Case Study 1. Treatment of latent TB infection.
A 32 year-old nurse at your correctional facility presents for yearly TB screening. He has no symptoms, no reported contact with any inmates with TB, but his TST measures 11 mm. A review of the record reveals that his TST last year measured 0mm. Chest radiograph reveals no significant abnormalities. What should be done for this nurse?

Discussion:
The initial step after diagnosis of latent TB is education. The nurse should be informed that persons with a normal immune system have approximately a 5% risk to develop active TB within the first two years after infection (conversion of a negative TB skin test to positive), and another 5% risk during the rest of their lives.19 All individuals with a positive skin test should be assessed for medical conditions that would increase the risk of progression to active TB. HIV is the single most important risk factor for progression to active disease; while ~10% of HIV-negative, otherwise immunocompetent persons will progress from TB infection to TB disease in a lifetime, ~10% of persons with HIV infection will progress YEARLY without treatment!20 All persons with latent TB infection should be offered HIV counseling and testing.

Treatment for latent TB infection usually consists of nine months of isoniazid. Isoniazid may be self-administered daily (5 mg/kg, maximum 300 mg), or may be administered directly observed twice-weekly (15 mg/kg, maximum 900 mg). Isoniazid can be hepatotoxic, causing clinically significant hepatitis in 0.1-1% of patients who take it for latent TB infection.21, 22 Persons should be screened for symptoms of hepatitis every month while taking isoniazid, and only a 1-month supply of the drug should be dispensed at a time. Persons at risk for hepatotoxicity (e.g. HIV, viral hepatitis, alcohol use) should have transaminases drawn prior to starting isoniazid and monthly thereafter until completion of therapy (see Case Study 2).

Those who are allergic or intolerant of isoniazid may be offered rifampin 10 mg/kg daily (maximum 600 mg) for four months. This regimen is much more expensive than isoniazid, and rifampin interacts with many other medications, particularly antiretrovirals. A two-month regimen of rifampin plus pyrazinamide was formerly recommended, but cases of severe hepatotoxicity and death were associated with this regimen.23 This regimen is considerably more toxic than nine months of isoniazid and is now generally not recommended for use.24 Adherence to the nine-month regimen is generally not very good. A large study of a shorter, once weekly combination of isoniazid and rifapentine is ongoing, and hopefully will provide an alternative to the current nine-month regimen.

In this case, the nurse was tested for HIV infection and was seronegative. He started on daily isoniazid which he took for nine months with only mild elevation in ALT and AST.

Case Study 2. Intolerance of TB medications.
A 25 year-old, HIV-negative woman was placed on 4-drug therapy (isoniazid, rifampin, pyrazinamide, and ethambutol) for culture-confirmed, extensive pulmonary tuberculosis. Three weeks after initiation of therapy, she presented to sick call complaining of a diffuse rash, fever, and fatigue. Laboratory studies were significant for aspartate aminotransferase (AST) of 423 (normal 0-40), alanine aminotransferase (ALT) 652 (normal 0-40), alkaline phosphatase 135 (normal 0-150), and total bilirubin 2.2 (normal 0-1.3). She was on no other medications and denied use of over-the-counter medications available at the facility canteen, herbal remedies, alcohol, or illicit drugs. How should she be managed at this point?

Discussion
Intolerance of drugs used to treat TB is a common problem. In addition to frequent gastrointestinal symptoms, three of the four first-line TB drugs (isoniazid, rifampin, and pyrazinamide) are potentially hepatotoxic. Hepatotoxicity associated with TB drugs is idiosyncratic, often not associated with drug dosage, and may have severe consequences as illustrated in this case.

The general principles of dealing with hepatotoxicity from TB medications are listed below:

• Mild increases in transaminases are common and often of no clinical significance. TB therapy should be stopped in the following cases:
  • ALT>3x the upper limit of normal and patient has symptoms of hepatitis OR
  • ALT>5x the upper limit of normal and patient is asymptomatic
• Elevated bilirubin in the setting of elevated transaminases is a marker of more severe hepatotoxicity and should prompt immediate discontinuation of TB drugs and close monitoring.
• If TB disease is mild, therapy may be held until ALT<2x the upper limit of normal. For patients with extensive or severe TB, switch to treatment with a non-hepatotoxic regimen (e.g. streptomycin + ethambutol + moxifloxacin) while ALT improves.
• Once symptoms resolve and ALT<2x the upper limit of normal, sequentially reintroduce TB drugs with close clinical and laboratory monitoring. One protocol adds back drugs 1 week apart, in the order ethambutol, rifampin, isoniazid, and pyrazinamide (order of lesser to greater potential for hepatotoxicity). In the case of severe hepatotoxicity, pyrazinamide may be omitted and the regimen extended to at least 9 months if isoniazid and rifampin are tolerated.
• Consult a TB expert if the patient cannot be treated with standard first-line therapy. Clinicians should not "make up" treatment regimens for drug intolerant patients.
• It is impossible to reliably predict which drug caused the hepatotoxicity; using a standard reintroduction protocol is essential.
• Monitoring for side effects of TB drugs should be performed no less often than monthly for patients being treated for either latent or active TB. Laboratory testing to screen for hepatotoxicity should be performed monthly only in patients at risk of hepatotoxicity (concurrent hepatotoxic drugs, chronic hepatitis, alcohol use, pregnancy, HIV).
• For patients with baseline elevated transaminases or cirrhosis, careful monitoring and expert consultation are essential. In the case of LTBI, the risks and benefits of LTBI treatment should be carefully considered prior to initiating treatment. Patients with TB disease may require alteration of the treatment regimen in concert with a TB expert.

In the above case, isoniazid, rifampin, and pyrazinamide were discontinued, and she was treated with daily ethambutol, moxifloxacin, and intramuscular streptomycin. Once the rash resolved and transaminases improved, drugs were sequentially reintroduced a week apart. The rash returned with addition of isoniazid, and the patient was successfully treated with six months of daily rifampin, pyrazinamide, and ethambutol.

References:
19 Horsburgh CR, Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med. 2004; 350(20):2060-7.
20 Pape JW, Jean SS, Ho JL, et al. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet. 1993; 342(8866):268-72.
21 Kopanoff DE, Snider DE, Jr., Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis. 1978; 117(6):991-1001.
22 Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA. 1999; 281(11):1014-18.
23 Stout JE. Safety of rifampin and pyrazinamide for the treatment of latent tuberculosis infection. Expert Opin Drug Saf. 2004; 3(3):187-98.
24 CDC. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR. 2003; 52(31):735-9.

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