Key Dates

Related Announcements

• February 1, 2024 - NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required). See NOFO  PAR-24-124.
• February 1, 2024 - NCCIH Natural Product Early Phase Clinical Trial Award (R33 Clinical Trial Required). See NOFO  PAR-24-116.
• January 20, 2024 - Feasibility Clinical Trials of Mind and Body Interventions for NCCIH High Priority Research Topics (R34 Clinical Trial Required). See NOFO PAR-24-084.
• December 21, 2023  - Investigator Initiated Clinical Trials of Complementary and Integrative Interventions Delivered Remotely or via mHealth (R01 Clinical Trial Required). See NOFO PAR-24-086.
• December 21, 2023 - NCCIH Multi-Site Feasibility Clinical Trials of Mind and Body Interventions (R01 Clinical Trial Required). See NOFO PAR-24-083. 
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)). See NOFO PA-20-195.  
• May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185.

Issued by

National Center for Complementary and Integrative Health (NCCIH)

National Institute on Aging (NIA)

Purpose

Purpose

The National Center for Complementary and Integrative Health (NCCIH) and other participating National Institutes of Health (NIH) Institutes, Centers, and Offices (ICOs) are soliciting projects to evaluate and elucidate interventions to prevent, reduce, and/or reverse chronic systemic inflammation and inflammation-related comorbidities and complications in people living with HIV/AIDS (PWH).

Background

The chronic systemic inflammation associated with HIV infection has been implicated in multiple serious comorbidities and complications, including but not limited to neuropathy, depression, dementia, chronic pain, renal and metabolic dysfunction, and neoplastic and autoimmune diseases. HIV-associated chronic inflammation starts early and is present even among those who are virally suppressed. It is widely thought to drive the unequal chronic disease burden PWH experience compared with those who are uninfected and is also a key contributor to the morbidity seen in older and aging PWH. Effective mitigation strategies for reducing this pathological chronic inflammation remain elusive, and pharmacologic anti-inflammatories are generally contraindicated for long-term use. There is a need to determine if reducing chronic systemic inflammation improves the prevalence and outcomes of conditions associated with and attributable to inflammation.

The root cause of the HIV hyperinflammatory state is believed to be the cytokine and immune dysfunction the viral infection triggers. However, there is evidence that chronic stress, lifestyle (e.g., diet, activity, sleep), environmental factors, and coinfections may also play a considerable role in the inflammatory response. The multifactorial quality of HIV-associated chronic inflammation, coupled with the lack of established treatment options, make it an ideal target for exploratory research on promising therapeutics, both conventional and complementary and integrative.

Research Objectives

The main objective of this NOSI is to encourage applications for clinical and basic and mechanistic research to develop, refine, and/or test interventions that reduce or prevent chronic HIV-associated inflammation, and evaluate whether this ultimately reduces the sequelae of that inflammation. This NOSI does not support applications proposing an intervention to address acute inflammation, such as that occurring after an injury and/or non-HIV infection. Proposals may evaluate intervention mechanisms, safety, feasibility, acceptability, and/or efficacy and test approaches that are both scalable and sustainable in real world contexts for diverse populations of PWH. In addition to interventions delivered by health care providers and systems, this NOSI encourages research delivered in community, educational, religious, and/or correctional settings. Interventions can be administered in person, remotely, or in a hybrid format.

This NOSI is comprehensive in its consideration of PWH across the lifespan and across sexual and gender identities, people with developmental disabilities or cognitive impairments (e.g., Alzheimer’s disease and related dementias), those with comorbid conditions (e.g., psychiatric or substance use disorders), or other at-risk populations such as pregnant and postpartum individuals, justice/legal system involved individuals, veterans, and members of the military. In addition, consideration of NIH-designated health disparity populations (many of whom are disproportionately impacted by HIV) is encouraged: specifically, racial and ethnic minority groups (see NOT-OD-15-089 and OMB Directive 15), people with lower socioeconomic status (SES), underserved rural communities, sexual and gender minority (SGM) groups, and people with disabilities. Please refer to specific bullets below to obtain information about priority populations for each participating ICO.

NIH is committed to supporting research to enhance diversity, equity, inclusion, and accessibility (DEIA) in biomedical and behavioral sciences research. Applicants are encouraged to discuss how they will foster these principles in their proposed research activities.

