# Presentation: 167385

## TREATMENT OF TUBERCULOSIS, 2003

**Division of Tuberculosis Elimination**
**Centers for Disease Control and Prevention**

*American Thoracic Society                   Centers for Disease Control and Prevention Infectious Diseases Society of America*

## Why a New TB Treatment Statement?

- Last TB treatment statement published in 1994
- Several new drugs available e.g., rifapentine, newer fluoroquinolones
- New research information on treatment regimens

## What’s New? (1)

- Provider/program responsibility for successful treatment, not the patient
- Patient-centered case management with emphasis on directly observed therapy (DOT)
- Evidence-based ratings of treatment options
- Role of two-month sputum cultures to identify patients at increased relapse risk

## What’s New? (2)

- Extend treatment for patients with drug-susceptible pulmonary TB at increased risk for relapse
- Role of new drugs (rifabutin, rifapentine, and  fluoroquinolones)
- Practical aspects of therapy: drug administration, fixed-dose combinations, adverse effects monitoring and management, and drug interactions

## What’s New? (3)

- Treatment completion defined primarily by number of doses ingested within specified time
- Description of special treatment situations:
- HIV/AIDS
- Children
- Extrapulmonary TB
- Culture-negative TB
- Pregnancy and breast feeding
- Hepatic and renal disease

## What’s New? (4)

- Updated guidelines for management of drug-resistant TB
- Recommendations compared with those of the World Health Organization (WHO) and the International Union Against TB and Lung Disease (IUATLD); WHO DOTS strategy described
- Current research status to improve treatment

## Fundamental Responsibility and Approach in TB Treatment

- Provider (or program) responsible for prescribing appropriate regimen AND ensuring successful completion of therapy
- Directly observed therapy (DOT) with patient-centered case management is preferred approach

## Isoniazid
Rifampin
Pyrazinamide
Ethambutol
Rifabutin*
Rifapentine

- Rifampin
- Pyrazinamide
- Ethambutol
- Rifabutin*
- Rifapentine

_**First-Line Drugs**_

_**Second-Line**__** **__**Drugs**_

**Antituberculosis Drugs**

- Streptomycin
- Cycloserine
- p-Aminosalicylic acid
- Ethionamide
- Amikacin or kanamycin*
- Capreomycin
- Levofloxacin*
- Moxifloxacin*
- Gatifloxacin*

*******	**Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

## Drug Abbreviations

- Ethambutol		EMB
- Isoniazid		INH
- Pyrazinamide	PZA
- Rifampin		RIF
- Rifapentine		RPT
- Streptomycin	SM

## Role of New Drugs (1)

**Rifabutin**:  For patients receiving medications having unacceptable interactions with rifampin (e.g., persons with HIV/AIDS)
**Rifapentine**:  Used in once-weekly continuation phase for HIV-negative adults with drug-susceptible noncavitary TB and negative AFB smears at completion of initial phase of treatment

## Role of New Drugs (2)

**Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin)**:  Used when
-     	-first-line drugs not tolerated;
- 	-strains resistant to RIF, INH, or EMB; or
- 	-evidence of other resistance patterns with fluoroquinolone susceptibility

## Factors Guiding Treatment Initiation 

- Epidemiologic information
- Clinical, pathological, chest x-ray findings
- Microscopic examination of acid-fast bacilli (AFB) in sputum smears
- Nucleic acid amplification test (when performed)

## When to Consider Treatment Initiation 

- Positive AFB smear
- Treatment should not be delayed because of negative AFB smears if high clinical suspicion:
- History of cough and weight loss
- Characteristic findings on chest x-ray
- Emmigration from a high-incidence country

## Baseline Diagnostic Examinations for TB

- Chest x-ray
- Sputum specimens (= 3 obtained 8-24 hours apart) for AFB microscopy and mycobacterial cultures
- Routine drug-susceptibility testing for INH, RIF, and EMB on initial positive culture

## Other Examinations to Conduct When TB Treatment Is Initiated (1)

- Counseling and testing for HIV infection
- CD4+ T-lymphocyte count for HIV-positive persons
- Hepatitis B and C serologic tests, if risks present

## Other Examinations to Conduct When TB Treatment Is Initiated (2)

- Measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, serum creatinine, and platelet count
- Visual acuity and color vision tests (when EMB used)

## IDSA/USPHS* Rating System for Treatment Recommendations

- A.	Preferred; should generally be offered
- B.	Alternative; acceptable to offer
- C.	Offer when preferred/alternative  regimens cannot be given
- D.	Should generally not be offered
- E.	Should never be offered

