Latent Tuberculosis Infection: A Guide for Primary Health Care Providers

†Intermittent regimens must be provided via directly observed therapy (DOT), i.e., health care worker observes the ingestion of medication.
*Isoniazid (INH) is formulated as 100 mg and 300 mg tablets. Rifapentine (RPT) is formulated as 150 mg tablets in blister packs that should be kept sealed until usage.
** The American Academy of Pediatrics recommends an INH dosage of 10-15 mg/kg for the daily regimen and 20-30 mg/kg for the twice weekly regimen.
***In the United States, the recommended regimen for treatment of LTBI in children is a 9-month course of INH. For the treatment of LTBI in infants, children, and adolescents when INH could not be tolerated or the child has had contact with a case patient infected with an isoniazid-resistant but rifamycin-susceptible organism the American Academy of Pediatrics recommends 6 months of daily rifampin (RIF) (180 doses) at a dosage of 10-20 mg/kg.

 

Special Considerations in the Treatment of LTBI

Contacts

Contacts are those with recent exposure to a person with known or suspected infectious TB (e.g., pulmonary or laryngeal TB with positive sputum smear). They should be evaluated immediately for LTBI and TB disease. If the TST or IGRA result is positive, the guidance below should be followed. Those who have negative results should be retested in 8–10 weeks after exposure has ended. However, if the chest radiograph is normal, LTBI 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 who have negative TST or IGRA results. Treatment should be continued until the results of the second test and other medical evaluation are known. For some high-risk contacts, a full course of LTBI treatment may be recommended even in the absence of a positive TST or IGRA result. Consult with your local TB control program about the management of such contacts.

• If person is exposed to known drug-susceptible TB or drug susceptibility is unknown:
  • Positive TST or IGRA result → Treat regardless of age with isoniazid (INH) or INH and RPT for those over 12 years of age

• If person is exposed to known isoniazid-resistant TB:
  • Positive TST or IGRA result → Treat with rifampin (RIF) for 4 months

• If person is exposed to known multidrug-resistant (MDR) TB:
  • Positive TST or IGRA result → Consult an expert in the treatment of MDR TB

• In general, TST or IGRA-positive contacts who can provide written documentation of prior adequate treatment for LTBI do not need to be retreated. Retreatment may be indicated for persons at high risk of becoming reinfected and progressing to TB disease (e.g., young children and immunosuppressed persons).

HIV-Infected Individuals

• HIV-infected individuals receiving ART 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.
• HIV-infected individuals who are otherwise healthy and are not taking ART can be considered for the 12-dose regimen.
• If the test for TB infection is negative, consider treatment if HIV-infected person had recent exposure to infectious TB, as discussed above.

Pregnancy

• After TB disease is excluded, consider immediate treatment for LTBI if the woman is HIV infected or a 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 the preferred regimen.
• Supplementation with 10-25 mg/d of pyridoxine (vitamin B6) is recommended.
• The 12-dose regimen is not recommended for pregnant women or women expecting to become pregnant during the treatment period.
• There is potential for an increased risk of hepatotoxicity during pregnancy and the first 2-3 months of the post-partum period.
• Consider delaying treatment for LTBI until 2-3 months post-partum unless there is a high risk of progression to TB disease (e.g., HIV infected, recent contact).

Breastfeeding

• Breastfeeding is not contraindicated in women taking INH.
• Supplementation with 10-25 mg/d of pyridoxine (vitamin B6) is recommended for nursing women and for breastfed infants.
• The amount of INH in breast milk is inadequate for treatment of infants with LTBI.

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.
• Testing of adults in close social contact with the child may be warranted to determine whether a person with infectious TB disease can be found. Consult with your local TB control program.
• Risk of INH-related hepatitis in infants, children, and adolescents is minimal.
• Routine monitoring of serum liver enzymes is not necessary unless the child has risk factors for hepatotoxicity.
• The preferred regimen for children aged 2 to 11 years is 9 months of daily INH.
• The 12-dose regimen is not recommended for children younger than 2 years of age.
• DOT should be considered for children of all ages, and is strongly recommended when the 12-dose regimen is used.

Additional Notes of Importance

• Old fibrotic lesions can represent previous TB disease. Persons with old fibrotic lesions with TST result of ≥5 mm of induration or a positive IGRA result and negative culture 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. The decision to treat for LTBI would be the same as for a person with a normal chest radiograph.
• The 12-dose regimen is not recommended for people presumed to be infected with INH or RIF-resistant M. tuberculosis.
• All doses of the 12-dose regimen should be given by DOT.

