A concept describes the purpose, scope, and objectives of a potential funding opportunity. Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research. Concepts are being posted to give interested researchers additional time to plan for application submissions.
Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.
- Identification of Immune and CNS Biomarkers of HIV Infection and Substance Abuse Comorbidity
- Improving Implementation of Seek, Test, Treat & Retain among PWID in International Settings
- Pre-Exposure Prophylaxis for HIV Prevention and Treatment for Substance Using Populations
- Identifying Neural Mechanisms Linking Psychosocial Stress to Pain and Opioid Use Disorder
- Co-operative and Competitive Use of ABCD Data
- Molecular Regulation of HIV Latency in Individuals with Substance Use Disorders (SUDs)
- Science-Based Quality Measurement and Management Development for Opioid Use Disorder Treatment
- Medications Development to Prevent and Treat Opioid Use Disorders and Overdose
Research Objectives: The FOA fosters biomarker research to advance clinical assessment of damages and functional reservation of host defense mechanism and comorbid complications at different phase of HIV-1 pathogenesis. Neuroimmunological profiling study is encouraged for comprehensive evaluation of blood and CSF soluble and cellular proteins and other molecules that change during HIV infection and accompanying inflammatory and neurodegenerative alterations. The study will enable identification of a set(s) of biomarkers that reflect the degree of damage and functional resilience ability of the defense system, and that will facilitate establishment of standards, and normal range of clinical lab tests that can detect early signs, and differentiate level of functional and structural deterioration of the compromised immune and neural system.
Background: HIV infection and chronic use of drugs of abuse (SUD) both change biological homeostasis and host defense mechanism. Current knowledge about the underlying inflammatory and degenerative process is largely based upon observations from small samples, suggesting altered signaling of a handful of pro-inflammatory and neurodegenerative molecules correlated with the diseases. The correlational data has limited clinical value, especially when information on molecules with anti-inflammatory or neuroprotective action is missing. A comparative assessment of blood and CSF samples will permit initial characterization and screen of molecular markers most representative of the compromised defense mechanism. The findings can then be validated by proof-of-concept studies to facilitate formation of a panel(s) of signatures that can be used for objective and quantitative assessment of disruptions in immune and neural system, and prediction of general immunity and functional resiliency of the patients.
Yu ‘Woody’ Lin, Ph.D. - Program Official, Integrative Neuroscience Branch/DNB
People who inject drugs (PWID) continue to have HIV incidence and prevalence above national averages in many places throughout the world. National responses to PWID often are weak and usually lag responses among other populations. Similarly, PWID engagement in HIV care generally lags behind other key populations as well as the larger population of people living with HIV. Even in some “general population epidemic” countries, HIV disparities in among PWID can limit the overall success of the UNAIDS 90-90-90 strategy. Seek, test, treat, and retain strategies need to be implemented in all key populations, including PWID in order to succeed. More service integration is needed in affected countries, including integration of HIV prevention and treatment for PWID and integration of drug use and HIV services, generally, along with attention to polysubstance use among PWID. This requires better models for program implementation and efforts to increase the implementation capacity of national HIV/AIDS programs among drug users.
This concept would support developing and testing implementation models that can be scaled-up in affected countries. Sustainable programs will need to align with national HIV/AIDS plans and provide models for large scale implementation, including QA/QC systems. This effort would include collaboration with national HIV/AIDS programs as well as major donors such as PEPFAR and Global Fund, which have platforms for reaching PWID and provide access to local epidemiology and services data. PEPFAR’s implementing partners include SAMHSA which provides specific substance use technical assistance in a number of countries. New donor programs include syringe services and drug treatment settings that can be leveraged to provide or actively link to additional HIV and substance use services. Some countries are developing new health financing systems that also can be leveraged to expand HIV prevention and treatment for PWID. In addition, projects would be encouraged to make use of existing NIH initiatives such as NIDA-funded researcher networks and IeDEA (NIH’s cohort of cohorts co-funded by NIDA) which provides clinical cohort platforms that can be leveraged for new research.
We plan to engage PEPFAR, Global Fund and SAMHSA, along with NIDA co-funded programs such as IeDEA as partners for these projects. Individual projects will be expected to leverage resources related to existing federal programs and align with national HIV/AIDS plans which generally have integration with US and international donor funding programs.
Dr. Richard Jenkins, Program Officer, Prevention Research Branch, Division of Epidemiology, Services and Prevention Research
Antiretroviral treatment (ART) used prophylactically in the form of pre-exposure prophylaxis (PreP; e.g., emtricitabine and tenofovir disoproxil fumarate [Truvada®]) is recommended for populations at high risk for HIV acquisition,, including individuals who have injected drugs in the past 6 months and have shared needles or works or been in drug treatment in the past 6 months. The seminal trial to date on the efficacy of PreP among injecting populations is the Bangkok Tenofovir Study, in which there were 17 HIV infections among the 1,204 participants taking tenofovir, compared with 33 infections among the 1,207 participants taking placebo (49% reduction in risk of HIV acquisition among those receiving tenofovir). The sample was recruited from methadone clinics and no data were reported on drug use or injection behavior, and no drug testing was performed (Choopanya K. et al. 2013). Consequently, the actual efficacy of PreP for active injectors, adherent methadone users or even non-injectors who actively use opiates and other drugs is unknown.
