Meeting Minutes - April 11, 2013

Office of AIDS Research Advisory Council
Thirty-sixth Meeting
April 11, 2013

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

Members Present: Dr. Sharon Hillier (Chair), Dr. Jack Whitescarver (Executive Secretary), Dr. Judith Auerbach, Dr. Stefano M. Bertozzi, Dr. David B. Clifford, Dr. Myron S. Cohen, Dr. Steven Deeks, Dr. Carrie E. Foote, Dr. Igor Grant, Dr. Lisa Jacobson, Dr. Ronald I. Swanstrom, Mr. Mitchell J. Warren, Dr. Judith N. Wasserheit, and Dr. Craig M. Wilson

Ex Officio Members Present: Dr. Rima Khabbaz

Invited Speakers and Guests: Dr. Beau Ances, Dr. Janice E. Clements, Dr. Ronald J. Ellis, Dr. Robert K. Heaton, Dr. H. Clifford Lane, Dr. Stuart A. Lipton, Dr. Eileen Martin, Dr. Justin McArthur, Dr. Avindra Nath, Dr. Richard W. Price, Dr. Ned Sacktor, Dr. Serena S. Spudich, and Dr. Steven P. Woods

Welcome and Meeting Overview

The National Institutes of Health Office of AIDS Research Advisory Council (OARAC) convened its thirty-sixth meeting on April 11, 2013 at 8: 30 a.m. at the Fishers Lane Conference Center in Rockville, Maryland.

Dr. Sharon L. Hillier served as OARAC Chair. She welcomed Council members, invited speakers, and guests and reminded everyone that this and future OARAC meetings will be webcast. The minutes of the November 8, 2012 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 OARAC and noted the significant level of interest in Neuro-AIDS. Dr. Whitescarver recognized six OARAC members whose terms will expire after the meeting - Drs. Judith Auerbach, David Clifford, Carrie Foote, Lisa Jacobson, Ronald Swanstrom, and Judith Wasserheit. He thanked them for their long-time support of OAR and commitment to AIDS research and presented each with a certificate of appreciation from the Secretary, HHS.

NIH AIDS Budget Update
Dr. Whitescarver referred OARAC members to the Trans-NIH AIDS Research Congressional Justification that was submitted as part of the President’s Budget Request for fiscal year (FY) 2014. He noted that the President’s proposed budget is based on the budget for FY 2012 and that the final budget for FY 2013 is still unknown. He stated that the budget figure for FY 2013 included in the justification was based on the continuing resolution level in place until March 27, 2013, when the sequestration took effect. The combination of the sequestration, rescission, and the HHS Secretary’s 1% transfer will reduce the NIH AIDS budget by approximately $175 million. Dr. Whitescarver noted that this was the lowest budget level the NIH has had since FY 2004.

Dr. Whitescarver also reported that in response to the sequestration, NIH will enact reductions for the remainder of FY 2013. Decisions on how much to cut grants have been left up to the Institutes, Centers, and Offices (ICOs), but all have been instructed to ensure that all aspects of the budget share in the reduction. As OAR does not make grants, its reductions are included in new regulations about conference support and travel, which require such activities to be approved based on how much the activity will cost. Dr. Whitescarver noted that this will exert a handicap for OAR, because a large portion of its activities includes think tanks and small conferences to stimulate new areas of research.

CONFLICT OF INTEREST STATEMENTS

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

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES

Dr. H. Clifford Lane, Deputy Director for Clinical Research and Special Projects and Director of the Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), provided an overview of the recent updates of the five treatment and prevention guidelines. The Panels that develop the guidelines are convened under the auspices of the OARAC, and the Guidelines are posted on AIDSinfo.nih.gov.

Dr. Lane reported that the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents were revised in February 2013. The update included a recommendation for initiating antiretroviral therapy (ART) in patients with early HIV infection. This update also recommended: genotype tropism testing as an alternative to a phenotypic assay before initiating a CCR5 antagonist regimen; a coformulation of elvitegravir, cobicistat, tenofovir, and emtricitabine as an alternative integrase-based regimen for treatment-naïve patients; and rilpivirine-based regimens as an alternative to NNRTI-based regimens only for patients with baseline viral loads less than 100,000 copies/mL. The drug interaction tables have been updated to include elvitegravir/cobicistat-related interactions.

The Panel for treatment guidelines for adults and adolescents also held its annual face-to-face meeting in March 2013 in conjunction with the 2013 Conference on Retroviruses and Opportunistic Infections. The Panel addressed issues related to financial conflicts of interest in view of the recent Institute of Medicine (IOM) Report. Dr. Lane noted that the Panel manages its conflicts of interest through financial disclosure by its members and adheres to the IOM’s recommendation that at least half of the Panel’s members have no conflicts of interest.

Dr. Lane noted that all of the Treatment Guidelines Panels have a continual rotation of members that involves a standard operating procedure for adding new members. He also reported that Dr. John Bartlett, who has co-chaired the Adult Guidelines Panel since its inception in 1996, has announced his resignation and will leave as soon as a new co-chair is named. Dr. Lane proposed that the selection of a new Co-Chair will be made by Drs. Whitescarver and Anthony S. Fauci, NIAID Director. OARAC concurred with this plan.

