CDC Urges Increased Awareness of Liver Injury During Isoniazid Therapy

Kate Traynor

BETHESDA, MD 04 March 2010—All patients receiving isoniazid treatment for latent tuberculosis infection (LTBI) should be alert to early signs of drug-related liver injury and stop taking the antiinfective at the onset of symptoms, according to public health experts.

Today's Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report describes 17 cases of liver injury that resulted in hospitalization or death among patients with LTBI who were receiving isoniazid, the standard therapy for the condition.

In all, 5 of the 17 patients required liver transplantation and 5 died, including one transplant recipient and two children. The case reports were obtained during 2004–08 as part of a CDC-led investigation of isoniazid toxicity in patients with LTBI.

Nine serious adverse events occurred in patients who had completed more than three months of therapy, according to the report.

The report states that all patients had been monitored for liver toxicity in accordance with American Thoracic Society recommendations for patients treated with isoniazid.

Among the 10 patients whose cases were thoroughly investigated by CDC at the request of state health departments, liver injury was diagnosed on the basis of symptoms, not laboratory values.

In three of these cases, the patients had no known risk factors for liver injury, indicating a need for careful monitoring of all isoniazid recipients, according to the report. CDC also notes that isoniazid-associated liver injury can be asymptomatic, further underscoring the need for careful monitoring.

Symptoms that signal the need to immediately cease isoniazid therapy and contact a health care provider include nausea, vomiting, abdominal discomfort, or unexplained fatigue, according to the report.

The FDA-approved labeling (PDF) for isoniazid tablets contains a boxed warning stating that isoniazid treatment has been associated with severe and sometimes fatal hepatitis.

According to the FDA-approved labeling for isoniazid products, the risk of hepatitis increases with age and alcohol use. For all isoniazid recipients, the labeling recommends a monthly review of symptoms that may indicate liver damage. For patients age 35 years or older, the labeling further recommends liver-enzyme testing at baseline and periodically during therapy.

The CDC report named "preexisting liver disease, HIV infection, injection-drug use, concurrent alcohol consumption, pregnancy or the immediate postpartum period (≤3 months after delivery), older age, and concomitant administration of medications with hepatotoxic potential" as predictors of isoniazid-induced liver injury.

CDC continues to recommend nine months of isoniazid therapy for the prevention of active tuberculosis in patients with latent disease. According to CDC, patients with LTBI who are treated with isoniazid require monitoring that includes

• Monthly clinical monitoring, including a brief physical examination, for the signs and symptoms of treatment-associated adverse events,
• Consideration of baseline liver-function testing for patients with HIV infection, chronic liver disease, pregnant or postpartum women, alcohol users, and, possibly, older patients,
• Routine liver-function testing for patients with abnormal baseline values,
• Evaluation and laboratory testing for patients at the first indication of an adverse event,
• Cessation of isoniazid therapy in asymptomatic patients whose serum transaminase values are five times the upper limit of the normal range, and
• Cessation of isoniazid therapy in symptomatic patients whose serum transaminase values are three times the upper limit of the normal range.