While noninflammation outcomes may be measured during studies funded through this NOSI, it is expected that the primary outcome(s) will be related to inflammation, co-occurring conditions, and mediators of the relationship between inflammation and the conditions. Inflammation should be defined by objective, validated, and reproducible tests (e.g., high-sensitivity C-reactive protein [hsCRP], erythrocyte sedimentation rate [ESR], D-dimer, and inflammatory cytokines). Studies are encouraged to quantify inflammation in multiple ways and evaluate the relationship between these different measures, as well as their association with target engagement and clinical or mechanistic outcomes. Basic, preclinical, and clinical research projects assessing safety, tolerability, dosing, feasibility, acceptability, and/or efficacy are appropriate.

Secondary noninflammatory outcomes may include those that are physical (e.g., body weight, renal disease, cardiovascular disease, gut microbiome, digestive function, heart rate variability [HRV]), psychological (e.g., mood, quality of life, sleep, cognition), and/or biochemical (e.g., lipid profiles, insulin resistance, DNA methylation, telomere lengths). Projects may test new or adapted interventions, novel combinations of multiple interventions, and/or new strategies to implement evidence-based interventions.

Studies responsive to this NOSI are expected to have one or more of the following features:

• Develop and/or evaluate interventions that address the causes, mechanisms, and/or sequelae of chronic inflammation in PWH in the presence and absence of antiretroviral therapy (ART).
• Include a theoretically informed conceptual model that specifies the hypothesized pathways between the intervention, inflammatory pathways, and distal health outcomes.
• Include appropriate measurement of objective and validated tests of chronic inflammation.
• Include justified sample size and power calculations appropriate for the outcomes being measured.
• Use appropriate study designs that allow for a rigorous evaluation of the intervention’s impact on the proposed outcomes, such as randomized controlled trials (e.g., individual, cluster-randomized, stepped wedge), quasi-experimental designs (e.g., regression discontinuity, interrupted time-series), or a rigorous alternative that includes a comparison condition. Methods consistent with plans for the assignment of participants, delivery of interventions, and sample size calculations should be documented in the application. Additional information is available at https://researchmethodsresources.nih.gov/.

Applications Not Responsive to the NOSI:

• Projects that do not focus specifically on chronic HIV-associated inflammation.
• Projects that do not prospectively test an intervention that targets chronic inflammation to promote physical and/or psychological health or quality of life among PWH.  
• Projects proposing to address inflammation occurring in response to an acute injury and/or HIV infection.
• Projects solely focused on   developing a model of the mechanism and/or impact of an intervention on chronic HIV-associated inflammation.
• Projects solely focused on   identifying  and evaluate novel, unvalidated measures of inflammation in PWH.
• Projects solely focused on   developing a protocol, manual of operations, or infrastructure for a clinical trial.
• Applications proposing to study only the effects of drugs known to be addictive. 

Applications nonresponsive to the terms of this NOSI will be withdrawn from consideration for this NOSI. Applicants are strongly encouraged to reach out to the relevant Scientific/Research Contact(s) listed in the Inquiries section of this NOSI to discuss whether their applications are responsive.

Institute and Center (IC)-Specific Application and Submission Information:

Applicants must select the IC and associated notice of funding opportunity (NOFO) to use for submission of an application in response to this NOSI. The selection must align with the IC requirements listed to be considered responsive to that NOFO. Nonresponsive applications will be withdrawn from consideration for this initiative. In addition, applications using NIH Parent Announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those NOFOs are acceptable and based on usual application-IC assignment practices.

Investigators are strongly encouraged to reach out to the relevant Scientific/Research Contact(s) listed in the Inquiries section of this NOSI to determine whether their proposed research is suitable for the selected IC.

National Center for Complementary and Integrative Health (NCCIH)

NCCIH promotes research on the use of complementary and integrative health approaches, which include those that are not typically part of conventional medical care and can be classified by their primary therapeutic input, including nutritional (e.g., botanicals, probiotics and microbial-based therapies, dietary supplements, and special diets), psychological (e.g., meditation, hypnosis, music-based interventions, relaxation therapies), physical (e.g., acupuncture, massage, chiropractic manipulation, other force-based manipulations, or devices related to these approaches), or a combination of psychological and physical input (e.g., yoga, tai chi, dance therapies, or some forms of art therapies).

The evidence for complementary and integrative health approaches’ potential to reduce inflammation is strong and growing. However, data is lacking on the safety, effectiveness, and underlying mechanisms of these interventions in PWH. NCCIH is seeking applications that will establish the mechanistic basis, feasibility, acceptability, and/or efficacy of complementary approaches that can be safely combined with ART to sustainably prevent, reduce, and/or reverse chronic inflammation in PWH across the lifespan, and ultimately evaluate whether this decreases HIV-related comorbidity and complications.

