Meeting Minutes - March 18, 2010

Office of AIDS Research Advisory Council
Thirtieth Meeting
March 18, 2010

National Institutes of Health
U.S. Department of Health and Human Services
5635 Fishers Lane Conference Center
Rockville, MD

Members Present: Dr. James W. Curran (Chair), Dr. Jack Whitescarver (Executive Secretary), Ms. Dawn Averitt Bridge, Dr. Coleen K. Cunningham, Dr. Sharon E. Frey, Dr. Gary W. Harper, Dr. Betsy C. Herold, Ms. Lynn Paige Nestor, Dr. Michael F. Summers, and Dr. Paul Volberding

Ex Officio Members Present: Dr. John G. Bartlett, Dr. Ralph J. DiClemente, Dr. Hazel Dean, Dr. Carl W. Dieffenbach, Dr. Igor Grant, Dr. Diana M. Lopez, Dr. Christel H. Uittenbogaart, Dr. Ronald O. Valdiserri, and Dr. Nelson L. Michael

Invited Speakers and Guests: Mr. James Albino, Dr. Gina M. Brown, Dr. Stacy Carrington-Lawrence, Dr. Rita B. Effros, Dr. Eric A. Engels, Dr. Carl Grunfeld, Dr. Kevin P. High, Dr. Priscilla Hsue, Dr. Lisa P. Jacobson, Dr. Albert Shaw, Dr. Glenn J. Treisman, and Dr. Victor Valcour

Welcome and Meeting Overview

The National Institutes of Health (NIH) Office of AIDS Research Advisory Council (OARAC) convened its thirtieth meeting at 8:30 a.m. at the Fishers Lane Conference Center in Rockville, Maryland. Dr. James W. Curran, Chair, welcomed the OARAC members, invited speakers, and guests.

The topic of the meeting was HIV/AIDS and aging. He noted the importance of this topic due to the increasing incidence of HIV and AIDS in individuals over 50 years of age, the reports of premature aging of HIV-infected individuals, and the increasing number of HIV-infected individuals who are living longer and growing older due to the benefits of antiretroviral therapy (ART). Dr. Curran noted that today’s meeting presentations would address the current epidemiology of the AIDS epidemic among older individuals in the U.S., the potential role of ART in accelerating aging, and the emerging comorbidities due to aging and HIV infection. He referred participants to the conference folder for information about the next two OARAC meetings. He stated that the fall meeting has been rescheduled to November 9, 2010. Dr. Curran also introduced Mr. Jules Levin, founder of the National AIDS Treatment Advocacy Project and long-term community advocate and educator on issues related to HIV and aging.

The minutes of the November 5, 2009 OARAC meeting were approved as submitted.

Director’s Report

Dr. Jack Whitescarver, Director of the Office of AIDS Research (OAR), welcomed everyone to this meeting of the OARAC. He also welcomed Dr. Hazel Dean, who was attending for Dr. Kevin Fenton of the Centers for Disease Control and Prevention (CDC). He thanked Dr. Colleen Cunningham, Dr. Sharon Frey, Ms. Lynn Nestor, and Dr. Michael Summers, whose extended OARAC terms will expire at the end of March, for their years of service and guidance. Dr. Whitescarver thanked departing OARAC Chair, Dr. James Curran, for his advice and leadership over the years.

NIH Personnel Changes

Dr. Whitescarver noted several recent personnel changes at NIH. He stated that Dr. Eric Green was named Director of the National Human Genome Research Institute (NHGRI) and began serving on December 1, 2009. Dr. Green was formerly the NHGRI Scientific Director and Director of the Division of Intramural Research. Dr. Alan Guttmacher was named the Acting Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development after the departure of Dr. Duane Alexander.

Dr. Whitescarver reported that: Dr. Raynard Kington, Principal Deputy Director of NIH, has announced that he will be leaving NIH in July 2010 to become President of Grinnell College in Grinnell, Iowa; Dr. Susan Shurin, formerly Deputy Director of the National Heart, Lung, and Blood Institute (NHLBI), has been named NHLBI Acting Director with the January 2010 departure of former Director Dr. Elizabeth Nabel; and Dr. Kenneth Warren, NIAAA Deputy Director, continues to serve as NIAAA Acting Director.

Dr. Whitescarver also announced that Mr. Francis Patrick "Pat" White has been appointed the NIH Associate Director for Legislative Policy and Analysis.

