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Guide for Primary Health Care Providers: Targeted
Tuberculin Testing and Treatment of Latent Tuberculosis Infection
2005
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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 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.
Last Reviewed: 05/18/2008 Content Source: Division of Tuberculosis Elimination
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
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