(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine, in collaboration with
the University of Massachusetts, have found that small changes in
a human gene, apolipoprotein CIII (apoC-III), which vary
in frequency among people of different ethnicity, may help predict
which HIV-1-infected patients are likely to develop lipid disorders
and be at increased risk for heart disease if they take a particular
class of anti-AIDS medicines known as protease inhibitors.
The study, published in the January issue of PLoS Medicine,
focuses on the abnormally high levels of triglycerides and low levels
of HDL, the “good” cholesterol, found in the blood of
HIV-1 infected patients on protease inhibitors as part of combination
antiretroviral therapy. These blood fats, known as lipids, put people
in the general population at risk for heart attack and stroke. In
their study of 626 patients with HIV-1 on antiretroviral therapy,
the researchers found that the lipid abnormalities stemming from
protease inhibitors varied by race/ethnicity and were associated
with variant forms of apoC-III.
The researchers cautioned that much larger, controlled studies would
be needed before findings from this initial study could be used
by physicians to help tailor antiretroviral regimens to individuals’
genetic profiles. They also emphasized that genetics is likely just
one factor involved in the race-related differences seen in the
lipid levels. Diet, exercise, and other environmental factors, they
noted, probably play a role as well.
Still, the study underscores the importance of examining the side
effects of antiretroviral drugs across all racial groups, not just
among Whites. Scientists said the need for testing the medicines
among diverse populations was particularly important as the drugs
begin to roll out in developing countries in Asia and Africa, home
to more than 95 percent of the estimated 25 million people around
the world who are living with HIV-1 infection.
If the findings are confirmed in larger studies, they could also
give physicians a new tool to start patients with HIV-1 on the most
appropriate antiretroviral regimen. For instance, people with a
genetic predisposition to high lipid levels could be steered away
from protease inhibitors or put on newer versions of these drugs
that are less likely to result in these lipid side effects. Patients
on antiretroviral therapy at highest risk could also be started
early on lipid-modifying therapy.
“This type of information could help us prevent what we fear
could be an epidemic of premature heart disease among HIV-1 positive
people on antiretroviral drugs for many years, ” says senior
author Muredach P. Reilly, MB, Assistant Professor
of Medicine at Penn.
The study is the largest pharmacogenetic analysis to date of metabolic
changes associated with antiretroviral drugs and the first to assess
the impact of ethnicity on pharamcogenetic effects in HIV-1 infection.
It comes nearly a decade after the development of protease inhibitors,
which revolutionized the treatment of AIDS by turning HIV infection
into a chronic but manageable disease rather than a death sentence.
There are now nine licensed protease inhibitors among the 25 antiretroviral
drugs approved for use in the United States. Protease inhibitors
are one of four classes of anti-AIDS drugs, each of which attacks
HIV-1 at a different point in its life cycle. To effectively suppress
the virus, HIV-1-infected patients need to take a combination of
drugs from at least two of the different classes.
The team emphasized that, despite the metabolic problems involved
with protease inhibitors and other antiretroviral drugs, the benefits
of the medicines still far outweigh the risks of serious side effects.
“These drugs still work,” says co-author Pablo
Tebas, MD, Associate Professor of Medicine at Penn. “They
The data on which the study was based came from blood samples of
a racially mixed group of 626 HIV-1-infected patients on antiretroviral
therapy enrolled in federally sponsored AIDS clinical trials across
the country, including 440 on regimens that included a protease
inhibitor. Researchers analyzed the DNA of these patients and examined
their lipid profiles when on stable antiretroviral therapy.
The researchers found abnormally high levels of triglycerides and
low HDL across all racial groups treated with antiretroviral therapy
that included a protease inhibitor. The increase in abnormalities
was more pronounced among Blacks, as compared with Whites, although
the overall lipid levels for Blacks remained lower than that for
the other groups. For example, Blacks on antiretroviral therapy
had approximately 20 percent lower triglycerides and 10 percent
higher HDL levels than whites.
The scientists also discovered that certain variants of the apoC-III
gene - known as SNPs, or single nucleotide polymorphisms - were
actually associated with lower lipid levels among Hispanics, but
this was not detectable in Blacks and Whites treated with protease
inhibitors. There were not enough Asians or Native Americans in
the sample to make any inferences about those groups.
“It’s become very clear that we can’t just look
at the White population and make inferences about side effects in
the rest of the population,” says first author Andrea S. Foulkes,
ScD, Assistant Professor of Biostatistics, University of Massachusetts,
The study was funded by the National Institute of Allergy and Infectious
Diseases with support provided by the federal government’s
AIDS Clinical Trials Group (ACTG) and the federally sponsored Centers
for AIDS Research (CFARs). It involved a team of researchers at
the University of Pennsylvania and University of Massachusetts,
Amherst, as well as ACTG investigators at the University of North
Carolina and Indiana University.
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