

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice. Note that AIDS application due dates are being used for this NOSI.

• PA-20-183 - NIH Research Project Grant (Parent R01 Clinical Trial Required)
  • Note: NHLBI and NINDS will accept only mechanistic studies that meet the NIH definition of a clinical trial (see NOT-HL-18-662 and NOT-NS-18-011) in response to PA-20-183 NIH Research Project Grant (Parent R01 Clinical Trial Required) and its reissues. For additional information, please see the NHLBI Policy Regarding Submission of Clinical Trial Applications Notice for help in identifying the most appropriate FOA (see NOT-HL-18-611).
• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-HL-21-025” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Shimian Zou, Ph.D.
NHLBI, Division of Lung Diseases
Telephone: 301-435-0065
Email: shimian.zou@nih.gov

Shimian Zou, Ph.D.
NHLBI HIV/AIDS Coordinator; Epidemiology; Transfusion
Telephone: 301-435-0065
Email: shimian.zou@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8014
Email: agrestia@nhlbi.nih.gov