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Tuberculosis Update

Tuberculosis Update. Jacqueline Peterson Tulsky, MD Pacific AETC Associate Clinical Professor, UCSF San Francisco General Hospital Positive Health Program. March 2004. Summary of Points. 1. Latent Tuberculosis Infection (LTBI) Rifampin + Pyrazinamide (PZA) for 60 doses

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Tuberculosis Update

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  1. Tuberculosis Update Jacqueline Peterson Tulsky, MD Pacific AETC Associate Clinical Professor, UCSF San Francisco General Hospital Positive Health Program March 2004

  2. Summary of Points 1. Latent Tuberculosis Infection (LTBI) • Rifampin + Pyrazinamide (PZA) for 60 doses NOT RECOMMENDED ANY MORE 2. Active TB Treatment • Avoid rifapentine • Caution with twice weekly rifampin or rifabutin • Stay calm in the face of immune reconstitution

  3. TB Screening

  4. TB Screening • Still important to do TB skin test on a 6-12 month routine basis • Frequency tied to TB risk factors • Symptom review, not x-ray for prior PPD positives • No anergy panels

  5. Quantiferon™ (QFT) • Blood test looking for immune response to TB antigen • Not yet approved for HIV-infected persons • Not useful for diagnosing M. avium disease

  6. Tuberculosis Screening Flowchart At-risk person Tuberculin test + symptom review Negative Positive Chest x-ray Normal Abnormal Possible Candidate for Rx of latent TB Treatment not indicated Evaluate for active TB

  7. Screening for TuberculosisChest Radiograph • To screen for active TB, obtain chest radiographs without waiting for TB skin test results • But, advanced AIDS patients can have active TB and normal chest radiographs

  8. Treatment of Latent Tuberculosis Infection(LTBI)ATS/CDC/IDSA GuidelinesMMWR August 8, 2003

  9. Isoniazid Therapy for LTBI HIV (+) Patients Location Regimens Reduction in TB Haiti* 12 mo INH vs placebo 83% Uganda 6 mo INH vs placebo 70% Zambia* 6 mo INHvs placebo70% Kenya* 6 mo INH vs placebo 40% *These trials also included a TST (-) study arm in which no protection was observed

  10. Treatment of LTBI: Current Guidelines Regimen Duration Interval Comments (months) Isoniazid 9 Daily Preferred regimen Twice-wkly DOT necessary Isoniazid 6 Daily Not for HIV+ Twice-wkly Not for HIV+; DOT necessary Rifampin 4 DailyFor INH-R ATS/CDC AJRCCM 2000;161:S221

  11. Treatment of LTBI: Current Guidelines • Rifampin or Rifabutin and PZA for 60 doses is contraindicated in all patients needing treatment for LTBI. (Rifampin or Rifabutin and PZA still okay for use in active TB with 1 or 2 other drugs.)

  12. More Severe Hepatotoxicity

  13. Rifampin plus PZA Hepatoxicity In 30 months ending June, 2003: • 48 cases of severe liver injury • 37 recovered • 11 died • Most deaths had onset of liver injury in 2nd month • 2 deaths in HIV positive persons CDC. MMWR, August 8, 2003

  14. Rifampin plus PZA Hepatotoxicity Hepatotoxicity RIF/PZA INH OR* (95% CI) N=307 N=282 Grade 1/2/3 45 (15%) 30 (11%) Grade 4† 9 (3%) 2 (1%) 8.05 (1.76-36.76) Total 54 (18%) 32 (11%) 1.65 (1.00-2.75) † Grade 4 toxicity - ALT ≥ 500 U/L or ≥ 250 with symptoms Jasmer et al. Ann Intern Med 2002;137:640-647.

