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U.S. Department of Health and Human Services

  

Guide for Primary Health Care Providers: Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection
2005

Treatment of Latent TB Infection

Treatment Regimens
Using an adaptation of the U.S. Public Health Service (USPHS) rating system, CDC and ATS have rated LTBI treatment regimens based on the strength of recommendation and the quality of the evidence that supports that recommendation (see Table 4).

TABLE 4: Treatment Regimens

Drug/Dose Frequency/
Duration
Rating*(Evidence)
HIV negative
HIV positive
Preferred Regimen
Isoniazid
Adult: 5 mg/kg
Children: 10-20 mg/kg
Maximum dose 300 mg
Daily x 9 months A (II) A (II)
Alternate Regimens
Isoniazid
Adult: 15 mg/kg
Children: 20-40 mg/kg
Maximum dose 900 mg
Twice weekly x 9 months§ B (II) B (II)
Isoniazid
Adults: 5 mg/kg
Maximum dose 300 mg
Daily x 6 months B (I) C (I)
Isoniazid
Adults: 15 mg/kg
Maximum dose 900 mg
Twice weekly x 6 months§ B (II) C (I)
Rifampin
Adults: 10 mg/kg
Children: 10-20 mg/kg
Maximum dose 600 mg
Daily x 4 months B (II) B (II)
Note:
A regimen of rifampin and pyrazinamide for the treatment of LTBI should generally not be offered due to risk of severe adverse events.

In situations in which rifampin cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted.

* Strength of the recommendation: A = preferred regimen; B = acceptable alternative; C = offer when A and B cannot be given

† Quality of the supporting evidence: I = randomized clinical trials data; II = data from clinical trials not randomized or from other population

§ Intermittent regimen must be provided via directly observed therapy (DOT), i.e., health care worker observes the ingestion of medication

Special Considerations in the Treatment of LTBI

Contacts
Contacts are those with recent, prolonged exposure to a person with known or suspected infectious TB (i.e., pulmonary or laryngeal TB with positive sputum smear). They should be evaluated immediately for TB disease and LTBI. If the TST is positive, the guidelines below should be followed. Those who have negative TST reactions should be retested in 8–10 weeks. However, treatment should be initiated in TST-negative children 5 years of age (note: some TB control programs may use a different age cutoff) and in immunocompromised persons of all ages; this should be continued until the results of the second test and other medical evaluation are known. This treatment is known as “window prophylaxis” and accounts for the time period immediately after exposure when a TST may remain negative.

  • If person is exposed to known drug-susceptible TB or drug susceptibility is unknown:
    • Positive TST result → treat regardless of age with isoniazid (INH) for 9 months preferred
    • Negative TST result → retest in 8 –10 weeks
  • If person is exposed to known isoniazid-resistant TB:
    • Positive TST result → treat for 4 months with rifampin (RIF)
    • Negative TST result → retest in 8–10 weeks
  • If person is exposed to known multidrug-resistant TB (MDR TB):
    • Positive TST result → An expert in the treatment of multidrug-resistant TB should be consulted.  
    • Negative TST result → retest in 8–10 weeks
  • In general, TST-positive contacts with a documented history of prior adequate treatment for LTBI do not need to be re-treated. Re-treatment may be indicated for persons at high risk of becoming re-infected and progressing to TB disease (e.g., immunocompromised persons)

HIV-infected Individuals

  • HIV-infected individuals should be treated with a 9-month regimen of INH.
  • Rifampin (RIF) is contraindicated in HIV-infected persons being treated with certain combinations of antiretroviral drugs. In those cases, rifabutin may be substituted for RIF (see CDC website at http://www.cdc.gov/tb for guidelines for the use of rifamycins and protease inhibitors or nonnucleoside reverse transcriptase inhibitors).
  • If TST result is negative, treat if person has recent, prolonged exposure to infectious TB or if there is ongoing risk for exposure.

