1. TB Update 2003 Jacqueline Peterson Tulsky, MD with thanks to Charles Daley, MD and Robert Jasmer, MD SF TB control and SFGH Pulmonary Department jtulsky@php.ucsf.edu Or www.cdc.gov/mmwr/

2. Summary of Points 1. Latent Tuberculosis Infection (LTBI) Rifampin and 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. 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 approved for HIV-infected persons Not useful for diagnosing M. avium disease

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

7. Screening for Tuberculosis Chest Radiograph To screen for active TB you should still perform chest radiographs

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

9. Isoniazid Therapy for LTBI HIV (+) Patients Location RegimensReduction in TB Haiti* 12 mo INH vs placebo83% Uganda6 mo INH vs placebo70% Zambia*6 mo INH 2 vs placebo 2 70% Kenya*6 mo INH vs placebo40% *These trials also included a TST (-) study arm in which no protection was observed

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

11. What Happened to Rifampin and PZA for 60 doses for Treatment of LTBI????

12. An immigrant was tested and found to be PPD positive. The follow-up chest xray was normal and the patient was recommended for LTBI Denied hepatitis history or alcoholism Offered and accepted short course therapy with 60 doses of Rifampin/PZA Provided meds by DOT without complaints until last week of therapy Severe hepatitis requiring hospitalization

13. The patient had missed 2 clinic appointments during the course of treatment. No labs during the course of the Rifampin/PZA, should have had labs twice. “However, because the patient did not speak English, comprehension might have been a barrier.”

14. New Guidelines For Treatment of LTBI April, 2000 – Safety and efficacy of 60 doses of Rifampin and PZA lead to its recommendation October, 2000 – 1 patient dies, surveillance starts October, 2000 to June, 2002 – Cohort data collected on Rifampin/PZA patients

15. More Severe Hepatotoxicity

16. Rifampin and 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

17. Rifampin/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.

18. Treatment of LTBI As of August, 2003 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.)

19. Treatment of LTBI (normal xray) HIV (–) persons –INH for 9 months is preferred over 6 HIV (+) persons –INH for 9 months HIV (–) and HIV (+) persons –Rifampin for 4 months

20. Treatment of LTBI Stable Fibrotic Scarring Acceptable regimens after active TB checked for include: –9 mos of INH* –4 months of rifampin  INH *preferred in HIV+ ATS/CDC AJRCCM 2000;161:S221

21. Treatment of LTBI Monitoring Elimination of routine baseline and follow- up liver function tests, except: –HIV infection –Others with increase risk hepatitis Emphasis is on clinical monitoring for signs and symptoms of drug side effect

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

23. Treatment of Tuberculosis ATS, CDC, IDSA MMWR June 20, 2003/52(RR11);1-77 www.cdc.gov/mmwr

24. Active TB and HIV 1.Ensuring completion of therapy is essential 2.Treatment of TB/HIV is the same as for HIV negative persons except: lOnce-weekly rifapentine regimens cannot be used lTwice-weekly rifampin or rifabutin should not be used if the CD4 cell count is < 100 cells/ul 3.Be alert for drug interactions and paradoxical reactions

25. Ensuring Completion 15 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.”

26. Adherence Related Concepts Reach = Contact + Connect Easy to Contact /Hard to Connect ex: Homeless, IDUs, Street Youth, Inmates Hard to Contact/Easy to Connect ex: Undocumented immigrants, foreign language

27. Definitions 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

28. Treatment of Tuberculosis 1.Four drugs until sensitivities of cultures back (RIPE) 2.Intitial phase: 3 drugs until 2 months passes 3.Continuation phase: 2 drugs (usually ____ and ______) for 4 or 7 months Continuation phase usually becomes two or three times a week dosing…..UNLESS ADVANCED HIV

29. Treatment of Tuberculosis 1. RIPE – Rifampin/Isoniazid/Pyrazinamide/Ethambutol 2.Intitial phase: 3 drugs RIP 3.Continuation phase: 2 drugs RI Continuation phase usually becomes two or three times a week dosing…..UNLESS ADVANCED HIV

