NHLBI AIDS Working Group: Refining Current Scientific Priorities & Identifying New Scientific Gaps in HIV-related Heart, Lung, Blood, and Sleep (HLBS) Research

Epidemiology

Scientific Gaps

Approaches to Gaps

• What is the incidence and prevalence of HIV-related heart failure (HF), heart failure with preserved ejection fraction (HFPEF), and heart failure with reduced ejection fraction (HFREF)?
• How to diagnose HIV-related HFPEF?
• What is the interplay of:
  • HIV specific risk factors-viral load, stage of disease, type & timing of anti-retroviral therapy (ART);
  • Inflammation;
  • Metabolic risk factors;
  • Genetics;
  • Environment; and
  • Social & lifestyle factors?
• Are there distinct phenotypes of HIV-related HFPEF?
• Does HF exacerbate HIV?
• What are the patterns of use if evidence-based HF medications in the HIV population?
• What are the outcomes in the HIV population with evidence based HF therapies?
• Who should be screened for HIV-related HF?
• How can we leverage big data?

Coronary Artery Disease (CAD) Epidemiology

• Is there a different HIV CAD phenotype/pathophysiology (e.g., calcification of plaques) in the well-treated HIV patients?
• How do we predict their cardiovascular (CV) risk?
• How do we translate to clinical practice?
• Can we learn from other inflammatory models like rheumatoid arthritis and psoriasis?
• Do we invest in existing cohorts or develop new ones? Need for HIV negative population?
• If we want to do a robust CV study, are current cohorts robust? What population do we need?

• Continue to leverage cohorts
• Collect HIV information in existing HF trials and include this in future trial design
• Enrich with standardized CV assessments i.e. echocardiography, carotid intima media thickness (CIMT), and other imaging
• Adjudicate events in cohorts
• Identify critical junctures in timeline of disease when more detailed assessments should occur
• Leverage cohort data, electronic health record, and biorepositories to more precisely phenotype HIV-related HF
• Enrich current cohorts with new populations to address CV focused questions?
• Use of non-human Simian immunodeficiency virus (SIV) primate models

CAD Epidemiology

• Precision medicine approach (including genetics) and translate back to the bench
• Correlate novel biomarkers with risk factors
• Leverage registries
• Well-characterized HIV cohorts with matched controls to identify rates of outcome

Pathophysiology

Scientific Gaps

Approaches to Gaps

• What are the mechanisms of HIV-related HF?
• Are there distinct patterns of HIV-related cardiac fibrosis?
• Are there differences in cardiac fibrosis in HIV vs. non-HIV models? If so, why?
• Are there differences in myocardial steatosis in HIV vs. non-HIV models? If so, why?
• How should we use biomarkers and imaging to characterize HIV-related HF?
• What biomarkers should we focus on?
• What does imaging tell us about the mechanisms of HIV-related HF?
• Can we use -omics to characterize HIV-related HFPEF?
• How can we use a systems biology approach to better characterize HIV-related HFPEF?

CAD Pathophysiology

• How to study HIV directly in cell subpopulations?
• What are the barriers to basic vascular function studies?
• If we inhibit inflammatory pathways, do we slow the pathogenesis of atherosclerosis?

• Systems biology-reverse translation approach from clinical phenotype (e.g., biomarkers) to animal models
• Biorepository (shared resource) for animal tissue/blood samples (e.g., primates), as well as from autopsies
• Identify biomarkers, phenotype from clinical cohort and verify mechanisms in animal models
• Need for improved HIV animal models (transgenic mice)
• Bioinformatics/deep phenotyping of imaging to delineate mechanisms of fibrosis and steatosis
• Biopsy studies (iPSC as an alternative?)
   

CAD Pathophysiology

• Precision medicine approach (including genetics, RNA seq); unbiased omics analysis/ in vitro diagnostic work of existing cohorts
• Biorepository of atherosclerotic samples

Prevention and Treatment

Scientific Gaps

Approaches to Gaps

• How can we best design future trials in HIV-related HFPEF?
• What novel therapies should be considered in HIV-related HFPEF?
• How can we enrich current studies with HIV-infected people?

CAD Treatment & Prevention

• How do we manage patients once diagnosed?
• Are there any differences in CAD progression in HIV adolescents vs. adults?
• Do we know if evidence-based therapies work? Are there novel therapies to consider? Do we need large trials?