Pregnancy

  • Consider immediate treatment for LTBI if the woman is HIV-infected or recent contact, and monitor
  • In the absence of risk factors, wait until after the woman has delivered to avoid administering unnecessary medication during pregnancy
  • INH daily or twice weekly (using DOT) is preferred regimen
  • Supplementation with 50 mg of pyridoxine (vitamin B6) is recommended

Breastfeeding

  • Breastfeeding is not contraindicated in women taking INH
  • Supplementation with 50 mg of pyridoxine (vitamin B6) is recommended for nursing women and for breastfed infants
  • Amount of INH in breast milk is inadequate for treatment of infants exposed to TB

Infants and Children

  • Infants and children under 5 years of age with LTBI have been recently infected and, therefore, are at high risk for progression to disease
  • Risk of INH-related hepatitis in infants, children, and adolescents is minimal
  • Routine monitoring of serum liver enzymes is not necessary
  • DOT should be considered

Additional Notes of Importance

  • Old fibrotic lesions can represent previous TB disease. Persons with TST result of ≥ 5 mm of induration and no active disease should be treated for LTBI.
  • Calcified solitary pulmonary nodules, calcified hilar lymph nodes, and apical pleural capping represent healed primary M. tuberculosis infection and do not increase the risk of TB disease. Persons should not receive treatment unless other risk factors are present.

Adverse Effects of Drugs Used to Treat LTBI

Many health care providers have concerns about treating patients for LTBI. These concerns are generally related to the length of treatment and the potential side effects of isoniazid (INH). As with any treatment, the physician must weigh the risks and benefits for each individual. Obtaining a detailed and accurate medical history and updating information at frequent intervals will detect persons who require close monitoring and aid the physician in determining the most appropriate course of action.  In addition, CDC guidelines, drug package inserts, and other authoritative medical sources should be consulted whenever there is a question about side effects or drug-drug interactions.

The sections that follow discuss some of the adverse effects of isoniazid and rifampin, as well as recommendations for monitoring during treatment and for assessing and ensuring adherence.

Possible adverse effects of INH

  • Asymptomatic elevation of serum liver enzyme concentrations occurs in 10%–20% of people taking INH. Increased enzyme concentrations can be accepted at up 5 times the upper limit of normal for patients who are free of hepatitis symptoms, if the serum bilirubin concentration is in the normal range. Liver enzyme concentrations usually return to normal even when treatment is continued.
  • Clinical hepatitis occurs in 0.1% to 0.15% of people taking INH, and is more common when INH is combined with other agents. Factors that may increase either these rates or the severity of hepatitis include alcohol consumption, underlying liver disease or risks for liver disease, and the concurrent use of other medications which are metabolized in the liver. Symptomatic hepatitis is rare in patients younger than 20 years of age, but severe and fatal cases have been reported, and younger patients should be monitored clinically with the same precautions as older patients.
  • Peripheral neuropathy occurs in less than 0.2% of people taking INH at conventional doses, and is more likely in the presence of other conditions associated with neuropathy such as diabetes, HIV, renal failure, and alcoholism. Pyridoxine (vitamin B6) supplementation is recommended in such conditions or to prevent neuropathy in pregnant or breastfeeding women.

Possible adverse effects of rifampin (RIF)

  • Hepatotoxicity, evidenced by transient asymptomatic hyperbilirubinemia, may occur in 0.6% of persons taking RIF. Hepatitis is more likely when RIF is combined with INH.
  • Cutaneous reactions, such as pruritis (with or without a rash), may occur in 6% of persons taking RIF. It is generally self-limited and may not be a true hypersensitivity; continued treatment may be possible.
  • Gastrointestinal symptoms such as nausea, anorexia, and abdominal pain are rarely severe enough to discontinue treatment.
  • Orange discoloration of body fluids is expected and harmless, but patients should be advised. Soft contact lenses may be permanently stained.
  • RIF interacts with a number of drugs, causing drug-drug interactions. It is known to reduce concentrations of methadone, warfarin, oral contraceptives, and phenytoin.
  • RIF is contraindicated, or should be used with caution, in HIV-infected individuals being treated with certain protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). In this situation, rifabutin may be substituted.

