Download File - Mayo Clinic Center for Tuberculosis

Tuberculosis Treatment
Jennifer Whitaker, MD, MS
Infectious Diseases Midwest Fellows’ Forum, Mayo Clinic, Rochester
April 26, 2014
©2013 MFMER | slide-1
Disclosures
• Pfizer Educational Grant for Learning and
Change
©2013 MFMER | slide-2
Objectives
• Review the treatment regimens for latent TB
infection (LTBI)
• Review the treatment regimens for drug-susceptible
TB disease
• Review adverse reactions to TB medications
©2013 MFMER | slide-3
Latent TB Infection (LTBI) Treatment
• Rationale
• To prevent the development of active disease
• Component of TB control
• Durability of protection against reactivation
depends on regional prevalence of TB and risk
for reexposure
• A decision to test for LTBI is a decision to treat
©2013 MFMER | slide-4
Targeted Testing for LTBI
High Likelihood of Exposure to TB
High Risk of Progression to Active TB
Close contacts of a person with
infectious TB disease
HIV Infection
Persons who have immigrated from
Recent LTBI test conversion (within past
areas of the world with high rates of TB 2 years)
Residents/employees of high-risk
History of prior, untreated TB or fibrotic
congregate settings (correctional
lesions on chest radiograph
health
facilities, homeless shelters, healthcare
care
facilities)
facilities)
Those receiving TNF-α antagonists for
treatment of autoimmune diseases
Solid organ transplant, lymphoma,
leukemia, head and neck cancer,
chemotherapy
Chronic kidney disease requiring
hemodialysis
Children who have positive LTBI test
©2013 MFMER | slide-5
Prior to Treatment
• Symptom screen
• Chest X-ray
• Rule out active disease
• Assess for medical conditions and medications
that may affect treatment choices
• Determine whether patient has ever been
treated for LTBI or TB disease
• Establish rapport with patient; explain therapy
and adverse effects
©2013 MFMER | slide-6
Which LTBI treatment regimens require
directly observed therapy (DOT)?
A) Daily isoniazid x 9 months
B) Twice weekly isoniazid x 9 months
C) Daily rifampin x 4 months
D) Weekly isoniazid + rifapentine
E) B & D
©2013 MFMER | slide-7
LTBI Treatment Regimens
MMWR. 2011;60(48):1650-3.
JAMA. 2005; 293:2776.
Medication(s)
Medication(s)
Recommended
Recommended
Recommended Regimen
Regimen
Regimen
Isoniazid
Isoniazid
Preferred:
Preferred:
Preferred:
Isoniazid
Isoniazid
Isoniazid 300
300
300 mg
mg
mg daily
daily
daily xxx 999 months
months
months
Alternative:
Alternative:
300
300 mg
mg daily
daily xx 66 months
months
900
900 mg
mg twice
twice weekly
weekly xx 99 months
months (DOT)
(DOT)
900
900 mg
mg twice
twice weekly
weekly xx 66 months
months (DOT)
(DOT)
Isoniazid + Rifapentine
Isoniazid 900 mg weekly x 12 weeks (DOT) +
Rifapentine once weekly x 12 weeks (DOT)
10-14 kg 300 mg
14.1-25 kg 450 mg
25.1-32 kg 600 mg
32.1-49.9 kg 750 mg
>50 kg 900 mg (maximum dose)
©2013 MFMER | slide-8
Current CDC recommendations state isoniazid +
rifapentine weekly x 12 weeks is an acceptable
alternative LTBI regimen for which groups with
high risk of developing active TB?
A) Persons ≥ 12 years old with recent LTBI test
conversion, recent exposure to contagious
TB, CXR consistent with healed pulmonary
TB, or HIV infection but not on antiretrovirals
B) Pregnant females
C) HIV-infected individuals on antiretroviral
therapy
D) A & C
E) A & B
MMWR. 2011;60(48):1650-3.
