Drug Induced Liver Injury Drug Induced Liver Injury Network (DILIN) Prospective Network (DILIN) Prospective Study: Initial ResultsStudy: Initial Results

Naga Chalasani, MD Naga Chalasani, MD for the for the

Drug Induced Liver Injury Drug Induced Liver Injury NetworkNetwork

BackgroundBackground

Although DILI is a rare clinical Although DILI is a rare clinical event, it is the most common event, it is the most common cause of acute liver failure in the cause of acute liver failure in the USUS

DILI is one of the most common DILI is one of the most common causes for medication withdrawal causes for medication withdrawal or lack of approval by the FDAor lack of approval by the FDA

A significant barrier for drug A significant barrier for drug developmentdevelopment

BackgroundBackground

Its epidemiology, Its epidemiology, etiopathogenesis, diagnosis, and etiopathogenesis, diagnosis, and natural history are poorly natural history are poorly understoodunderstood

DILIN is a federally funded DILIN is a federally funded consortium of 5 clinical centers consortium of 5 clinical centers and DCCand DCC

DILINDILIN

Duke Clinical ResearchDuke Clinical Research Institute (PI – Rochon) Institute (PI – Rochon)

U. Conn (PI - Bonkovsky)U. Conn (PI - Bonkovsky) U. Mich (PI - Fontana)U. Mich (PI - Fontana) IU (PI- Chalasani)IU (PI- Chalasani) UNC (PI- Watkins)UNC (PI- Watkins) UCSF (PI-Davern)UCSF (PI-Davern) NIDDK (Serrano, Seeff, Hoofnagle)NIDDK (Serrano, Seeff, Hoofnagle)

Clinical Centers

Data Coord. Ctr.

DILIN: Scope of RecruitmentDILIN: Scope of Recruitment

~12.8 million lives~12.8 million lives~12.8 million lives~12.8 million lives

UCSF

U Mich

IUU Conn

UNC

AimAim

To report the initial findings of the To report the initial findings of the etiology and clinical etiology and clinical characteristics of patients with characteristics of patients with drug induced liver injury (DILI) drug induced liver injury (DILI) enrolled into the enrolled into the “DILIN “DILIN Prospective Study”Prospective Study”

DILIN Prospective DILIN Prospective StudyStudy Multicenter, prospective, and Multicenter, prospective, and

observational studyobservational study Patients with suspected Patients with suspected

idiosyncratic DILI with no idiosyncratic DILI with no competing etiology occurring competing etiology occurring within 6-months are eligiblewithin 6-months are eligible

DILI due to acetaminophen were DILI due to acetaminophen were not includednot included

Eligibility CriteriaEligibility Criteria

Children ≥ 2 years and adultsChildren ≥ 2 years and adults Pre-defined biochemical criteria Pre-defined biochemical criteria

- AST or ALT > 5 ULN twice - AST or ALT > 5 ULN twice consecutivelyconsecutively

- Alk Phos > 2 ULN twice consecutively- Alk Phos > 2 ULN twice consecutively

- Bilirubin ≥ 2.5 mg/dl- Bilirubin ≥ 2.5 mg/dl

- Specific criteria for patients with pre-- Specific criteria for patients with pre-existing liver diseaseexisting liver disease

MethodsMethods

Patients were seen in the GCRCPatients were seen in the GCRC Patients followed up to 24 months Patients followed up to 24 months

depending on their biochemistries depending on their biochemistries at 6 months after enrollmentat 6 months after enrollment

Extensive baseline evaluations to Extensive baseline evaluations to exclude competing etiologiesexclude competing etiologies

Samples of serum, urine, DNA, Samples of serum, urine, DNA, and peripheral lymphocytes and peripheral lymphocytes

Causality AssessmentCausality Assessment

A panel of study hepatologists A panel of study hepatologists systematically assessed the systematically assessed the strength of causal relationship strength of causal relationship between implicated agent and liver between implicated agent and liver injuryinjury

RUCAM, DILIN-specific causality RUCAM, DILIN-specific causality grading, data completeness forms grading, data completeness forms are filled by 3 hepatologistsare filled by 3 hepatologists

Causality finally assessed based on Causality finally assessed based on consensusconsensus

Chronic DILIChronic DILI

Persistent biochemical Persistent biochemical abnormalities at 6 months abnormalities at 6 months following the onset of acute DILIfollowing the onset of acute DILI

Histological or radiological or Histological or radiological or clinical evidence of chronic liver clinical evidence of chronic liver disease at 6 monthsdisease at 6 months

Patients with known HCV or HBV Patients with known HCV or HBV or cirrhosis were not assessed or cirrhosis were not assessed for chronic DILIfor chronic DILI

Total Enrollment (9/04 – Total Enrollment (9/04 – 8/06)8/06)

TotalTotal

U ConnU Conn 3939

IndianaIndiana 5454

UCSFUCSF 3535

MichiganMichigan 5252

UNCUNC 5353

TotalTotal 233233

Although 233 patients were enrolled, data from 169 patients were available for this presentation

DemographicsDemographics

Age (mean ± S.D.)Age (mean ± S.D.) 48.3 ± 18.648.3 ± 18.6

FemalesFemales 60%60%

African-AmericansAfrican-Americans 13%13%

BMI (Kg/m2, mean ± BMI (Kg/m2, mean ± S.D.)S.D.)

