HIV Infected African Americans May Not Be Receiving Effective Dosages of Antiretroviral Treatment to Combat AIDS

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A new study from researchers at Johns Hopkins University, published this month in the journal Drug Metabolism and Disposition, reveals that many African-Americans infected with HIV may not be receiving effective dosages of an important antiretroviral used to combat the onset of AIDS.

After investigating the preliminary dosing studies, completed before the drug was FDA approved in 2007, the researchers discovered that the demographics of the study were biased towards primarily European-Americans, who lack important proteins used in the removal of maraviroc from the body, allowing for the drug to maintain effect levels in-between dosages. By not taking into account that nearly half of all African Americans have different metabolic capacities for the drug, maraviroc researchers may have overlooked that many of those receiving treatment have proteins that naturally remove the active ingredients.

"Because African-Americans are disproportionately affected by HIV infection, it is doubly important that we get the dosing right, assistant professor of pharmacology at Johns Hopkins University School of Medicine, Namandje Bumpus, Ph.D., said.

Found with a simple genetic test to identify an active gene producing the CYP3A5 protein, whose primary function is to remove chemicals like maraviroc from the body, the researchers say that clinicians could better tailor dosages to the individual by now taking into account the presence of the protein.

As a protein abundantly found in the liver and intestinal tract, CYP3A5 makes many drugs like maraviroc more water-soluble by the addition of a chemically bonded oxygen, that allows the body to remove the drugs through the urinary pathway. Due to the fact that most European-Americans have inherited two dysfunctional copies of the CYP3A5 gene, between 80 and 90 percent have no active CYP3A5 protein, however, roughly 45 percent of all African-Americans carry two functional copies of the gene and an abundance of CYP3A5; a problem for clinicians that prescribe normal dosages to both African and European Americans.

To test the effects that these proteins would have on the efficacy of maraviroc treatments, the research team grouped a small test study of 24 individuals into three subcategories depending on whether they had zero, one or two active copies of the CYP3A5 gene. Then, they administered a single 300mg dose of maraviroc and tested the concentration in the patients' blood 10 times over the course of 32 hours. The results found that patients with two active copies dropped below a concentration of 59%, on average dipping below the lowest effective level of treatment against HIV.

"The trend we saw was that the more function CYP3A5 a person had, the faster maraviroc was processed and left the body, so the lower its concentration in the bloodstream" Bumpus says. "What's nice is that, if a larger study confirms that we are underdosing this group, a simple genetic test prior to dosing decisions could rectify the situation."

The researchers are hopeful that this study has opened the eyes to clinicians currently underprescribing to a large demographic of the HIV infected population, and hope that their work highlights the underlying importance of diversifying clinical trials to look more demographically like the population the treatments are intended for.

For more information visit:

https://www.eurekalert.org/pub_releases/2014-08/jhm-doh082714.php