Adverse Effects of Drugs Used to Treat LTBI

Some 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 medications. As with any treatment, the health care provider must weigh the risks and benefits for each individual. Obtaining a detailed and accurate medical history, and updating information at frequent intervals, will identify persons who require close monitoring; this will aid the health care provider 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 INH and rifamycins, 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; and liver enzyme concentrations usually return to normal even when treatment is continued. It is generally recommended that INH be withheld if a patient’s transaminase level exceeds 3 times the upper limit of normal if associated with symptoms or 5 times the upper limit of normal if the patient is asymptomatic.
• Clinical hepatitis occurs in about 0.1% of people taking INH, and is more common when INH is combined with other hepatotoxic agents. Factors that may increase either of these rates or the severity of hepatitis include daily 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. Younger patients with underlying risk factors for liver disease 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. It 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 only in such conditions or to prevent neuropathy in pregnant or breastfeeding women.

Possible adverse effects of Rifampin (RIF) and Rifapentine (RPT)

• 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. They are generally self-limited and may not be a true hypersensitivity; continued treatment may be possible.
• Rarely, rifamycins can be associated with hypersensitivity reactions, including hypotension, nephritis or thrombocytopenia, and manifested by symptoms such as fever, headache, dizziness/lightheadedness, musculoskeletal pain, petechiae, and pruritis.
• 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 beforehand. Soft contact lenses and dentures may be permanently stained.
• RIF and RPT interact with a number of drugs, causing drug-drug interactions. They are known to reduce concentrations of methadone, warfarin, hormonal contraceptives, and phenytoin. Women using hormonal contraceptives should be advised to consider an alternative method of contraception (e.g., a barrier method).
• RIF is contraindicated, or should be used with caution, in HIV-infected individuals being treated with certain antiretroviral medications. Substitution of rifabutin for RIF in the 4-month regimen many be considered for such patients. RPT should not be used in HIV-infected persons taking antiretroviral therapy.

Patient Monitoring and Education During Treatment

To ensure safe and efficacious treatment for LTBI, the health care provider should periodically assess the patient’s progress. This evaluation involves clinical monitoring and laboratory testing, as well as patient education.

Clinical Monitoring

• Patients should visit the health care provider who is managing their treatment on a monthly basis to be assessed for the following:
  • Signs of hepatitis
  • Adherence to medication regimen
  • Symptoms of possible adverse drug reactions or interactions
• Patients being treated for LTBI who experience possible adverse reactions should be advised to stop medication and consult their health care provider immediately.

Patient Education

• Explain the disease process and rationale for medication in the absence of symptoms or radiographic abnormalities.
• Review the importance of completing treatment for LTBI.
• Discuss possible side effects of LTBI medications that may include:
  • 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 health care provider.

Laboratory Testing

• Baseline laboratory testing (measurements of serum AST, ALT, and bilirubin) is not routinely necessary.
• Laboratory testing 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 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 wait until the next clinic visit to stop treatment.
• It is generally recommended that medication be withheld if a patient’s transaminase level exceeds 3 times the upper limit of normal if associated with symptoms or 5 times the upper limit of normal if the patient is asymptomatic.

Assessing Adherence

Many variables affect a patient’s adherence to the medication regimen for treatment of LTBI. Episodes of nonadherence should be recognized 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 Barriers

• Misinformation or confusion about certain issues such as
  • The meaning of TST results, for example, a positive TST result is thought to be normal or common in all foreign-born persons
  • Differences between injections, vaccines, and TST
  • The words “positive” and “negative” as they relate to test results
  • Modes of TB transmission and prevention
  • Exposure vs. becoming infected
  • 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
• Culture and language
• Religious practices (e.g., fasting from food)

Treatment Barriers

• Complexity and duration of treatment
• Medication side effects
• Obtaining refills
• Frequency of office visits
• Cost, including insurance co-payment

Techniques to Improve Adherence

• Collaborate with local health department to provide treatment.
  • DOT, if patient is high risk (e.g., HIV infected, young child, or TB contact)
  • DOT should be provided with the 12-dose regimen or other intermittent regimens
  • Case management to coordinate care and services
  • Free or low-cost medication
  • Rewards for adherence (incentives) such as grocery store or restaurant vouchers, nutritional supplements, cell phone minutes, or movie tickets
  • Enablers to overcome barriers such as free van transportation or bus tickets
• Provide patient education and instructions in patient’s primary language at every visit.
• Ensure confidentiality.
• Suggest or provide patient reminders such as pill box, calendar, or timer.

Post-Treatment Follow-Up

• Patient should receive documentation that includes TST or IGRA results, chest radiograph results, names and dosages of medication and duration of treatment. The patient should be instructed to present this document any time future TB testing is required.
• Providers should re-educate patient about the signs and symptoms of TB disease and advise them to contact the 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.