Dr. Whitescarver announced three upcoming OAR-sponsored meetings. He stated that OAR will convene a comprehensive "think tank" on behavioral and social science prevention research in late summer or early fall of 2010. The think tank will be organized by Dr. Ellen Stover of the National Institute of Mental Health, and co-chaired by Dr. Thomas Coates and Dr. Judith Auerbach. Participants in this meeting will include U.S. and international experts in a broad range of scientific disciplines. They will inventory NIH-sponsored AIDS research in the areas of behavioral and social science and will generate recommendations to the NIH for future directions. Second, Dr. Whitescarver reported that OAR will convene a summit under the auspices of the Microbicides Research Working Group to obtain expert advice and guidance on the future scientific agenda for NIH-sponsored microbicides research. The third meeting sponsored by NIH, in collaboration with the International AIDS Society, the Agence Nationale de Recherche sur le SIDA, and the Austrian Federal Ministry of Science and Research, is a workshop entitled, "Towards a Cure: HIV Reservoirs and Strategies to Control Them," which will be convened in conjunction with the IAS Conference in Vienna.

Conflict Of Interest Statements

Dr. Whitescarver asked Council members to review and sign the conflict of interest statement provided to them. He reminded the Council members of the importance of this process.

Budget Overview

Dr. Whitescarver stated that the fiscal year (FY) 2010 NIH AIDS research budget increased by 2.2 percent over the FY 2009 funding level. He noted that the increase is below the rate of inflation. Dr. Whitescarver stated that the FY 2011 President’s budget request to Congress includes an approximate 3.2 percent increase over the FY 2010 level, as a result of the efforts of Dr. Francis Collins, Director of NIH and others. He noted that this increase is near the rate of inflation.

President’s National AIDS Strategy

Dr. Whitescarver stated that several OAR staff members serve on the Inter-Agency Task Force and its subcommittees to develop the President’s National AIDS Strategy. He reported that subcommittees have been established to address three major goals: 1) reducing the incidence of HIV; 2) increasing access to care and improving outcomes; and 3) reducing health disparities. Dr. Whitescarver introduced Mr. James Albino from the White House Office of National AIDS Policy.

International AIDS Society

Dr. Whitescarver reported that the International AIDS Society (IAS) conference will be held in Washington D.C. in July 2012. He noted that this meeting has not taken place in the U.S. since 1990, but because President Obama has removed the ban on entry of HIV-infected individuals into the U.S., the meeting can now again be held in the U.S. He noted that OAR will play a role in planning this international conference.

Dr. Whitescarver introduced a guest to OARAC, Dr. Julio Montaner, President of IAS, Professor of Medicine at the University of British Columbia, and Clinical Director of the Centre for Excellence in HIV/AIDS. Dr. Montaner provided an update on recent IAS activities. He noted that the 18th IAS conference will be held in Vienna, Austria from July 18 to 23, 2010. He stated that the conference will be an important event in the history of the HIV/AIDS epidemic.

OAR Strategic Plan and Bypass Budget

Dr. Whitescarver stated that OARAC members will be provided a copy of the FY 2011 Trans-NIH AIDS Research By-Pass Budget Estimate and Trans-NIH Plan for HIV-Related Research, which have been merged into one comprehensive document. It has been reformatted and restructured to address the major goals of the President’s National AIDS Strategy.

Meeting Overview

Dr. Whitescarver stated that today’s meeting is an extension of discussions the Council held previously on research to address HIV-associated comorbidities, coinfections, and other complications. Today’s meeting will focus on research on HIV and aging. He noted that the Trans-NIH Strategic Plan addresses this topic in a broad sense across all of the areas of science. Dr. Whitescarver stated that he is looking to OARAC to assist in identifying specific areas of research that OAR could consider for targeted resources to enhance NIH’s efforts in this area.

Dr. Stacy Carrington-Lawrence, Chair of the OAR Coordinating Committee on Etiology and Pathogenesis, provided an overview of the topic of HIV and aging. She discussed the timeliness and importance of this research topic and stated that NIH is positioned to be at the forefront of research on the complexities of HIV infection in older adults. She stated that OARAC members and speakers will broadly examine what is known about HIV and aging and will identify scientific opportunities, gaps, and priorities in this area.

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES

Dr. John G. Bartlett, Professor of Medicine and Chief of Infectious Diseases at the Johns Hopkins University School of Medicine and Co-Chair of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents, presented an update on the activities of each of the OARAC Working Groups for Treatment and Prevention Guidelines.

Dr. Bartlett reported that a Guidelines Panel Leadership Meeting was held in conjunction with the annual Conference on Retroviruses and Opportunistic Infections (CROI) on February 1, 2010. At the meeting, the leadership of the five guidelines panels, along with representatives from several international guidelines panels, discussed how each of these groups address a variety of subjects, including potential conflicts of interest of panel members.

Dr. Bartlett reported that revisions of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents were released on World AIDS Day, December 1, 2009. The revisions addressed: when to start antiretroviral therapy (ART); which ART regimen to start; resistance testing; HIV-2 infection; and hepatitis C virus (HCV) coinfection. The revisions included updates to several tables in the guidelines. Dr. Bartlett stated that the updated guidelines recommend starting ART when CD4+ cell counts are between 350 and 500 cells/mm3. Dr. Bartlett also stated that half of the panel members favored initiating ART at CD4+ cell counts above 500 cells/mm3. However, half of the panel members felt that initiating ART at these levels should be optional, as there could be benefit to delaying treatment, such as addressing factors that could affect long-term treatment and adherence including depression, homelessness, substance abuse, and addiction. Dr. Bartlett reviewed the arguments for and against early initiation of ART.

