November 20, 2002

UCSD-Led Consortium to Study Effects Of
Anti-Retroviral HIV Therapy on Nervous System Disease

NIH calls $22 million effort "important and timely"

Potent drug therapies used in the treatment of HIV disease have dramatically improved the health and longevity of infected individuals. What effect they have on the neurological complications associated with HIV disease, and whether long-term use of these powerful drug combinations has a direct effect on the central nervous system (CNS), will be the focus of a $22.3 million six-center study called CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research), funded by the National Institutes of Health.

"It is important that as we develop marvelous new treatments that improve the medical management of HIV infection, we also pay attention to the brain," said Igor Grant, M.D., professor of psychiatry at the UCSD School of Medicine and director of the CHARTER program.

The five-year project brings together clinical and research centers at UCSD, Johns Hopkins University in Baltimore, Mt. Sinai School of Medicine in New York, University of Texas Medical Branch in Galveston, University of Washington in Seattle and Washington University in St. Louis.

"This is an important and timely study," said Dianne Rausch, Ph.D., Deputy Director of the Center for Mental Health Research on AIDS of the National Institute of Mental Health (NIMH). CHARTER is funded both by the NIMH and the National Institute of Neurological Disorders and Stroke (NINDS). "With effective drug treatments available in this country, more and more people are living longer with HIV. As these drugs become available globally, including in developing countries, this number will increase dramatically. We must understand the burden of neurological disease in people living with HIV in a treatment environment in order to more effectively address their needs and set priorities for long-term management."

The collaborative project will include a cross-sectional study of about 400 new patients annually across the six centers, leading to a cumulative 1,600 evaluations conducted over a four-year period. This component of the study will provide snapshots of detailed information about prevalence and qualitative features of neurological and cognitive-behavioral complications in a broad group of individuals of different ages, ethnicities and genders at varying stages of infection, receiving varying treatments.

In addition, a subset of about 600 of these patients will be followed over time, receiving semi-annual evaluations to carefully monitor their health status, including the new onsets, exacerbations or improvements of neurocognitive impairment and other neurological complications. Data will be gathered using sophisticated neuromedical and behavioral testing, both structural and functional brain imaging, and biological testing to measure immune status, virus, and concentrations of anti-retroviral and other drugs in the body and specifically in the CNS.

This study will also provide one of the first evaluations of the disorders of lipid metabolism that sometime complicate HIV treatments, from the standpoint of neurological complications associated with these disorders.

"The driving force behind this study is the recognition that despite significant improvements in the medical status of HIV infected individuals, there continue to be neurological and neuropsychological aspects that do not respond as well," said Grant, who is also director of the long-running HIV Neurobehavioral Research Center (HNRC) at UCSD. "With anti-retroviral therapy, the incidence of neurological complications is lessened, but not as much as other complications associated with HIV infection. To have a healthy body but an unhealthy brain is a disconnect with long range implications for the individuals themselves, in addition to being a public health concern."

Illustration of abnormal white matter  (yellow patches) in subject with HIV encephalitis (bottom row) compared to HIV+ subject without HIV encephalitis (top row). Photo courtesy Terry Jernigan, Ph.D.

The incursion of HIV into the brain and CNS can lead to inflammation, nerve cell damage and abnormalities in the brain's white matter, where bundles of interconnecting cells that serve as a major terminal for communication of the brain's incoming and outgoing signals become disordered. Complications range from learning or memory deficits, to impairment of cognitive or motor skills, to full-blown dementia and loss of motor skills. Some persons develop a disabling type of nerve pain and numbness. In addition, depression and anxiety occur at a higher rate in people with HIV infection.

Documentation of the incidence of neurological and neuropsychological disorders in HIV infected persons has increasingly improved since first observed in people with AIDS in the early '80s.

One aspect of HIV-related neurocognitive disorders is that symptoms can be intermittent, rather than steadily degenerative, as is seen in conditions like Alzheimer's or Parkinson's disease. In the absence of rigorous neurocognitive testing, people infected with HIV may self-report perceived impairment such as forgetfulness or slowing of mental functions that may be related to anxiety or other issues. Conversely, they may not be aware of mild deficits that go undetected by the health provider during routine exams.

An estimated one-third of people with HIV who have no medical symptoms have some subtle neurocognitive deficits, according to Grant. For those with mild to more advanced medical symptoms, as many as 45% have mild cognitive impairment, and 55% or more of people with advanced AIDS have neurological involvement, increasing in number proportionate to the severity of the disease.

Approximately 5-7 % of people with advanced AIDS develop dementia, characterized by cognitive impairments that are so severe and widespread as to disable the individual in day-to-day life functioning, said Grant.

One area of study will be how effective anti-retroviral therapy is in terms of limiting infection of the CNS by the virus and reducing neurological complications. The research will consider host factors, for example, how the body, especially the brain, responds immunologically to the virus. In addition the team will study background factors, such as drug abuse, that might modify this response, as well as viral factors, such as genetic changes HIV undergoes by virtue of being in the brain tissue, or as a result of exposure to various antiviral medications.

In addition, said Grant, the project will evaluate protective or damaging effects of anti-retrovirals. For example, there is speculation that these drugs may interfere with the mitochondria, modify lipid metabolism, and perhaps thereby increase risk of stroke or other neurological complications. HNRC investigators have also observed the appearance of an uncommon but severe type of damage to the white matter of the brain associated with modern therapies. One objective of CHARTER is to unravel the mechanisms of this complication.

The interaction of these potent drugs with other medications such as psychotropic drugs used to treat mood disorders will also be studied, as well as the drugs' ability to penetrate the blood-brain barrier.

Under Grant's overall direction, UCSD School of Medicine will serve as the coordinating center, providing administrative oversight; centralized resources for protocol coordination, data management and information systems, and statistical support; and protocol development and quality assurance.

Directors of the participating clinical sites are J. McArthur, M.B.B.S., M.P.H., at Johns Hopkins; S. Morgello, M.D., and D. Simpson, M.D. at Mt. Sinai; J. A. McCutchan, M.D., at UCSD; B. Gelman, M.D., Ph.D., at University of Texas, Galveston; A. Collier, M.D. and C. Marra, M.D., at University of Washington, and D. Clifford, M.D. at Washington University.

UCSD and Veterans Affairs San Diego Health System faculty with leadership roles in the CHARTER Coordinating Center include Ronald Ellis, M.D., Ph.D. of the department of neurosciences, and Thomas Marcotte, Ph.D. of the department of psychiatry who, along with Allen McCutchan, will serve as co-directors of CHARTER.

Other UCSD/VA based faculty serving as core directors and their areas of responsibility are Daniel Masys, M.D., data management and information systems; Ian Abramson, Ph.D., statistics; Robert Heaton, Ph.D. and J. Hampton Atkinson, M.D., neurobehavior; Scott Letendre, M.D., laboratory, pharmacology and immunology; Terry Jernigan, Ph.D., neuroimaging, and Joseph Wong, M.D., virology.

Ellis also serves as neuromedical core director, and Shondra Neumayer, R.N., F.N.P.,  will coordinate activities as CHARTER manager and Michelle Frybarger, M.S. as Manager, Data Management and Information Systems. 

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