It's an Achilles'
heel of HIV therapy: The AIDS virus can sneak into the
brain to cause dementia, despite today's best medicines.
are beginning to test drugs that may protect against the
memory loss and other symptoms of so-called neuroAIDS, which
afflicts at least one in five people with HIV and is
becoming more common as patients live longer.
With nearly 1
million Americans, and nearly 40 million people worldwide,
living with HIV, that's a large and under-recognized toll.
"That means HIV
is the commonest cause of cognitive dysfunction in
young people worldwide," says Justin McArthur, vice chairman
of neurology at Baltimore's Johns Hopkins University,
who treats neuroAIDS. "There's no question it's a
major public-health issue."
most powerful anti-HIV drugs do help by suppressing levels
of the virus in blood--so that there's less to
continually bathe the brain--they can't cure
neuroAIDS. Why? HIV seeps into the brain very soon
after someone is infected, and few anti-HIV drugs can
penetrate the brain to chase it down.
"Despite the best
efforts of (anti-HIV) therapy, brain is failing," says
Harris Gelbard, a neurologist at the University of
Rochester Medical Center. He is part of a major new effort
funded by the National Institutes of Health to find
the first brain-protecting treatments.
What's now called
neuroAIDS is much different from the AIDS dementia of
the epidemic's early years, when patients often had horrific
brain symptoms similar to end-stage Alzheimer's,
unable to move or talk. They'd die within six months.
medication has resulted in a more subtle dementia that
strikes four years or more before death: At first patients
forget phone numbers and their movements slow. They
become less able to juggle multiple tasks.
Some worsen until
they can't hold a job or perform other activities, but
not everyone worsens--and doctors can't predict who
will. In a vicious cycle, the memory loss makes many
forget their anti-HIV pills, so the virus rebounds.
that neuroAIDS reduces patients' mental function by
If HIV patients
live long enough, many specialists worry, nearly all of
them may suffer at least some brain symptoms.
longer with HIV in the brain," explains Kathy Kopnisky
of the NIH's National Institute of Mental Health, which is
spending about $60 million investigating neuroAIDS. "And
they're aging, so they're going through the normal
brain aging-related processes" that can make people
vulnerable to Alzheimer's and other brain diseases.
this is a different type of dementia from any caused by
Alzheimer's or Parkinson's, and drugs for those
brain-degenerating diseases so far are proving
disappointing against neuroAIDS.
government-funded attack has two fronts:
- First, to figure out which of the powerful
anti-HIV cocktails are the best bet for HIV
patients with memory problems.
A few of today's
HIV-suppressing drugs, such as nevirapine, abacavir,
AZT, and indinavir, can penetrate the blood-brain barrier,
says Ron Ellis, MD, of the University of
California, San Diego.
But no one knows
if using those drugs instead of others will slow the
brain damage once neuroAIDS symptoms begin. Early next year
Ellis will begin a study of 120 such
patients--at UCSD, Johns Hopkins, and Washington
University in St. Louis--to try to tell, by randomly
assigning them to either a brain-penetrating cocktail
or different drugs.
- Second, to find drugs that protect nerve cells
from the inflammation-triggered toxic chain
reaction that seems to be how HIV wreaks its
candidates are the epilepsy drug valproic acid and lithium,
a drug long used in manic depression. Both inhibit an
enzyme, called GSK-3b. The body normally makes the
enzyme, but too much is poisonous. In the brain, HIV
knocks that careful balancing act out of whack, leading to
death of connections key to memory and other neuronal
In a recent
pilot study, Gelbard found tantalizing signs that valproic
acid might increase brain connections in a few neuroAIDS
patients, and improve their symptoms. He's about to
begin a second-stage study to try to tell if the
effect is real; a similar pilot trial with lithium is
Seeking a one-two
punch, Gelbard also hopes to soon begin a human study
of an experimental drug that targets a second inflammatory
protein HIV uses to trigger brain cells to kill
themselves. (Lauran Neergaard, AP)