Dr. Lane reported that the Pediatric Panel recently revised the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection and these were posted online in November 2012. The Panel is currently revising the recommendations in regards to when to start antiretroviral therapy and what regimen to start with in treatment-naïve patients, and how to manage treatment failure. The Panel also is developing new sections on Hepatitis B and C and tuberculosis.

Dr. Lane stated that the Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States were last updated in July 2012. The Panel is in the process of simplifying the drug table and revising the sections on antepartum and intrapartum management. The Panel also is updating the section on neonatal antiretrovirals management taking into account the recent Mississippi “cure” case and its implications.

Dr. Lane noted that both the pediatric opportunistic infections (OI) and adult OI guidelines were last updated in 2009. He reported that the Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children have been updated and are undergoing final clearance. The revised Guidelines will be posted online in late 2013.

Dr. Lane stated that the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents also are being revised. The revised adult OI guidelines are expected to be published later this year. He noted that all of the sections have been updated and will be released on AIDSinfo.nih.gov.

Dr. Lane thanked all of the Panel Co-Chairs, Executive Secretaries, and volunteer members for their efforts in ensuring the guidelines are revised to reflect the most recent clinical findings.

DISCUSSION

OARAC members asked Dr. Lane to describe how the Panels update the guidelines. Dr. Lane explained how the Panels use subgroups to review and update sections based on recent clinical trial results and the subgroups then propose revisions to the overall Panel. He noted that this has served as an effective peer review process.

INTRODUCTION TO THE MEETING TOPIC

Drs. David Clifford and Igor Grant introduced the topic of Neuro-AIDS since they had organized the scientific presentations for today’s meeting. They noted there is an increasing incidence of HIV-associated neurological disorders (HAND) and peripheral neuropathies in HIV-infected individuals in the U.S. and worldwide.

Dr. Grant noted that even in this era of ART, as many disabilities and complications associated with HIV have disappeared or lessened, allowing HIV-infected individuals to live longer, neurological complications of infection have increased. He estimated that about 40 percent of persons living with HIV, including those receiving ART, experience HAND. He noted that while these neurological complications are not the dementias seen in the 1980s, HAND still affects quality of life, adherence to treatment, and risky behaviors. Thus, they remain important to patients and society. He commented that peripheral neuropathies also are persistent. He cited data from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study that indicate as individuals age with HIV, up to 70 percent of patients older than 55 years show signs of peripheral neuropathy, which also can affect quality of life. Dr. Grant stated that the neurological complications of HIV infection remain underappreciated. He suggested that this OARAC meeting could help identify scientific priorities and opportunities for NIH research on HIV-associated central nervous system (CNS) and peripheral nervous system (PNS) complications. He also suggested that the treatment guidelines Panels consider the evolution of CNS events in view of emerging data on the increased likelihood of neurocognitive complications the longer treatment is delayed.

Dr. Clifford commented that the neurological complications of HIV are an important area for research. He emphasized the need to look forward, even with the current budgetary challenges, and to focus on the critical scientific questions of how to make treatments more effective in order to protect and optimize brain function in HIV-infected individuals.

Dr. Whitescarver noted the field of research on HAND was highlighted in Dr. Avindra Nath’s presentation at the International AIDS conference in July 2012. He commented that the clinical profile of AIDS is continuing to evolve and OAR looks to OARAC for help in setting the scientific priorities where they are most needed. He also noted that OAR is reorganizing its strategic plan and OAR staff to coordinate activities across NIH that are focused more on HIV-associated co-morbidities including Neuro-AIDS.

EPIDEMIOLOGY OF HIV-ASSOCIATED NEUROLOGICAL DISORDERS AND PERIPHERAL NEUROPATHIES IN THE CART ERA

Dr. Justin McArthur, Professor in the Department of Neurology at Johns Hopkins University, described the incidence of HIV-associated neurological complications in the U.S. and worldwide. He noted that while certain neurological disorders associated with opportunistic infections have decreased with the use of ART where it is available and patients can tolerate the toxicities and side effects, there is still a high incidence in many areas of the world where ART is not accessible and where four primary opportunistic infections of the CNS, including TB meningitis, cryptococcal meningitis, toxoplasmosis, and progressive multifocal leukoencephalopathy (PML), continue to be prevalent. He commented that there is still a gap even in the U.S. between the number of individuals infected with HIV and the number of those who know their serostatus, enter care, and achieve viral suppression.

Dr. McArthur stated that the incidence of neuropathy in the U.S. has declined based on the data from the HIV Outpatient Study (HOPS). He noted that of the estimated 1.2 million HIV-infected individuals in the United States, about half have sensory neuropathy and about 138,000 experience moderate to severe neuropathic pain. He commented that there are no degenerative or neuroprotective therapies to address the course of peripheral neuropathy. In addition, sensory neuropathy primarily affects small-caliber nerve fibers that are difficult to assess. He stated that HIV-associated neuropathy remains an important untreated condition.