Dr. Bartlett stated that the Opportunistic Infections Working Group plans to completely review and update the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents in 2010. The Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children were updated in September 2009. A core working group will meet in spring 2010 to review plans for future updates.

Dr. Bartlett stated that revisions to the Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States are expected in April or May 2010. The updates will include: specific descriptions of the criteria used to categorize the recommendations; “boxed” recommendations with strength and quality ratings; and updates on recent international clinical trials. The revisions also will include: an updated drug resistance section; a caution on the use of boosted protease inhibitors (PIs) in infants; discussion of new data on the feeding of pre-masticated food to infants; and contact information for the National Perinatal HIV Consultation and Referral Service (Perinatal HIV Hotline).

Dr. Bartlett stated that revisions to the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection are expected in May 2010. The updates will address when to start ART based on CD4+ levels and what ART regimen to start. Revisions also will include: boxed recommendations with strength and quality measurements; modifications of the drug appendix; and conversion of toxicity management hyperlinks to table format.

Dr. Bartlett raised several topics that were discussed by all of the Working Groups: 1) whether there should be a formal external review of the guidelines documents by an outside entity; 2) the conflict of interest policy; 3) whether to produce a pocket-size version of the guidelines; and 4) whether to produce a shortened version of the guidelines, and if so, whether to retain the longer version. Dr. Bartlett noted that the Working Groups are in the process of complying with the Institute of Medicine (IOM) conflict of interest guidelines.

Dr. Bartlett concluded by asking for discussion on the impact of the guidelines on clinical practice. He asked whether the guidelines are used by practitioners, what are the potential shortcomings, in what areas is more clarity needed, and where errors are being made in the application of the guidelines. Dr. Bartlett suggested that some of this information could be collected through large cohort studies.

DISCUSSION

OARAC members, speakers, and guests discussed the potential value of starting ART early to reduce HIV transmission. There was a consensus that the guidelines documents are useful and are used frequently by practitioners. Suggestions included developing pocket-size and shortened versions of the guidelines while retaining the longer versions; collaborating with other Federal agencies to obtain direct feedback on the guidelines from practitioners; collecting data on the number of Internet "hits" to specific sections of the guidelines; and developing specific mechanisms to disclose and monitor for conflict of interest and to address intellectual conflict of interest.

EPIDEMIOLOGY OF THE EPIDEMIC IN THOSE OVER 50

To begin OARAC’s consideration of the meeting’s topic, Dr. Lisa Jacobson, Associate Professor, Johns Hopkins University, discussed the epidemiology of the HIV epidemic in people over 50 years of age. She cited CDC statistics showing a recent marked increase in the number of individuals over the age of 50 years who are living with HIV/AIDS and the recent increase in HIV diagnoses in individuals over the age of 40 years.

Dr. Jacobson discussed two large, standardized observational cohorts with substantial data on individuals aged 50 years and older, including the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS). She focused her presentation on findings from the MACS, an ongoing prospective study of the natural history and treatment histories of HIV-infected men who have sex with men (MSM) and bisexual men in the United States. Dr. Jacobson noted the importance for collecting similar demographics and rates of recreational drug use among HIV-seronegative and HIV-seropositive individuals in the MACS.

Dr. Jacobson reviewed findings from the MACS on HIV, aging, and frailty. She reported that the majority of individuals aged 50 years and older surviving with HIV had been infected at a younger age. She stated that, compared to younger counterparts, older HIV-infected men experienced: faster rates of progression to AIDS and death in the absence of therapy; a 36 percent increase in mortality for each 10 years of age; and an increased likelihood of dying from AIDS, despite a median 13.9 year survival time after progression to AIDS in the antiretroviral therapy (ART) era. She noted that the risk for a frailty-related phenotype in HIV-seropositive individuals increased with the duration of infection in the absence of therapy and that this phenotype was associated with an increased risk for developing or dying from AIDS.

Dr. Jacobson also noted that older individuals in the MACS cohort tend to have smaller immediate increases in CD4+ cell counts with initiation of ART. She described lower long-term CD4+ counts in older men who start ART at CD4+ cell counts less than 350 compared with older men who began ART at higher CD4+ levels.

Dr. Jacobson stated that HIV is a chronic disease associated with many age-associated comorbidities and complications. She suggested that age may be the appropriate time axis for making comparisons between populations based on HIV serostatus. She suggested the need to examine all causes of mortality and AIDS versus non-AIDS mortality among HIV-seropositive individuals. She stated that life-expectancy for MACS participants is 79 years in HIV-uninfected men, 69 years in HIV-seropositive men who will die of non-AIDS causes, and 49 years for HIV-seropositive men who will die of AIDS.

