Tuberculosis Series: Treatment

After a diagnosis of tuberculosis, either latent or active, has been made, a provider must assume the responsibility of ensuring that patient receives the appropriate antibiotic regimen, as well as the necessary follow up to ensure the patient is taking the antibiotics as prescribed. The patient will need to take multiple oral antibiotics for a year, and medication adherence is required to ensure elimination of the infection.

Reasons for treating latent tuberculosis infection mainly center around the risk a person has of experience tuberculosis disease and subsequently infecting other people. Per CDC guidelines, people who are high risk include:

• People with a positive TB blood test
• People with a tuberculin skin test reaction >/= 5 mm AND:
  • HIV +
  • Had recent contact with someone who has active TB disease
  • Visible fibrotic changes on CXR (+ old TB)
  • Recipients of organ transplants
  • Anyone immunosuppressed
• People with a tuberculin skin test reaction >/= 10 mm AND:
  • From, or spent long periods of time in, a country where TB is common
  • IV drug users
  • Live or work in high risk environment (incarcerated, homeless shelters, nursing homes, hospitals, mycobacteriology lab personnel)
  • Is a child under the age of 4, or <18 and exposed to high risk adults

Drug Regimens

Some of the medication regimens must be performed under Directly Observed Therapy (DOT). Notice, rifampin and pyrazinamide are not combined in the treatment of latent TB due to risk of severe liver injury and death.

Treatment regimens consist of oral antibiotics that include a 3 month isoniazid and rifapentine regimen (known as 3HP), a 4 month rifampin regimen, or 6-9 months of isoniazid. The most preferred Latent Tuberculosis Infection (LBTI) drug regimen is the 4 month, daily rifampin approach because it only involves one medication and is therefore less likely to cause as many side effects. Only in situations where a patient is concurrently taking medications that interact with rifampin would an alternative drug therapy be used.

Current drug regimen for treatment of Latent TB Infection per the CDC

A common treatment regimen for LTBI is that of 3HP, a once weekly isoniazid-rifapentine for 12 weeks. This regimen was initially recommended for all adults who were not HIV+, but was recently updated to include more groups. Of note, this regimen is not recommended for women who are planning on or are currently pregnant. Additionally, because it involves two medications a patient may experience more side effects. Updated guidelines now include the following groups:

• Ages 2 and up
• +HIV/AIDS infection as long as they are being actively treated and using antiretroviral medications that have acceptable interactions with rifapentine
• Will be amenable to Direct Observation Therapy (DOT) or self-administered therapy in persons older than 2. The health care provider should decide which method is preferred based on patient knowledge.

Treatment of TB Disease

TB Disease occurs when Mycobacterium tuberculosis bacteria begin replicating in a person’s body and their immune system is unable to respond effectively. A person typically has a LTBI for many years, then undergoes a change in health resulting in an immunocompromised state. The weakened immune system is then unable to keep the TB bacteria dormant within the body and the bacteria begin to replicate.

TB disease is also treated with multiple antibiotic regimens that must be completed in full and taken on schedule. First line agents include the same RIF and INH drugs that are used in LTBI, in addition to pyrazinamide (PZA) and ethambutol (EMB). These four antibiotics used in various regimens to treat TB are collectively known as “RIPE.” The difference in treatment regimens from LTBI to TB disease involves a continuation phase beyond an initial treatment period. The continuation period can span anywhere from 4 to 7 months depending on treatment regimen chosen. A longer continuation phase, ie 7 months, is targeted for patients with more advanced TB disease, risk factors, or in some patients whose sputum culture remains TB+ during treatment.

Drug Susceptible TB Disease

• Regimen 1, first line for patients with newly diagnosed pulmonary TB
  • First INH+RIF+PZA+EMB used for 7 days a week for 8 weeks, or 5 days a week for 8 weeks.
  • Then INH+RIF used for 7 days a week for 18 weeks, or 5 days a week for 18 weeks.
• Regimen 2, used alternatively to regimen 1, preferred for situations in which direct observational treatment is not always possible.
  • First INH+RIF+PZA+EMB used for 7 days a week for 8 weeks, or 5 days a week for 8 weeks.
  • Then INH+RIF used 3 times weekly for 18 weeks.
• Regimen 3, not commonly used and not preferred for patients with HIV or more advanced TB disease. Missing a dose may lead to treatment failure or disease resistance and relapse.
  • First INH+RIF+PZA+EMB used for 3 times weekly for 8 weeks.
  • Then INH+RIF used 3 times weekly for 18 weeks.
• Regimen 4, not to be used in patients who are HIV+ or patients who have TB bacteria present on smear and/or advanced disease. Doses cannot be missed.
  • First INH+RIF+PZA+EMB used for 7 days a week for 2 weeks, then twice weekly for 6 weeks.
  • Then INH+RIF used 3 times weekly for 18 weeks.

(Treatment for TB Disease - CDC)

Treatment Resistant Tuberculosis

There are several types of drug resistant TB strains that can be found in the world. These bacteria are not responsive to one of the first line RIPE drugs.

Multidrug resistant TB (MDR TB) – bacteria resistant to at least 2 RIPE antibiotics, and of the two at least one must be INH or RIF.

Extensively drug resistant TB (XDR TB) – bacteria resistant to both INH and RIF, as well as any fluoroquinolone, and resistant to at least one of the following second line antibiotics: amikacin, capreomycin, kanamycin.

Treatment of LTBI in Pediatric Patients

Children, especially those who are very young, are by default considered immunocompromised in comparison to adults. Therefore, children are at an increased risk of developing TB disease after initial infection of the Mycobacterium. Treatment is recommended for all children who test positive for a LTBI. A child should also receive LTBI treatment if they are living in close proximity to an adult with known active TB disease.