Dr. McArthur commented that HAND is characterized by apathy, negative effects on attention and new learning, cognitive dysfunction, motor impairment, increased stretch reflexes and mild rigidity, and gait impairments or clumsiness. These conditions affect the individual’s ability to adhere to medical care and protective sex measures. He noted that individuals with HAND are more likely to relapse to substance abuse. He commented that HAND includes HIV-associated dementia (HAD), mild neurocognitive disorder (MND), and asymptomatic neurocognitive impairment (ANI). While the prevalence and incidence of HAD and MND have declined since the introduction of ART, the prevalence of ANI is increasing, and patients with ANI are five times more likely to progress to symptomatic neurocognitive impairment. He also noted that survival rates are three times worse for patients with HAND than for those without it.

Dr. McArthur stated that the HIV-infected population in the United States is aging due to ART and that age is a major risk factor for HIV-associated neurological dysfunction. Amyloid deposition also is more common among individuals dying with HIV infection, possibly as a result of age, although the pattern of deposition differs from that seen among patients with Alzheimer’s disease. Sustained inflammation in the CNS is another major contributor to the neurocognitive effects of HIV infection. He noted that sustained inflammation in the CNS is present in patients who have viral suppression due to ART. He described several other risk factors for HAND including gender, alcohol or substance abuse, viral coinfections (e.g., hepatitis C), nutritional deficiencies, accelerated atherosclerosis, and psychiatric comorbidities (e.g., stress or major depression).

Dr. McArthur commented that the development of agents to treat HAND has focused primarily on strategies to prevent inflammation. However, most of these agents have little to no effect on HAND and some classes of antiretroviral drugs have been shown to be neurotoxic. He cited a recent study that suggests efavirenz may cause a decline in memory.
Dr. McArthur cautioned against complacency and the assumption that immunologic and virologic suppression of HIV will control the CNS effects of HIV infection. He emphasized that HAND remains a hidden epidemic, even in aviremic patients, and the brain could serve as a sanctuary for persistent HIV infection. He suggested that neurocognitive screening is needed for HIV-infected patients and that this should be recommended in the treatment guidelines. He proposed that more research is needed on the interaction between age-related and HIV-related cognitive impairments. In addition, he suggested that better screening techniques for HAND are needed and should be developed and validated.

DIAGNOSIS AND ASSESSMENT OF HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Dr. Robert Heaton, Professor and Vice-Chair of Academic Affairs in the Department of Psychiatry at the University of California, San Diego, discussed the assessment and clinical significance of HAND. He noted that in the ART era, HAND is typically mild to moderate in severity. He commented that impairments affecting new learning, working memory, executive function, and delayed recall are relatively stable, while cognitive fluctuations can be seen with changes in treatment. He noted that HIV-associated neurocognitive impairment can be correlated with unemployment, decreased independence in activities of daily living, cognitive difficulties in daily life activities, poor driving, and poor adherence to ART, as well as with early mortality from all causes.

Dr. Heaton commented that in order to classify as HAND, neurocognitive and functional impairments should be attributable, at least partially, to HIV infection and not to comorbid conditions. The diagnosis and clinical assessment typically includes a comprehensive neurocognitive battery that examines multiple domains known to be vulnerable to HIV. He noted that all neurocognitive tests have normative standards that correct for the normal effects of aging, differences in education, and other factors that may affect cognition.

Dr. Heaton stated that the patient’s risk for HAND depends primarily on having been successfully treated with ART and achieved an undetectable viral load, and if the patient has a history of severe immunosuppression. He stated that among asymptomatic patients, the prevalence of impairment is higher among patients in CHARTER, a study conducted in the ART era, than among those study participants in the HIV Neurobehavioral Research Center (HNRC) HNRC-500, a study conducted during the pre-ART era. He noted that the known duration of HIV infection among the CHARTER group is about three times that among the HNRC-500 group, and patients in CHARTER are more likely to have had a low nadir CD4+ cell count. He commented that the CHARTER data also suggest that detectable virus in the cerebrospinal fluid (CSF) and the severity of comorbidities can predict the likelihood for developing neurocognitive impairments.

Dr. Heaton proposed several potential research priorities including studies on: the factors that influence the appearance of HAND in acute or early infection; the effects of early ART initiation to prevent HAND; the role of host and viral genetics on the incidence and course of neurocognitive impairments; and the factors leading to the increased prevalence of HAND with age. He also suggested that there is a need to develop better screening tools for HAND and the incorporation of these improved tools in routine clinical care.

NEUROIMAGING AS A BIOMARKER FOR HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Dr. Beau Ances, Assistant Professor of Neurology at Washington University, addressed the role of neuroimaging as a noninvasive procedure to diagnose HAND. He commented that currently HAND is often defined by how well patients perform on neuropsychological testing and in their daily activities.

Dr. Ances described several imaging techniques that are available to look at the interaction between astrocytes and the neurons, as well as blood flow to these parts of the brain. He commented on the use of: magnetic resonance spectroscopy (MRS) to study specific metabolites; volumetric brain segmentation to measure quantitative changes associated with viral infection within specific sections of the brain; diffusion tensor imaging to measure changes in the white matter; and arterial spin labeling to measure blood flow delivered to the brain. He noted that the most recently developed technique, resting-state functional connectivity magnetic resonance imaging, can be used to identify correlations and networks among different areas of the brain at a resting state.

