Latent Tuberculosis Infection: A Guide for Primary Health Care Providers
Treatment of Latent TB Infection
There are four treatment regimens available for the treatment of latent TB infection (LTBI) (see Table 2). Providers should choose the appropriate regimen based on the following:
- Drug-susceptibility results of the presumed source case (if known)
- Coexisting medical conditions
- Potential for drug-drug interactions
While all the regimens are effective, health care providers should prescribe shorter regimens when possible. Patients are more likely to complete shorter treatment regimens.
For persons who are at especially high risk for TB disease and are either suspected of nonadherence or are given an intermittent dosing regimen, directly observed therapy (DOT) for LTBI treatment should be considered.
12-Dose (Isoniazid [INH] and Rifapentine [RPT]) Regimen
The 12-dose regimen is a combination of INH and RPT given in 12 once-a-week doses. Some people refer to the 12-dose regimen of INH and RPT as “3HP.” The 12-dose regimen of INH and RPT can be given under directly observed therapy (DOT) or self-administered therapy (SAT). Health care providers should choose the mode of administration (DOT or SAT) based on local practice, individual patient attributes and preferences, and other considerations including risk of progression to severe forms of TB disease.
The 12-dose regimen of INH and RPT is recommended for people 2 years of age or older, including people with HIV/AIDS who are taking antiretroviral medications that have acceptable drug-drug interactions with RPT, such as efavirenz and raltegravir.
The 12-dose regimen of INH and RPT is NOT recommended for the following individuals:
- Children younger than 2 years of age
- People with HIV/AIDS who are taking antiretroviral medications with clinically significant or unknown drug interactions with RPT*
- People presumed to be infected with INH or rifampin (RIF)-resistant M. tuberculosis
- Pregnant women, or women expecting to become pregnant during the 12-week regimen
Rifampin (RIF) Regimen
A 4-month regimen of RIF is another treatment option, especially for persons who cannot tolerate INH or who have been exposed to INH-resistant TB. LTBI treatment with RIF should be given daily for 4 months. RIF should not be used to treat HIV-infected persons taking some combinations of ART*. In situations where RIF cannot be used, sometimes another drug, rifabutin, may be substituted.
* Information about drug-drug interactions between specific anti-mycobacterial agents including rifamycins (rifampin, rifabutin, and rifapentine) and antiretroviral agents is available at Department of Health and Human Services, Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescentsexternal iconexternal icon.
Isoniazid (INH) Regimen
There are two options for treatment with INH:
- 9-month regimen
- 6-month regimen
If an INH regimen is used, the 9-month regimen is preferred because it is more efficacious. Treatment of LTBI for 6 months rather than 9 months may be more cost-effective and result in greater adherence by patients; therefore, health care providers may prefer to implement the 6-month regimen rather than the 9-month regimen. Every effort should be made to ensure that patients adhere to LTBI treatment for at least 6 months. The 6-month regimen is not recommended for people with HIV/AIDS, children, or people with chest x-ray findings suggestive of previous TB disease.
*INH is formulated as 100 mg and 300 mg tablets.
†RPT is formulated as 150 mg tablets in blister packs that should be kept sealed until use.
‡Intermittent INH regimens must be provided via directly observed therapy (DOT), that is, a health care worker observes the ingestion of medication. DOT or self-administered therapy (SAT) may be used for the 12-dose regimen of INH and RPT.
§Rifampin (rifampicin; RIF) is formulated as 150 mg and 300 mg capsules.
‖The American Academy of Pediatrics acknowledges that some experts use RIF at 20–30 mg/kg for the daily regimen when prescribing for infants and toddlers (American Academy of Pediatrics. Tuberculosis. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. />31st ed. Itasca, IL: American Academy of Pediatrics; 2018:829–853).
¶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.
Contacts are people who have been exposed to a person with known or suspected infectious TB (e.g., pulmonary or laryngeal TB with a positive sputum smear). Contacts should be evaluated immediately for LTBI and TB disease. If their tuberculin skin test (TST) or interferon-gamma release assay (IGRA) result is positive, and TB disease is excluded, they should be considered high priority for LTBI treatment (see the guidance below). Contacts who have negative test results should be retested 8 to10 weeks after their last exposure to infectious TB. This is because it can take 2 to 8 weeks after being infected with M. tuberculosis for the body’s immune system to mount a response detectable by the tests.
