In the past few years, the normally reticent scientific community heralded as revolutionary new medications for Hepatitis C, saying the drugs would bring a major shift in the treatment of the chronic and potentially fatal viral infection that affects 150 million people worldwide.
They were right. These direct-acting drugs, which attack the processes that fueled the virus's growth, resulted in cure rates well over 95 percent in a matter of weeks to a few months. They also gave new hope to the many people co-infected with HIV as well as Hepatitis C, who could now rid their bodies of the latter.
Now, a University of Rhode Island pharmacy professor and a graduate student have discovered potential complications in the regimen. The Hepatitis C drug sofosbuvir can adversely interact with HIV drug tenofovir disoproxil, reports Bingfang Yan, professor of biomedical and pharmaceutical sciences in the College of Pharmacy/Academic Health Collaborative. Tenofovir disoproxil is listed as an essential medicine by the World Health Organization. These Hepatitis C and HIV drugs are manufactured and sold by Gilead Sciences Inc. as Sovaldi and Viread, respectively.
"Sovaldi has become a standard of Hepatitis C therapy since its approval in December 2013," Yan said of the drug, which is as expensive as it is effective, with a 12-week course of treatment costing as much as $75,000 or more.
He and graduate student Yuanjun Shen report their findings in the Journal of Hepatology in a letter to the editor titled "Covalent Inhibition of Carboxylesterase-2 (CES-2) by Sofosbuvir and its Effect on the Hydrolytic Activation of Tenofovir Disoproxil."
Yan noted that Sovaldi -- and other Hepatitis C medications such as Harvoni and EPCLUSA that contain sofosbuvir -- are often used in combination with additional medications to combat co-infections with other viruses such as HIV and Hepatitis B. Emerging evidence has linked Sovaldi-containing regimens to severe liver and kidney toxicity or reactivation of the other virus. Earlier this year the U.S. Federal Drug Administration ordered placement of the agency's most prominent warning on these drugs after studies showed they could reactivate Hepatitis B in people who have that virus and Hepatitis C.
This new study by Yan and Shen shows that sofosbuvir inhibits the hydrolysis (decomposition in water) of tenofovir disoproxil, affecting the drug-activating CES-2 enzyme irreversibly. "This decreases the therapeutic activation of tenofovir disoproxil with implications of increased kidney toxicity," Yan said.
"CES-2 is generally considered as a detoxification enzyme," Yan said, "it is abundant in the liver and kidney." "The enzyme (CES-2) normally breaks down through hydrolysis, activating such medicines as tenofovir disoproxil or inactivating such medicines as aspirin," he explained. With the enzyme rendered useless by Sovaldi, these medications cannot work fully and can accumulate at toxic levels.
For now, Yan said doctors should prescribe the medications with instructions to take them at different times or different routes. The HIV medication can be administered first, or through the skin; and the Hepatitis C medication can be taken orally at a later time, he suggested. Yan said clinical trials are needed to fully analyze the impacts of these medications when taken in combination.
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Shen, Y., & Yan, B. (2016). Covalent inhibition of carboxylesterase-2 by sofosbuvir and its effect on the hydrolytic activation of tenofovir disoproxil. Journal of Hepatology. DOI: 10.1016/j.jhep.2016.11.025