Treatment for Latent TB Infection in Children

Treatment of TB Disease in Children

TB disease in children is treated with several of the RIPE antibiotics taken for 6 to 9 months. Follow up is very important in child cases of TB disease, as it is with all cases of anti-TB medication regimens, but if a child misses doses before medication completion the child can quickly return to an ill state.

HIV Coinfection with TB

The most important step, besides completion of treatment, in the approach to HIV coinfection with TB is diagnosing the coinfection of TB. All patients with a new HIV diagnosis should be screened for TB and TB disease, as well as any patients with a history of HIV experiencing a new onset of immunocompromised state. It should be noted that patients who are HIV+ can have erroneous TB skin test results, and for this reason a TB blood test is recommended. For patients who are not receiving antiretroviral therapy (ART) at TB diagnosis, ART should be initiated in addition to anti-TB medications. One exception to this approach is in the case of patients experiencing TB meningitis, in which case ART should be prescribed starting after the first 8 weeks of anti-TB treatment.

TB Treatment in Pregnant Women

What sort of monitoring is needed during treatment?

For active cases of TB in the US, a designated TB clinic is assigned to the patient for the administration of DOT. Additionally, clinic professionals will seek out friends, family members, and coworkers of anyone diagnosed with active TB to evaluate the need for further screening, monitoring and treatment of LTBI. Patients who are diagnosed with a LTBI need to be managed by their primary care physician as most TB clinics do not have the capacity to manage LTBI.

The CDC recommends at minimum a monthly clinic visit during treatment to assess medication adherence and identify signs or symptoms of adverse drug reactions. Treatment should be stopped if the patient develops anorexia, nausea, vomiting, abdominal pain, dark urine, jaundice, rash, persistent fatigue, easy bruising, or paresthesia of the hands and feet. Patients should be advised to refrain from alcohol ingestion during treatment due to increased risk of hepatotoxicity.

• Hepatitis is the most important adverse effect of latent TB treatment. It usually occurs within the first three months of treatment, and people with advanced age or daily alcohol consumption are at greatest risk. Overall incidence of hepatotoxicity is 0.1% with isoniazid and 0.6% with rifampin. 
• Peripheral neuropathy is another known adverse effect of isoniazid. The incidence is under 0.2%, and those at highest risk are pregnant and breastfeeding women, diabetics, alcoholics, HIV patients, and patients with uremia. Pyridoxine supplementation should be provided to these high-risk groups.
• Cutaneous reactions occur in up to 6% of people taking rifampin. They are generally self-limited. Thrombocytopenia is a rare complication of rifampin therapy. 

Baseline laboratory testing and periodic laboratory monitoring are not routinely indicated during treatment of latent TB. Some exceptions to this warrant monitoring ALT, AST, and bilirubin, to be measured before and during the course of treatment. Those exceptions apply to the following groups:

• Patients with chronic liver disease (including active hepatitis B or C)
• Heavy drinkers of alcohol
• HIV infected patients
• Pregnant women
• Post-partum women for the first three months after delivery.

If hepatic transaminases exceed 3 times the upper limit of normal in asymptomatic patients, or 5 times the upper limit of normal in patients with symptoms, treatment should be withheld.

The CDC recommends these steps for patients not in a directly observed therapy regimen:

• Take medications at the same time each day
• Set a watch alarm as a reminder
• Organize weekly pills in a pill box
• Keep medications in an easy to view area
• Put notes around your house as memory triggers
• Ask a family member or friend to help remind you
• Check off days you have taken your medication on a calendar

Patient Resistance to LTBI Treatment

Instructing a patient who feels healthy to take 12 weeks or more of medication, even after a chest xray clears them of active lung infection, can be a very confusing notion to anyone newly diagnosed with LTBI. This is especially true for immigrant and refugee populations, as in most areas of the world patients receive the BCG vaccination early in childhood. This vaccine will result in positive PPD skin tests for up to 4 years after vaccination, rendering the use of this screening method obsolete. Additionally, the BCG vaccine is not 100% effective, and conversion to a positive PPD test due to TB exposure occurs at a rate of 2-3% per year. In most areas with high TB rates, the majority of the population is PPD positive by the age of 20. Therefore, the PPD skin test is not widely used in developing countries.

Another source of confusion centers around what is understood about TB as an infection vs a disease. In developing countries, a chest xray is performed if the diagnosis of a TB infection is considered. If the chest xray does not show cavitary lesions of an active infection, no medications are prescribed. If the xray does show abnormalities, including evidence of tuberculosis pulmonary disease, medication regimens are prescribed. In this setting, patients only take medications when they have active tuberculous pulmonary disease. Therefore, it is important to explain the treatment protocols for LTBI in the US.

To help the patient make sense the differences in approach, the provider needs to back up several steps and explain medical practices pertaining to TB in the United States vs developing countries. It may also be helpful to differentiate “tuberculosis infection” from “tuberculosis disease” or “illness in the lungs.” If a patient has tuberculosis infection, without evidence of disease in the lungs, we recommend that they take a single medicine for 4 months to prevent tuberculosis disease later in life. If they do have evidence of tuberculosis disease in the lungs on chest xray, then we recommend they take 3 – 4 medications for 6 – 9 months, and we would be concerned about the possibilities of them spreading the disease to other close contacts. Usually with this type of explanation, as well as the emphasis on the importance of the medication in preventing future disease, a patient is amenable to the prescriptions and schedule.

Other considerations must be taken into account when approaching the treatment of LTBI with patients who are not born in the US. Please see our Approach to Patients page for more information.

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