TREATMENT OF TUBERCULOSIS, 2003

1
TREATMENT OF TUBERCULOSIS, 2003
American Thoracic Society
Centers for Disease Control and Prevention
Infectious Diseases Society of America

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

2
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

3
Whats 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

4
Whats 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

5
Whats 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

6
Whats 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

7
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

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Antituberculosis Drugs
First-Line Drugs
Second-Line Drugs

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol
• Rifabutin
• Rifapentine

• 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
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Drug Abbreviations

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

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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

11
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

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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)

13
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

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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

15
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

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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)

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IDSA/USPHS Rating System for Treatment
Recommendations
Strength of the Recommendation
Quality of Supporting Evidence

• 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

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

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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)

20
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
  

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Algorithm to Guide Duration of Continuation-Phase
Treatment for Culture-Positive TB Patients
Place patient on initial-phase regimen INH,
RIF, EMB, PZA for 2 months
Isspecimen collected at end of initial phase (2
months) culture positive?
NO
YES
Give continuation-phase treatment of INH/RIF
daily or twice weekly for 4 months
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Algorithm to Guide Duration of Continuation-Phase
Treatment for Culture-Positive TB Patients
(Continued)
Wasthere cavitation on initial CXR?
YES
NO
Is thepatient HIV positive?
Give continuation-phase treatment of INH/RIF
daily or twice weekly for 7 months
NO
YES
Give continuation- phase treatment of INH/RIF
daily or twice weekly for 4 months
Give continuation- phase treatment of INH/RIF
daily for 7 months
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Treatment of Culture-Positive TB (1)
(Rated AI in HIV-negative, AII in HIV-positive
patients)
Initial Phase
2 months - INH, RIF, PZA, EMB daily (56 doses,
within 8 weeks)
Continuation Phase

• 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)

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
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Treatment of Culture-Positive TB (2)
Twice-Weekly Options (Rated AII for
HIV-negative, BII for HIV-positive patients)
Initial Phase
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)
Continuation Phase

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

Regimen rated BII for HIV-positive patients
with CD4 T-lymphocytes cell count gt100/µl. Not
recommended for those with CD4 T-lymphocytes
cell count lt 100/µl
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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)
Continuation Phase

• 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)

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Treatment of Culture-Positive TB (4)
Regimens without Pyrazinamide(Rated CI for
HIV-negative, CII for HIV-positive patients)
Initial Phase
2 months - INH, RIF, EMB daily (56 doses, within
8 weeks)
Continuation Phase

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

Twice weekly dosing is not recommended for
persons with CD4 T-lymphocytes cell count lt
100/µl
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Algorithm to Guide Rifapentine (RPT) Usein
Continuation Phase
Is the patient HIV positive?
NO
YES
Not eligible for RPT
Wasthere cavitation on initial CXR?
NO
YES
Not eligible for RPT
Wasthe sputum AFB smear positive at 2 months?
NO
YES
Not eligible for RPT
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Algorithm to Guide Rifapentine (RPT) Usein
Continuation Phase (Continued)
IsRPT considered for treatment?
YES
NO
Isspecimen collected at endof initial phase (2
months) culture positive?
YES
NO
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Treatment of Culture-Positive TB
Rifapentine in Continuation Phase (Rated BI
for HIV-negative, EI for HIV-positive patients)
Initial Phase

• 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)

Continuation Phase
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)
Regimen is limited to noncavitary disease in
HIV-negative patients. Sputum must be smear
negative at completion of 2 months of treatment
30
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
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Algorithm to Guide Treatment of Culture-Negative
TB (Continued)
Isinitial culture positive?
NO
YES
Wastheresymptomaticor chest x-ray improvement
after 2 months of treatment?
Continue treatment for culture-positive TB
NO
YES

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

Give continuation- phase treatment of INH/RIF
dailyor twice weekly for2 months
32
Treatment of Culture-Negative TB
Initial Phase
2 months - INH, RIF, EMB, PZA daily (56 doses,
within 8 weeks)
Continuation Phase

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

All cultures are negative, but evaluation at 2
months reveals clinical and chest x-ray response
to antituberculosis drug therapy
33
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

34
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

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Treatment Monitoring (3)

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

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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

37
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

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Management of Initial Phase Treatment
Interruptions

• If lapse gt 14 days, start from beginning
• If lapse lt 14 days, continue treatment to
  complete total doses warranted (if can be
  completed within 3 months)

39
Algorithm for Management of Treatment
Interruptions in the Initial Phase
How long is the interruption?
Is it lt 14 days?
NO
YES
Start over from the beginning
Is the treatment completed within 3 months?
NO
YES
Continue treatment to complete total doses
warranted
40
Management of Continuation Phase Treatment
Interruptions

• If received gt 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

41
Management of Continuation Phase Treatment
Interruptions

• If received lt 80 continuation-phase doses and
• 1) lapse lt 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

42
Algorithm for Management of Continuation Phase
Treatment Interruptions
What is the total percentage of doses completed?
Is it lt80?
NO
YES
-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
Is theduration of interruption lt3 months?
YES
NO
Continue treatment if not completed in6 months,
start initial phase 4-drug regimen from beginning
Start initial phase 4-drug regimen from beginning
43
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
44
Common Adverse Reactions to Drug Treatment (2)
Caused by Adverse Reaction Signs and Symptoms
Isoniazid Peripheral neuropathy Tingling sensation in hands and feet
Pyrazinamide Gastrointestinalintolerance 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
45
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
46
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

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Relapse (1)

• A patients 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

48
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

49
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

50
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

51
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)

52
Special Treatment SituationsHIV/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

53
Special Treatment Situations(Children and
Adolescents) (1)

• Use DOT
• Treat young children (lt5 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 lt15 years old Defined as
upper-lobe infiltration and cavitation associated
with sputum production
54
Special Treatment SituationsChildren and
Adolescents (2)

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

55
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
56
Special Treatment SituationsPregnancy 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

57
Special Treatment SituationsPregnancy 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

58
Special Treatment SituationsRenal 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

59
Special Treatment SituationsRenal Insufficiency
and End-Stage Renal Disease (2)

• 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

60
Special Treatment SituationsHepatic 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

61
Special Treatment SituationsHepatic 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

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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

63
Continuing Education Credits (2)

• Continuing education credit will be awarded
  through
• CDCs Public Health Training Network (PHTN)
• http//phppo.cdc.gov/phtnonline or
• MMWR at http//www.cdc.gov/mmwr

64
Treatment Guidelines Online Availability

• CDCs Morbidity and Mortality Weekly Report
• http//www.cdc.gov/mmwr
• American Thoracic Society
• http//www.thoracic.org/adobe/statements/treattb.
  pdf

65
Additional TB Resources

• For additional information on tuberculosis,
  visit the Division of Tuberculosis Elimination
  Web site at
• http//www.cdc.gov/tb