Dr. Jacobson described the strengths of observational cohort studies including: 1) comparison of groups of similar risk; 2) standardized, complete, longitudinal data collected with uniform frequency before and after treatment; and 3) collection of participants’ specimens and storage in centralized repositories.

NORMAL AGING VERSUS AGING WITH HIV: SYNERGY OR PARALLEL MECHANISMS

Dr. Kevin High, Professor of Medicine, Wake Forest University School of Medicine, discussed the similarities and differences of normal aging compared with aging in HIV-infected individuals. Regarding the question of synergy versus parallel pathways, he stated that synergy between HIV infection and the aging process would lead to accelerated aging, whereas parallel mechanisms (or multiple pathways) would lead to multiple comorbidities as HIV-infected individuals age.

Dr. High discussed several immune effects of normal aging: thymic atrophy and decreased naïve T cell regeneration; decreased T cell diversity; and T cell senescence, particularly of CD8+ cells that express the CD28 marker, which is known to be associated with HIV progression and other immune responses. He stated that synergistic effects of HIV infection and aging are reduced naïve T cell numbers; reduced naïve CD4+ cell diversity; and an increase in senescent T cells. He stated that these changes are accompanied by low levels of immune activation and inflammation.

Dr. High discussed parallel mechanisms of HIV and aging. He noted the earlier appearance of age-associated, non-disease comorbid conditions in HIV-infected individuals. He stated that aging and HIV are similarly associated with: increased wound healing by fibrosis and associated collagen deposition in the kidney and, possibly, in gut-associated lymphoid tissue; declines in the immune response; increases in systemic inflammation; and depletion of physical reserves. He suggested that biomarkers for physical reserves are predictive of disease outcomes in HIV-infected individuals who have progressed to advanced illness. He also suggested that the effects of HIV on systemic immune activation and inflammation are similar to the "inflamm-aging" theory of normal aging.

Dr. High discussed a recent Workshop on HIV Infection and Aging that conducted a review of the current knowledge base on HIV and aging from available cohorts. Workshop participants identified high priority research questions in this field. They also delineated the need for: animal models, especially older non-human primate models for SIV studies; improved biomarkers of aging; functional status and comorbidity measures in cohorts; carefully selected control groups; and longitudinal data.

Dr. High also noted the importance of including geriatric concepts in HIV research of middle-aged and older adults. This requires the overall integration of quality of life, physical function, and treatments required for HIV disease control. He stated that a variety of important functional status measures could be easily integrated into HIV research cohorts. He noted existing collaborations among the NIH-supported Centers for AIDS Research (CFARs) and the Claude D. Pepper Older Americans Independence Centers that include measures of functional status.

ARV THERAPY AND DISEASES OF “AGING”

Dr. Paul Volberding, Professor of Medicine at the University of California, San Francisco, Chief of Medical Service, San Francisco Veterans Affairs Medical Center, and OARAC member, discussed the interactive effects of ART and diseases of aging. He stated that the expanded life expectancy of HIV-infected individuals with the advent of ART is even more pronounced in what he called the "new" ART era in which viral suppression is achieved in most patients.

Dr. Volberding stated that viral suppression does not restore normal health, and healthcare practitioners increasingly will be faced with geriatric concerns as HIV-infected individuals age. He noted this is being seen in the VA system. He stated that individuals who begin ART after their CD4+ counts have fallen to less than 200 generally do not achieve a normal CD4+ cell count even after 10 years of viral suppression.

Dr. Volberding stated that recent research suggests two possible sources of persistent immune activation and inflammation caused by HIV, despite successful ART: 1) low levels of persistent active viral replication in the gut, and 2) persistent, but undetectable, levels of peripheral HIV. Dr. Volberding also suggested a role for cofactors in the development of comorbid conditions in HIV-infected individuals who are aging.

Dr. Volberding presented research findings showing that successfully treated HIV-seropositive individuals do not have a normal lifespan, particularly if therapy is started late. He noted that almost two-thirds of all deaths in HIV-seropositive populations in the late ART era are from non-AIDS associated causes.

Dr. Volberding noted the role of lifestyle factors, antiretroviral (ARV) toxicities, and HIV disease itself may result in the development of many non-AIDS defining comorbidities in HIV-seropositive populations. He suggested this is an important area for future research.

Dr. Volberding concluded by providing a mechanistic rational for starting therapy in all HIV-infected individuals as soon as possible, citing: increased T cell activation and inflammation in untreated disease; the dramatic decrease in inflammation with treatment; and the association of low CD4+ counts at the onset of therapy with greater residual inflammation during ART. He stated that although U.S. guidelines recommend early treatment in the majority of HIV-infected individuals, most individuals still enter treatment and care too late. Dr. Volberding suggested the need for discussion among NIH, CDC, and other agencies to understand the barriers to bringing people into care and keeping them in care.

