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Research Priorities for Cardiovascular Complications in HIV Infection/AIDS
October 13, 2004
The National Heart, Lung, and Blood Institute convened a Working Group
of investigators on October 13, 2004, in Bethesda, Maryland to discuss
the current state of knowledge, identify gaps in knowledge, and make specific
recommendations to the NHLBI for planning and prioritizing its research
efforts on the cardiovascular complications of Human Immunodeficiency
Virus (HIV) infection and AIDS.
HIV infection is a devastating worldwide epidemic that, by the close
of 2003, was responsible for the death of over 20 million people. Currently,
34.6 to 42.3 million individuals are living with HIV infection. Over 90
percent of HIV infections occur in the developing world where availability
of treatments and prophylaxis for opportunistic infections is limited
or nonexistent. In industrialized countries such as the U.S., mortality
from HIV infection has dramatically decreased due to the availability
of highly active, anti-retroviral therapy (HAART). However, cardiovascular
complications are emerging as new healthcare challenges in surviving individuals.
Cardiovascular disorders found in people with HIV infection or AIDS in
seemingly excess numbers and/or at accelerated rates (compared with non-HIV-infected
people of similar age) include: myocardial infarction, cerebrovascular
disease, myocarditis, dilated cardiomyopathy, pulmonary hypertension,
pericardial effusion, and venous thromboembolism. Although definitive
pathogenetic links have not been established, endothelial dysfunction
and metabolic abnormalities such as insulin resistance, dyslipidemias,
fat redistribution (lipodystrophy), hyperlactatemia, and mitochondrial
dysfunction are prevalent in those with HIV infection and may predispose
to, or hasten, development of various cardiovascular disorders. The relative
impact of traditional cardiovascular risk factors versus HIV-associated
factors, including antiretroviral therapy (ART) toxicity, on cardiovascular
outcomes is not known.
Another compelling concern that transcends national borders is the potential
for mitochondrial and cardiac toxicity of nucleoside analog reverse transcriptase
inhibitors (NRTIs) when they are administered prenatally to prevent vertical
HIV transmission. Infants may evade HIV infection, yet suffer irreversible
mitochondrial damage whose long-term consequences are unknown.
The Working Group agreed that data published so far are insufficient
to ascertain the overall incidence, prevalence, clinical course, and--most
importantly--the clinical significance of cardiovascular disorders in
HIV-infected and AIDS patients. The current state of knowledge is largely
derived from retrospective single-center or single-cohort studies that
lack the design and power to yield far-reaching conclusions. Demographic
profiles of cohorts in different locations within the U.S. are dissimilar
and obtaining cardiovascular epidemiologic information in larger, geographically
balanced, HIV/AIDS cohorts has only recently begun.
Determining the pathogenesis of atherosclerosis and other cardiovascular
disorders in the presence of HIV infection is confounded by uncertainty
about the contributions made by many variables, including: HIV infection
itself; co-infection(s); immune status; inflammatory status; exposure
to antiretroviral therapy; other drug use/abuse; underlying genetic susceptibility;
general nutritional status; and pre-existing, traditional, cardiovascular
risk factors. The need to measure and control for these variables adds
significant complexity to HIV clinical studies. For instance, HAART therapy
typically consists of several different classes of drugs (usually NRTIs,
nonNRTIs, and protease inhibitors) taken in combinations that frequently
change (the median time for switching drug regimens is only one year).
Another major obstacle to data interpretation in previous studies has
been the lack of thorough baseline cardiovascular risk profile information.
As an example, insulin resistance varies enormously (6-fold) within the
population at large, so lack of pre-infection and pre-treatment insulin
resistance data may significantly limit the conclusions that may be drawn
about the effect of specific therapies or HIV-related variables.
Augmented communication and collaboration among physicians and researchers
in HIV and cardiovascular areas would help achieve informed comprehensive
care of patients and prevent missed opportunities for hypothesis-driven
- Promote interaction between researchers in different specialties and
disciplines (e.g., cardiovascular and HIV; basic and clinical). Disseminate
information about ongoing cardiovascular studies in large cohorts, such
as the Multi-center AIDS Cohort Study (MACS), the Women's Interagency
HIV Study (WINS), and the Adult AIDS Clinical Trials Group (AACTG).
The NHLBI might, perhaps, provide a regular forum for this purpose.
- Encourage hypothesis-driven, prospective, randomized, appropriately
controlled studies that include HIV-negative subjects whenever possible.
- Incorporate comprehensive, pre-treatment, baseline assessments into
clinical studies to help explain apparent excess cardiovascular risk
with HIV infection.
- Define the role of mitochondria in metabolic and cardiovascular complications
associated with NRTI therapy. This would include the relationships among
mitochondrial DNA depletion, genetics, and energetics, and the potential
for pediatric cardiac disease from NRTIs.
- Describe the epidemiology of specific cardiovascular disorders in
HIV populations to provide a context for ranking research priorities.
- Study the contributions of infection, inflammation, HAART, and traditional
risk factors to the pathogenesis of atherosclerosis in HIV patients.
Ascertain whether interventions would reduce CV risk, and if so, what
should be the indications for use and treatment targets. Determine which
surrogate endpoints (e.g., carotid intimamedial thickness, electron
beam CT, endothelial dysfunction) might be useful.
- Define mechanisms of heart muscle disease in association with HIV
infection, including the role of myocarditis.
- Develop an NHLBI central tissue bank that would serve as a resource
for clinical and basic HIV researchers.
- Determine mechanisms of actions and metabolic toxicities of antiretroviral
agents when used alone and in combination with other CVD prevention
therapies, such as statins, other lipid-lowering drugs, hypoglycemic
agents, anti-platelet drugs, anticoagulants, and antihypertensive drugs.
- Evaluate patient factors in relation to metabolic complications and
cardiovascular complications, including pharmacogenomics, sex and racial
differences, and age.
- Develop animal models to better understand mechanisms of ART toxicities.
The report will be posted on the NHLBI public web site.
Diane Reid, M.D., NHLBI, NIH
Working Group Members
Chair: Gerald M. Reaven, M.D., Falk Cardiovascular Research Center,
Stanford University Medical Center
- Michael P. Dube, M.D., Indiana University School of Medicine
- Marshall J. Glesby, M.D., Ph.D., Weill Medical College of Cornell
- Priscilla Hsue, M.D., San Francisco General Hospital
- Robert C. Kaplan, Ph.D., Albert Einstein College of Medicine
- William Lewis, M.D., Emory University School of Medicine
- Kendall B. Wallace, Ph.D., University of Minnesota
NHLBI Staff Members:
- Cheryl McDonald, M.D.
- Jamie Varghese, Ph.D.
Last updated: March 17, 2005