• Leverage ongoing pilot studies of novel interventions to assess impact on CVD endpoints, i.e. antifibrotic therapies
• Leverage cohorts to better characterize HIV-related HFPEF and identify distinct subgroups for future trials.
• Design targeted future precision medicine trials.
• Future studies in HIV-related CVD should focus on CAD and HF endpoints

CAD Treatment & Prevention

• Phenotype well-characterized HIV cohorts with matched controls to identify rates of outcome
• Small/intermediate trials to identify interventions
   

Epidemiology

Scientific Gaps

Approaches to Gaps

• Clinical features – How is HIV related lung disease similar or different to the same lung disease in the non-HIV infected subjects? What are the risks of chronic lung diseases in people with HIV (COPD, fibrosis, PH, cancer)?
• What is the prevalence of sleep disorders in HIV and do sleep disorders relate to clinical outcomes in HIV?
• Need for Biomarkers to
  • Provide insight into pathogenic mechanisms and to define novel molecular phenotypes
  • Identify patients at risk and those who are not at risk
  • To serve as markers of disease which take long times to occur

• Leveraging of existing cohorts with biospecimens by incorporating high quality measures of lung health (Clinical presentation, imaging, PFTs, existence of sleep disorders, recurrence of Infections in the ART treated)
• Omics (TOPMed): couple whole-genome sequencing (WGS) and other –omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data from studies focused on heart, lung, blood and sleep (HLBS) disorders in HIV infected populations.
• Development of predictors of disease development and progression

Pathophysiology

Scientific Gaps

Approaches to Gaps

• Why and how does chronic inflammation and immune dysfunction persist in the lung of HIV-infected subjects despite seemingly adequate control of systemic viral replication in patients on ART?
  • Is HIV controlled in the lung or is it a reservoir?
  • Are other viruses or altered microbial environment driving the response?
• How does chronic HIV infection lead to lung remodeling and dysfunctional repair mechanisms?
• How is tobacco modulating lung disease in HIV-infected subjects?
• Do antiretroviral therapies directly cause lung disease?
• Are there shared mechanisms that allow HIV lung disease to serve as an accelerated human model for non-HIV lung disease?
• Do chronic diseases in the blood and heart share similar pathophysiologic mechanisms? i.e. Is the same chronic inflammation found in the lung important for the development of cardiovascular disease in HIV infection?
• Does chronic intermittent hypoxemia from sleep-disordered breathing contribute to inflammation, oxidative injury, and end-organ disease in HIV?
• How does circadian chronobiology affect immune responses, metabolic regulation, and vascular health in HIV?

• Detailed analysis of the lung microbiome, virome, and fungome at all stages of HIV infection and study on the systemic effect of microbiome dysregulation (dysbiosis) on the onset of disease.
• Metabolomics and transcriptomics approaches to detect alterations in gene regulation and downstream metabolic pathways.
• Epigenetic approaches to gene regulation.
• Development of innovative animal models of HIV-related lung disease.
• Need leveraging not only large existing cohorts of HIV-infected subjects, but also cohorts of non-HIV infected subjects with similar lung diseases (COPD, pulmonary HTN, cancer, etc) to determine differences and similarities between the two populations.
• Cooperation between scientists and cohorts studying similar pathophysiologic mechanisms (i.e. inflammation, immune dysfunction) in different organ systems.

Therapy and Implementation

Scientific Gaps

Approaches to Gaps

• Is standard therapy for common lung diseases appropriate and effective in HIV-infected subjects?
  • Are novel approaches to enhance immune function and reduce inflammation needed?
  • Do perturbations in the lung microbial environment (bacteria, viruses, fungi) need to be addressed through either improved antimicrobial agents or enhancement of immune function?
• Will effective treatment for cessation of tobacco use modulate disease progression?
• Are approaches to reduce chronic inflammation and improve immune function in the lung similar to those in other organs?
• Does screening and treatment of sleep and circadian rhythm disorders improve clinical outcomes in HIV?

• Use of large cohorts of HIV-infected and uninfected subjects with the same lung disease for therapeutic comparisons.
• Since many of the diseases in question take years to progress need to develop and/or define surrogate markers of disease progression.
• Linking established smoking cessation programs with HIV-treatment.
• Standardization of lung health measures among various cohorts (both HIV-infected and non-infected) to allow appropriate comparisons.
• Targeted funding of cohorts and intervention trials (HIV and non-HIV infected) that are willing to incorporate measures of lung and sleep health.
• Cooperation between scientists and cohorts evaluating treatment for chronic diseases in different organ systems.

