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Drug Induced Liver Injury Network

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  • 1. Drug Induced Liver Injury Network (DILIN) Prospective Study: Initial Results Naga Chalasani, MD for the Drug Induced Liver Injury Network
  • 2. Background
    • Although DILI is a rare clinical event, it is the most common cause of acute liver failure in the US
    • DILI is one of the most common causes for medication withdrawal or lack of approval by the FDA
    • A significant barrier for drug development
  • 3. Background
    • Its epidemiology, etiopathogenesis, diagnosis, and natural history are poorly understood
    • DILIN is a federally funded consortium of 5 clinical centers and DCC
  • 4. DILIN
    • Duke Clinical Research Institute (PI – Rochon)
    • U. Conn (PI - Bonkovsky)
    • U. Mich (PI - Fontana)
    • IU (PI- Chalasani)
    • UNC (PI- Watkins)
    • UCSF (PI-Davern)
    • NIDDK (Serrano, Seeff, Hoofnagle)
    Clinical Centers Data Coord. Ctr.
  • 5. DILIN: Scope of Recruitment ~12.8 million lives UCSF U Mich IU U Conn UNC
  • 6. Aim
    • To report the initial findings of the etiology and clinical characteristics of patients with drug induced liver injury (DILI) enrolled into the “DILIN Prospective Study”
  • 7. DILIN Prospective Study
    • Multicenter, prospective, and observational study
    • Patients with suspected idiosyncratic DILI with no competing etiology occurring within 6-months are eligible
    • DILI due to acetaminophen were not included
  • 8. Eligibility Criteria
    • Children ≥ 2 years and adults
    • Pre-defined biochemical criteria
    • - AST or ALT > 5 ULN twice consecutively
    • - Alk Phos > 2 ULN twice consecutively
    • - Bilirubin ≥ 2.5 mg/dl
    • - Specific criteria for patients with pre- existing liver disease
  • 9. Methods
    • Patients were seen in the GCRC
    • Patients followed up to 24 months depending on their biochemistries at 6 months after enrollment
    • Extensive baseline evaluations to exclude competing etiologies
    • Samples of serum, urine, DNA, and peripheral lymphocytes
  • 10. Causality Assessment
    • A panel of study hepatologists systematically assessed the strength of causal relationship between implicated agent and liver injury
    • RUCAM, DILIN-specific causality grading, data completeness forms are filled by 3 hepatologists
    • Causality finally assessed based on consensus
  • 11. Chronic DILI
    • Persistent biochemical abnormalities at 6 months following the onset of acute DILI
    • Histological or radiological or clinical evidence of chronic liver disease at 6 months
    • Patients with known HCV or HBV or cirrhosis were not assessed for chronic DILI
  • 12. Total Enrollment (9/04 – 8/06)
    • Although 233 patients were enrolled, data from
    • 169 patients were available for this presentation
    233 Total 53 52 35 54 39 Total UNC Michigan UCSF Indiana U Conn
  • 13. Demographics 13% African-Americans 16% Pre-existing liver disease 9% Children 27 ± 7 BMI (Kg/m2, mean ± S.D.) 60% Females 48.3 ± 18.6 Age (mean ± S.D.)
  • 14. Pattern of Liver Injury 53% Hepatocellular 22% Cholestatic 25% Mixed Percent
  • 15. Implicated DILI Drugs / CAM 22 Multiple Drugs / CAM 74 Single Rx Drug 4 Single CAM %
  • 16. Drug Class for Single Implicated Agent 7 Anticonvulsants 4 Antidepressants 4 NSAIDs 4 Antineoplastics 40 Antimicrobials % Drug Class 6 CAM Products 22 Others 5 Peptide-biologics 3 Gen.anesthestics 5 Choles-lowering % Drug Class
  • 17. Implicated Antimicrobials – Single agent DILI
    • Bactrim (9)
    • Augmentin (17)
    • Macrobid (14)
    • Ketek (5)
    • Levaquin (5)
    • Anti-retroviral (9)
    • Anti TB (12)
  • 18. Signs and Symptoms 31 Fever 68 Dark Urine 51 Anorexia 59 Nausea 48 Abdominal Pain 66 Jaundice % 96 Any symptoms 23 Δ Mental Status 49 Itching 27 Rash 36 Vomiting %
  • 19. Signs and Symptoms 50 Liver Biopsy: 10 Extrahepatic Manifestations 18 Steroid treatment 2 Lymphadenopathy 8 Hepatomegaly %
  • 20. Biochemistries ( mean ± s.d.) Peak Onset 407 ± 412 287 ± 256 Alk Pho (IU/L) 10.5 ± 10 5.3 ± 5.5 Bilirubin (mg/dl) 907 ± 980 722 ± 835 ALT (IU/L) 962 ± 2116 652 ± 831 AST (IU/L)
  • 21. Final Causality Assessment (n=68) 1.5% Unlikely 15% Possible 13% Probable 28% Definite 43% Very Likely Percent
  • 22. Outcome Reported to the DCC Thus Far 20% Chronic DILI 2% Liver Transplant (event related up to 6 months) 12.7% Death (within 6 months)
  • 23. Conclusions (1)
    • Our prospective study represents a systematic effort to recruit patients with clinically important DILI in a robust fashion
    • Antimicrobials and anticonvulsants are the most common classes of agents to cause DILI
  • 24. Conclusions (2)
    • The incidence of chronic DILI is higher than previously anticipated
    • Extensive clinical data and biosamples are available for conducting clinical and mechanistic ancillary studies including genetic analysis to predict risk factors and outcome
  • 25. DILIN Team of Investigators
    • NIDDK
    • Jose Serrano, MD
    • Leonard Seeff, MD
    • Jay Hoofnagle, MD
    • DCC
    • Jim Rochon, PhD
    • John McHutchison, MD
    • Don Rockey, MD
    • Katherine Berezny
    • U. Conn
    • Herb Bonkovsky, MD
    • Bob Rosson, MD
    • Jim Freston, MD
    • Laura Glynn
    UNC Paul Watkins, MD Paul Hiyashi, MD Susan Pusek IU Naga Chalasani, MD Larry Lumeng, MD Audrey Corne, RN UCSF Tim Davern, MD M. Bonacini, MD Dalia Mowad U. Mich Bob Fontana, MD H. Conjeevaram, MD Suzanne Welch