- I.	At least one properly randomized trial with clinical endpoints
- II.	Clinical trials that either are not randomized or were conducted in other populations
- III. 	Expert opinion

_**Strength of the Recommendation**_

_**Quality of Supporting Evidence**_

- *IDSA-Infectious Diseases Society of America;                                       USPHS-U.S. Public Health Service

## Treatment Regimens 

- Four regimens recommended for treatment of culture-positive TB, with different options for dosing intervals in continuation phase
- Initial phase: standard four drug regimens (INH, RIF, PZA, EMB), for 2 months, (except one regimen that excludes PZA)
- Continuation phase: additional 4 months or (7 months for some patients)

## Why Extend Continuation-Phase Treatment for 3 Months?

- Cavitary disease and positive sputum culture  at 2 months associated with increased relapse in clinical trials
- Extended continuation phase decreased relapses in silicotuberculosis (from 20% to 3%)

## When to Extend Continuation-Phase Treatment for 3 Months? 

- Cavitary pulmonary disease and positive sputum cultures at completion of initial phase
- Initial phase excluded PZA
- Once-weekly INH and rifapentine started in  continuation phase and sputum specimen collected at the end of initial phase is culture positive
- HIV-infected with positive 2-month sputum culture

## Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients

- Isspecimen collected at end of initial phase (2 months) culture positive?

**NO**

**YES**

- Place patient on initial-phase regimen:
- INH, RIF, EMB, PZA for 2 months

- Give continuation-phase treatment of INH/RIF daily or twice weekly for 4 months

**Algorithm to Guide Duration of Continuation-Phase Treatment for ****Culture-Positive TB Patients**

## Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients (Continued)

- Give continuation-phase treatment of INH/RIF daily or twice weekly for 7 months

- Give continuation- phase treatment of INH/RIF daily or twice weekly for 4 months

**NO**

**YES**

- Wasthere cavitation on initial CXR?

**NO**

**YES**

- Is thepatient HIV positive?

**Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients ****(Continued)**

- Give continuation- phase treatment of INH/RIF daily for 7 months

## Treatment of Culture-Positive TB (1)

- Initial Phase

- Continuation Phase

- *	Continuation phase increased to 7 months if initial chest x-ray shows cavitation                and specimen collected at end of initial phase (2 months) is culture positive

- (Rated: AI in HIV-negative, AII in HIV-positive patients)

- 2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks)

- Options:
- 4 months - INH, RIF daily (126 doses, within 18 weeks)
- 4 months - INH, RIF twice / week (36 doses, within 18 weeks)
- 7 months - INH, RIF daily (217 doses, within 31 weeks)*
- 7 months - INH, RIF twice / week (62 doses, within 31 weeks)*

## Treatment of Culture-Positive TB (2)

- Continuation Phase

**Treatment of Culture-Positive TB (2)**

**Twice-Weekly Options** (Rated: AII for HIV-negative, BII for HIV-positive patients*)

- 0.5 months - INH, RIF, PZA, EMB daily (10-14 doses, within 2 weeks)
- THEN
- 1.5 months - INH, RIF, PZA, EMB twice / week (12 doses, within 6 weeks)

- Options:
- 4 months - INH, RIF twice / week (36 doses, within 18 weeks)
- 7 months - INH, RIF twice / week (62 doses, within 31 weeks)

- Initial Phase

## Treatment of Culture-Positive TB (3)

**Treatment of Culture-Positive TB (3)**

**Thrice-Weekly Options** (Rated: BI for HIV-negative, BII for HIV-positive patients)

- Initial Phase

- 2 months - INH, RIF, PZA, EMB 3 times / week (24 doses, within 8 weeks)

- Options:
- 4 months - INH, RIF  3 times / week (54 doses, within 18 weeks)
- 2)   7 months - INH, RIF  3 times / week (93 doses, within 31 weeks)

## Treatment of Culture-Positive TB (4)

**Treatment of Culture-Positive TB (4)**

**Regimens without Pyrazinamide**(Rated: CI for HIV-negative, CII for HIV-positive patients)

- Continuation Phase

- 2 months - INH, RIF, EMB daily (56 doses, within 8 weeks)

- Initial Phase

- Options:
- 7 months - INH, RIF daily (217 doses, within 31 weeks)
- 2) 	7 months - INH, RIF twice / week (62 doses, within 31 weeks)*

## Algorithm to Guide Rifapentine (RPT) Usein Continuation Phase

**NO**

**YES**

**Algorithm to Guide Rifapentine (RPT) Use****in Continuation Phase**

- Is the patient HIV positive?

**NO**

**YES**

**NO**

- Wasthere cavitation on initial CXR?

**YES**

- Wasthe sputum AFB smear positive at 2 months?

