Study Finds Subtle Brain Damage in Some HIV Patients in Drug Therapy

Researchers have found subtle damage in the brains of HIV-positive patients whose viral load is effectively suppressed by anti-retroviral therapy. In one of the first studies of its kind, researchers from the San Francisco Veterans Affairs Medical Center (SFVAMC) used a combination of MRI brain imaging, recording of electrical brain activity, and behavioral tests to compare the size and function of brains of HIV-positive patients on antiretroviral therapy with those of healthy subjects.

Although it is not known whether any or all of the damage occurred before patients started drug therapy, even minor damage that is present now should serve as a warning, says Linda Chao, PhD, the study’s lead author and an assistant adjunct professor with the Magnetic Resonance Unit of the SFVAMC and the Departments of Psychiatry and Radiology at University of California, San Francisco (UCSF). “People are starting to get lax about AIDS now,” Chao says. “You see people on antiretroviral medications and they seem fine. But the take-home message of our study is that antiviral medications might not be stopping brain damage. When we put patients’ brains under closer scrutiny, we saw that they were affected.”

“The results of our study raise the concern of brain injury in HIV subjects who are on treatment, even among those who are virally suppressed,” says the study’s senior investigator, Michael Weiner, MD, of the Magnetic Resonance Unit, SFVAMC, and the Departments of Radiology, Psychiatry, Medicine and Neurology at UCSF. “What we don’t know is whether or not these changes occurred some time ago, prior to effective treatment, or whether these changes represent ongoing injury.”

The study appears in the November 14 issue of NeuroReport. HIV or human immunodeficiency virus, the pathogen that causes AIDS or acquired immunodeficiency syndrome, can produce neurological abnormalities in any part of the nervous system, including the brain. Symptoms of HIV brain damage may include depression, memory loss, a slowing of mental and physical response time and sluggishness in limb movement. These symptoms can progress to a severe disorder known as HIV dementia, an advanced stage of neurological damage that, before the advent of antiretroviral drug therapy, afflicted some 20 percent of HIV patients. These patients experienced such symptoms as severe memory loss and cognitive impairment, tremors, hyperactive reflexes, immobility, and loss of speech.

Now that antiretroviral drugs have become widely accessible in the U.S., the prevalence of HIV dementia and other neurological problems associated with HIV have sharply declined. But the drugs do not eliminate the virus: they merely suppress it. And while HIV can make its way through the blood-brain barrier (the body’s natural defense mechanism that prevents many blood-borne substances from passing into brain tissue), antiretroviral drugs are largely excluded by the barrier.

Taking the first steps to determine how the virus may be affecting the brains of people taking antiretroviral drugs, Chao and her research team compared 39 people who tested positive for HIV who had been taking antiretroviral drugs for at least three months with 39 control subjects not infected by the virus. The HIV-positive group was further divided into two subgroups: a “virally suppressed” group whose 16 members had no detectable virus in blood samples, and a “viremic” group whose 23 members had substantial virus in blood samples. Whether virally suppressed or viremic, all subjects in these groups were healthy with no symptoms of HIV infection.

Study participants ranged in age from 25 to 57 years. All had from 12 to 20 years of education, and no one with a history of substance abuse or psychiatric or neurological disorders was included in the study. Due to inherent difficulties in determining when HIV infection has taken place, this information was not available for study participants.

Three separate techniques were used to assess neurological health of study participants:

• Recording of brainwaves during task performance. Researchers recorded subjects’ contingent negative variation (CNV), a type of brainwave, while subjects performed a reaction time test. The CNV is considered to be a measure of anticipation and preparation potential as well as an indication of a person’ s ability to initiate physical action.
• Neuropsychological testing. Participants performed a battery of tests designed to assess memory and mental agility.
• MRIs. Magnetic resonance imaging was used to measure the size of various parts of the brains of 31 HIV patients and 35 control subjects.

