TB Grand Rounds Reynard McDonald, MD & Henry Fraimow, MD January 30, 2007 Outline Overview of 2006 ATS statement regarding hepatotoxicity of anti-tb therapy Case examples highlighting management of patients with drug-induced hepatitis Question and answer segment 1
Speaker: Reynard McDonald, MD Medical Director, NJMS Global Tuberculosis Institute Professor of Medicine at New Jersey Medical School Chairman of New Jersey TB Medical Advisory Board Medical Consultant for regional chest clinics in NJ Consults with provider on every multi-drug resistant case of TB in the state Background (1) Drug induced hepatitis is defined as serum AST level >3x upper limits of normal (ULN) in presence of symptoms or >5x ULN in absence of symptoms INH, RIF, and PZA are all potential causes of hepatic injury and should be stopped immediately if hepatitis occurs Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol ATS, CDC, & IDSA. Treatment of Tuberculosis. MMWR 2003;52(No. RR-11):43-45 2
Background (2) 2 or more non-hepatotoxic anti-tb medications, such as EMB, SM, Amikacin/Kanamycin, Capreomycin, or a fluoroquinolone (Levofloxacin or Moxifloxacin) may be used until cause of hepatitis is identified Once AST level decreases to <2x ULN and symptoms have significantly improved, restart 1st-line medications in sequential fashion Close monitoring, with repeat measurement of serum AST and bilirubin and symptom review, is essential in managing these patients ATS, CDC, & IDSA. Treatment of Tuberculosis. MMWR 2003;52(No. RR-11):43-45 Levels of Toxicity Mild toxicity AST level <5x ULN Moderate toxicity AST level 5 10x ULN Severe toxicity AST level >10x ULN ATS, CDC, & IDSA. Treatment of Tuberculosis. MMWR 2003;52(No. RR-11):43-45 3
Patient History GA is 65 y/o Filipino female nurse with a ductal carcinoma of right breast Patient presented to hospital in Dec. 2003 for right mastectomy While in the hospital, patient was found to have an abnormal CXR Bronchoscopy was done of which smears were negative and cultures grew pansensitive TB Mid-Jan. 2004, patient developed nausea/vomiting with symptoms worsening until Feb. 2004 Lab Results & Clinical Course 1-3-04 1-9-04 2-25-04 3-3-04 Treatment started with RIPE AST 24 ALT 14 AST 399 ALT 598 AST 186 ALT 370 AP 86 AP 116 AP 88 TB 0.47 TB 5.59 TB 4.7 DB 3.54 DB 3.7 Started INH, EMB, Levaquin 1-21-04: Patient complained of nausea/vomiting 2-28-04: RIPE stopped 4
Lab Results & Clinical Course 3-8-04 AST 68 ALT 142 AP 90 TB 3.9 DB 1.2 Continued INH, EMB, Levaquin; added PZA 3-10-04 AST 815 ALT 583 AP 94 TB 5.6 DB 1.7 PZA stopped; continued INH, EMB, Levaquin 3-12-04 AST 483 ALT 488 AP 86 TB 6.2 DB 0.2 3-17-04 AST 86 ALT 184 AP 76 TB 3.4 DB 1.5 Continued INH, EMB, Levaquin; added RIF 3-9-04: Patient complained of nausea/vomiting Lab Results & Clinical Course 3-19-04 AST 52 3-23-04 AST 34 4-23-04 AST 21 10-3-04 INH, RIF stopped ALT 114 ALT 58 ALT 8 AP 63 AP 79 AP 69 TB 4.2 TB 3.2 TB 1.0 DB 2.1 DB 1.5 DB 0.4 3-26-04: Stopped RIF, EMB, INH, Levaquin daily; started INH, RIF 2x weekly 5
6 11-12-04 6-14-04 7-9-04 8-6-04 5-6-05 9-24-04 8-27-04 5-14-04 4-23-04 3-23-04 3-1-04 M.tb 1-23-04 S:RIPES M.tb Bron. Wash 12-17-03 Sensitivities Culture Smear Specimen Date Bacteriology Bacteriology Questions & Comments Questions & Comments
Recommendations Regarding TB Drug-Induced Liver Injury (DILI) ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. Hepatotoxicity of Anti-TB Therapy An increase in ALT is more specific for hepatocellular injury than an increase in AST An increase in AST may also signify an abnormality in muscle, heart or kidney ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. 7
Pretreatment Clinical Evaluation Obtain history that includes risk factors for hepatotoxicity Evaluate for signs of liver disease (e.g., liver tenderness, hepatosplenomegaly, jaundice, caput medusa, spider angiomata, ascites, edema) Review previous lab values when available Consider screening for viral hepatitis for ID users, people born in endemic areas (i.e., Asia, Africa, Pacific Islands, Eastern Europe, Amazon Basin), HIV-infected, chronic hemodialysis patients, those with occupational exposure to infected blood, etc. ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. Patient Education Provide culturally and linguistically-appropriate printed instructions to patients Instruct patients to: Stop medications in case of hepatitis symptoms (nausea, vomiting, abdominal discomfort, unexplained fatigue, etc.) and contact clinic Keep follow-up appointments Avoid alcohol use and other hepatotoxic medications (over-the-counter and prescription) ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. 8
Treatment of TB Disease: Regimen Selection Treatment without PZA might utilize INH & RIF for 9 mos. with EMB until drug susceptibility testing is completed Consider RIF and EMB with fluoroquinolone or cycloserine for 12-18 mos. in patients with cirrhosis EMB with a fluoroquinolone, cycloserine, and capreomycin or aminoglycoside for 18-24 mos. may be an option for patients with encephalopathic liver disease Aminoglycosides are avoided in severe, unstable liver disease due to concerns about renal insufficiency or bleeding from injected medications in patients with thrombocytopenia or coagulapathy ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. Treatment of TB Disease: Clinical Monitoring Face-to-face monthly assessments and patient education for adverse drug events are essential DOT enhances treatment adherence and monitoring ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. 9
