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Tuberculosis Treatment

Tuberculosis Treatment. Jennifer Whitaker, MD, MS Infectious Diseases Midwest Fellows’ Forum, Mayo Clinic, Rochester April 26, 2014. Disclosures. Pfizer Educational Grant for Learning and Change. Objectives. Review the treatment regimens for latent TB infection (LTBI)

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Tuberculosis Treatment

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  1. Tuberculosis Treatment Jennifer Whitaker, MD, MS Infectious Diseases Midwest Fellows’ Forum, Mayo Clinic, Rochester April 26, 2014

  2. Disclosures • Pfizer Educational Grant for Learning and Change

  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. 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. Targeted Testing for LTBI

  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. Which LTBI treatment regimens require directly observed therapy (DOT)? • Daily isoniazid x 9 months • Twice weekly isoniazid x 9 months • Daily rifampin x 4 months • Weekly isoniazid + rifapentine • B & D

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

  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? • 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 • Pregnant females • HIV-infected individuals on antiretroviral therapy • A & C • A & B MMWR. 2011;60(48):1650-3.

  10. Isoniazid (INH) + Rifapentine (RPT) • INH/RPT weekly x 3 mo (DOT) noninferiorto 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

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

  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. 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 RespirCrit Care Med. 2000;161(4 Pt 2):S221.

  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. 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. 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. Treatment of Drug-Susceptible TB Disease

  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. 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. 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 sterilizingability • Non-pyrazinamide based regimen = 9 months

  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 2003. http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf

  23. In what cases should the continuation phase of TB therapy be prolonged from 4 months to 7 months? • HIV co-infection • Cavitary disease with positive cultures at end of initiation phase • Initiation regimens of Isoniazid, Rifampin, and Ethambutol, without use of PZA • B and C

  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. http://www.cdc.gov/MMWR/PDF/rr/rr5211.pdf

  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, cavitarydisease, or HIV infection ChaulkCP, 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. 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

  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. 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.

  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. 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. Rifampin Drug Interactions • Rifampin induces its own metabolism during the first 2 weeks • Induces cytp450 system & decreaseslevels of: • Steroids,OCP/estrogen • Protease inhibitors • Warfarin • Antiepileptics • Methadone, morphine • Digoxin, calcium channel blockers, β-blockers • Azoles + many others

  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 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%)

  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. 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. 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. 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. 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. 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. 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

  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. 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. 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? CurrHIV/AIDS Rep. 2012 September ; 9(3): 259–266. • Targeted tuberculin testing and treatment of latent tuberculosis infection. (ATS/CDC/IDSA). Am J RespirCrit Care Med. 2000;161(4 Pt 2):S221. • Sterling TR, Villarino ME, BorisovAS, 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.Treatmentof 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. Which LTBI treatment regimens require directly observed therapy (DOT)? • Daily isoniazid x 9 months • Twice weekly isoniazid x 9 months • Daily rifampin x 4 months • Weekly isoniazid + rifapentine • B & D JAMA 2005; 293:2776 MMWR. 2011 Dec 9;60(48):1650-3.

  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? • 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 • Pregnant females • HIV-infected individuals on antiretroviral therapy • A & C • A & B MMWR. 2011;60(48):1650-3.

  45. In what cases should the continuation phase of TB therapy be prolonged from 4 months to 7 months? • HIV co-infection • Cavitary disease with positive cultures at end of initiation phase • Initiation regimens of Isoniazid, Rifampin, and Ethambutol, without use of PZA • B and C

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