27 ± 727 ± 7

ChildrenChildren 9%9%

Pre-existing liver Pre-existing liver diseasedisease

16%16%

PercentPercent

HepatocellularHepatocellular 53%53%

CholestaticCholestatic 22%22%

Mixed Mixed 25%25%

Pattern of Liver InjuryPattern of Liver Injury

%%

Single Rx Drug Single Rx Drug 7474

Single CAM Single CAM 44

Multiple Drugs / Multiple Drugs / CAMCAM 2222

Implicated DILI Drugs / CAMImplicated DILI Drugs / CAM

Drug Class for Drug Class for SingleSingle Implicated Implicated AgentAgent

Drug ClassDrug Class %%

AntimicrobialsAntimicrobials 4040

AnticonvulsanAnticonvulsantsts

77

AntineoplasticAntineoplastics s 44

AntidepressanAntidepressantsts

44

NSAIDsNSAIDs 44

Drug ClassDrug Class %%

Gen.anesthestiGen.anesthesticscs 33

Choles-Choles-loweringlowering 55

Peptide-Peptide-biologicsbiologics 55

CAM ProductsCAM Products 66

OthersOthers 2222

Implicated Antimicrobials – Implicated Antimicrobials – Single agent DILISingle agent DILI

Bactrim (9)Bactrim (9)

Augmentin (17)Augmentin (17)

Macrobid (14)Macrobid (14)

Ketek (5)Ketek (5)

Levaquin (5)Levaquin (5)

Anti-retroviral (9)Anti-retroviral (9)

Anti TB (12)Anti TB (12)

Signs and SymptomsSigns and Symptoms

%%

JaundiceJaundice 6666

NauseaNausea 5959

AnorexiaAnorexia 5151

Dark UrineDark Urine 6868

FeverFever 3131

Abdominal Abdominal PainPain 4848

%%

VomitingVomiting 3636

RashRash 2727

ItchingItching 4949

ΔΔ Mental Mental StatusStatus 2323

Any Any symptomssymptoms 9696

%%

HepatomegalyHepatomegaly 88

LymphadenopatLymphadenopathyhy 22

Extrahepatic Extrahepatic ManifestationsManifestations 1010

Liver Biopsy:Liver Biopsy: 5050

Steroid Steroid treatmenttreatment 1818

Signs and SymptomsSigns and Symptoms

OnsetOnset PeakPeak

AST (IU/L)AST (IU/L) 652 ± 831 652 ± 831 962 ± 2116 962 ± 2116

ALT ALT (IU/L)(IU/L) 722 ± 835 722 ± 835 907 ± 980 907 ± 980

Alk Pho Alk Pho (IU/L)(IU/L) 287 ± 256 287 ± 256 407 ± 412 407 ± 412

Bilirubin Bilirubin (mg/dl)(mg/dl) 5.3 ± 5.55.3 ± 5.5 10.5 ± 1010.5 ± 10

Biochemistries (Biochemistries (mean ± mean ± s.d.)s.d.)

PercentPercent

DefiniteDefinite 28%28%

Very LikelyVery Likely 43%43%

ProbableProbable 13%13%

PossiblePossible 15%15%

UnlikelyUnlikely 1.5%1.5%

Final Causality Assessment Final Causality Assessment (n=68)(n=68)

Outcome Reported to Outcome Reported to the DCC Thus Farthe DCC Thus Far

Death (within 6 Death (within 6 months)months)

12.7%12.7%

Liver Transplant Liver Transplant (event related up to 6 (event related up to 6 months)months)

2%2%

Chronic DILIChronic DILI 20%20%

Conclusions (1)Conclusions (1)

Our prospective study represents Our prospective study represents a systematic effort to recruit a systematic effort to recruit patients with clinically important patients with clinically important DILI in a robust fashionDILI in a robust fashion

Antimicrobials and Antimicrobials and anticonvulsants are the most anticonvulsants are the most common classes of agents to common classes of agents to cause DILIcause DILI

Conclusions (2)Conclusions (2)

The incidence of chronic DILI is The incidence of chronic DILI is higher than previously anticipatedhigher than previously anticipated

Extensive clinical data and Extensive clinical data and biosamples are available for biosamples are available for conducting clinical and conducting clinical and mechanistic ancillary studies mechanistic ancillary studies including genetic analysis to including genetic analysis to predict risk factors and outcomepredict risk factors and outcome

DILIN Team of DILIN Team of InvestigatorsInvestigators

NIDDKNIDDKJose Serrano, MDJose Serrano, MDLeonard Seeff, MDLeonard Seeff, MDJay Hoofnagle, MDJay Hoofnagle, MD

DCCDCCJim Rochon, PhDJim Rochon, PhDJohn McHutchison, MDJohn McHutchison, MDDon Rockey, MDDon Rockey, MDKatherine BereznyKatherine Berezny

U. ConnU. ConnHerb Bonkovsky, MDHerb Bonkovsky, MDBob Rosson, MDBob Rosson, MDJim Freston, MDJim Freston, MDLaura GlynnLaura Glynn

UNCUNCPaul Watkins, MDPaul Watkins, MDPaul Hiyashi, MDPaul Hiyashi, MDSusan PusekSusan Pusek

IUIUNaga Chalasani, MDNaga Chalasani, MDLarry Lumeng, MDLarry Lumeng, MDAudrey Corne, RNAudrey Corne, RN

UCSFUCSFTim Davern, MDTim Davern, MDM. Bonacini, MDM. Bonacini, MDDalia MowadDalia Mowad

U. MichU. MichBob Fontana, MDBob Fontana, MDH. Conjeevaram, MDH. Conjeevaram, MDSuzanne WelchSuzanne Welch