- Not eligible for RPT

- Not eligible for RPT

- Not eligible for RPT

## Algorithm to Guide Rifapentine (RPT) Usein Continuation Phase (Continued)

**YES**

- IsRPT considered for treatment?

**NO**

- Isspecimen collected at endof initial phase (2 months) culture positive?

**YES**

**NO**

**Algorithm to Guide Rifapentine (RPT) Use****in Continuation Phase ****(Continued)**

## Treatment of Culture-Positive TB

- Initial Phase

- Continuation Phase

**Treatment of Culture-Positive TB**

**Rifapentine in Continuation Phase**  (Rated: BI for HIV-negative*, EI for HIV-positive patients)

- *	Regimen is limited to noncavitary disease in HIV-negative patients.    Sputum must be smear negative at completion of 2 months of treatment

- Options:
- 2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks)
- 0.5 months - INH, RIF, PZA, EMB daily (10-14 doses, within 2 weeks)
-     THEN1.5 months - INH, RIF, PZA, EMB twice / week (12 doses, within 6 weeks)

- Options:
- 1)  4 months - INH, RPT once weekly (18 doses, within 18 weeks)
- 2)  7 months - INH, RPT once weekly (31 doses, within 31 weeks)

## Algorithm to Guide Treatment of Culture-Negative TB

- High clinical suspicion for active TB despite negative smears based on:

- Abnormal chest x-ray
- Clinical symptoms
- No other diagnosis
- Positive tuberculin skin test

- Patient placed on initial phase regimen:
- INH, RIF, EMB, PZA for 2 months

## Algorithm to Guide Treatment of Culture-Negative TB (Continued)

**Algorithm to Guide Treatment of ****Culture-Negative TB**** (Continued)**

- Give continuation- phase treatment of INH/RIF dailyor twice weekly for2 months

**NO**

**YES**

- Wastheresymptomaticor chest x-ray improvement after
- 2 months of treatment?

**NO**

**YES**

- Isinitial culture positive?

- Continue treatment for culture-positive TB

- Discontinue treatment
- Patient presumed to have LTBI
- Treatment completed

## Treatment of Culture-Negative TB*

- Initial Phase

- Continuation Phase

- *	All cultures are negative, but evaluation at 2 months reveals clinical and chest x-ray response to antituberculosis drug therapy

- 2 months - INH, RIF, EMB, PZA daily (56 doses, within 8 weeks)

- Options:
- 2 months - INH, RIF daily (56 doses, within 8 weeks)
- 2) 	2 months - INH, RIF twice / week (16 doses, within 8 weeks)

## Treatment Monitoring (1)

- Monthly sputum for AFB smear and culture (until 2 consecutive cultures negative)
- Serial sputum smears every 2 weeks to assess early response
- Additional drug-susceptibility tests if culture-positive after 3 months of treatment

## Treatment Monitoring (2)

- Periodic (minimum monthly) evaluation to assess adherence and identify adverse reactions
- Repeat chest x-ray:
- 	-At completion of initial treatment phase for patients with initial negative cultures
-     -At end of treatment for patients with culture-negative TB
-     -Generally not necessary for patients with culture positive TB

## Treatment Monitoring (3)

- Renal function, AST, ALT, bilirubin, and platelet count if abnormalities at baseline
- Visual acuity and color vision monthly if EMB used > 2 months or doses > 15-20 mg/kg

## Determining Drug Completion (1)

- Completion primarily defined by number of ingested doses within specified time frame
- Examples
- 	1) 	6-month daily regimen (7 days/wk) =  		  at least 182 doses of INH and RIF, and          	  56 doses of PZA
- 	2) 	6-month daily regimen (5 days/wk) =		at least 130 doses

## Determining Drug Completion (2)

- Specified doses must be administered
- 	1) 	Within 3 months for initial phase
- 	2) 	Within 6 months for 4-month continuation 			phase
- $	Consider therapy interrupted if target doses _not_ met within specified time period

## Management of Initial Phase Treatment Interruptions 

- If lapse _>_ 14 days, start from beginning
- If lapse < 14 days, continue treatment to complete total doses warranted (if can be completed within 3 months)

## Algorithm for Management of Treatment Interruptions in the Initial Phase

**Algorithm for Management of Treatment Interruptions**** ****in the Initial Phase**

**YES**

- Start over from the beginning

- Is the treatment completed within 3 months?

- Continue treatment to  complete total doses warranted

**NO**

**NO**

**YES**

- How long is the interruption?

- Is it < 14 days?