Sometimes LTBI treatment is given to people who are at high risk for rapidly developing TB disease even if they have a negative TST or IGRA result and less than 8 to 10 weeks have passed since they were last exposed to TB. This includes children younger than 5 years of age (note: some TB control programs may use a different age cutoff) and immunocompromised persons of all ages. Treatment should be continued until the results of the second test and other medical evaluation are known. For some high-risk contacts, such as people with HIV/AIDS, 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 with the 12-dose regimen of INH and RPT for individuals 2 years of age or older, or with INH or RIF regardless of age
- If person is exposed to known INH-resistant TB:
- Positive TST or IGRA result → Treat with RIF for 4 months
- If person is exposed to known RIF-resistant TB:
- Positive TST or IGRA result → Treat with INH alone
- 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 re-infected and progressing to TB disease (e.g., young children and immunosuppressed persons).
People with HIV/AIDS
- LTBI treatment for people with HIV/AIDS should be provided in consultation with an expert in the management of HIV and TB coinfection.
- The 12-dose regimen of INH and RPT is recommended for people with HIV/AIDS who are taking antiretroviral medications that have acceptable drug-drug interactions with RPT, such as efavirenz and raltegravir. The 12-dose regimen of INH and RPT is NOT recommended for people with HIV/AIDS who are taking antiretroviral medications with clinically significant or unknown drug interactions with RPT.
- The 9-month regimen of INH is another treatment option for people with HIV/AIDS.
- The 6-month regimen of INH is not recommended for people with HIV/AIDS.
- Rifampin (RIF) is contraindicated in people with HIV/AIDS who are being treated with certain combinations of antiretroviral drugs. In those cases, rifabutin may be substituted for RIF.
- If the test for TB infection is negative, consider LTBI treatment if the person has had recent exposure to infectious TB, as discussed above.
- After TB disease is excluded, consider immediate treatment for LTBI if the woman is 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) for 9 months is the preferred treatment regimen.
- Supplementation with 10-25 mg/d of pyridoxine (vitamin B6) is recommended.
- The 12-dose regimen of INH and RPT 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., recent contact).
- Breastfeeding is not contraindicated in women taking INH or RIF.
- Supplementation with 10-25 mg/d of pyridoxine (vitamin B6) is recommended for nursing women and for breastfed infants.
- The amount of INH or RIF in breast milk is inadequate for treatment of infants with LTBI.
- RIF can cause orange discoloration of body fluids, including breast milk.
Infants and Children
- Because of their young age, infants and young children with LTBI are known to have been recently infected and, therefore, are at high risk for progressing to disease.
- Testing adults who have been 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 12-dose regimen of INH and RPT is recommended for children 2 years of age or older. Alternative LTBI treatment regimens include 4 months of daily RIF and 9 months of daily INH.
- The 6-month regimen of INH is not recommended for children.
- DOT should be considered for children of all ages.
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.
- Treatment must be modified if the patient is a contact of an individual with drug-resistant TB disease. Consult a TB expert if the known source of TB infection has drug-resistant TB.
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.
- Cutaneous reactions, such as pruritis (with or without a rash), may occur in some 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, such as breast milk, 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 medications that have clinically significant or unknown drug interactions with RPT.
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.
- All patients receiving LTBI treatment should be evaluated at least monthly for the following:
- Adherence to the prescribed regimen
- Signs and symptoms of TB disease
- Adverse reactions (such as hepatitis)
- Patients being treated for LTBI who experience possible adverse reactions should be advised to stop medication and consult their health care provider immediately.
- 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:
- Unexplained anorexia
- Brown urine (color of coffee or cola)
- 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
- Discuss management of common side effects and the need to report to health care provider.
- Baseline laboratory testing (measurements of serum AST, ALT, and bilirubin) is not routinely indicated for all patients at the start of LTBI treatment.
- 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, brown 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.
Many variables affect a patient’s adherence to LTBI treatment. Using shorter treatment regimens can help patients complete treatment. Therefore, healthcare providers should prescribe the more convenient shorter regimens, when possible.
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.
- Long waiting time for appointment and referrals
- Long waiting time in provider’s office
- Inconvenient office hours
- Complicated telephone system (not “user-friendly”)
- Misinformation or confusion about certain issues such as
- The meaning of test results
- 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 TB
- Co-existing medical conditions
- Culture and language
- Religious practices (e.g., fasting from food)
- Complexity and duration of treatment
- Medication side effects
- Obtaining refills
- Frequency of office visits
- Cost, including insurance co-payment
- Collaborate with the local health department to provide treatment.
- DOT, 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
- 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.
- Patients should receive documentation that includes TST or IGRA results, chest radiograph results, names and dosages of medication and duration of treatment. Patients should be instructed to present this document any time future TB testing is required.
- Providers should re-educate patients about the signs and symptoms of TB disease and advise them to contact their medical provider if he or she develops any of these signs or symptoms.
- Serial or repeat chest radiographs are not indicated unless the patient develops signs or symptoms suggestive of TB disease.