Dr. Ances stated that studies using MRS have demonstrated chronic inflammation in the subcortical brain regions in HIV-infected patients including those on ART. He noted that significant volumetric differences associated with chronic HIV infection were observed. He reported that arterial spin labeling has shown that cerebral blood flow is significantly lower in patients with HAND and that blood flow decreases during early or acute infection and becomes progressively worse as neurocognitive impairment increases. He commented that ART appears to restore blood flow in HIV-infected patients, but it does not restore flow to the level seen in HIV-uninfected individuals. Neuroimaging has shown that aging, methamphetamine use, and HIV infection independently affect brain volume. He noted that changes in neuroimaging biomarkers may precede symptomatic changes.

Dr. Ances proposed that neuroimaging can be used in diagnosing HAND. He suggested that the development and application of advanced neuroimaging techniques will lead to a better understanding of HIV-associated neurological disorders.

DISCUSSION

OARAC members and presenters discussed the importance of addressing HAND in the DHHS treatment guidelines. They suggested that additional research is needed on the functional deficits associated with HAND, both before and after ART. Several presenters commented that women are at higher risk for HAND although the biological, behavioral, and social factors that account for these differences are not known and warrant further studies. Additional research on neurological complications in HIV-infected pediatric patients also was encouraged since encephalopathy is more prevalent and severe in these patients when ART is delayed.

Several OARAC members noted that the data regarding the importance of nadir CD4+ cell counts, chronic inflammation, and HIV disease in the progression of HAND is almost identical to that presented by cardiologists. Speakers and OARAC members proposed increased interactions among neurologists, cardiologists, and infectious disease experts.

BIOMARKERS FOR HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Dr. Richard Price, Associate Professor of Neurology at the University of California, San Francisco (UCSF), presented on several biomarkers that can be used to diagnose and clinically manage HIV-associated neurological complications. He stated that biological and laboratory-based markers can provide a snapshot of the biological state and complement the neurological phenotypes observed through neuroimaging and neuropsychological testing.

Dr. Price described how biomarkers of active disease can be used to: establish targets for ART and adjuvant therapies; identify potentially reversible components of neurological disease; and provide objective end points of treatment effects. He suggested that cerebral spinal fluid (CSF) biomarkers, including CSF HIV viral load, neurofilament light chain (NFL), and neopterin, are especially useful because the CSF is in contact with the brain and spinal cord and permits the exchange of molecules through diffusion and flow. He noted that CSF is available for sampling with low morbidity and many patients are amenable to multiple samplings for longitudinal studies. He described a targeted, cross-sectional study exploring changes in clinical background and guide biomarkers, immune and inflammatory markers, and CNS markers among HIV-infected patients at various CD4+ cell counts, those with HAND, virally suppressed patients, and elite controllers. He also outlined another study using an untargeted, exploratory approach to examine correlations between guide biomarkers and different pathways underlying HAND.

Dr. Price emphasized the importance of a priori classifications of study participants and the need to collect specimens in clinical trials. While CSF biomarkers are not used in clinical trials, he suggested that these could be useful both in patient selection and as trial endpoints. He proposed that additional research is needed to determine how best to integrate CSF biomarkers in clinical trials and routine clinical practice.

HOST AND VIRAL GENETIC FACTORS THAT INFLUENCE NEUROLOGICAL DISORDERS ASSOCIATED WITH HIV INFECTION

Dr. Avindra Nath, Clinical Director at the National Institute of Neurological Diseases and Stroke, described the important role of host genetics in the development of HAND. He noted that some of the current data on host genetics is from a subset of HIV-infected patients who never developed HAND. He provided an overview of the effects of genetic polymorphisms in cytokine, chemokine, and neurotransmitter pathways on HIV pathogenesis. He suggested several other mechanisms by which host genetics can influence HIV neuropathogenesis including the regulation of HIV replication, as well as factors affecting permeability of the blood brain barrier.

Dr. Nath provided an overview of several studies on the ApoE gene and its role in HAND. While the CHARTER study has not identified an association between ApoE4 and HAND, a more recent study has shown that older HIV-infected individuals with the ApoE4 allele are more likely to develop dementia. He described another study that showed CSF ApoE levels are lower in HIV-infected individuals without ApoE4. Both the in vitro studies and several cohort studies suggest that the ApoE genotype influences HIV set point, ApoE levels, and progression of neurological disease.

Dr. Nath described several other host genes including the gene encoding the cytokine MCP-1/CCL, which is elevated in individuals with HAD, and a point mutation in CCR5 that may be important in neurocognitive decline. He noted that the genotype of tumor necrosis factor alpha and the macrophage chemokine receptor CX3CR1 also appear to affect HIV-associated neurological progression. Human leukocyte antigen (HLA) alleles also have been implicated in the risk for HAD, but HLA*B27 is the only one that appears to be significant. He also commented that polymorphisms in the host restriction factor APOBEC3G, a key player in cellular antiviral properties, may influence CNS disease-free survival.

