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Do Patients with Chronic Liver Disease Face Higher DILI Risk?

<ѻý class="mpt-content-deck">— Research suggests a link of which drug developers should be aware, expert says
MedpageToday

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SAN FRANCISCO -- Individuals with certain types of chronic liver disease may be particularly susceptible to drug-induced liver injury (DILI), and the pharmaceutical industry should take this population into account during drug development, an expert said here.

Indeed, some research suggested that drug-induced liver injury is linked with a higher risk of poor outcomes in patients with pre-existing liver disease, said Naga Chalasani, MD, of Indiana University School of Medicine in Indianapolis.

Chalasani gave the Hyman J. Zimmerman Hepatotoxicity State-of-the-Art Lecture entitled "DILI in Chronic Liver Disease -- The Next Major Hurdle" at the Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases (AASLD).

He went over certain drugs that are either reported or predicted to have an increased risk of hepatoxicity in liver disease, including anti-tuberculosis drugs, such as INH, rifampin or pyrazinamide, and highly active antiretroviral therapy (HAART) such as nevirapine -- where patients with chronic hepatitis C or hepatitis B were associated with increases in the risk of liver toxicity.

"But experts have agreed that immune reconstitution with antiretroviral therapy may lead to reactivation of an underlying viral infection," Chalasani said, characterizing this as an "important confounder."

Chalasani presented unpublished data from his research group in which they investigated the role of underlying liver disease and its role in increased risk of all-cause drug-induced liver injury. They examined data on 10 prescription medications, including common antibiotics such as ciprofloxacin, levofloxacin, amoxicillin-clavulanate, and azithromycin, from the Indiana Health Exchange, and compared the frequency of suspected DILI between individuals with likely chronic liver disease and two control groups with no biochemical evidence of liver disease over a 10-year period.

Overall, they found that the frequency of suspected DILI in the chronic liver disease cohort was about six-fold higher than either control group. Their hypothesis going into the study was that individuals with chronic liver disease are not at increased risk for DILI due to common hepatotoxic agents.

Chalasani's group also found evidence that DILI had an impact on outcomes for patients with chronic liver disease, with the frequency of death or liver transplant within 6 months of suspected drug-induced liver injury (20% in the chronic liver disease group vs 8%-14% in the control groups).

"Going into this, we didn't think there would be a higher risk [of poor outcomes], but we are starting to see this," Chalasani said. "There is a suggestion that if you have chronic liver disease and you develop drug-induced liver injury, you may be at a higher risk of death."

The unpublished data also found that moderate to severe liver disease was an independent predictor of 6-month mortality in patients with acute DILI, Chalasani said.

One study suggested that non-alcoholic fatty liver disease also seemed to play a role in the development of drug-induced liver injury, he said, citing a small 2007 study that found NAFLD was "strongly associated with DILI."

Chalasani then reviewed how the pharmaceutical industry screens a compound for hepatotoxic potential, calling preclinical screening "more like an art than a science."

"The [industry] paradigm is not designed to detect hepatotoxic potential in patients with underlying liver disease," Chalsani noted. "Some of these therapies need to be tailored for chronic liver disease patients."

One example was potentially using animals with diet-induced non-alcoholic steatohepatitis (NASH) in preclinical testing, he said.

He suggested the potential for revisions to industry standards, such as , which is designed to pick up hepatoxicity in drug trials, adding that the FDA may be looking to revise its that addressed drug-induced liver injury in premarketing clinical evaluation.

Chalasani mentioned , a partnership involving industry, regulators, and academics who are now developing "best practices for managing various aspects of this issue."

Primary Source

American Association for the Study of Liver Diseases

Chalsani N "DILI in Chronic Liver Disease -- The Next Major Hurdle" AASLD 2018.