• Hematological abnormalities in ART-treated HIV patients and inflammation
  • Coagulation and endothelial activation and co-morbidities in treated HIV patients
  • Platelet function and interactions in HIV infection
  • CD4 T cell restoration failure in HIV patients under ART
  • Age-related acquisition of somatic mutations and their association with HIV infection

• Cell and gene therapy for HIV cure – from Berlin to Boston and now

• Prevention of transfusion-transmission of HIV and global blood safety
  Compelling 

Coagulation and endothelial activation and co-morbidities in treated HIV patients:

• How does HIV impact hematopoiesis, particularly megakaryocytic development and function, and what are the implications for bleeding and thrombosis?
• What are the mechanisms resulting in the hypercoagulable state observed in HIV infection? What is the contribution of HIV infection versus that of HIV medications?
• What is the role of endothelial, monocyte and/or platelet activation and what is the interplay between these cells?
• How do HIV and the resulting inflammation affect coagulation factors, such as VWF, FVIII and fibrinogen, and what is the impact on thrombotic risk?
• What is the role of neutrophil extracellular trap (NET) formation in HIV-associated hypercoagulability?
• How common are vascular events in treated HIV patients, both VTE and arterial events?
• What is the role of inflammation, immune dysregulation, or endothelial, platelet, and coagulation activation in the etiology of vascular events in HIV infection?
• How to address coagulation and endothelial activation to reduce CVD risk in HIV infection?

Platelets in HIV infection:

• Is platelet-mediated chronic inflammation, which is characteristic of HIV/AIDS, also a failure to resolve inflammation so that it becomes chronic?
• What are the effects of ART on platelet function and how does ART combined with tobacco smoke further potentiate platelet dysregulation and chronic inflammation and CVD?

CD4 T cell restoration failure in HIV patients under ART:

• Why do inflammation and CD4 T cell restoration failure occur in HIV-infected patients on ART?
• What is the mechanism for CD4 lymphopenia in subjects with effective viral suppression by ART?
• What is the role of microbial translocation, inflammatory lipids, coinfection, residual HIV replication, or regulatory dysfunction?
• What are the precise determinants of immunological failure?
• Is there an organ-specific determinant, for example, gut mucosal, bone marrow, thymus, or peripheral lymph nodes?
• Can blood provide an indication of tissue-based inflammation in HIV, a liquid biopsy?
• Is it a consequence or cause of inflammation?
• What is its relationship to viral persistence, co-pathogens e.g. CMV, or gut microbiota?
• What are the best options for correction?

Age-related acquisition of somatic mutations and its association with HIV infection:

• What is the relationship between clonal hematopoiesis of indeterminate potential (CHIP) and inflammation?
  • Does clonal hematopoiesis produce clones that drive inflammation?
  • Does inflammation increase the acquisition or expansion of clonal populations of HSCs?
• Is HIV infection associated with accelerated acquisition or expansion of clonal hematopoiesis?

Cell and gene therapy for HIV cure – From Berlin to Boston and now:

• What is the role of allogeneic HCT with wild-type donors, i.e. is the presence of GVHD critical? Is there a need for CCR5 modification?
• What is the best and safest gene modification technology?
• What are efficient strategies for hematopoietic stem cell expansion?
• What are the novel technologies for less or nontoxic conditioning prior to transplantation of gene-modified cells?
• How to combine HCT with other approaches including novel immunotherapy-based strategies, such as CAR-T cells, bi-specific antibodies (DARTs or Dual-Affinity Re-Targeting and BiTEs or Bi-specific T-cell Engager) or immunotoxin-labeled antibodies, to cure HIV?
• How to target and enhance homing of immunotherapy to latent reservoirs and access B cell follicles?
• What are the cells harboring latent virus?
• What is the role of checkpoint inhibitors in HIV control/eradication?

• What is the current epidemiology of HIV transfusion-transmission in developing countries?
• How to design and implement effective intervention strategies based on the epidemiology in specific settings to reduce transfusion-transmission of HIV and other blood-borne infections to improve global blood safety?
• How do we improve blood safety for HIV worldwide?