DISCUSSION

OARAC members, speakers, and guests discussed the presentations by Drs. Jacobson, High, and Volberding. The discussion addressed the importance of including HIV-infected and -uninfected cohorts in the MACS; the possible contribution of ART toxicities to the aging process; the role of functional status measures in predicting outcomes in HIV-infected individuals; and the need for the integration of aging research in the context of research on specific diseases and conditions.

PRESENTATIONS ON ACCELERATED AGING

Innate Immunity and Susceptibility
Dr. Albert Shaw, Associate Professor of Medicine, Yale University, provided an overview of HIV interactions with the innate immune system, and immune senescence in the aging immune system. He reported on various HIV interactions with components of the innate immune system, including monocytes, macrophages, neutrophiles, dendritic cells, Natural Killer cells, and others. He described the theory that substantial disruption of mucosal tissue by HIV infection causes innate immune activation. He also outlined results from studies on innate immune activation with SIV in non-human primates.

Dr. Shaw described the effects of normal aging on immune activation based on prospective observational cohort studies of young and older adults who were not immune compromised. Dr. Shaw stated that analysis of peripheral blood mononuclear cells (PMBCs) isolated from study participants prior to vaccination for influenza revealed various age-associated changes in the activity of key cytokines and interleukins that led to impaired T cell function. He suggested that there is intricate interplay between immune responses and HIV. Dr. Shaw proposed that further studies in this area are needed.

Aging of the Immune System

Dr. Rita Effros, Professor, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, described the effects of aging on the adaptive immune system responses to acute and latent infections. She reported on the impact of latent viruses acquired at an early age on the aging immune system. Dr. Effros described an in vitro model of repeated antigen stimulation of CD8+ T cells, as would occur with chronic, latent infection. She stated that this model produces massive T cell proliferation until the cells reach a state of replicative senescence that she defined as an irreversible state of growth arrest in cells that are unable to further divide.

Dr. Effros described research on associations between T cell senescence and mortality in HIV-infected and -uninfected populations. She stated that earlier death in older populations has been found to be associated with short T cell telomeres, a high proportion of senescent T cells, and cytomegalovirus (CMV) seropositivity. She also noted that T cell senescence in HIV-infected individuals is associated with faster progression to AIDS.

Dr. Effros also commented on associations among T cell senescence and organ function in older populations. She stated that high proportions of senescent T cells are associated with increased risk for osteoporotic fractures and increased bone loss. She stated that factors known to be associated with low bone mass that are particularly relevant in HIV-infected populations include aging, atherosclerosis, and dyslipidemia.

Dr. Effros discussed several possible strategies to prevent or treat replicative senescence including: physical removal of senescent cells; gene therapy; and pharmacologic treatment. She noted that there remain many unanswered scientific questions in this area of research.

Discussion

OARAC members, speakers, and guests discussed research on ARV drugs that affect T cell telomerase; the impact of senescent T cell suppression of CD8+ T cell activity; and whether inflammation should be suppressed or augmented to improve immune function with aging. The discussion also addressed the possible interactive role of chronic inflammation from CMV and other infections with HIV in the aging of the immune system; whether early initiation of ART helps prevent accelerated aging of the immune system; and the quality of the immune system following immune reconstitution with ART. There also was discussion of HIV and aging research sponsored by the National Institute on Aging (NIA), as well as NIA’s collaborations with the CFAR program.

PRESENTATIONS ON CO-MORBIDITIES DUE TO AGING AND HIV INFECTION

HIV and Cardiovascular Disease

Dr. Priscilla Hsue, Associate Professor of Medicine, University of California, San Francisco, discussed the topic of HIV and cardiovascular disease (CVD). She noted that HIV-infected individuals present with myocardial infarction (MI) at younger ages; have higher rates of restenosis after stenting; may experience pathology similar to cardiac transplant patients; have higher rates of atherosclerosis; and experience increased vascular age, compared with uninfected individuals. She described research that shows HIV infection is an independent predictor of all causes of mortality, acute coronary syndrome, and repeat revascularization. She also noted that exposure to some ART regimens is independently associated with an increased risk of MI, although untreated HIV disease is associated with a higher CVD risk than treated disease.

Dr. Hsue described two surrogate markers for atherosclerosis and CVD events in HIV-infected individuals, including carotid artery intima-media thickness (IMT) and brachial artery flow-mediated dilation. She stated that research on IMT shows that HIV disease is associated with the same level of CVD risk as diabetes mellitus and smoking, and is equivalent to about a 5 to 9 year increase in age. She stated that research on brachial artery flow-media dilation shows that vascular function improves rapidly with initiation of ART, but it does not return to normal levels.