NIDA has funded surprisingly little research on the several key question related to PreP use among substance using populations The primary goal of this RFA is to examine the role of PreP in substance use trajectories and or treatments, including:
- To what degree do substance use or HIV providers recommend or adopt PreP for substance using patients at risk for HIV (e.g., injection drug use)?
- To what degree does substance use affect access and adherence to PreP?
- How does drug use interact with PrEP efficacy, including injection as well as polydrug use with substances that independently affect immune function?
- Where does PreP fit within a comprehensive program for prevention of HIV acquisition?
This concept is squarely in line with high overarching HIV/AIDs priorities (NOT-15-137):
- Reducing Incidence of HIV/AIDS, including: developing and testing pre-exposure prophylaxis candidates and methods of delivery, especially those that mitigate adherence issues; and developing, testing, and implementing strategies to improve HIV testing and entry into prevention services.
- Next generation of HIV therapies with better safety and ease of use including: developing and testing HIV treatments that are less toxic, longer acting, have fewer side effects and complications, and easier to take and adhere to than current regimens. Additionally, implementation research to ensure initiation of treatment as soon as diagnosis has been made, retention and engagement in these services, and achievement and maintenance of optimal prevention and treatment responses.
Shoshana Y. Kahana, Ph.D., Health Scientist Administrator, Services Research Branch, Division of Epidemiology, Services and Prevention Research
Psychosocial stress, defined as socioenvironmental demands that tax the adaptive capacity of the individual, is a major risk factor for opioid use disorders (OUDs). Psychosocial stress may impact OUD risk by altering cognitive and affective function and facilitating the development of affective disorders. Stressful environments have been associated with pronounced negative affect and affective disorders, and impairments in reasoning, memory, inhibitory and cognitive control. In addition to cognitive and affective outcomes, exposure to psychosocial stress has been shown to modulate pain perception and tolerance to opioid analgesics, which can also contribute to the potential for opioid abuse and addiction. For example, adverse childhood experiences such as verbal and sexual abuse, low family income, and early parental loss, have been associated with an increase in pain-related medical conditions during adulthood.
OUDs show high comorbidity with affective disorders such as major depression and anxiety. Further, opioid misuse rates among chronic pain patients are influenced by negative affect. Neurobiological changes in overlapping brain areas, circuits and neurochemistry have been implicated in chronic pain, depression, anxiety, and substance use disorders. Initial findings suggest that individuals with affective disorders exhibit blunted endogenous opioid function, which is associated with altered pain sensitivity and response to opioid medications. Furthermore, healthy individuals with lower endogenous opioid release are more likely to develop chronic pain and report more pain in laboratory assessments of pain, suggesting that natural variations in the endogenous opioid system produce individual differences in pain severity and processing. Collectively, these data suggest a complex multidimensional relationship between psychosocial stress, cognitive/affective processing, pain, and OUDs. However, important questions remain regarding the underlying mechanisms related to behavior, genetics, epigenetics, neural circuitry, and endogenous opioid function.
The goal of this initiative is to promote basic and clinical research directed at: (1) elucidating the neurobiological and behavioral mechanisms by which psychosocial stress alters pain sensitivity or cognitive/affective processes, biases opioid use, maintains opioid seeking and increases the risk of relapse; and (2) identifying the factors and the associated mechanisms of action underlying resilience or vulnerability to psychosocial stress-induced alterations in pain sensitivity or affective/cognitive functioning as it relates to OUD.
The Adolescent Brain Cognitive Development (ABCD) Study recently commenced releasing data to the public, and given the size and complexity of the dataset, one concern is how to ensure that the data are widely used. Recently, there has been considerable discussion regarding the need for increased rigor and reproducibility in neuroimaging research. A concern with big datasets is that the large number of analyses being performed combined with the increased likelihood of finding statistically significant effects results in a greater number of false positives being published. One approach towards addressing both the above concerns is to hold competitions and hackathons (meetings where multiple participants gather to engage in collaborative computer programming) geared towards model development where a part of the data remains unseen and therefore available for model validation. The attention deficit hyperactivity disorder 200 (ADHD-200) competition is one example that provided valuable insights into ADHD diagnosis in particular, and development of neuroimaging biomarkers, in general. The ABCD study currently offers a unique opportunity towards encouraging such endeavors in the realm of substance use and other mental disorders because data are collected at 1-2 year intervals and collection is ongoing; datasets beyond the baseline study visit are therefore automatically concealed from model developers.
