Research Priorities for Cardiovascular Complications in HIV Infection/AIDS

Discussion:

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 research.

Recommendations:

General Recommendations:

• 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.

Specific Recommendations:

• 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.

Publication Plans:

The report will be posted on the NHLBI public web site.

NHLBI Contact:

Diane Reid, M.D., NHLBI, NIH
reiddm@mail.nih.gov

Working Group Members

Chair: 

• Gerald M. Reaven, M.D., Falk Cardiovascular Research Center, Stanford University Medical Center

Members:

• Michael P. Dube, M.D., Indiana University School of Medicine
• Marshall J. Glesby, M.D., Ph.D., Weill Medical College of Cornell University
• 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.