©2013 MFMER | slide-1 Tuberculosis Treatment Jennifer Whitaker, MD, MS Infectious Diseases Midwest...

©2013 MFMER | slide-1©2013 MFMER | slide-1

Tuberculosis Treatment

Jennifer Whitaker, MD, MSInfectious Diseases Midwest Fellows’ Forum, Mayo Clinic, Rochester

April 26, 2014

©2013 MFMER | slide-2

Disclosures

• Pfizer Educational Grant for Learning and Change


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


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


Targeted Testing for LTBI High Likelihood of Exposure to TB High Risk of Progression to Active TBHigh Likelihood of Exposure to TB High Risk of Progression to Active TB

Close contacts of a person with infectious TB disease

Persons who have immigrated from areas of the world with high rates of TB

Residents/employees of high-risk congregate settings (correctional facilities, homeless shelters, health care facilities)

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 areas of the world with high rates of TB

Recent LTBI test conversion (within past 2 years)

Residents/employees of high-risk congregate settings (correctional facilities, homeless shelters, healthcare facilities)

History of prior, untreated TB or fibrotic lesions on chest radiograph

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


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


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


Medication(s) Recommended Regimen

Isoniazid Preferred:Isoniazid 300 mg daily x 9 months



Alternative:300 mg daily x 6 months900 mg twice weekly x 9 months (DOT)900 mg twice weekly x 6 months (DOT)

LTBI Treatment RegimensMedication(s) Recommended Regimen



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)

MMWR. 2011;60(48):1650-3.JAMA. 2005; 293:2776.


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.


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


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







LTBI Treatment RegimensMedication(s) Recommended Regimen








Rifampin Rifampin 600 mg daily x 9 months





Rifampin Rifampin 600 mg daily x 4 months

Isoniazid + Rifampin Isoniazid 300 mg daily x 3 months+ Rifampin 600 mg daily x 3 months

MMWR. 2011;60(48):1650-3.JAMA. 2005; 293:2776.


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


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.


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


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


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 bi-weekly 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


Treatment of Drug-Susceptible TB Disease

Initial Phase

• First 8 weeks of treatment• Most bacilli killed during this phase• 4 drugs used

Continuation Phase

• 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


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)


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


Current Preferred Regimens for Drug-Susceptible 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 semi-

dormant 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


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


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


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


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.


Recommended Treatment Regimens for Drug-Susceptible Organisms

ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77. http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf

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

;


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.


Treatment of Culture-negative Pulmonary TB


Continuation phase is shortened to 2 months


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.


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


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


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%)


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


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


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


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


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 culture-positive after 3 months of treatment



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


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


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


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


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


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; 293:2776MMWR. 2011 Dec 9;60(48):1650-3.


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.


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-1 Tuberculosis Treatment Jennifer Whitaker, MD, MS Infectious Diseases Midwest...

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