Patient Monitoring and Education During Treatment

To ensure safe and efficacious treatment for LTBI, the provider should periodically assess the patient’s progress. This evaluation involves the following:

Laboratory Testing

  • Baseline laboratory testing (measurements of serum AST, ALT, and bilirubin) at the start of LTBI therapy is recommended for patients with any of the following factors:
    • Liver disorders
    • History of liver disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis)
    • Regular use of alcohol
    • Risks for chronic liver disease
    • HIV infection
    • Pregnancy or the immediate postpartum period (i.e., within 3 months of delivery)
  • Baseline testing can be considered on an individual basis, especially for patients taking other medications for chronic medical conditions.
  • After baseline testing, routine periodic retesting is recommended for persons who had abnormal initial results and other persons at risk for hepatic disease.
  • At any time during treatment, whether or not baseline tests were done, laboratory testing is recommended for patients who have symptoms suggestive of hepatitis (e.g., fatigue, weakness, malaise, anorexia, nausea, vomiting, abdominal pain, pale stools, dark urine, chills) or who have signs of jaundice. Patients should be instructed, at the start of treatment and at each monthly visit, to stop taking treatment and to seek medical attention immediately if symptoms of hepatitis develop and not to wait until a clinic visit to stop treatment.
  • AST or ALT elevations up to 5 times normal can be accepted if the patient is free of hepatitis symptoms, and up to 3 times normal if there are signs or symptoms of liver toxicity.

Clinical Monitoring

  • Patients should visit the health care provider who is managing treatment on a monthly basis for
    • Brief physical assessment for signs of hepatitis
    • Assessment of adherence
    • Review of symptoms of possible adverse drug reactions or interactions
  • Patients taking INH or RIF who experience possible adverse reactions should be advised to stop medication and consult their physician immediately

Patient Education

  • Explain the disease process and rationale for medication in absence of symptoms or radiographic abnormalities
  • Review the importance of completing treatment for LTBI
  • Discuss possible side effects of LTBI medications such as
    • Fever
    • Unexplained anorexia
    • Dark urine (color of coffee or cola)
    • Icterus
    • Rash
    • Persistent paresthesia of hands and feet
    • Persistent fatigue or weakness lasting 3 or more days
    • Abdominal tenderness, especially in right upper quadrant
    • Easy bruising or bleeding
    • Arthralgia
    • Nausea
    • Vomiting
  • Discuss management of common side effects and the need to report to physician

Assessing Adherence

Many variables affect a patient’s adherence to the medication regimen for treatment of LTBI. Episodes of nonadherence should be detected and addressed as soon as possible. Some examples of barriers to adherence are noted in the section that follows.

Office-Related Variables

  • Long waiting time for appointment and referrals
  • Long waiting time in provider’s office
  • Inconvenient office hours
  • Complicated telephone system (not “user-friendly”)

Patient-Related Variables

  • Misinformation about topics such as
    • The TST; for example, a positive TST result thought to be normal or common in all foreign-born persons
    • Differences between injections, vaccines, and TST 
    • The words “positive” and “negative”
    • Transmission and prevention
    • Safety of family and friends around someone with LTBI
  • Residential instability
  • Lack of financial resources
  • Poor access to health care
  • Stigma associated with tuberculosis
  • Co-existing medical conditions

Treatment Variables

  • Visits for administering, reading, and counseling between TST and QFT
  • Complexity and duration of treatment
  • Medication side effects
  • Obtaining refills
  • Frequency of office visits

Techniques to Improve Adherence

  • Collaborate with local health department to provide
    • DOT, especially if intermittent therapy is desirable or if patient is high risk (e.g., HIV infected or TB contact)
    • Case management to coordinate care and services
    • Free or low-cost medication
    • Incentives (rewards for adherence)
      • Grocery store or restaurant vouchers
      • Nutritional supplements
      • Movie tickets
    • Enablers (to overcome barriers)
      • Free van transportation or bus tickets
      • Effective patient education
  • Provide patient education and instructions in patient’s primary language
  • Reinforce patient education at each visit
  • Ensure confidentiality
  • Suggest or provide patient reminders such as pill box, calendar, timer

Posttreatment Follow-Up

  • Patient should receive documentation of TST or QFT results and treatment completion that includes name, dates, chest radiograph, and dosage and duration of medication. The patient should be instructed that he or she should present this document any time future testing is required.
  • Patient should be re-educated about the signs and symptoms of TB disease and told to contact his or her medical provider if he or she develops any of these signs or symptoms.
  • Regardless of whether the patient completes treatment for LTBI, serial or repeat chest radiographs are not indicated unless the patient develops signs or symptoms suggestive of TB disease.

 


Released October 2008
Centers for Disease Control and Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of Tuberculosis Elimination - http://www.cdc.gov/tb

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