Dr. Hsue described several markers for inflammation that are independent risk predictors for CVD in HIV-infected individuals. She also noted a strong relationship between T cell dysfunction, inflammation, and CVD. Dr. Hsue presented research findings showing "elite controllers" of HIV (HIV-seropositive individuals with no detectable HIV RNA in the absence of ART) have higher levels of CVD risk compared with HIV-uninfected individuals.

Dr. Hsue discussed links between the emerging concept of HIV immunopathogenesis and HIV-associated CVD. She suggested that CVD in HIV-infected individuals may be mediated by the aging of the immune system.

Dr. Hsue listed several questions that represent persistent gaps in knowledge in the area of HIV, aging, and CVD: 1) What is the optimal first line ARV regimen and what is the optimal time to start ART in patients with CVD? 2) Standard ART strategies are associated with residual inflammation, so will there be a cardiovascular benefit of further reducing viral load and presumably HIV-associated inflammation? 3) What role will anti-inflammatory or other immune-based therapeutics have in the standard treatment strategies? 4) Are newer ARV regimens, such as CCR5 inhibitors or integrase inhibitors, associated with unique CVD profiles? 5) Should treated HIV infection be considered a CVD equivalent? 6) Can findings from HIV-associated atherosclerosis be applied to other chronic inflammatory diseases?

HIV, Aging, and Cancer

Dr. Eric Engels, Senior Investigator, Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, described the intersection of HIV, aging, and cancer. He stated that Kaposi’s sarcoma (KS), non-Hodgkin’s lymphoma (NHL), and cervical cancer are AIDS-defining, virus-associated cancers and frequently present in HIV-infected populations. Several non-AIDS-defining cancers are associated with a moderately elevated risk with HIV-infection and are common in HIV-infected populations, including lung cancer, anal cancer, liver cancer, and Hodgkin’s lymphoma. Dr. Engels stated that another group of cancers do not occur more frequently in HIV-infected populations, but are somewhat common in the general population, particularly with aging.

Dr. Engels stated that the increased risk both for AIDS-defining cancers and non-AIDS-defining cancers in HIV-infected individuals results from immune suppression. He stated that the increased risk of other cancers with aging is caused by the accumulation of DNA mutations in the body. He noted that HIV-infected individuals tend to develop some cancers at a younger age than the general population. He suggested that this observation is largely an artifact related to the age distribution of the populations at risk for these cancers, rather than a general acceleration of age-related processes that lead to cancer.

Dr. Engels described the trends over time in the overall cancer burden among HIV-infected individuals in the United States and the factors driving these changes. He described data from the HIV/AIDS/Cancer Match Study that show a steep decline in the incidence of AIDS-defining cancers across all age groups, beginning before the introduction of ART, and a continual, gradual decline ever since. He noted that, in contrast, the incidence of non-AIDS-defining cancers in HIV-infected individuals has increased steeply over the same timeframe. He suggested that the increase in disease burden from non-AIDS defining cancers is driven mostly by an increase in the number of HIV-infected individuals and the aging of the HIV-infected population.

Dr. Engels concluded with the need to better understand the role of HIV in the pathogenesis of non-AIDS-defining cancers. He stated that the dramatic rise in cancer morbidity and mortality in HIV-infected individuals requires a renewed focus on improved cancer prevention and screening. He stated that HIV-infected individuals with cancer have a worse prognosis and have unique treatment needs compared with HIV-uninfected individuals. He discussed the need to develop improved therapies for this population.

Central Nervous System Complications of Aging with HIV

Dr. Victor Valcour, Associate Professor, Department of Medicine, Division of Geriatrics and Department of Neurology, University of California, San Francisco, described the effects of HIV and aging on central nervous system (CNS) complications. He stated that HIV-infected peripheral monocytes readily cross the blood-brain barrier to form a reservoir of HIV-infected perivascular macrophages. He suggested that this reservoir may be responsible for many HIV-associated CNS complications. Dr. Valcour described findings that suggest dementia in HIV-infected individuals correlates more closely with the amount of brain inflammation than with the amount of virus in the brain, and that ART has no impact on the frequency of cognitive impairment.

Dr. Valcour discussed the impact of aging on neurocognitive impairment in HIV-infected individuals. He stated that research findings on brain metabolic activity demonstrate an acceleration of 15 to 20 years in the apparent age of the brain in HIV-infected individuals. He stated that an acceleration of just 10 years may lead to high rates of age-associated dementia in HIV-infected individuals in their 60s, compared with HIV-seronegative populations.

Dr. Valcour described a model of dementia, aging, and HIV, suggesting that age-related and non-age-related factors contribute to multifactorial brain damage and clinical presentation of cognitive, behavioral, or motor disorders. He also discussed factors that differentially affect older HIV-infected individuals, compared with younger HIV-infected individuals. These factors include: longer duration of infection and chronic immune activation; longer duration of ART; greater risk from previous exposure to more toxic ARVs; greater risk for incomplete viral suppression with prior therapy; delayed diagnosis; and greater duration of immunosuppression.