## Management of Continuation Phase Treatment Interruptions

- If received _>_ 80% continuation-phase doses and:
- 	1) sputum AFB smear negative on initial presentation, further therapy not necessary
- 	2) sputum AFB smear positive on initial presentation, continue to complete full course

## If received < 80% continuation-phase doses and: 
    1) lapse < 3 months duration, continue to complete full course (as long as all doses can be completed within 6 months)
    2) lapse was 3 months or greater, then start initial phase 4-drug regimen from the beginning

- If received < 80% continuation-phase doses and:
-     1) lapse < 3 months duration, continue to complete full course (as long as all doses can be completed within 6 months)
-     2) lapse was 3 months or greater, then start initial phase 4-drug regimen from the beginning

## Algorithm for Management of Continuation Phase Treatment Interruptions

**Algorithm for Management of Continuation Phase Treatment Interruptions**

- -Additional treatment may _not_ be necessary if sputum was AFB smear negative at baseline
- -If sputum smear was positive, continue treatment to complete planned total number of doses warranted

**NO**

**YES**

- Is it  <80%?

- Is theduration of interruption <3 months?

- Start initial phase  4-drug regimen from beginning

- What is the total percentage of doses completed?

**NO**

**YES**

- Continue treatment; if not completed in6 months, start initial phase 4-drug regimen from beginning

## Common Adverse Reactions to Drug Treatment (1)

| Caused by | Adverse Reaction | Signs and Symptoms |
| --- | --- | --- |
| Any drug | Allergy | Skin rash |
| Ethambutol | Eye damage | Blurred or changed vision
Changed color vision |
| Isoniazid,
Pyrazinamide,
or
Rifampin | Hepatitis | Abdominal pain
Abnormal liver function test 
results
Fatigue
Lack of appetite
Nausea
Vomiting
Yellowish skin or eyes
Dark urine |

**Common Adverse Reactions to ****Drug Treatment (1)**

## Common Adverse Reactions to Drug Treatment (2)

| Caused by | Adverse Reaction | Signs and Symptoms |
| --- | --- | --- |
| Isoniazid | Peripheral neuropathy | Tingling sensation in hands and feet |
| Pyrazinamide | Gastrointestinalintolerance
Arthralgia
Arthritis | Upset stomach, vomiting, lack of appetite
Joint aches
Gout (rare) |
| Streptomycin | Ear damage

Kidney damage | Balance problems
Hearing loss
Ringing in the ears
Abnormal kidney function test results |

## Common Adverse Reactions to Drug Treatment (3)

| Caused by | Adverse Reaction | Signs and Symptoms |
| --- | --- | --- |
| Rifamycins
Rifabutin
Rifapentine
Rifampin | Thrombocytopenia

Gastrointestinal intolerance
Drug interactions | Easy bruising
Slow blood clotting 
Upset stomach
Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment |

## Drug Interactions 

- Relatively few drug interactions substantially change concentrations of antituberculosis drugs
- Antituberculosis drugs sometimes change concentrations of other drugs
- 	-Rifamycins can decrease serum concentrations of many drugs, (e.g., most of the HIV-1 protease inhibitors), to subtherapeutic levels
-     -Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels

## Relapse (1)

- A patient’s cultures become and remain negative while receiving antituberculosis drugs, but at some point after completion of therapy:
- patient develops culture-positive TB disease   again, or
- 2)	patient experiences clinical or radiographic deterioration consistent with active TB disease
- Most relapses occur within the first 12 months after completion of therapy

## Relapse (2)

- Patients with cavitation on initial chest radiograph and a positive culture at completion of 2 months of therapy are at increased risk of relapse with standard 6-month regimens
- Patients with relapse are at increased risk for acquired drug resistance, especially if the therapy was not directly observed

## Treatment Failure

- Defined as positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured
- Single new drug should never be added to a failing regimen; it may lead to acquired resistance to the added drug
- Add at least three new drugs (e.g., fluoroquinolone, ethionamide, and an injectable drug:  SM, amikacin, kanamycin, or capreomycin) to the existing regimen being cognizant of the possibility of drug resistance

## Drug Resistance (1)

- Established only by drug-susceptibility testing
- Treatment of TB caused by drug-resistant organisms should be done in close consultation with an expert
- Patients not on DOT in the past or who had irregular treatment are at risk of drug resistance

## Drug Resistance (2)

- Consider the following expanded regimen for drug resistance:
- INH, RIF, PZA, EMB plus three additional  agents based on probability of in vitro susceptibility (e.g., fluoroquinolone, ethionamide, or an injectable drug: SM, amikacin, kanamycin, or capreomycin)