©2013 MFMER | slide-9
Isoniazid (INH) + Rifapentine (RPT)
• INH/RPT weekly x 3 mo (DOT) noninferior to 9 mo daily
INH (self-administered) in randomized open label trial
• N=7731, mostly HIV(-) in Brazil, Canada, Spain, and US
• ≥ 12 years old (later ≥ 2 yo) + 1 of 4 high-risk groups (recent LTBI test
conversion, recent exposure to contagious TB, CXR consistent with
healed pulmonary TB, HIV infection and not on ARVs with + LTBI test
or close TB contact)
• Completion rate was 82% for INH/RPT and 69% for INH
(p<0.01)
• Hepatoxicity greater in INH than INH/RPT (2.7% vs 0.4%;
p<0.001)
• Higher rates of permanent drug discontinuation due to an
adverse event in the rifapentine/INH group (4.9 % vs. 3.7 %;
p=0.009)
N Engl J Med. 2011 Dec;365(23):2155-66
©2013 MFMER | slide-10
Isoniazid + Rifapentine
• Further study is needed for:
• Completion /efficacy without DOT
• Durability of protection/ efficacy/toxicity in
those with HIV (also with antiretrovirals)
• Efficacy/toxicity in other groups without
recent infection (prior to TNF-α inhibitors)
• Utility where the incidence of TB is high
©2013 MFMER | slide-11
LTBI Treatment Regimens
MMWR. 2011;60(48):1650-3.
JAMA. 2005; 293:2776.
Medication(s)
Medication(s)
Recommended
Recommended
Recommended Regimen
Regimen
Regimen
Isoniazid
Isoniazid
Preferred:
Preferred:
Preferred:
Isoniazid
Isoniazid
Isoniazid 300
300
300 mg
mg
mg daily
daily
daily xxx 999 months
months
months
Alternative:
Alternative:
Alternative:
300
300
300 mg
mg
mg daily
daily
daily xxx 666 months
months
months
900
900
900 mg
mg
mg twice
twice
twice weekly
weekly
weekly xxx 999 months
months
months (DOT)
(DOT)
(DOT)
900
900
900 mg
mg
mg twice
twice
twice weekly
weekly
weekly xxx 666 months
months
months (DOT)
(DOT)
(DOT)
Isoniazid
Isoniazid ++ Rifapentine
Rifapentine Isoniazid
Isoniazid
Isoniazid 300
900
900 mg
mg weekly
weekly xx 12
12 weeks
weeks(DOT)
(DOT) ++
Rifapentine
Rifapentine
Rifapentine once
once
once weekly
weekly
weekly xxx 12
12
12 weeks
weeks
weeks (DOT)
(DOT)
(DOT)
10-14
10-14
10-14 kg
kg 300
300 mg
mg
14.1-25
14.1-25
14.1-25 kg
kg 450
450 mg
mg
25.1-32
25.1-32
25.1-32 kg
kg 600
600 mg
mg
32.1-49.9
32.1-49.9
32.1-49.9 kg
kg 750
750 mg
mg
>50
>50
>50 kg
kg
kg 900
900
900 mg
mg
mg (maximum
(maximum
(maximum dose)
dose)
dose)
Rifampin
Rifampin
Rifampin
Rifampin 600
600 mg
mg daily
daily xx 49 months
months
Isoniazid + Rifampin
Isoniazid 300 mg daily x 3 months
+ Rifampin 600 mg daily x 3 months
©2013 MFMER | slide-12
Pyridoxine and Isoniazid – Who Needs It?
• Those at increased risk for peripheral neuropathy
• Diabetes mellitus
• Alcohol dependence
• HIV
• Chronic kidney disease
• Malnutrition
• Pregnant/breastfeeding women
©2013 MFMER | slide-13
Monitoring of LTBI Therapy
• Everyone should have initial clinical evaluation prior to starting
therapy with monthly clinical monitoring for signs/symptoms of
hepatitis and adherence to medication while on therapy
• For weekly INH/RPT, ask about signs/symptoms with each dose
• Baseline liver enzyme testing in those with:
•
•
•
•
•
Underlying liver disease
HIV infection
Pregnant /postpartum (≤ 3 mo after delivery)
Regular alcohol consumption
Medication(s) with potential hepatotoxicity
• Routine lab monitoring during treatment for those whose baseline
liver function tests are abnormal or those at risk for hepatic disease
Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221.
©2013 MFMER | slide-14
When Should LTBI Therapy be Stopped?