Dr. Valcour presented research findings on the role of macrophages in dementia in HIV-infected individuals. He explained that, among HIV-seropositive individuals, those with dementia were more likely to have a higher level of virus in macrophages in the brain, and to have detectible levels of HIV in circulating monocytes, compared with individuals with no dementia. Furthermore, ART cleared circulating monocytes of detectible levels of HIV in individuals without dementia, but not in individuals with dementia.

Dr. Valcour described research suggesting that amyloid protein deposits, which are known to be associated with Alzheimer’s disease, are more common in the brains of HIV-infected individuals than in HIV-uninfected individuals. He stated that that ART does not appear to impact amyloid deposition. He also outlined the possible role of TDP-43 and alpha-synuclein proteins in dementia in HIV-infected individuals.

Dr. Valcour concluded that HIV-related cognitive disorders remain prevalent even with ART and are more frequent with increasing age. Aging with HIV disease predisposes to an accelerated aging phenotype.

Body Composition, Metabolism, and Atherosclerosis in HIV Infection

Dr. Carl Grunfeld, Professor of Medicine, University of California, San Francisco, and Chief of Metabolism and Endocrine Sections, Veterans Affairs Medical Center, described the effects of HIV and aging on body composition, metabolism, and CVD. He discussed aging and mortality and stated that the disease an individual dies from may be more related to their genetic make-up and environmental exposure than to aging, per se. While immune senescence plays an important role in both HIV infection and aging, he noted that the consequences of that senescence are different for HIV-infected individuals.

Dr. Grunfeld stated that normal changes in body composition with aging include weight gain, obesity, decreased muscle mass, and infiltration of muscle by fat (sarcopenia). He noted that muscle wasting disease (cachexia) observed with HIV disease and AIDS is also associated with decreased muscle mass and muscle infiltration by fat.

Dr. Grunfeld described a multivariate analysis showing that HIV infection does not accelerate changes in body composition when controlling for the lower starting levels of fat and muscle mass in HIV-infected individuals. He stated that the major predictors for decreased skeletal muscle mass in HIV-infected individuals are age, level of exercise, and change in CD4+ count. He stated that excess muscle loss in some HIV-infected individuals is a disease effect, not an effect of accelerated aging.

Dr. Grunfeld stated that by age 30 to 40 years, most individuals have reached a stable profile for the metabolic parameters of triglyceride, low density lipoprotein (LDL), high density lipoprotein (HDL), obesity, insulin resistance, etc. He stated that normal aging and HIV infection cause little change in metabolic profile, although various ARV regimens affect metabolic parameters.

Dr. Grunfeld suggested that increased mortality is caused by prolonged exposure to various risk factors. He proposed that HIV acts as an additional risk factor that may explain the increase of CVD seen in HIV-infected individuals.

Dr. Grunfeld discussed two accelerated aging syndromes, Werner’s syndrome and progeria, in comparison to HIV disease. He suggested that the mechanisms leading to CVD in these accelerated aging syndromes and HIV disease may be different than CVD development in normal aging.

Dr. Grunfeld concluded that he is not sure what will be gained from a scientific perspective by focusing on accelerated aging in HIV research. He suggested identifying specific diseases that are accelerated by HIV infection and exploring the basis for this acceleration.

Discussion

OARAC members, speakers, and guests discussed the presentations by Drs. Hsue, Engels, Valcour, and Grunfeld. The discussion addressed possible causes for the decreased prevalence of and mortality from KS and NHL before the onset of ART and the effects of global age-associated defects in DNA repair on cancer development in HIV-seropositive individuals. The discussion also addressed whether HIV accelerates aging, focusing on the importance of applying techniques used in the study of aging and multimorbidity to the study of aging and HIV. There also was discussion on the potential effects of immune activation, senescence, and accelerated immunological aging on HIV-associated comorbidities, as well as the need to understand the interplay of aging, frailty, and the diseases and conditions that are more prevalent in HIV-infected individuals.

Psychosocial Aspects of Aging with HIV

Dr. Glenn Treisman, Professor and Director, AIDS Psychiatry Service, Johns Hopkins Hospital, presented the hypothesis that HIV is a psychiatric epidemic. Dr. Treisman stated that psychiatric patients are: at increased risk for HIV infection; less likely to receive ART and remain on ART; less likely to have undetectable viral loads; and more likely to die sooner than HIV-seropositive individuals with no psychiatric illness. He stated that HIV-infected individuals with mental illness are being disenfranchised from psychiatric care, medical care in general, and clinical trials. However, he stated that HIV-infected mentally ill individuals who visited the Johns Hopkins psychiatric clinic at least once had better outcomes.

