Latent Tuberculosis Infection: A Guide for Primary Health Care Providers

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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 3).

TABLE 3: Treatment Regimens

Drug/Dose	Frequency/Duration (Doses)	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 (270 doses)	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§ (76 doses)	B (II)	B (II)
Isoniazid Adults: 5 mg/kg Children: Not recommended Maximum dose 300 mg	Daily x 6 months (180 doses)	B (I)	C (I)
Isoniazid Adults: 15 mg/kg Children: Not recommended Maximum dose 900 mg	Twice weekly x 6 months§ (52 doses)	B (II)	C (I)
Rifampin Adults: 10 mg/kg Children: 10-20 mg/kg Maximum dose 600 mg	Daily x 4 months (120 doses) Daily x 6 months (180 doses)	B (II)	B (III)

Note: 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; III = expert opinion
§  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 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 guidelines below should be followed. Those who have negative results should be retested in 8–10 weeks. 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 contacts at very high risk 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) for 9 months preferred
• If person is exposed to known isoniazid-resistant TB:
  • Positive TST or IGRA result → treat for 4 months with rifampin (RIF)
• If person is exposed to known multidrug-resistant TB (MDR TB):
  • Positive TST or IGRA result → Consult an expert in the treatment of multidrug-resistant 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 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 guidelines for the use of rifamycins and protease inhibitors or nonnucleoside reverse transcriptase inhibitors).
• If TB test result is negative, treat 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.
• 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 (see below).
• 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 or a positive IGRA result 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. The decision to treat for LTBI would be the same as for a person with a normal chest radiograph.

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 isoniazid (INH). 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 RIF, 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 to 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 about 0.1% 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 beforehand. 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. Women using oral contraceptives should be advised to consider an alternative method of contraception.
• 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 health care provider should periodically assess the patient’s progress. This evaluation involves the following:

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 health care provider 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 health care provider.

Laboratory Testing

• Baseline laboratory testing (measurements of serum AST, ALT, and bilirubin) are 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 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.

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 Variables

• Misinformation about topics such as
  • The TST; 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”
  • 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
• Culture and language
• Religious practices i.e., fasting from food

Treatment Variables

• 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, young child, 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
  • Cell phone minutes
  • 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

Post-Treatment Follow-Up

• Patient should receive documentation of TST or IGRA results and treatment completion that includes name, dates, chest radiograph result, 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.
• 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.