Dr. Nath noted that a limited number of studies are addressing host genetics in HIV-associated neuropathogenesis. He proposed that additional research is needed to better understand the genetic mechanisms that protect against the establishment of an HIV reservoir in the brain and associated neuroinflammatory responses. He commented that these studies can be challenging, particularly in the ART era, when many antiretroviral drugs themselves cause toxicity and could therefore confound genetic studies. Dr. Nath proposed the establishment of a DNA repository from well-characterized, prospectively followed cohorts.

AGING AND HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Dr. Ned Sacktor, Professor of Neurology at Johns Hopkins University School of Medicine, described the increasing incidence and prevalence rates of HIV-associated dementia. He commented that more than half of the individuals infected with HIV will reach the age of 50 years by 2015 and that 15 percent of new HIV diagnoses are among individuals older than 50 years.

Dr. Sacktor noted that both age and HIV serostatus appear to contribute to neurocognitive decline. In the Hawaii HIV Aging Study, HIV-infected individuals older than 50 years are twice as likely to be diagnosed with MND or HAD. He stated that among HIV-infected individuals with dementia, older individuals show greater deficits in executive function, compared with younger individuals. Among individuals with normal cognition or asymptomatic neurocognitive decline at baseline, older individuals are more likely to transition to MND by one year of follow-up. He noted that in the Multicenter AIDS Cohort Study (MACS) Longitudinal Aging Study, HIV-infected adults older than 40 years of age show a slight worsening in executive function over 5 years compared with younger HIV-infected individuals.

Dr. Sacktor stated that vascular factors, CD4 nadir, ApoE-4 genotype, diabetes, and insulin resistance appear to be associated with dementia in older HIV-infected patients. The MACS data suggest an association between increased intima medial thickness and high glucose levels and poor motor performance. He noted that the CHARTER data also show an interaction between age and systolic blood pressure, body mass index, cholesterol level, and AIDS diagnosis with respect to neurocognitive decline. He described another study that has shown an association between vascular risk factors and slower processing speed; however, treatment with statins or antihypertensive medications improved cognitive performance. He noted several other factors associated with HAND in older patients including interactions between HIV viral proteins and the CNS, as well as chronic inflammation in the CNS.

Dr. Sacktor noted that Alzheimer’s disease has been proposed as a potential cause of cognitive impairment among older HIV-infected individuals. He noted that neuroimaging studies have shown abnormal amyloid accumulation in the brains of HIV-infected individuals, and amyloid plaques are seen more frequently among HIV-infected individuals than among uninfected controls. He commented that amyloid accumulates in a diffuse pattern in HIV-infected individuals, as opposed to the neuritic pattern seen in patients with Alzheimer’s disease.

Dr. Sacktor stated that Dr. Ances’ neuroimaging study showed decreased cerebral blood flow among HIV-infected individuals compared with HIV-uninfected controls. He suggested that this decrease may result from lower brain reserve in younger patients, but from vascular and potential neurodegenerative disease in older patients. He also pointed out several limitations in studying HAND in older patients, including age at the time of seroconversion, duration of HIV infection and HIV stage, shifting regimens of ART and timing of ART initiation, and survivorship bias in longitudinal studies. He proposed that additional research is needed on: identifying differences between potential causes of cognitive impairment; specific biomarkers to assess cognitive impairment in older HIV-infected patients; additive or synergistic effects between HIV infection and age; the role of age-related immune changes in HAND; and age-related differences in sensitivity to antiretroviral drug effects on cognition.

ROLE OF SUBSTANCE USE ON THE MANIFESTATIONS OF HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Dr. Eileen Martin, Professor of Psychiatry at Rush University Medical Center, described how neurocognitive functions are affected by HIV and substance use. She described laboratory evidence that demonstrates that the combination of HIV infection and substance abuse result in significant cellular damage and other negative effects in the brain; however, this evidence has not been translated to clinical or epidemiological studies. She noted that HAND was equally prevalent among addicts, occasional drug users, and individuals who do not use drugs.

Dr. Martin summarized the results from several studies on executive function, neuro-AIDS, and drug abuse. These studies looked particularly at the prefrontal cortex, which plays a prominent role in both HIV-associated cognitive decline and changes caused by drug abuse. She noted that among individuals who use several substances, those who are HIV-infected show impairments in spatial and verbal working memory. She commented that HIV-infection and drug abuse also impair decision-making as measured by the Iowa Gambling Task, and together they show an additive effect. She noted that implicit learning, as measured by a motor skills learning task, was affected primarily by HIV serostatus.

Dr. Martin stated that there are sex and gender differences in the effects of HIV serostatus on implicit learning. She noted that women escalate the use of methamphetamine and cocaine more rapidly than men do. Women also are more vulnerable to stimulant addiction and experience more severe withdrawal symptoms and relapse more frequently. She reported that crack cocaine use is particularly associated with rapid HIV disease progression among women. She also noted that data from the Women’s Interagency HIV Study (WIHS) show a difference in verbal memory between substance users and non-users among HIV-infected women.

Dr. Martin suggested that lessons can be learned from addiction research. She commented that working memory and impulsive choice, which are key functions among drug users that are affected by HAND, can be modified by cognitive remediation. She noted that it is not clear whether improved cognition is an additional benefit of substance use treatment. She suggested that additional research is needed on gender-specific treatment approaches.

