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INH-associated hepatotoxicity underreported in patients with latent TB

Isonicotinic acid hydrazide-associated hepatotoxicity is a leading cause of drug-induced liver injury in the United States, and a majority of cases found in patients with latent tuberculosis are underreported to the CDC, according to published findings.

Researcher Paul H. Hayashi, MD, MPH, division of gastroenterology and hepatology, University of North Carolina, and colleagues analyzed data from the Drug-Induced Liver Injury Network (DILIN) of cases where isonicotinic acid hydrazide (INH)-associated hepatotoxicity was present or suspected. They investigated whether clinicians adhered to American Thoracic Society (ATS) guidelines for stopping INH, or isoniazid, and how often these cases were reported to the CDC.

Paul H. Hayashi

“Although studies have suggested a low incidence of severe hepatotoxicity, underreporting is suspected,” the researchers wrote. “The [DILIN] is a multicenter study funded by the [NIH] to create a large registry of well-characterized cases of idiosyncratic drug-induced liver injury for clinical and translational studies.

“We assessed completeness of reporting to the CDC by examining whether our cases appeared in the CDC report.”

The researchers evaluated delays in INH discontinuance, based on ATS criteria and hepatotoxicity severity using the Severity Index Score. Reporting to the CDC was measured by matching patients based on age, latency, indication, reporting period and comorbidities.

From 2004 to 2013, 69 cases of INH were reported to the DILIN of which 60 cases met inclusion criteria. Seventy percent of these patients were women (median age, 49 years), and 97% had been prescribed INH for tuberculosis (TB).

According to the research, the median delay between meeting the ATS criteria for stopping and discontinuance of INH was 9 days. Fifty-five percent of patients maintained INH therapy for more than 7 days after the ATS criteria for stopping were met, and 40% continued for more than 14 days.

Analysis showed delays in stopping were associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, nine continued taking INH for more than 7 days after meeting stopping criteria. Only one of 25 cases of INH hepatotoxicity eligible for reporting to the CDC was reported.

“The CDC report obtained clinical details on only 10 of their 17 cases reported from 2004 through 2008,” the researchers wrote. “Of the 25 DILIN cases that should have been reported … only one appeared to be among the 10 CDC cases with a detailed clinical history based on matched age, duration of therapy, delay in stopping INH, comorbidities and outcome.”

The researchers concluded: “Our registry draws attention to an important minority of latent TB patients who are harmed by suboptimal adherence and prolonged drug exposure. Underreporting is common, so the true incidence of such cases is significantly larger than currently captured. Failures to avoid such severe iatrogenic injury are particularly difficult to countenance when the latent TB patient was otherwise healthy before therapy and simply needed better education, reminders, or monitoring.” – by Melinda Stevens

Disclosure: Hayashi reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.