Treatment of TB Disease Baseline Testing & Biochemical Monitoring Baseline transaminases, bilirubin, alk. phos., and creatinine and a blood platelet count are recommended Periodic measurement of PT and INR to assess hepatic synthesis function in patients with pre-existing severe liver disease Periodic measurements during treatment should be made when baseline abnormalities are present and for patients who chronically consume alcohol, take other potentially hepatotoxic medications, or who have viral hepatitis or history of liver disease, HIV infection, or prior TB DILI ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. Treatment of TB Disease Interventions for Hepatotoxicity 1st-line drugs, especially RIF, should not be discontinued for mild GI complaints Stop medications immediately and evaluate patient promptly if transaminase levels >5x ULN (with or without symptoms) or >3x ULN with jaundice and/or hepatitis symptoms Test for hepatitis A, B, and C viruses and evaluate patient for biliary disease, alcohol use, and other hepatotoxic drugs Some experts recommend interrupting treatment for lesser increases in patients with cirrhosis or encephalopathy Treat with at least 3 anti-tb agents less likely to cause hepatotoxicity until specific causes of abnormalities can be determined ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. 10
Treatment of TB Disease: Rechallenge After ALT returns to <2x ULN, RIF may be restarted with or without EMB After 3-7 days, INH may be reintroduced, subsequently rechecking ALT If symptoms recur or ALT increases, the last drug added should be stopped Rechallenge with PZA may be hazardous for patients who experience prolonged or severe hepatotoxicity but tolerate reintroduction with RIF and INH. PZA may be discontinued permanently and treatment extended to 9 mos. ATS. Amer J Respir Crit Care Med. 2006; 174:935-952. Treatment of TB Disease: Patient History JG is 32 y/o post partum (2 mon.) graduate student who emigrated to the US in Sept. 2000 from China In Jan. 06 she had a TST placed as part of a school admission examination and her result was positive (>30mm) A CXR and chest CT scan were done and were reported to be abnormal (interstitial infiltrates particularly in upper lung zones) 11
CXR 1-3-06 CT 1-9-06 12
Smear and Culture Results samples were smear positive for AFB Culture grew M.tb that was pansusceptible to all 1 st line drugs and she was started on DOT with RIPE Bacteriology Findings Date Specimen Smear Culture 1-18-06 2+ M.tb 1-19-06 2+ M.tb 2-10-06 Positive M.tb 2-11-06 Positive M.tb 2-21-06 M.tb 2-22-06 Positive M.tb 3-14-06 M.tb 4-11-06 5-11-06 5-17-06 7-11-06 8-08-06 9-05-06 13
Drug-O-Gram Questions & Comments 14
Speaker: Henry Fraimow, MD Infectious Disease Specialist at Cooper University Hospital in Camden, NJ Provides inpatient and outpatient general ID and HIV care Conducts research in antimicrobial activity mechanisms of action and resistance Medical Consultant at Camden County Chest Clinic Founding member of New Jersey TB Medical Advisory Board Patient History 48 y/o U.S. born male referred to the Camden Chest Clinic in 9/06 Named as a contact to infectious TB case Spent 4 hours during dinner at friend s house, another guest was subsequently diagnosed as smear + pulm/laryngeal TB 9/23/06: TST was administered (4 weeks post exposure) 15 mm No history of prior TST or exposure to TB 15
Physical Examination 10/11/06: patient evaluated at Camden Chest Clinic (6 weeks post exposure) C/o mild to moderate cough x1 month productive of clear sputum, + allergies, denied constitutional symptoms PMHx: Hypertension, Borderline DM Meds: Lisinopril, Allegra Exam: Wt. 310 lbs., Temp 99.3, otherwise normal 16
Questions & Comments Smear Results AFB smear and culture x3 sent (1 st one collected in the clinic) on 10/11, subsequent specimens collected on 10/12, 10/13 Treatment deferred pending results of sputum specimens Clinic notified that all specimens smear negative 17
Culture Results & Evaluation Clinic notified at 3 weeks (11/6/06) that 2 of 3 cultures now growing M.tb; ultimately all 3 specimens grew 11/8/06: patient re-evaluated at Chest Clinic Cough better, no new symptoms Temp 99.1, Wt 319 lbs, exam otherwise unchanged 18
Questions & Comments 19
Laboratory Results New sputum x3 sent Baseline labs obtained AST 31, ALT 45 (ULN 40), Bili 0.5, AlkP 51 Treatment with IRPE initiated with DOT All new specimens smear negative Questions & Comments 20
Response to Treatment (1) 11/22/06: clinic visit (2 weeks of IRPE) Afebrile, Wt. 316 lbs Cough decreased, no other new symptoms No GI symptoms 12/20/06: clinic visit (6 weeks of IRPE) Clinically unchanged, no new symptoms Isolate pan-sensitive Ethambutol D/C d DNA fingerprint identical to the Index Case Second set of cultures (11/6, 11/7, 11/8) all negative Response to Treatment (2) 1/8/07: patient called to complain of 2 day hx of initially diarrhea then 1 day of vomiting, dark urine, fever IRP held, patient evaluated in Chest Clinic and lab studies done ALT 789, AST 241, GGT 100, AlkP 46, Bili 0.5 Remained off meds On 1/16/07, repeat labs ALT 366, AST 92, normal AlkP and Bili 21
Follow-Up On 1/24/07, patient seen by field worker, reported feeling better, and remains off meds Repeat labs: ALT 183 AST 68 Next clinic visit: 1/31/07 What to do now? Final Comments Thank you!!! 22