January 23, 2006

Race/Ethnicity Differences in Gene Predict Lipid Disorder and Heart-Disease Risk
in HIV-1 Infected Patients Taking Protease Inhibitors
Findings Could Help Physicians Tailor Antiretroviral Regimens

(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 prolong life.”

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, Amherst.

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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This release is available online at http://www.uphs.upenn.edu/news/News_Releases/jan06/HIV1hrtrsk.htm