30. Treatment of HIV and TB Strongly recommend daily therapy if CD4 count <100 cells/ml HIV positive at any stage of infection - The continuation phase of treatment with weekly (yes weekly!) Rifapentine and INH NOT recommended

31. HIV and TB Drug-Drug Interactions Antiretroviral Drugs and TB drugs –NRTIs and NRSI okay –NNRTI and PIs some interaction due to liver metabolism

32. TB and HIV Drug-Drug Interactions Rifamycins Decrease in PIs and NNRTIs (L & S on speed) Rifampin > rifapentine > rifabutin Inducers of CYP3A Increase in serum concentration rifabutin* (L & S after lunch) Delavirdine and PIs Inhibitors of CYP3A *Rifampin and rifapentine are not substrates of CYP3A

33. TB and HIV Drug-Drug Interactions Protease Inhibitor Rifabutin Antiretroviral Regimen Dose Dose Nelfinavir, indinavir, 150 mg daily or nelfinavir-consider  to or amprenavir* 1500 mg q12hr 300 mg intermittently indinavir-consider  to 1000 mg q 8hrs amprenavir-no change Saquinavir* 300 mg daily or No change intermittently Ritonavir** 150 mg biw No change Lopinavir/ritonavir** 150 mg biw No change *+ 2 nucleosides ** + 2 nucleosides and/or NNRTI Burman and Jones. AJRCCM 2001;162:7

34. Treatment of HIV-related Tuberculosis Drug-Drug Interactions Antiretroviral Rifabutin Antiretroviral Regimen Dose Dose Nonnucleosides Efavirenz* 450-600 mg daily or biw No change Nevirapine* 300 mg daily or intermittently No change Nucleosides 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

35. HIV and TB Drug-Drug Interactions Rifampin-based regimens: –Ritonavir (600 mg bid) + Normal dose Rifampin (600 mg) –Efavirenz (800 mg daily) + Normal dose Rifampin (600 mg) –Do not use rifampin with low-dose ritonavir/PI combinations. Burman and Jones. AJRCCM 2001;162:7

36. 35 year old woman with AIDS and CD4 of 45 developed active TB. Treated with 4 drug, then 3 drugs for 1 month by DOT. Thoughtful HIV specialist saw pt, they agreed together to start AZT/3TC/Indinavir. TB clinic changed patient from _________ to ________ and decreased the dose by half.

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

38. 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 coughing, losing weight and finally has a fever. Chest x-ray shows recurrent TB infection. What is the key question in this patient’s medication history?

39. ARE YOU STILL TAKING YOUR ARV THERAPY? WHY IS THIS SO IMPORTANT?

40. TB and HIV Drug-Drug Interactions Protease Inhibitor Rifabutin Antiretroviral Regimen Dose Dose Nelfinavir, indinavir, 150 mg daily or or amprenavir* 300 mg intermittently indinavir-consider to 1000 mg q 8hrs SO, if NOT TAKING Indinavir, Rifabutin dose IS TOO LOW. TB resistance can develop within 30 days if on single drug therapy!! MUST COORDINATE HIV and TB MEDS

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

42. Paradoxical Reactions Immune 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)

43. Paradoxical Reaction Worsening Radiograph

44. Paradoxical Reactions Immune 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/ mm 3 –median viral load > 500,000 copies/ml

45. Paradoxical Reactions Management Diagnosis of exclusion –Treatment failure, drug toxicity, other infection –Often start treatment for presumed relapse or reactivation Severe reactions –Corticosteroids or –Hold ARV therapy (Controversial)

46. Extra pulmonary TB Disease More common as HIV advances Be sure to rule out pulmonary disease Guidelines recommend 9-12 months in patients with: –Meningeal TB Corticosteroids may be useful in some forms of extrapulmonary TB

47. Summary of Points 1. Latent Tuberculosis Infection (LTBI) Rifampin and 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

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