Newly discovered genetic variants could explain why a common medication doesn’t protect all
ORLANDO, Fla. — Some people’s genes may stop an antiretroviral drug from protecting them against HIV, a genetics study suggests.
The drug, called tenofovir, is used for preventing as well as treating an HIV infection. But success in prevention has been mixed, with studies reporting between 78 to 92 percent success rates. It wasn’t clear why the drug didn’t protect everyone.
Now, studies reveal that rare genetic variants can prevent tenofovir from becoming active in the body, pharmacologist Namandjé Bumpus of Johns Hopkins University School of Medicine reported April 8 at the 2019 Experimental Biology meeting.
People who have HIV or who are at risk of contracting HIV, such as someone whose partner has the virus, take an inactive form of the drug that must be activated in the body in a two-step process. Scientists knew enzymes called kinases are required, but weren’t sure which of the many kinases in the human body convert the drug to its active form.
An enzyme called adenylate kinase 2 attaches one phosphate atom and another enzyme, creatine kinase, tacks on a second to spur the drug to action, Bumpus and colleagues discovered. Variants of the kinases are rare: Only 18 adenylate kinase 2 variants were found among 906 people whose DNA was tested.
Separately, the researchers tested whether the variants affected the ability of adenylate kinases to activate tenofovir. Of 477 people taking the drug, seven people with variants predicted to disable the enzyme didn’t have the active version of tenofovir in their blood. That result hints that the variants do affect the drug’s effectiveness.
A few other people who didn’t have harmful variants also didn’t have the active drug in their blood, suggesting that they may not have been taking tenofovir correctly. Bumpus hopes to repeat the study with people known to be taking the drug as prescribed.
The findings are too preliminary to predict whether tenofovir will protect a particular person against HIV. “The goal is to use this for precision medicine,” Bumpus said, “but we don’t think we’re there yet.”
N. Bumpus. Genetic variations of the kinases that phosphorylate drugs. Experimental Biology 2019, Orlando, Fla., April 8, 2019.
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