The purpose of the proposed FOA is to invite applications that utilize ABCD data (baseline measures only) towards enhancing rigor and reproducibility through meetings centered on collaborative- or competition-style use of ABCD data. Applications emphasizing the development of predictive models of group/individual differences, with the overarching goal of predicting behavioral and clinical outcomes in future time-points, are particularly encouraged.
The overall goals of this initiative are:
- Widening use of the ABCD dataset
- Enhancing rigor and reproducibility towards better predictive models
- Facilitating collaboration between clinical and computational researchers on SUD research
Patients with chronic substance use or SUDs can present unique challenges for HIV prevention, treatment, disease progression, medical consequences, potential cure, and responses to vaccines or therapeutics. Understanding the molecular processes regulating HIV latency, especially with respect to SUDs and reservoirs such as the brain, will provide foundational knowledge for the development of future therapeutics to treat HIV in individuals with and without SUDs.
This initiative will support Omics studies (e.g. transcriptomic, epigenomic, epitranscriptomic, proteomic, metabolomic) that address outstanding questions regarding HIV latency or reservoirs in the context of chronic substance use or SUDs. Some of the major questions that we anticipate will be addressed are:
- What are the detailed molecular mechanisms regulating the formation or reactivation of latent HIV in the genome?
- How do these molecular mechanisms differ in the different cellular reservoirs that harbor latent HIV?
- How do addictive substances impact these processes?
John Satterlee, Ph.D., DNB Coordinator for Trans-NIH Programs and Activities, Division of Neuroscience and Behavior
Although there are many fine programs, the overall quality of opioid use disorder (OUD) treatment in the United States is suboptimal. The one-size-fits all, episode-based model is still too common. Effective interventions are too seldom provided. Patients are not sufficiently assessed for comorbidities or use of prescribed substances. Payers limit coverage for what is often a chronic condition. Programs and payers still hold that people who relapse are just not ready for treatment, discharge them, and tell them to come back when they are ready. Too often, they never come back. Patients and families have no idea what to look for, and often end up paying tens of thousands of dollars, even with insurance, for programs that were never going to be sufficient.
Over at least the past two decades the field has attempted to develop and implement quality measures as a quality improvement strategy. These include the widely-used treatment initiation and engagement measures, the SAMHSA National Outcome Measures, measures developed and implemented in various State initiatives or by professional organizations, and even outcome measures instituted in the British National Health Service Payment for Results pilot, the main result of which was that fewer patients completed a course of treatment.
Dozens of quality measures exist for substance use disorder treatment, and there are repeated calls to develop more. Those that exist mostly were developed by consensus panels of knowledgeable, well-meaning individuals, and then “tested” to determine if they can be measured adequately in whatever data sources is being used, are at a level where they need to be improved, and so forth. Then, generally, the measures are put on a list, sometimes adopted by states and payers, included pay for performance schemes. Too often, nothing changes. Sometimes, implementing quality measures in this fashion makes things worse.
What has been missing is rigorous, scientific development and examination of the measures, before they are put on a list, of both how they may be improved, and the effects of the improvement, both intended and unintended. The purpose of this proposed initiative is to fund research to do just that.
Investigators funded under this activity would identify high-priority targets for improvement in OUD treatment, and develop a plan for how they might be improved. They then would either select existing measures or develop novel measures related to the target area. They would rigorously test these plans for improvement to see if the measures improve and, if they do, whether patient outcomes also improved. They would also carefully examine any unintended consequences, as well as the economics of the measures and improvement activities. They would also consider whether casemix adjustment would be needed to fairly compare clinicians or programs, etc., on these measures. They would also develop materials and disseminate materials to make it easier for other similarly situated entities to implement these measures and improvement strategies.
Sarah Duffy, Ph.D., Associate Director for Economics Research, Division of Epidemiology, Services and Prevention Research
Description: Given the current opioid use and overdose crisis in the country, the purpose of this Funding Opportunity Announcement is to support research that accelerates the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose. This project is part of the NIH initiative to establish a public-private partnership to address the opioid crisis via more effective and safe ways to prevent and treat opioid use disorders and overdose (https://www.nih.gov/opioid-crisis)
Application may include preclinical or clinical research studies that will have high impact and quickly yield the necessary results to advance closer to FDA approval medications that are safe and effective to prevent and treat OUDs and overdose.
The compounds to be evaluated can be small molecules or biologics. They can be tested in pre-clinical models and/or for the clinical manifestations of OUDs such as withdrawal, craving, relapse, or overdose. Applications may focus on the development of new chemical entities, new formulations of marketed medications available for other indications, or combinations of medications that hold promise for the treatment of OUDs and overdose.
Through this FOA, NIDA seeks to fast-track the discovery and development of medications to prevent and treat OUDs or opioid overdose and to advance them in the FDA's drug development approval pipeline.
Ivan Montoya, M.D., Division of Therapeutics and Medical Consequences