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Genetic Variation May Reduce Maraviroc's Efficacy in African Americans

September 2, 2014

A large number of HIV-positive African Americans receiving treatment with maraviroc (Selzentry, Celsentri) may be on subtherapeutic levels of the drug, according to newly published research.

Maraviroc is an HIV entry inhibitor; it is the only U.S. Food and Drug Administration-approved antiretroviral that specifically targets the CCR5 co-receptor to which HIV typically binds in the first stage of entry into a CD4+ cell. It is not recommended for use in first-line therapy, in large part because it is dosed twice-daily and due to the necessity for an extra test to confirm that a person's virus is CCR5 tropic. However, it is sometimes prescribed to those for whom other options are unavailable, or to treatment-experienced individuals who are CCR5 tropic. Maraviroc is also being investigated for its potential value in HIV prevention, particularly as an option in pre-exposure prophylaxis.

Researchers at Johns Hopkins University previously found that a particular gene, CYP3A5, played a potentially key role in accelerating maraviroc metabolization. Earlier research also indicated that CYP3A5 gene expression can vary widely by ethnicity, leading the Johns Hopkins team -- a collaboration of Yanhui Lu, Craig Hendrix, M.D., Edward Fuchs, P.A.-C., and Namandjé Bumpus, Ph.D. -- to postulate that maraviroc's antiretroviral activity might be affected by CYP3A5 polymorphism.

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To wit, the Hopkins team conducted an open-label, single-dose study involving 24 HIV-negative adult volunteers. Volunteers were split into three groups of eight depending on CYP3A5 genotype: The homozygous dysfunctional group had two non-functioning CYP3A5 alleles; the heterozygous group had one CYP3A5*1 (i.e., wild-type) allele and one non-functioning allele; and the homozygous wild-type group had a pair of CYP3A5*1 alleles. Seventeen of the 24 volunteers were African American, and six volunteers were female.

The researchers found that maraviroc drug concentrations in plasma were significantly lower -- and drug clearance was significantly higher -- among volunteers in the homozygous wild-type group than among volunteers in the other two groups. Mean area-under-the-curve concentrations were 41% lower and apparent oral clearance was 66% higher in the homozygous wild-type group than the homozygous dysfunctional group; both findings were statistically significant.

"The reduced maraviroc exposure in homozygous carriers for CYP3A5*1 is an impactful finding since CYP3A5 is more frequently expressed in people with African ancestry, especially when combined with the fact that African Americans are disproportionately infected with HIV-1 and at greater risk of acquiring HIV-1 infection compared to European Americans," the researchers write in the study manuscript, which was published online in Drug Metabolism and Disposition on Aug. 12. Nearly half of all African Americans are believed to be homozygous CYP3A5*1 carriers.

"Because African-Americans are disproportionately affected by HIV infection, it is doubly important that we get the dosing right," study co-author Bumpus said in a Johns Hopkins press release. "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."

In the meantime, the findings may give some health care providers pause when considering maraviroc for their African-American patients. "The results of the study may explain in part the disappointing results of maraviroc-based therapy, even in patients found to have CCR5-tropic virus at baseline," suggested Paul Sax, M.D., the director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital in Boston. "In circumstances in which a clinician might consider use of maraviroc in an African-American patient, if there are other options that are fully active these might be preferred until the data from this study can be clarified or confirmed elsewhere."

According to the Hopkins release, Bumpus also noted that the study findings point to the importance of ensuring that clinical trial populations reflect the ethnic diversity of the people who are expected to receive the treatment being explored in the trial.

Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.

Follow Myles on Twitter: @MylesatTheBody.


Copyright © 2014 Remedy Health Media, LLC. All rights reserved.



This article was provided by TheBodyPRO.com. It is a part of the publication HIV JournalView.
 

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