The biggest difference in test results between groups came from the contingent negative variation brainwave recordings. When Chao charted the magnitude of brainwaves during the computer task performance test, she found that while CNV activity among HIV-negative participants surged shortly after appearance of the first image, it remained nearly flat among both the viremic and virally suppressed HIV-positive participants. Lack of CNV response is generally an indication of damage or destruction to brain cells in the basal ganglia, a part of the brain that coordinates motor behavior and one of two brain structures where HIV tends to concentrate.

Chao also found that among control subjects, the stronger their CNV activity, the faster their response time. But there was no correlation between CNV activity and response time among HIV-positive participants. Nevertheless, HIV-positive participants had just as good response times as control subjects. There is a possible explanation, says Chao: the flat CNVs recorded among the HIV-positive participants are possibly an indication that HIV has damaged the normal neurological linkage between a stimulus (for example, a hand touching a hot pan) and a reaction (pulling the hand away). But the fact that response times were equal could mean that alternate neurological pathways that compensate for the disruption have developed in the brains of the HIV-positive subjects.

To assess where HIV-triggered damage might be occurring in the brain, Chao examined the relationship between the strength of CNV activity during the reaction-time test, with MRIs of study subjects’ caudate nuclei, a substructure of the basal ganglia. She found that the weaker the CNV among HIV-positive participants the more reduced the caudate volume. “The basal ganglia is a part of the brain known to carry one of the highest viral burdens,” she says. Because there is also evidence that the CNV partially originates in this part of the brain, finding this correlation [between weak CNVs and reduced caudate volume] is a nice tie-in that gives us more confidence in our conclusions about where and how damage is occurring.”

MRI measurements also revealed that the volume of the brain structure known as the thalamus was smaller both in viremic and in virally suppressed participants than in controls, an indication of damage in this region. The thalamus serves as a relay station for sensory information.

Results of the behavioral tests were mixed. On several tests, there were no differences between the three groups. And on all tests virally suppressed patients scored as well as the control group. But on three tests, scores of viremic participants were significantly lower than those of virally suppressed participants and the controls. “People with lower scores like these might not be able to do such things as type as fast as before, and they might not have as good attention or mental flexibility as the people who scored higher,” Chao says. “But unless they were challenged daily, this is something they probably wouldn’t notice, because these are the kinds of things that are more easily compensated for.”

Previous studies have already shown that when viral load is reduced by antiretroviral therapy, behavioral performance improves. But in running several kinds of tests and comparing their results, the research team was able to scrutinize their findings in a new light. To determine whether injury is ongoing, Weiner says, follow-up studies that assess HIV-positive patients over a longer time period are needed.

Additional study authors are Valerie A. Cardenas, PhD, assistant adjunct professor and Dieter J. Meyerhoff, PhD, associate professor, both of the Magnetic Resonance Unit, SFVAMC and Department of Radiology, UCSF; Johannes C. Rothlind, PhD, assistant adjunct professor, Department of Psychiatry, UCSF; and Derek L. Flenniken. B.S., and Joselyn A. Lindgren, M.S., staff research associate, both of the Magnetic Resonance Unit, SFVAMC.

The study was funded by a grant from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

ADDITIONAL INFORMATION ON TESTS ADMINISTERED TO STUDY SUBJECTS:

* Recording of brainwaves during task performance. Study participants viewing a computer were shown two successive images. The first image, an X, served as an alert that the second image, a plus sign (+), would appear within two to 20 seconds. Immediately upon appearance of the second image, participants were to press a button with the index finger of their dominant hand. During the test, researchers recorded a type of brainwave called the contingent negative potential or CNV, which is considered to be a measure of the subjects’ anticipation and preparation potential as well as their ability to initiate physical action. The basal ganglia is one of the brain structures thought to contribute to the CNV. It coordinates motor behavior and is also one of two brain structures where HIV tends to concentrate.

* Neuropsychological testing. A battery of tests that assess mental agility were administered to participants. Among others, these included a test that requires connecting dots in sequence between letters and numbers, one that requires slipping different sizes of pegs into holes on a board, a memory test that entails recalling a list of 16 words immediately after hearing them read aloud and then again half an hour later, and a test that requires participants to quickly process information about the names of colors displayed either in the same color as the name (for example, “red” written in red) or in a different color (“red” written in blue.)