Prevention, Control, and Treatment

Scientific Gaps

Approaches to Gaps

Compelling Questions

• What are the unique opportunities in T4 implementation science research (ISR) for people living with (PLWHIV), and specifically in heart, lung, blood, and sleep research?
• How can NHLBI best address challenges and maximize opportunities regarding T4 ISR for PLWHIV?
• How can the NHLBI facilitate training for investigators to develop relevant T4 ISR expertise to address health issues for PLWHIV?
• How can we best leverage existing networks for T4 ISR for PLWHIV? Platforms (e.g. PEPFAR)?
• What are the lessons learned, challenges, and approaches to establishing and utilizing networks/platforms both domestically and globally?
• How do we [researcher/scientists/providers] identify benefit to patients; and fully communicate those benefits?
• How do we use IS to identify opportunities for reorganization of care systems to provide comprehensive long-term HIV care for PLWHIV?
• Transfusion safety remains an unsolved problem worldwide; how can IS be utilized to promote transfusion safety in resource poor settings?
• How can the scientific community provide accurate data on PLWHIV?
• How do we support research on discoveries to be made in epidemiology for PLWHIV?
• Should IS research focus on the “low hanging fruit” and start with people already in care for HIV?
• How can qualitative research on PLWHIV be promoted and sustained?

Notable Challenges for Implementation Science

• Not all discoveries need to be new – identifying the discoveries amenable for implementation is necessary; furthermore, communicating the importance of non-novel ideas is essential for implementation science
• Identifying opportunities to leverage PEPFAR’s investment in non-PEPFAR countries is essential
• Identifying patient perception on prognosis is critical in assessing patient-centered outcomes for PLWHIV
• For the field to advance and provide added value to PLWHIV, funders should consider other funding schemes.

Overall Recommendations

Thematic Area 1 - Research Opportunities Encompassing the Patient

• Consider support of research that address patient concerns including organ system failure (HTN, COPD, coagulopathy, renal, endocrine, hepatic disorders) as well as psychiatric/behavioral concerns
• Tobacco exposure for PLWHIV
• Health disparities and understanding worse outcomes for men (e.g. Asia & Africa)
• Focus on smoking cessation in PLWHIV in low resource settings
• Hypertension control for PLWHIV is essential
• Prevention of TB (implementation of TB screening)
• Retention in care for at risk populations (e.g. youth, MSM, high risk individuals) should be explored
• Encourage PLWHIV to prioritize HLBS disease management for co-morbid conditions

Thematic Area 2 - Research Opportunities - Provider

• Physician detailing is not well established in the field so how to do it and what tools are needed is essential for providers to develop this capacity
• There are opportunities for delivery of chronic disease management through HIV clinics (integration vs. referral vs. task shifting vs. community)
• Consider how to promote the best utilization of care for non-stigmatized disease (e.g., HTN) for PLWHIV
• Research is needed to determine how providers should prioritize disease management for PLWHIV
• Providers need to know how to manage poly-pharma for multiple HLBS co-morbid conditions
• Providers should be encouraged to utilize task shifting, community health workers, and other tools to impact health of PLWHIV
• Providers should also address retention in care for PLWHIV in at risk populations (e.g. youth, MSM, high risk individuals)

Thematic Area 3 - Research Opportunities – Health System

• Organization of care systems is important for comprehensive long-term HIV care, however the knowledge for how to undertake this re-organization to effectively address long-term is lacking
• Transfusion safety remains an unsolved problem worldwide; how health care systems can improve transfusion safety especially in low resource settings is essential
• Identify roles for joint ventures between NIH or NHLBI with AHRQ or the VA or other federal entities will be essential for address PLWHIV; currently populations within the federal health care system are HIV positive
• Research that explores health services research and payment modeling in health is needed to improve the health of PLWHIV
• Adaption of guideline implementation for health systems in low resource settings is essential due to the global burden of HIV
• Utilization of qualitative research to improve health systems to improve comprehensive long-term HIV care is needed
• Understanding how health systems can promote retention in care for PLWHIV in at risk populations (e.g. youth, MSM, high risk individuals)

Thematic Area 4 - Crosscutting Opportunities

• To address the need for more researchers, a focus on mid-career as well as early-stage investigators is essential
• NIH should consider implementation science specific K awards to promote the careers of early-stage investigators with interest in the IS/HIV field both globally and domestically
• Consider implementation science T32 award and allow broader HIV focus
• Explore NIAID/NIDA models for encouraging mid-career and early-career K awards for implementation science;
• Consider getting other non-HLBS researcher/investigators into the HLBS implementation science space (could also mentor early career investigators)