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While many new treatments for HIV infection have appeared on the market over the last 20 years, AIDS patients have had access to drugs that will allow them to live longer.
"These drugs are miracles," said Dr. Richard N. Greenberg, an infectious disease specialist at the University of Kentucky. "Before the advent of antiretroviral drugs, HIV infection was a death sentence. Now, taken correctly, the life of a person infected with HIV is almost normal."
However, many of these antiretroviral drugs (ARVs), including a clbad of drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been linked to liver disease. In fact, liver disease has become the leading cause of non-AIDS-related death in HIV-infected patients, accounting for nearly one in five deaths.
But new research published in the Journal of Hepatology could be one step closer to developing treatments that help HIV patients without increasing their risk of cardiovascular or hepatic disease. A group led by Changcheng Zhou, Ph.D. at the University of Kentucky has established a pathway that appears to be responsible for the adverse side effects of efavirenz, a drug widely prescribed for NNRTIs.
Like all organisms, humans are exposed to chemical compounds that would be toxic without metabolic mechanisms that mitigate their effects. A receptor called Pregnant X (PXR) plays a vital role in this process. The underlying mechanisms responsible for an adverse effect of antiretroviral drugs – the accumulation of fat in the liver – had not yet been identified. Zhou et al were curious: did ARVs interact with PXR to increase lipid levels?
Using naive mice and a new liver-specific murine model, they established that efavirenz "activated" the PXR target genes in vivo and in vitro, thereby stimulating fatty acid uptake and cholesterol synthesis in ways that dose dependent. A translational mouse model (expressing human PXR instead of mouse PXR) was used to confirm these results.
"These findings provide insights into the mechanism by which antiretroviral therapy induces dyslipidemia and identify potential targets for treatment to mitigate the increased risk of cardiovascular and hepatic diseases conferred by efavirenz" Zhou said.
Greenberg, who collaborated with Zhou in this study, sees this research as both a guide for clinicians and an open door for further research.
"Translational medicine starts with a mechanism," Greenberg said. "Now that we have found a pathway leading to an accumulation of fat in the liver, we can search for useful applications, including possible treatments to alleviate the side effects of PXR agonists such as efavirenz."
"In the meantime, clinicians should keep abad of this research and be vigilant on the part of their patients who have been prescribed PXR agonists."
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