Dr. Treisman described how the complex interactions between age and psychiatric conditions can lead to a worsening of mental illness and disease progression to AIDS. He proposed the need for different treatment approaches depending on whether a mental illness is caused by chemical imbalances, environmental factors, or behavioral factors. He also described how disenfranchised individuals who have negative experiences with healthcare practitioners can lead to a self-reinforcing cycle of distrust of medical care providers. He stated that the older the patients are, the more entrenched they become in this cycle.

Dr. Treisman discussed depression and dementia, citing MACS data showing a two-and-a-half fold increase in depression with the development of AIDS. Dr. Treisman stated that the part of the brain most damaged by HIV is the subcortical area, leading to dyskinesia, dementia, and depression. He stated that this triad of conditions leads to apathy, inertia, irritability, personality deterioration, and a slowing of thought processes, or “AIDS dementia.” He noted that these subcortical effects are specifically associated with treatment non-adherence and that aging further reduces treatment adherence in this population.

Dr. Treisman discussed the interaction of personality disorders and HIV disease. He noted that robust personality disorders do not improve with ART. He stated that individuals with personality disorders tend to use the most resources for the least gain, and that this situation tends to worsen as the affected individuals age. He also noted the importance of treating addiction in individuals with mental illness and stated it takes more effort to successfully treat older individuals with addictions than younger individuals.

Although data show that individuals with mental illness respond to care, Dr. Treisman concluded that the disenfranchisement of this population is causing a faster spread of the HIV epidemic. He emphasized the need to include mentally ill HIV-infected individuals in healthcare settings and the need for more research on the interactions of mental illness with HIV infection and aging.

HIV, Sex, and Aging

Dr. Gina Brown, OAR Coordinator of Microbicides Research and Coordinator of the Women and Girls Research Program, outlined aspects of HIV and aging in women. She described statistics showing higher percentages of new HIV diagnoses in women compared with men in middle-aged and older racial/ethnic populations. She noted that high-risk heterosexual transmission causes the majority of HIV infections in women over the age of 45 years. She described a study showing that women over the age of 50 years learn about HIV and AIDS predominately from television, as well as from friends, family, and newspapers. Few women in the study learned about HIV and AIDS from a healthcare provider. None of the participants learned about HIV and AIDS from the Internet.

Dr. Brown described several known and potential behavioral risk factors for HIV transmission in aging women, including: use of erectile dysfunction drugs by male partners without the use of condoms; sexual networks of older individuals; the stigma associated with discussing an HIV diagnosis or sexual behaviors in older populations; and social isolation. She also discussed potential biological risk factors, including vaginal changes caused by decreased estrogen levels and changes in the immune system caused by thymic involution.

Dr. Brown noted conflicting research findings from several small U.S. studies on HIV disease progression in women compared to men. A large study in Europe, Australia, and Canada showed similar morbidity between men and women while studies in the U.S. showed faster disease progression for HIV-infected men compared with HIV-infected women. She suggested that the differences in findings between the U.S. and the international studies may be attributable to differences in healthcare access.

Dr. Brown suggested the need for additional research studies in women on HIV and aging to explore sex-based HIV transmission risks; reproductive health; bone health; lipid physiology; cardiovascular health; general immune function; age and sex effects on immune activation and regulation; and responses to ART.

Dr. Brown also noted a need for additional research on women to address normal aging versus aging with HIV disease; menopause and HIV interactions; immune activation and decline with HIV and aging; responses to treatment; and interactions with concurrent illness.

Discussion

OARAC members, speakers, and guests discussed the interactions among various mental illnesses and personality disorders with aging and HIV, the need for guidelines on the treatment of HIV-infected individuals with mental illness, and the need to integrate treatment for mental illness into primary care practice. They also addressed: the effects of comorbidities on HIV outcomes in women; the need for research on the role of healthcare access; healthcare quality; and biological, psychiatric, and behavioral factors in gender differences in HIV disease outcome.

PUBLIC COMMENTS

Mr. Jules Levin suggested that more research is needed on: the relevance of senescence to earlier and accelerated development of comorbidities in HIV-infected individuals; the need to educate clinicians, providers, and patients on the evaluation of comorbidities associated with aging; the level of healthcare services required by aging HIV-infected individuals; and the marginalization of older individuals in healthcare settings. He also commented that additional studies are needed on the care and treatment of HIV and HCV coinfected individuals.

Mr. James M. Friedman, Executive Director of the American Academy of HIV Medicine, stated that the Academy has partnered with the American Geriatric Society to develop clinical guidelines for practitioners in the area of HIV/AIDS, comorbidities, and aging. He commented on the importance of providing healthcare practitioners with immediate access to the best information available on this topic.

CLOSING COMMENTS

Dr. Curran thanked OARAC members, speakers, and guests for their participation. The meeting adjourned at 3:35 p.m. on March 18, 2010.

Signed:

/Jack Whitescarver, Ph.D./
Jack Whitescarver, Ph.D., Executive Secretary

/James W. Curran, M.D., M.P.H./