• Liver enzymes are:
• ≥ 3 times upper limit of normal
range and patient has symptoms
OR
• ≥ 5 times upper limit of the normal range and
patient has no symptoms
©2013 MFMER | slide-15
Pregnant Women
• For most LTBI treatment can be delayed until
after delivery, unless they have significant
immunocompromising conditions, HIV, or recent
TB contact
• INH is safe during pregnancy
• Preferred LTBI treatment regimen is 9 months of INH
with pyridoxine
• INH is safe for breastfeeding, give with pyridoxine
©2013 MFMER | slide-16
LTBI Treatment Key Points
• Test and treat those at high risk for TB exposure and/or
progression to active disease
• Isoniazid daily x 9 months or Isoniazid + rifapentine
weekly x 3 months with DOT (with caveats) are
preferred regimens
• LTBI treatment regimens that include weekly or biweekly dosing require DOT
• Prior to treatment for LTBI, patients need clinical
evaluation + CXR to rule out active TB disease
• While on therapy patients need monthly clinical
monitoring; baseline liver enzymes for those at risk
©2013 MFMER | slide-17
Treatment of Drug-Susceptible TB Disease
Initial Phase
Continuation
Phase
• First 8 weeks of treatment
• Most bacilli killed during this phase
• 4 drugs used
• After first 8 weeks of TB disease
treatment (18 or 31 weeks duration)
• Bacilli remaining after initial
phase are treated with at least 2
drugs
©2013 MFMER | slide-18
First Line TB Drug Abbreviations
• Rifamycins:
• Rifampin (Rifampicin, RIF, R)
• Rifabutin (RFB)
• Rifapentine (RPT)
• Isoniazid (INH, H)
• Pyrazinamide (PZA, Z)
• Ethambutol (EMB, E)
• Streptomycin (SM, S)
©2013 MFMER | slide-19
Mechanisms of Action
• Rifampin
• Binds to RNA polymerase and blocks RNA synthesis;
• Bactericidal; Sterilizing activity due to activity against
semi-dormant bacteria
• Isoniazid
• Inhibits mycolic acid synthesis
• Bactericidal
• Pyrazinamide
• Potent sterilizing ability within acidic environment of
areas of acute inflammation, suppuration
• Ethambutol
• Cell wall inhibition
©2013 MFMER | slide-20
Current Preferred Regimens for DrugSusceptible TB disease:
• Isoniazid, Rifampin, Pyrazinamide, Ethambutol
• Isoniazid & Rifampin are the cornerstones
• Both are bactericidal against rapidly dividing mycobacteria
• Rifampin also exhibits excellent late sterilizing effect on semidormant organisms
• Non-INH based regimen = usually 9 months
• Non-Rifampin regimen = 12-18 months (variable)
• Pyrazinamide
• Potent sterilizing ability
• Non-pyrazinamide based regimen = 9 months
©2013 MFMER | slide-21
Standard TB Therapy for Drug-Susceptible
Disease
• Initial Phase:
• 4 drugs for 2 months (8 weeks)
• Rifampin, isoniazid, pyrazinamide, ethambutol
• Okay to stop ethambutol, once it is known that
isolate is susceptible to rifampin, isoniazid, and
pyrazinamide
ATS/CDC/IDSA. Treatment of Tuberculosis. MMWR 2003.
http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf
©2013 MFMER | slide-22
In what cases should the continuation phase of
TB therapy be prolonged from 4 months to 7
months?
A. HIV co-infection
B. Cavitary disease with positive cultures at end
of initiation phase
C. Initiation regimens of Isoniazid, Rifampin, and
Ethambutol, without use of PZA
D. B and C
©2013 MFMER | slide-23
Standard TB Disease Continuation Therapy
• Continuation Phase:
• Rifampin & Isoniazid for 4 months (18 weeks)
• Six months (26 weeks) total course of therapy
• If PZA not used in initiation, then 7 months (31 wk) continuation
• Continuation Phase: for cavitary disease
AND positive cultures after initiation phase
• Rifampin & Isoniazid x 7 months (31 weeks) if cavitary disease
at diagnosis and positive cultures after initiation phase at 2
months
• Rifapentine should not be used
• Nine months (39 weeks) total course of therapy
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf
©2013 MFMER | slide-24
Noncompliance or Abandonment of Therapy
is Major Impediment of TB Treatment
• Directly observed therapy (DOT) has been
shown to:
• Facilitate treatment completion rates and
bacteriologic evidence of cure
• Decrease acquired and primary drug resistance
• Decrease relapse rates
• CDC and American Thoracic Society (ATS)
recommend consideration of DOT for all and
• Especially for those with drug resistant organisms,
cavitary disease, or HIV infection
Chaulk CP, et al. JAMA. 1998;279(12):943.
Chaulk CP, et al. JAMA. 1995;274(12):945.
Weis SE, et al. N Engl J Med. 1994;330(17):1179.
