The Centers for Disease Control (CDC) has reported severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month regimen of rifampicin (US: rifampin) with pyrazinamide (RZ). On the basis of these initial reports, CDC has cautioned clinicians in the use of this therapy. To estimate the incidence of RZ-associated severe liver injury CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI. Analysis found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI.

The revised ATS/CDC recommendations are endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI. Rifampicin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease.

This regimen should generally not be offered to persons with LTBI for either HIV-negative or HIV-infected persons and should never be offered to patients who:

• are concurrently taking other medications associated with liver injury;

• drink excessive amounts of alcohol, even if alcohol use is discontinued during treatment;

• have underlying liver disease; or

• have a history of isoniazid (INH)-associated liver injury.

If the potential benefits of this regimen outweigh the risk for severe liver injury and death associated with it, use of RZ might be considered in carefully selected patients, but only if:

• the preferred or alternative regimens (i.e., 9 months of daily or biweekly INH, 6 months of daily or biweekly INH, or 4 months of daily rifampicin) are judged not likely to be completed and

• oversight by a clinician with expertise in the treatment of LTBI can be provided.

A TB/LTBI expert should be consulted before RZ is offered. In addition, patients should be asked whether they have had liver disease or adverse effects from taking INH or other drugs, informed of potential hepatotoxicity of the RZ regimen, and advised against the concurrent use of potentially hepatotoxic drugs, including over-the-counter drugs such as paracetamol (acetaminophen).

To facilitate periodic clinical assessments of persons taking an RZ regimen (clinicians should dispense no more than a 2-week supply (with a daily PZA dose of <20.0 mg/kg/d [maximum daily PZA dose: 2.0 g], and a twice-weekly dose of <50.0 mg/kg/d [maximum twice-weekly PZA dose: 4.0 g]).

Patients should be reassessed in person by a health-care provider at 2, 4, 6, and 8 weeks of treatment for adherence, tolerance, and adverse effects. The 8-week assessment also should be used to document treatment completion. At each visit, health-care providers who speak the patient’s own language should instruct the patient to stop taking RZ immediately and seek medical consultation if abdominal pain, emesis, jaundice, or other symptoms of hepatitis develop. Provider continuity is recommended for optimal monitoring.

For persons taking this regimen, serum aminotransaminases (AT) and bilirubin should be measured at baseline and at 2, 4, 6, and 8 weeks of treatment. Because the majority of these patients had onset of symptoms of liver injury after the fourth week of therapy they should be monitored throughout the entire course of treatment. Use of RZ should be discontinued immediately and not resumed for any of the following findings:

• AT greater than five times the upper limit of normal range in an asymptomatic person,

• AT greater than normal range when accompanied by symptoms of hepatitis, or

• a serum bilirubin concentration greater than the normal range, whether or not symptoms are present.

The risk for progression from LTBI to active TB is increased substantially in persons with HIV infection. Therefore, as recommended previously for the treatment of all persons in whom LTBI is diagnosed, voluntary HIV counselling and testing should be offered routinely.

Recommendations against the use of RZ for treatment of LTBI do not apply to the appropriate use of rifampicin and PZA in multidrug regimens for the treatment of persons with active TB disease.

Reference: CDC. Adverse Event Data and Revised American Thoracic Society/CDC Recommendations Against the Use of Rifampicin and Pyrazinamide for Treatment of Latent Tuberculosis Infection. Morbidity and Mortality Weekly Report, 52: 735-739 (2003).

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adverse drug reactions. A signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information". All signals must be validated before any regulatory decision can be made.