DISCUSSION

OARAC members and presenters discussed the need for more research on the biological and social differences in the effects of substance abuse and HIV infection on HAND and cognition. They suggested that additional research also is warranted on the combined effects of HIV serostatus and alcohol or nicotine use on cognition.

OARAC members and speakers also discussed systems biology approaches to the study of HAND. They suggested that the scope of brain banks be expanded to include cells and other tissues, as well as the development of software to explore potential systems. OARAC members noted the lag time between neurocognitive damage and their clinical manifestations. They commented that definitive clinical end points will be needed in order to change clinical practice. They suggested that data from existing cohorts may be useful in providing this information. 

VASCULAR DISEASE AND COGNITIVE IMPAIRMENT IN HIV: MULTIPLE OPPORTUNITIES FOR PREVENTION AND TREATMENT

Dr. Ronald Ellis, Professor of Neurology at the University of California, San Diego (UCSD), presented on the vascular and neurocognitive complications associated with HIV disease. He cited that the increasing number of HIV-infected patients experiencing strokes was not explained by underlying opportunistic diseases. This observation was consistent with reports that stroke-associated hospitalization rates for HIV-infected individuals were increasing at the same time that these rates were decreasing for the general population. In a study of more than 2,000 HIV-infected patients in cohort studies at UCSD, researchers have found that these strokes were related to factors, such as diabetes, hyperlipidemia, hypertension, and obesity, that are commonly associated with treatment-related metabolic syndrome. He noted that these comorbidities were not simply co-occurring conditions, but were related to both HIV infection and, in some cases, to ART.

Dr. Ellis stated that another common occurrence among HIV-infected individuals on ART is an increase in visceral fat, which results in abdominal obesity. He noted that while this accumulation arises partly from the lipodystrophy syndrome, fat itself is a metabolic organ that generates hormones and promotes inflammation through phenotypic changes in macrophages within the adipose tissue. He proposed that visceral adipose inflammation may contribute to the neurocognitive impairment seen among HIV-infected patients. He commented that a recent study has found a statistically significant association between waist circumference, a surrogate marker of visceral adiposity, and neurocognitive impairment.

Dr. Ellis described the neurovascular unit, a set of tissues, structures, and metabolic functions organized to fine-tune blood flow in real time to the needs of a particular tissue. He noted that insulin resistance, hyperlipidemia, central obesity, and hypertension can affect the neurovascular unit. He commented that HIV infection has been associated with abnormal resting and functional changes in blood flow and that these abnormalities do not resolve completely with ART; rather, they appear to be associated with a premature aging phenotype. He described several pathophysiological changes that converge on the neurovascular unit.

Dr. Ellis proposed that interventions for neurocognitive impairment may require therapies targeted to multiple pathways. He noted that one intervention, the growth hormone-releasing hormone Tesamorelin, has been shown to reduce adiposity, increase blood levels of insulin and insulin growth factor 1 (IGF-1), and improve neurocognitive function. He suggested that additional research is needed on the association between vascular complications and neurocognitive impairment in HIV-infected individuals.

ADVANCES IN THE REAL-WORLD IMPACT OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS

Dr. Steven P. Woods, Associate Professor of Psychiatry in the HIV Neurobehavioral Research Program at UCSD, presented on cognitive impairments that significantly and independently affect daily living activities across a wide range of outcomes, including basic living skills and more complex outcomes such as medication adherence and quality of life. He described the current model that suggests that memory, executive function, and psychomotor deficits lead to changes in basic skills and overall well-being. He noted that this model does not consider translational neurocognitive abilities or bridge constructs, such as the relationship between working memory and decision making, that are drawn from cognitive neuroscience and bridge higher-level processes with real-world outcomes.

Dr. Woods described current studies that are exploring how combining translational abilities with strong cognitive predictors can be used to more accurately assess neurocognitive deficits. These studies are measuring prospective memory with a multitasking exercise to identify HIV-associated neurocognitive deficits. He noted that there is a need to consider the ways to measure functional outcomes. He commented that when standard, validated self-reporting measures are used to assess neuropsychological dysfunction related to real-world problems, the proportion of patients found to have real-world deficits is low. However, when these patients are asked to perform tasks, the number of participants who show deficits increases. He commented that technology is playing an increasing role in activities of daily living, but traditional measures do not assess participants’ capacity to perform these tasks. He reported that scientists are developing more realistic, Web-based tasks to assess the effects of HAND more accurately. These studies have shown that individuals with HAND are nine times more likely to fail at a shopping task that mimics what a customer may do online. These studies have shown that comorbidities, such as depression or drug abuse, also influence cognitive functions, translational abilities, and real-world outcomes. He noted that increasing age also can affect the rate of dependence for HIV-infected individuals.

Dr. Woods stated that there are currently no non-antiretroviral approaches that have been shown to be effective against HAND; however, non-pharmacological based interventions may prove useful. He stated that only three studies to date have examined neurocognitive rehabilitation among HIV-infected individuals, and only one of these studies has used a real-world functional outcome. He described an approach that uses theory-driven applications from cognitive neuroscience to improve memory and cognitive function. He suggested that neuropsychological findings should be translated into structured neurocognitive therapies to improve real-world outcomes. Dr. Woods proposed that there is a need for innovative approaches to measure cognitive function, as well as creative technology driven approaches to improve the assessment of cognitive disorders and predict real-world outcomes. He emphasized that there is an urgent need to translate what works in clinical studies in this field to the real-world.

