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The
way the body metabolizes the commonly prescribed anti-retroviral drug Sustiva
(efavirenz) may contribute to cognitive impairment by damaging nerve cells, new
Johns Hopkins research suggests, according to a report in ScienceDaily on
September 27. The study was published online in the Journal of Pharmacology and
Experimental Therapeutics.
Nearly
half of the people living with HIV will eventually develop some form of brain
damage that, while mild, can affect the ability to drive, work, or participate
in many activities. It has long been assumed that the disease was causing the
damage, but Hopkins researchers say the drug efavirenz (brand name Sustiva,
also found in Atripla) may play a key role.
Efavirenz
is known to be very good at controlling the virus and is one of the few that
crosses the blood-brain barrier and can target potential reservoirs of virus in
the brain. Doctors have long believed that it might be possible to alleviate
cognitive impairment associated with HIV by getting more drugs into the brain,
but researchers say more caution is needed because there may be long-term
effects of these drugs on the brain.
“People
with HIV…can't stop taking anti-retroviral drugs. We know what happens then and
it's not good,” says Norman J. Haughey, PhD, an associate professor of
neurology at the Johns Hopkins University School of Medicine. “But we need to
be very careful about the types of anti-retrovirals we prescribe, and take a
closer look at their long-term effects. Drug toxicities could be a major
contributing factor to cognitive impairment in patients with HIV.”
Researchers
obtained samples of blood and cerebrospinal fluid from HIV-positive patients
enrolled in the NorthEastern AIDS Dementia study who were taking efavirenz.
They looked for levels of the drug and its various metabolites, which are
substances created when efavirenz is broken down by the liver. Performing
experiments on neurons cultured in the lab, the investigators examined the
effects of 8-hydroxyefavirenz and other metabolites and found major structural
changes when using low levels of 8-hydroxyefavirenz, including the loss of the
important spines of the cells.
Haughey
and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to
brain cells than the drug itself and, even in low concentrations, causes damage
to the dendritic spines of neurons. The dendritic spine is the information
processing point of a neuron, where synapses—the structures that allow
communication among brain cells—are located.
In
the case of efavirenz, a minor modification in the drug's structure may be able
to block its toxic effects but not alter its ability to suppress the virus.
Namandje N. Bumpus, PhD, one of the study's other authors, has found a way to
modify the drug to prevent it from metabolizing into 8-hydroxyefavirenz while
maintaining its effectiveness as a tool to suppress the HIV virus.
“Finding
and stating a problem is one thing, but it's another to be able to say we have
found this problem and here is an easy fix,” Haughey says.
The Friends of AIDS Foundation is
dedicated to enhancing the quality of life for HIV positive individuals and
empowering people to make healthy choices to prevent the spread of the HIV
virus. To learn more about The Friends of AIDS Foundation, please visit: http://www.friendsofaids.org.
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