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©2013 MFMER | slide-1 Tuberculosis Treatment Jennifer Whitaker, MD, MS Infectious Diseases Midwest Fellows Forum, Mayo Clinic, Rochester April 26, 2014.

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Presentation on theme: "©2013 MFMER | slide-1 Tuberculosis Treatment Jennifer Whitaker, MD, MS Infectious Diseases Midwest Fellows Forum, Mayo Clinic, Rochester April 26, 2014."— Presentation transcript:

1 ©2013 MFMER | slide-1 Tuberculosis Treatment Jennifer Whitaker, MD, MS Infectious Diseases Midwest Fellows Forum, Mayo Clinic, Rochester April 26, 2014

2 ©2013 MFMER | slide-2 Disclosures Pfizer Educational Grant for Learning and Change

3 ©2013 MFMER | slide-3 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

4 ©2013 MFMER | slide-4 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

5 ©2013 MFMER | slide-5 Targeted Testing for LTBI High Likelihood of Exposure to TBHigh Risk of Progression to Active TB High Likelihood of Exposure to TBHigh 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 TBHigh 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

6 ©2013 MFMER | slide-6 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

7 ©2013 MFMER | slide-7 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

8 ©2013 MFMER | slide-8 Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Alternative: 300 mg daily x 6 months 900 mg twice weekly x 9 months (DOT) 900 mg twice weekly x 6 months (DOT) LTBI Treatment Regimens Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Alternative: 300 mg daily x 6 months 900 mg twice weekly x 9 months (DOT) 900 mg twice weekly x 6 months (DOT) Isoniazid + RifapentineIsoniazid 900 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT) kg 300 mg kg 450 mg kg 600 mg kg 750 mg >50 kg 900 mg (maximum dose) MMWR. 2011;60(48): JAMA. 2005; 293:2776.

9 ©2013 MFMER | slide-9 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):

10 ©2013 MFMER | slide-10 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 Dec;365(23):

11 ©2013 MFMER | slide-11 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

12 ©2013 MFMER | slide-12 Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Alternative: 300 mg daily x 6 months 900 mg twice weekly x 9 months (DOT) 900 mg twice weekly x 6 months (DOT) LTBI Treatment Regimens Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Alternative: 300 mg daily x 6 months 900 mg twice weekly x 9 months (DOT) 900 mg twice weekly x 6 months (DOT) Isoniazid + RifapentineIsoniazid 300 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT) kg 300 mg kg 450 mg kg 600 mg kg 750 mg >50 kg 900 mg (maximum dose) Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Alternative: 300 mg daily x 6 months 900 mg twice weekly x 9 months (DOT) 900 mg twice weekly x 6 months (DOT) Isoniazid + RifapentineIsoniazid 900 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT) kg 300 mg kg 450 mg kg 600 mg kg 750 mg >50 kg 900 mg (maximum dose) RifampinRifampin 600 mg daily x 9 months Medication(s)Recommended Regimen IsoniazidPreferred: Isoniazid 300 mg daily x 9 months Alternative: 300 mg daily x 6 months 900 mg twice weekly x 9 months (DOT) 900 mg twice weekly x 6 months (DOT) Isoniazid + RifapentineIsoniazid 900 mg weekly x 12 weeks (DOT) + Rifapentine once weekly x 12 weeks (DOT) kg 300 mg kg 450 mg kg 600 mg kg 750 mg >50 kg 900 mg (maximum dose) RifampinRifampin 600 mg daily x 4 months Isoniazid + RifampinIsoniazid 300 mg daily x 3 months + Rifampin 600 mg daily x 3 months MMWR. 2011;60(48): JAMA. 2005; 293:2776.

13 ©2013 MFMER | slide-13 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

14 ©2013 MFMER | slide-14 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.

15 ©2013 MFMER | slide-15 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

16 ©2013 MFMER | slide-16 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

17 ©2013 MFMER | slide-17 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

18 ©2013 MFMER | slide-18 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

19 ©2013 MFMER | slide-19 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)

20 ©2013 MFMER | slide-20 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

21 ©2013 MFMER | slide-21 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 = months (variable) Pyrazinamide Potent sterilizing ability Non-pyrazinamide based regimen = 9 months

22 ©2013 MFMER | slide-22 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

23 ©2013 MFMER | slide-23 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

24 ©2013 MFMER | slide-24 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.

25 ©2013 MFMER | slide-25 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.

26 ©2013 MFMER | slide-26 Recommended Treatment Regimens for Drug-Susceptible Organisms ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11): 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 ;

27 ©2013 MFMER | slide-27 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.

28 ©2013 MFMER | slide-28 Treatment of Culture-negative Pulmonary TB ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77. Continuation phase is shortened to 2 months

29 ©2013 MFMER | slide-29 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.

30 ©2013 MFMER | slide-30 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

31 ©2013 MFMER | slide-31 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

32 ©2013 MFMER | slide-32 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 1 st 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%)

33 ©2013 MFMER | slide-33 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

34 ©2013 MFMER | slide-34 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

35 ©2013 MFMER | slide-35 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

36 ©2013 MFMER | slide-36 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

37 ©2013 MFMER | slide-37 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 ATS; CDC; IDSA. Treatment of Tuberculosis. MMWR 2003;52(RR-11):1-77.

38 ©2013 MFMER | slide-38 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

39 ©2013 MFMER | slide-39 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 > mg/kg or EMB with renal failure

40 ©2013 MFMER | slide-40 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

41 ©2013 MFMER | slide-41 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

42 ©2013 MFMER | slide-42 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 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 Dec;365(23): 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

43 ©2013 MFMER | slide-43 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 Dec 9;60(48):

44 ©2013 MFMER | slide-44 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):

45 ©2013 MFMER | slide-45 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


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