NEUROPROTECTIVE STRATEGIES AND NEURO-AIDS

Dr. Stuart Lipton, Professor of Medicine at the Sanford Burnham Medical Research Institute, presented a model of HIV-related neuronal damage and HAND. This model accounts for HIV proteins, such as gp120 and Tat, that drive brain macrophages to adopt a pro-inflammatory phenotype and activates several enzymatic pathways leading to synaptic damage, astrocyte dysfunction, metabolic derangement and oxidative damage, and ultimately, the neurodegeneration that result in HAND. He noted that macrophages, astrocytes, and neurons also have been implicated in neurodegenerative diseases such as Parkinson’s disease. 

Dr. Lipton noted that 99 percent of the drugs developed for the brain fail because of problems with clinical tolerability. He described an approach to clone and characterize brain receptors that mediate neuroprotection and then test drugs that operate at these receptors. He reported on a study that uses chemokine analogs to block the ability of gp120 to bind the chemokine receptor CXCR4 and induce degeneration of adult neural precursor cells. Trans-nasal administration of this analog prevents neurodegeneration in vitro and in mice.

Dr. Lipton proposed that more research is needed on additional neuroprotective pathways, as well as the development and validation of multiple preclinical models. He noted that early- and mid-stage drug development projects should be a priority for NIH since the pharmaceutical industry will not invest in them. He also suggested the integration of drug discovery and development groups into academic centers that are conducting studies on the clinical and neuropsychological aspects of HAND.

DISCUSSION

OARAC members and presenters discussed a possible role for the newly established National Center for Advancing Translational Sciences in supporting early- and mid-stage drug development for Neuro-AIDS. They also noted that while intranasal drug delivery could be effective, additional studies are needed to translate the findings from mouse studies to humans.

EVIDENCE FOR COMPARTMENTALIZATION, AND THE CELLS INVOLVED IN NEURO-AIDS

Dr. Ronald Swanstrom, Professor of Biochemistry and Biophysics at the University of North Carolina at Chapel Hill, presented on compartmentalization of HIV in the CSF. He noted that HIV is detected in the CSF approximately 8 days after infection and that several cell types circulate in the CSF that may serve as targets for the virus. He reported that HIV detected in the CSF is often found in macrophages, which are longer lived, and able to infect cells with lower CD4 densities. He commented that macrophage-tropic virus is usually not detected in the blood, and it is not transmitted.

Dr. Swanstrom reported that in some patients with HAND, the T-cell–tropic virus found in the blood decays rapidly following ART initiation, while the macrophage-tropic virus in the CNS decays more slowly. In these cases, macrophage-tropic virus is phylogenetically distinct from T-cell–tropic virus. He stated that this contrasts with findings from other patients with HAND, where CNS virus decays more rapidly in response to ART, and it is genetically identical to the virus found in the blood. This suggests that the CNS virus has arisen from clonal amplification of T-cell tropic virus in the blood or within the CNS itself.

Dr. Swanstrom noted that in studies of HIV-infected infants and young children, roughly half of the children show compartmentalized virus by the age of 3 years. He commented that HIV is sequestered in the CNS early in life, moves through an intermediate and an equilibrated state (with the same virus in the blood and CSF), and that approximately 50 percent of the children will eventually reach frank compartmentalization (different virus or viral evolution in blood versus CSF). He stated that in a small study of newly infected adults, virus compartmentalization is seen in approximately one-third of the patients over the first 2 years and that early CNS sequestration also is seen in these patients.

Dr. Swanstrom described a model based on the concept that HIV infection can induce inflammation that brings infected T cells from the periphery into the CNS, and that sustained replication within the CNS promotes the evolution of macrophage-tropic virus. He noted that the National Neuro-AIDS Tissue Consortium is studying samples of virus in the blood versus the CSF to determine where macrophage-tropic virus replicates in the brain and whether this virus replicates anywhere else in the body. He proposed that these studies may provide insight on HIV infection and the CNS, as well as the progression of disease to Neuro-AIDS.

UTILITY OF ANIMAL MODELS FOR NEURO-AIDS RESEARCH

Dr. Janice Clements, Professor of Medicine and Molecular and Comparative Pathobiology at Johns Hopkins University, presented the SIV model of HIV-associated CNS disease. She noted that the use of this model has yielded contributions to vaccine research, as well as critical findings on immune activation, determinants of viral CNS tropism, and acute infection in the brain. She commented that HIV research is in a different era now, one in which all potential latent reservoirs must be identified and characterized, and that animal models can be useful in this research. She suggested that SIV models also can be used to develop and test therapies to purge latent virus while protecting the CNS from immune activation. She commented that macrophage-tropic virus is not always CNS-tropic in the SIV model, and recent mouse data suggest that macrophages can be present in all tissues because of seeding from the yolk sac.