  15. Treatment of LTBI (normal CXR) • HIV-negative persons • INH for 9 months is preferred over 6 months • HIV-negative persons • INH for 9 months • HIV-negative and HIV-positive persons • Rifampin for 4 months

  16. Treatment of LTBI: Stable Fibrotic Scarring • Acceptable regimens after active TB is ruled out: • INH for 9 mos* • Rifampin  INH for 4 months *preferred in HIV+ ATS/CDC AJRCCM 2000;161:S221

  17. Treatment of LTBI:Monitoring • Routine baseline and follow-up liver function tests in: • HIV infection • Others with increased risk of hepatitis • Emphasis is on clinical monitoring for signs and symptoms of drug side effects

  18. Treatment of LTBIMonitoring for INH-induced Hepatitis Increased risk for hepatitis?* Yes No Check baseline LFTs Monthly symptom review Abnormal Normal < 4 X upper limit of normal ≥ 4 X upper limit of normal *HIV + Pregnant/postpartum Chronic liver disease Alcohol abuse Give INH and repeat LFTs periodically Hold INH

  19. Treatment of TuberculosisATS, CDC, IDSAMMWR June 20, 2003/52(RR11);1-77www.cdc.gov/mmwr

  20. Active TB and HIV • Ensure completion of therapy (essential) • Treatment of TB/HIV is the same as for HIV-negative persons except: • Once-weekly rifapentine regimens cannot be used • Twice-weekly rifampin or rifabutin should not be used if the CD4 cell count is < 100 cells/ul • Be alert for drug interactions and paradoxical reactions

  21. Ensuring Completion of Treatment is Essential “The responsibility for successful treatment is clearly assigned to the public health program or private provider, not to the patient.” “It is strongly recommended that the initial treatment strategy utilize patient-centered case management with an adherence plan that emphasizes direct observation of therapy.”

  22. Adherence: Concepts Reach = Contact + Connect • Easy to Contact /Hard to Connect e.g.: Homeless, IDUs, street youth, inmates • Hard to Contact/Easy to Connect e.g.: Undocumented immigrants, foreign language

  23. Adherence: Concepts Corollaries of “Hard-to-Reach” • Provider-resistant patients • Patient-resistant providers • Patient-resistant systems and institutions * Rubel AJ and Garro LC. Public Health Reports, 1992;Vol 107

  24. Treatment of Tuberculosis • Use 4 drugs until sensitivity results are available (RIPE) • Intitial phase: 3 drugs for 2 months • Continuation phase: 2 drugs for 4 or 7 months Continuation phase: dosing is usually two or three times per week UNLESS ADVANCED HIV (requires daily dosing)

  25. Treatment of Tuberculosis • RIPE – Rifampin*/Isoniazid/ Pyrazinamide/Ethambutol • Initial phase if known pan-sensitive: 3 drugs RIP* • Continuation phase: 2 drugs (usually RI*) * In patients on antretroviral therapy for HIV, rifampin may be contraindicated; rifabutin may be substituted

  26. Treatment of HIV and TB If CD4 count <100 cells/ml • Daily TB therapy is strongly recommended HIV positive at any stage of infection • Once-weekly Rifapentine plus INH is NOT recommended in continuation phase of treatment

  27. Treatment of HIV and TB(One possible strategy) Start 4-drug TB regimen On HAART No Yes Continue and adjust dosages CD4 200-350 CD4 <200 CD4 > 350 Begin HAART in 2 wks Begin HAART in 2 mos No HAART

  28. HIV and TB: Drug-Drug Interactions • Antiretroviral Drugs and TB drugs • NRTIs okay • NNRTI and PIs may interact with TB drugs due to liver metabolism

  29. TB and HIV: Drug-Drug Interactions Rifamycins Increase in rifabutin serum concentration* Rifampin > rifapentine > rifabutin Inducers of CYP3A Inhibitors of CYP3A Decrease in PI and NNRTI concentration Delavirdine and PIs *Rifampin and rifapentine are not substrates of CYP3A

  30. TB and HIV: Drug-Drug Interactions Protease Inhibitor Rifabutin Antiretroviral Regimen* Dose Dose Amprenavir or 150 mg daily or No change Fosamprenavir 300 mg tiw Atazanavir 150 mg qod or tiw No change Indinavir 150 mg daily or Consider  to 1000mg q 8 h 300 mg tiw Nelfinavir 150 mg daily or Consider  to 1000 mg q8 h 300 mg tiw Saquinavir Rifabutin and saquinavir should not be used together * + 2 nucleosides CDC Guidelines, 1/20/04

  31. TB and HIV: Drug-Drug Interactions Protease Inhibitor Rifabutin Antiretroviral Regimen Dose Dose Ritonavir* 150 mg qod or tiw No change Lopinavir/ritonavir* 150 mg qod or tiw No change Ritonavir (any dose) 150 mg qod or tiw with saquinavir, indinavir, amprenavir, fos-amprenavir, or atazanavir* * + 2 nucleosides and/or NNRTI CDC Guidelines, 1/20/04