©2013 MFMER | slide-25
Recommended Treatment Regimens for
Drug-Susceptible Organisms
Evidence Ratings:
A=preferred, B=acceptable alternative, C= when A&B cannot be given, E=never
I=randomized controlled trial, II=Clinical trials, not randomized or done in other populations
;
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf
©2013 MFMER | slide-26
Key Points: Treatment of TB Disease
• Initiation:
• RIF/INH/PZA/EMB until susceptibilities
confirmed
• Can stop EMB if susceptible to RIF/INH/PZA
• RIF/INH/PZA for 8 weeks
• Continuation:
• RIF/INH for 18 weeks
• If PZA not used in initiation or if patient has
cavitary disease + positive cultures at 8 wks,
then RIF/INH continued for 31 weeks
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
©2013 MFMER | slide-27
Treatment of Culture-negative Pulmonary TB
Continuation phase is
shortened to 2 months
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
©2013 MFMER | slide-28
Treatment of Extrapulmonary TB Disease
• Generally the same treatment as for pulmonary
TB
• Addition of corticosteroids for:
• TB pericarditis
• TB meningitis
• Recommended that duration of therapy be
extended to 9-12 months for TB meningitis
• May extend to 18 months for tuberculoma
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
Thwaites GE, Nguyen DB, et al. N Engl J Med 2004;351(17):1741.
©2013 MFMER | slide-29
Rifampin Adverse Effects
• Most Common:
• Rash, generally self-limited. True hypersensitivity
rare.
• Nausea/vomiting
• Hepatotoxicity: (usually cholestatic; bilirubin is a
clue)
• Orange discoloration of body fluids
Less Common:
• Influenza-like syndrome
• Cytopenias - WBC, platelets
• Nephrotoxicity; interstitial nephritis
• Hypersensitivity reactions
©2013 MFMER | slide-30
Rifampin Drug Interactions
• Rifampin induces its own metabolism during the
first 2 weeks
• Induces cyt p450 system & decreases levels of:
•
•
•
•
Steroids, OCP/estrogen
Protease inhibitors
Warfarin
Antiepileptics
• Methadone, morphine
• Digoxin, calcium channel blockers, β-blockers
• Azoles + many others
©2013 MFMER | slide-31
Isoniazid Adverse Effects
• Transient asymptomatic elevation of AST/ALT in 10-15%
(usually in 1st 4-8 weeks of therapy) – usually resolves
• Hepatotoxicity / hepatitis
• Increased in HIV (4x), HCV (5x) or both HIV-HCV (14x) co-infections
• Usually in 1st 4-8 weeks of therapy) – typically 0.1-1% risk without
underlying liver disease
• Rapid improvement (AST/ALT) after stopping drugs - clue to INH
toxicity
• Peripheral neuropathy – give vitamin B6 (10-50 mg/day)
to prevent
• Hypersensitivity (fever, rash)
• (+) ANA (< 20%)
• Lupus-like reaction (<10%)
©2013 MFMER | slide-32
Ethambutol Adverse Effects
• Retrobulbar / optic neuritis -  visual field;  red-green
color discrimination
• Monitoring - Visual acuity & color vision (baseline
and monthly)
• Other: peripheral neuropathy (rare)
• Contraindications:
• Pre-existing optic neuritis (from any cause)
• Inability (i.e. young pt. age) to report visual
disturbances
©2013 MFMER | slide-33
Pyrazinamide Adverse Effects
• Hepatotoxicity / hepatitis – modest rises in
transaminases; Slow hepatic/transaminase
recovery is clue to PZA toxicity
• Hyperuricemia – gout is rare (but is often board
question)
• Arthralgias - particularly of shoulders
• Other: GI upset, rash, glucose dysregulation
©2013 MFMER | slide-34
Approach to Hepatitis
• INH, RIF, & PZA can cause drug-induced liver
injury (ALT > 3x upper limit normal +
symptoms or ALT > 5x ULN without
symptoms)
• Asymptomatic increase in AST occurs in ~20%
treated with standard 4-drug regimen
• In absence of symptoms, therapy should not
be altered for modest elevations of AST
• Frequency of lab monitoring should be increased
• In most cases, asymptomatic AST elevations resolve
spontaneously
©2013 MFMER | slide-35
Approach to Hepatitis
• If drug induced liver injury (AST >3x +
symptoms or >5x without symptoms) then stop
hepatotoxic drugs
• Evaluate for other causes than drugs (viral
hepatitis, etc)
• Suspect medications should be restarted one by
one after AST is <2x ULN
• Restart RIF (+EMB) first, if no rise in ALT after 1
week,
• Restart INH, if no rise in ALT after 1 week,
• If RIF and INH are tolerated & hepatitis was severe,
do not restart PZA
©2013 MFMER | slide-36
Sputum Culture Monitoring During
Pulmonary TB Treatment
• Serial sputum smears every 2 weeks to assess
early response
• Monthly sputum for AFB smear and culture
(until 2 consecutive cultures negative)
• Repeat drug-susceptibility tests if culturepositive after 3 months of treatment
ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.