Dr. Clements described the acute phase of infection in the SIV macaque model which occurs from 4 to 21 days post-inoculation and involves a robust innate immune response. The early stages of immune activation and viral replication are similar between the brain and the periphery, with expression of the major histocompatibility complex class II and CD68 molecules, and rapid control of the infection. She noted that in some animals that control is lost, and the animals develop CNS disease. She suggested that the CSF viral load and CCL2 levels can predict which animals will develop CNS disease.

Dr. Clements summarized several studies using the SIV model of ART that showed the level of latently infected CD4+ cells is similar to that seen in HIV-infected patients on ART, and the CSF viral load is similar to that seen in the plasma. She noted that while ART reduces viral load, it does not affect the level of viral DNA, and gp41 and CD68 expression persists. Further study has shown that viral DNA in the brain declines significantly at 4 days in animals on ART but rebounds by 12 days, suggesting reactivation of a potential reservoir. She stated that this contrasts with the level of viral DNA in the spleen that does not decline, suggesting the spleen is seeded earlier than the brain and that there may be a window of opportunity to protect the brain.

Dr. Clements described preliminary results from studies comparing CNS-penetrant with CNS-non-penetrant ART, as well as the development of an assay to look more closely at latency in macrophages and microglia cells. She suggested that microglia and other macrophage lineages are likely to be latent reservoirs for HIV infection and that an increased understanding of these reservoirs will facilitate the next era of HIV eradication.

EARLY PHASE OF HIV INFECTION AND EVENTS IN THE ACUTE STATE THAT PLAY A ROLE IN VULNERABILITY TO NEURO-AIDS

Dr. Serena Spudich, Associate Professor of Neurology at Yale University School of Medicine, presented data from the Primary Infection Stage CNS Events Study (PISCES) and the Bangkok Acute HIV Cohort. Both of these studies address when HIV reservoirs are established in the CNS and when neuro-inflammation is established in the course of the disease. She noted that while these studies focus on different HIV clades, the two study populations are similar. In both studies, HIV appears in the CNS early in infection and persists over time in the majority of participants. She reported that based on genotyping, phylogeny trees, and deep genetic sequencing, most of the study participants showed evidence of equilibration within one year of infection, although a small number of participants showed evidence of emerging compartmentalization, and others showed compartmentalized virus early on. She stated that inflammation also occurs early in the CNS and increases over time. Dr. Spudich commented that it is still not clear whether the CNS represents a latent reservoir for HIV infection despite the presence of virus and inflammation. She noted that a subset of participants also show early control of virus in the CSF, but it is not clear whether this control is clinically relevant or evidence of a delayed viral set point.

Dr. Spudich described the findings from these studies that indicate impairment of neuropsychological performance in a small subset of participants. She noted that these impairments correlate with CSF viral load and with elevations in injury markers such as NFL and beta-amyloid. She suggested that neuronal injury is likely driven by the inflammation associated with HIV infection; however, it is not clear whether neuronal injury and the resulting neuropsychological impairment are influenced by other factors.

Dr. Spudich noted that in both studies, all of the patients who began ART early achieved plasma and CSF viral suppression and remained suppressed at two years of follow-up. She commented that it is not clear whether early initiation of ART will alleviate or normalize inflammation over time. She suggested that there is some evidence that the trajectory of neuropsychological performance impairment improves upon initiation of ART, but it is not clear whether early initiation of ART directly improves performance. Dr. Spudich proposed that longitudinal studies are needed to determine if early HIV infection in the CSF affects neurocognitive impairment. She also suggested that randomized clinical studies would be ideal to facilitate decision making on treatment and to determine whether screening for acute infection is important for HIV disease outcomes.

DISCUSSION

OARAC members and presenters discussed the possible implications of the findings described by Drs. Clements and Spudich in the context of the “Berlin” and “Mississippi” patients, who appear to be functionally cured. They also discussed the clinical implications of viral compartmentalization and the need for more longitudinal samples. OARAC members emphasized the importance of focusing more on inflammation in the CNS since it becomes self-sustaining in many neurodegenerative diseases once pathogenesis begins. They noted that systemic inflammation also can play a role in neurological dysfunction.

OARAC members discussed data from several studies conducted by the Adolescent Medicine Trials Network for HIV/AIDS Interventions that indicate a majority of treatment-naïve, HIV-infected youth show signs of HAND. OARAC members proposed that there is a critical need to conduct additional research on the neurological effects of HIV infection and ART in adults, adolescents, and children.

PUBLIC COMMENTS

No members of the public requested time to comment.

CLOSING COMMENTS

Dr. Hillier thanked Drs. Grant and Clifford and OAR staff for organizing the meeting. She also thanked the members, speakers, and guests for their broad consideration of research on HIV-associated neurological complications. Dr. Whitescarver thanked all of the speakers for their presentations and acknowledged the valuable advice and guidance provided by OARAC members in identifying scientific priorities and opportunities in the field of Neuro-AIDS research. He also thanked the retiring OARAC members for their service on the Council.

ADJORN

The meeting was adjourned at 5:00 p.m. on April 11, 2013.

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

/ Sharon L. Hillier, Ph.D./
Sharon L. Hillier, Ph.D., Chair