NIH/NIMH – Understanding the Mechanisms of Neuropsychiatric Side Effects and Neurological Toxicities of HIV Medicines (R21 Clinical Trial Not Allowed)

March 12, 2019 by School of Medicine Webmaster

This Funding Opportunity Announcement (FOA) invites innovative research grant applications focused on identifying potential mechanisms and risk factors underlying HIV treatment associated neuropsychiatric symptoms and neurological toxicities experienced by some people living with HIV infection.

This FOA utilizes the Exploratory/Developmental Grant (R21) mechanism, which supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical research. An R21 grant application should not have extensive background material or preliminary information. Extensive preliminary data demonstrating feasibility is an indication that the project is beyond the scope of this FOA. Applicants can provide appropriate justification for the proposed work through literature citations, data from other sources, or analytical and computational models.


Treatment with anti-retroviral therapy (ART) is recommended for all people living with HIV infection. Initiating ART early after HIV infection results in optimal health outcomes including the time prior to and during pregnancy, and during breast-feeding. ART reduces the amount of HIV in the body and prevents further HIV transmission provided there is good adherence to treatment. ART has advanced HIV infection to a treatable, chronic disease despite the known side effects which may complicate disease management.

The Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV present the side effects of ART (AIDSinfo HIV Medicines and Side Effects). These guidelines indicate that less than 10% of ART-naive patients enrolled in randomized trials exhibit treatment-limiting adverse events. NIMH has issued FOAs to support assessment of the potential for CNS toxicity due to HIV and ART on HIV induced CNS dysfunction (PA-17-100, and PAR-13-267). Research responsive to this FOA is targeted to better understand the risk factors and mechanisms involved in ART-mediated neuropsychiatric symptoms and toxicities which can then inform the development of next generation therapies with fewer side effects and neurotoxicities.

Findings of new onset neuropsychiatric adverse events (NP-AEs) within hours to months after initiation of ART, or upon switching ART regimens, may become an issue in some individuals. These adverse events may also become apparent when new HIV treatment regimens are made available to a greater number of patients following successful clinical trials. The neuropsychiatric symptoms include depression and anxiety disorders, mood and sleep disorders and suicidal ideation. Recent preliminary findings of neurological toxicity associated with ART exposure during a window of human development has been realized during an observational surveillance study (AIDSinfo HIVAIDS News) conducted after a successful clinical trial. The combination of drugs within ART regimens are highly efficacious at targeting different steps in the life cycle of HIV. Distinguishing how ART exposure may induce neuropsychiatric symptoms and neurological toxicities in some people living with HIV disease may involve discerning any underlying co-morbid medical disease(s) and co-exposure to other medications. This FOA encourages applications to develop a greater understanding of the molecular, cellular, physiological and developmental mechanisms involved in ART-mediated NP-AEs and neurological toxicities.

It is important to distinguish between acceptable side effects of innovative and vital HIV medicines versus unacceptable toxicity. For example, stavudine (d4T) was discontinued from ART regimens as first line HIV therapy in the United States and is not recommended for use in pregnant women due to unacceptable side effects (AIDSinfo Guidelines). Understanding the mechanisms of NP-AEs and neurological toxicity is key to being able to predict who will be at risk. For example, research findings indicate that some people living with HIV infection may experience NP-AEs due to their individual genetic capability to metabolize ART regimens containing the drug efavirenz. This FOA also encourages applications to design toxicity assays specific for the central nervous system based on understanding the mechanisms of action of NP-AEs in order to guide risk assessment, or to guide development of the next generation of HIV therapies with fewer mental health side effects across the lifespan.

Successful diagnosis and management of peripheral and central nervous system side effects and toxicities associated with ART will help to ensure continued use of ART regimens and will improve the quality of life for people living with HIV.

Specific Areas of Research Interest

The specific goal of this FOA is to support innovative research projects to identify risk-factors and understand ART-induced mechanisms underlying the neuropsychiatric adverse events and neurological toxicities experienced by some people with HIV disease on therapy, and to identify modifiable targets or individuals at high risk for timely interventions. Projects responsive to this FOA would focus on basic and preclinical research including paradigms and models that have the potential to translate from basic research and in vitro primary cell models to animals in order to advance novel therapeutic strategies that may extend to clinical trials in the future.

Specific research priorities include but are not limited to those listed below.

  • Identify the functional mechanisms involved in ART-induced NP-AEs. This may include potential impacts on the blood-brain barrier, neural circuits involved in depression, anxiety or dreams, inter and intracellular signaling including inter-organellar function among the cell’s network of mitochondria, the nucleus, endoplasmic reticulum, peroxisomes, lysosomes and Golgi apparatus;
  • Determine the potential for cumulative neurotoxic effects with ART exposure across the lifespan. This may include development of model systems using primary cells that reflect human physiology in the context of HIV and exposure to suppressive ART, modeling pharmacokinetics and pharmacodynamic responses in the CNS and new methods to measure brain tissue exposure to ART using innovative modeling methods;
  • Discern individual predictors of neuropsychiatric adverse events, or alternative factors driving neuropsychiatric symptoms and neurological toxicities with ART exposure. These may include genetic and epigenetic predispositions, polypharmacy with psychotropic drugs, other drug-drug interactions and mental health history;
  • Develop innovative assay(s) for predicting and detecting ART-mediated NP-AEs and neurological toxicity including development of clinically useful biomarkers to predict NP-AEs onset across the lifespan;
  • Design preventative and/or therapeutic strategies based on identification of the ART-responsive target(s) involved in the functional mechanisms that may lead to neuropsychiatric symptoms and/or neurological toxicities.

Applications for Exploratory/Developmental Research Grant awards should include projects distinct from those supported through the traditional R01 activity code. For example, long-term projects, or projects designed to increase knowledge in a well-established area are not appropriate for this FOA. Applications submitted to this FOA should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

Specimen and Other Resources

The development of novel in vitroex vivo or in vivo models for research on ART-induced NP-AEs and neurological toxicities that reflect current clinical phenotypes in the context of HIV infection are encouraged. The use of human specimen resources from large NIH-funded HIV-related studies listed below is also encouraged. These resources include but are not limited to those listed below.

  • National NeuroAIDS Tissue Consortium (NNTC) including the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Study;
  • AIDS Clinical Trials Group (ACTG)
  • Multi-Center AIDS Cohort Study (MACS)
  • Women’s Interagency HIV Study (WIHS)
  • National Center for Advancing Translational Sciences (NCATS Assay Guidance Manual)

The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application’s Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. Applicants should include all requested information as indicated in Section IV.2 PHS Human Subjects and Clinical Trials Information.

Deadline:  April 2, 2019 (letters of intent); May 2, 2019 (full proposals)


Filed Under: Funding Opportunities