The standard therapy in patients with latent tuberculosis, defined as a positive tuberculin skin test without evidence of active tuberculosis, is isoniazid for at least six months. However, because of potential toxicity, especially hepatitis, and poor adherence to the medication regimen, a shorter two-month course of pyrazinamide and rifampin has been suggested for treatment of latent tuberculosis in patients with human immunodeficiency virus (HIV) infection. Guidelines from the Centers for Disease Control and Prevention and the American Thoracic Society include three choices for the management of latent tuberculosis: (1) isoniazid for six to nine months, (2) rifampin for four months, or (3) rifampin and pyrazinamide for two months. However, cases of severe liver toxicity have been noted with the two-drug regimen. Jasmer and associates conducted a multicenter, prospective, open-label trial to compare the toxicity and therapy adherence of the two-month regimen of rifampin and pyrazinamide with the six-month regimen of isoniazid in persons with latent tuberculosis but no HIV infection.
Patients who were at least 17 years of age and who would ordinarily be treated for latent tuberculosis were included in the study. Exclusion criteria included pregnancy, HIV infection, elevated creatinine levels or liver enzyme test results, and a history of gout. Participants were divided into two groups, receiving either rifampin (600 mg daily) and pyrazinamide (20 mg per kg daily) for two months (307 patients) or isoniazid (300 mg daily) for six months (282 patients). Serum levels of liver enzymes and bilirubin were measured after one month and again at three months in the patients receiving isoniazid. Patients receiving the two-drug regimen also had a complete blood count and measurement of uric acid and creatinine levels after one month of treatment.
In patients with liver function test results greater than five times normal (grade 3 hepatotoxicity on the World Health Organization [WHO] classification), treatment with study medications was stopped unless some other cause of elevated liver enzymes, such as alcohol abuse, could be found. In patients with liver function test results greater than 10 times normal (grade 4 hepatotoxicity on the WHO classification), the treatment regimen was discontinued permanently.
Among participants having liver enzyme tests, hepatotoxicity developed more frequently in those receiving the rifampin-pyrazinamide regimen (26 percent) than in those receiving isoniazid (16 percent). The rifampin-pyrazinamide regimen was significantly more likely to be discontinued because of hepatotoxicity. Other adverse events occurred equally among the two groups, except for skin rash, which was significantly more common among the patients receiving the rifampin-pyrazinamide regimen. Treatment completion was similar among the two groups.
The authors conclude that the short-course treatment for latent tuberculosis using pyrazinamide and rifampin is associated with a higher risk of hepatotoxicity compared with the six-month course of isoniazid in adults without HIV infection. The short-course, two-drug regimen should be used cautiously and with early liver-injury evaluation to decrease the possibility of severe liver toxicity.