  32. Treatment of HIV-related TuberculosisDrug-Drug Interactions Antiretroviral Rifabutin Antiretroviral Regimen Dose Dose NNRTIs Efavirenz* 450 mg daily or 600 mg tiw No change Nevirapine* 300 mg daily or tiw No change Delaviridine Rifabutin and delavirdine should not be used together NRTIs 2-3 nucleosides 300 mg daily or biw No change PI + NNRTI Efavirenz or nevirapine 300 mg daily or biw Consider  + PI (except ritonavir) dose of indinavir * + 2 nucleosides Burman and Jones. AJRCCM 2001;162:7

  33. HIV and TBDrug-Drug Interactions • Rifampin-based regimens: • PIs • Ritonavir (600 mg bid) + usual dose Rifampin (600 mg) • Rifampin should not be used with unboosted PIs or with low-dose ritonavir/PI combinations • NNRTIs • Efavirenz (800 mg daily) + usual dose Rifampin (600 mg) • Nevirapine (200 mg bid) + usual dose Rifampin (600 mg) (limited data) • Rifampin and delavirdine should not be used together CDC Guidelines, 1/20/04

  34. Case 35 year old woman with AIDS and CD4=45 developed active TB. TB treated with 4 drugs, then 3 drugs for 1 month by DOT. Thoughtful HIV specialist saw pt, they agreed together to start HIV treatment with AZT/3TC/Indinavir. TB clinic changed patient from _________ to ________ and decreased the dose by half.

  35. Case TB clinic changed patient from Rifampin 600mg daily to Rifabutin 150mg daily (half the normal dose).

  36. Case In follow-up after 1 more month, patient decreased from 3 drugs to 2 drugs for TB. 4 months after initial diagnosis, the TB staff note patient has cough, weight loss, and fever. Chest x-ray suggests recurrent TB infection. What is the key question in this patient’s medication history?

  37. Case • ARE YOU STILL TAKING YOUR ARV THERAPY? • WHY IS THIS SO IMPORTANT?

  38. TB and HIV Drug-Drug Interactions Protease Inhibitor Rifabutin Antiretroviral Regimen Dose Dose Indinavir 150 mg daily or Consider  to 1000mg q 8 h 300 mg tiw SO, if this patient is NOT TAKING Indinavir, the Rifabutin dose is TOO LOW. TB resistance can develop within 30 days if on single drug therapy!! MUST COORDINATE HIV and TB MEDS

  39. Treatment of HIV and TB Start 4-drug TB regimen On HAART No Yes Continue and adjust dosages CD4 200-350 CD4 <200 CD4 > 350 Begin HAART in 2 wks Begin HAART in 2 mos No HAART

  40. Paradoxical ReactionsImmune Restoration Syndromes • Paradoxical reaction - transient worsening of condition after initiation of treatment; not the result of treatment failure • Common manifestations (new or worsening): • Adenopathy • Pulmonary infiltrates • Serositis • Cutaneous or CNS lesions (spots)

  41. Paradoxical ReactionWorsening Radiograph

  42. Paradoxical ReactionsImmune Restoration Syndromes • Three case series: 6-36% occurrence • Median 15 days after starting ARV therapy • Most patients have advanced HIV disease • median CD4 cell count of 35 cells/ mm3 • median viral load > 500,000 copies/ml

  43. Paradoxical ReactionsManagement • Diagnosis of exclusion • DDx: Treatment failure, drug toxicity, other infection • Often start treatment for presumed relapse or reactivation • Severe reactions • Corticosteroids or • Hold ARV therapy (controversial)

  44. Extrapulmonary TB Disease • More common as HIV advances • Must rule out pulmonary disease • Guidelines recommend treatment for 9-12 months in patients with: • Meningeal TB • Corticosteroids may be useful in some forms of extrapulmonary TB

  45. Summary of Points 1. Latent Tuberculosis Infection (LTBI) • Rifampin + PZA NOT RECOMMENDED 2. Active TB Treatment • Avoid rifapentine • Caution with twice weekly rifampin or rifabutin (daily treatment if CD4 <100) • Stay calm in the face of immune reconstitution

  46. TB Update 2003 jtulsky@php.ucsf.edu or www.cdc.gov/mmwr/

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