## Special Treatment SituationsHIV/AIDS

- Treatment for HIV-positive patients same as for HIV-negative patients, except
- Once-weekly INH-rifapentine in continuation phase is contraindicated in HIV-positive patients
- Twice-weekly INH-RIF or INH-rifabutin should _not_ be used in patients with CD4+   T-lymphocyte counts less than 100/l
- Every effort should be made to use a rifamycin-based regimen for the entire course of therapy

## Special Treatment Situations(Children and Adolescents)* (1)

- Use DOT
- Treat young children (<5 years old) with three (rather than four) drugs in initial phase (i.e., INH, RIF, and PZA)
- EMB not recommended unless increased likelihood of INH resistance or diagnosis of adult-like TB**

-  *	Defined as persons <15 years old
- **	Defined as upper-lobe infiltration and cavitation associated with sputum production

## Special Treatment SituationsChildren and Adolescents (2)

- Thrice-weekly therapy not recommended
- Recommended duration of treatment is 6 months (absence of factors associated with increased risk of relapse)

## Special Treatment Situations Extrapulmonary TB

- Similar treatment regimen for pulmonary TB*
- 6- to 9-month regimens that include INH and RIF are effective
- Corticosteroids used as adjunctive therapy for patients with TB meningitis and pericarditis
- If PZA cannot be used in the initial phase, continuation phase must be increased to 7 months

- *	Except for central nervous system (CNS) TB,  including meningitis; length of therapy is 9-12 months

## Special Treatment SituationsPregnancy and Breastfeeding (1)

- Untreated TB represents greater hazard to a woman and her child than treatment of disease
- Treatment of pregnant woman with suspected TB should be started if probability of TB is moderate to high
- Initial phase treatment regimen should consist of INH, RIF, and EMB

## Special Treatment SituationsPregnancy and Breastfeeding (2)

- SM should not be substituted for EMB because of possible teratogenic effects
- PZA not generally recommended for pregnant women in the United States

## Special Treatment SituationsRenal Insufficiency and End-Stage Renal Disease (1)

- Renal insufficiency complicates management of TB because some antituberculosis medications are cleared by the kidneys
- Dosage should not be decreased because peak serum concentrations may be too low; smaller doses may decrease drug efficacy

## Dosing interval of antituberculosis drugs should be increased
Most drugs can be given 3 times weekly after hemodialysis; for some drugs, dose must be adjusted

- Most drugs can be given 3 times weekly after hemodialysis; for some drugs, dose must be adjusted

**Special Treatment Situations****Renal Insufficiency and End-Stage ****Renal Disease (2)**

## Special Treatment SituationsHepatic Disease (1)

- Must consider regimens with fewer hepatotoxic agents for patients with liver disease
- _Recommended regimens:_
- Treatment without PZAInitial phase (2 months):  INH, RIF, and EMBContinuation phase (7 months):  INH and RIF
- Treatment without INHInitial phase (2 months):  RIF, PZA, and EMBContinuation phase (4 months): RIF, EMB, and PZA

## Special Treatment SituationsHepatic Disease (2)

- _Recommended regimens:_ (continued)
- Regimens with only one potentially hepatotoxic drug
- RIF should be retained
- Duration of treatment is 12-18 months
- Regimens with no potentially hepatotoxic drugs
- Duration of treatment is 18-24 months

## Continuing Education Credits (1)

- Participants will be able to receive one of the following:
- Continuing Medical Education (CME) credit = 3.75
- Continuing Nursing Education (CNE) credit = 4.3
- Continuing Education Unit (CEU) = 0.43
- Certified Health Education Specialist (CHES)  credit = 3.5
- Participants are required to read and study the treatment guidelines, take a test, and complete an evaluation

## Continuing Education Credits (2)

- Continuing education credit will be awarded through:
- CDC’s Public Health Training Network (PHTN)
-    _[http://phppo.cdc.gov/phtnonline](http://phppo.cdc.gov/phtnonline)_  or
- MMWR at _[http://](http://www.cdc.gov/mmwr)__[www.cdc.gov/mmwr](http://www.cdc.gov/mmwr)_

## Treatment Guidelines Online Availability

- CDC’s Morbidity and Mortality Weekly Report:
- _[http://](http://www.cdc.gov/mmwr)__[www.cdc.gov/mmwr](http://www.cdc.gov/mmwr)_
- American Thoracic Society:
- 	_[http://www.thoracic.org/adobe/statements/treattb.pdf](http://www.thoracic.org/adobe/statements/treattb.pdf)_

## Additional TB Resources

- For additional information on tuberculosis, visit the Division of Tuberculosis Elimination Web site at:
- _[http://](http://www.cdc.gov/tb)__[www.cdc.gov/tb](http://www.cdc.gov/tb)_