Areas of interest to NCCIH include but are not limited to:

• Mind and body (e.g., mindfulness, sleep, force-based manipulation, traditional Chinese medicine, yoga, breathing exercises) interventions to reduce inflammation
• Trials that evaluate nutritional or natural product therapies, including special diets, botanicals, probiotics, microbial-based therapies, and dietary supplements, that can be used to reduce inflammation concurrently with ART without creating product-drug interactions
• Complementary and integrative interventions that specifically target the microbiome and metabolome with the aim of preventing or reducing chronic inflammation
• Studies to describe and elucidate the mechanisms by which complementary and integrative therapies affect inflammation
• Trials that aim to evaluate sex differences in response to complementary and integrative therapies targeting chronic inflammation
• Trials that evaluate a standardized nutritional regimen or component to reduce chronic inflammation
• Multicomponent interventions, incorporating multiple mind and body and/or natural product therapies, that address HIV-associated chronic inflammation and their sequelae 

National Institute on Aging (NIA)

NIA is interested in research that falls within NIA’s mission to support genetic, biological, clinical, behavioral, social, and economic research on aging. Recent studies indicate PWH experience accelerated biological aging, which may increase the risk of earlier onset of geriatric syndromes. Chronic inflammation is a hallmark of aging and is also linked to increases in age-related comorbidities among PWH. Understanding the underlying mechanisms of chronic inflammation and developing targeted interventions to mitigate its effects is essential for improving the long-term health outcomes of PWH in the era of modern antiretroviral therapy.

For behavioral and social research, NIA supports mechanism-focused intervention development to promote healthy aging at the individual, dyadic, family, group, systems, institutional, and population levels. Specific to this NOSI, NIA welcomes applications proposing interventions relevant to the potential causes, mechanisms, and/or sequelae of inflammation in the context of HIV for people in mid- to late-life.

NIA’s behavioral and social intervention research program follows the NIH Stage Modelwhich offers a framework to: (1) support development of efficacious interventions that are defined by their principles; and (2) ensure that these efficacious interventions can be administered in the community or in health systems with fidelity to the intervention’s principles. This includes the development, testing, and validation of scalable training materials and procedures so that these interventions can be delivered with fidelity in community settings or health systems. Settings can include the home, community, or formal care settings, such as physician offices, via telehealth, in nursing homes, assisted living facilities, nursing and rehabilitation centers, hospitals, adult day care, and specialized hospice settings. Applications for NIA support of behavioral and social clinical trials research are expected to identify research proposals using the NIH Stage Model framework, described in detail here.

Areas of interest to NIA include but are not limited to:

• Understanding how the mechanisms of inflammation in chronic HIV infection contribute to immune-cell senescence and premature aging in PWH
• Investigating senescence biomarkers across the lifespan and determining the premature aging process in PWH
• Identifying strategies to mitigate the impact of chronic inflammation on aging-related outcomes
• Understanding the role of chronic inflammation in frailty pathogenesis
• Evaluating geroscience therapeutic approaches and measuring the effects on chronic inflammation
• Facilitating physical activity, healthy eating, high quality sleep, proactive health care seeking, treatment adherence social engagement, other health behaviors for midlife and older adults living with HIV
• Supporting stress management for midlife and older adults living with HIV facing additional social or structural barriers to well-being
• Configuring social networks, built environments, services etc. to better serve midlife and older adults living with HIV

Application and Submission Information

This notice applies to due dates on or after June 5, 2024 and subsequent receipt dates through November 13, 2024.

Submit applications for this initiative using one of the following notices of funding opportunities (NOFOs) or any reissues of these announcement through the expiration date of this notice.  

• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)  
• PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
• PAR-24-083 NCCIH Multi-Site Feasibility Clinical Trials of Mind and Body Interventions (R01 Clinical Trial Required)
• PAR-24-084 Feasibility Clinical Trials of Mind and Body Interventions for NCCIH High Priority Research Topics (R34 Clinical Trial Required)
• PAR-24-086 Investigator Initiated Clinical Trials of Complementary and Integrative Interventions Delivered Remotely or via mHealth (R01 Clinical Trial Required)
• PAR-24-116 - NCCIH Natural Product Early Phase Clinical Trial Award (R33 Clinical Trial Required)
• PAR-24-124 - NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required)

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

• For funding consideration, applicants must include “NOT-AT-24-035" (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

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed notice of funding opportunity.

Scientific/Research Contact(s)

Sekai Chideya-Chihota, MD, MPH
National Center for Complementary and Integrative Health (NCCIH)
Phone: 240-552-2994
Email: sekai.chideya@nih.gov

Ann Namkung, MPH
National Institute on Aging
Phone: 301-496-6838
Email: ann.namkung@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)

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: debbie.chen@nih.gov