©2013 MFMER | slide-37
Clinical Monitoring During Pulmonary TB
Treatment
• Periodic (minimum monthly) evaluation to review
adherence and identify adverse reactions
• Repeat chest x-ray:
• After 2 months treatment for patients with
negative cultures
• As clinically indicated for worsening
• At end of treatment
©2013 MFMER | slide-38
Diagnostic Monitoring During Pulmonary
TB Treatment
• Liver enzymes at baseline; HIV testing at
baseline; hepatitis testing if indicated; monthly
liver enzymes if indicated
• Renal function and CBC if abnormalities at
baseline
• Visual acuity and color vision at baseline if EMB
used and monthly
• If EMB used > 2 months or
• EMB dose > 15-20 mg/kg or
• EMB with renal failure
©2013 MFMER | slide-39
TB Treatment in Pregnancy/Breastfeeding
• INH considered safe in pregnancy/breastfeeding
• Risk of hepatitis increased in peripartum period
• Pyridoxine (25 mg/day) recommended if INH is administered
during pregnancy, administer to infant if breastfeeding
• RIF & EMB considered safe in pregnancy &
breastfeeding
• PZA - little information in pregnancy, generally
avoided in US
• Safe for breastfeeding
• Benefits of PZA may outweigh the risk (drug resistant cases)
• WHO & IUATLD recommend this drug for use in pregnant
women with tuberculosis
©2013 MFMER | slide-40
Key Points: TB Drug Adverse Effects
• INH, RIF, & PZA can cause drug-induced liver
injury
• ALT > 3x upper limit normal + symptoms or ALT > 5x without
symptoms
• Stop medications if this occurs until liver enzymes are <2x
upper limit of normal
• EMB can cause optic neuritis
• Monitor visual acuity & color vision
• Pyridoxine is given with INH to prevent
peripheral neuropathy
• PZA may exacerbate gout; generally avoid in
pregnancy
©2013 MFMER | slide-41
References
• Blumberg HM, Leonard MK Jr, Jasmer RM. Update on treatment of tuberculosis and
latent tuberculosis infection. JAMA 2005; 293:2776.
• CDC. Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct
Observation to Treat Latent Mycobacterium tuberculosis Infection. MMWR 2011;
60(48):1650.
• Person AK, Sterling TR. Treatment of latent tuberculosis infection in HIV: shorter or
longer? Curr HIV/AIDS Rep. 2012 September ; 9(3): 259–266.
• Targeted tuberculin testing and treatment of latent tuberculosis infection.
(ATS/CDC/IDSA). Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221.
• Sterling TR, Villarino ME, Borisov AS, et al. TB Trials Consortium PREVENT TB
Study Team. Three months of rifapentine and isoniazid for latent tuberculosis
infection. N Engl J Med. 2011 Dec;365(23):2155-66.
• ATS; CDC; IDSA.Treatment of Tuberculosis. MMWR 2003 Jun 20;52(RR-11):1-77.
• Chaulk CP, et al. JAMA. 1998;279(12):943.
• Chaulk CP, et al. JAMA. 1995;274(12):945.
• Weis SE, et al. N Engl J Med. 1994;330(17):1179.
• Thwaites GE, Nguyen DB, et al. Dexamethasone for the treatment of tuberculous
meningitis in adolescents and adults. N Engl J Med. 2004;351(17):1741
©2013 MFMER | slide-42
Which LTBI treatment regimens require
directly observed therapy (DOT)?
A) Daily isoniazid x 9 months
B) Twice weekly isoniazid x 9 months
C) Daily rifampin x 4 months
D) Weekly isoniazid + rifapentine
E) B & D
JAMA 2005; 293:2776
MMWR. 2011 Dec 9;60(48):1650-3.
©2013 MFMER | slide-43
Current CDC recommendations state isoniazid +
rifapentine weekly x 12 weeks is an acceptable
alternative LTBI regimen for which groups with
high risk of developing active TB?
A) Persons ≥ 12 years old with recent LTBI
test conversion, recent exposure to
contagious TB, CXR consistent with
healed pulmonary TB, or HIV infection but
not on antiretrovirals
B) Pregnant females
C) HIV-infected individuals on antiretroviral
therapy
D) A & C
MMWR. 2011;60(48):1650-3.
E) A & B
©2013 MFMER | slide-44
In what cases should the continuation phase of
TB therapy be prolonged from 4 months to 7
months?
A. HIV co-infection
B. Cavitary disease with positive cultures at end
of initiation phase
C. Initiation regimens of Isoniazid, Rifampin, and
Ethambutol, without use of PZA
D. B and C
©2013 MFMER | slide-45