Acute pancreatitis associated with boceprevir: a case report

(1)

braz j infect dis.2014;18(4):454–456

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Case

report

Acute

pancreatitis

associated

with

boceprevir:

a

case

report

Juliana

Miguel

Bilar

∗

_,

_Roberto

_José

_{Carvalho-Filho,}

Carolina

Frade

Magalhães

Girardin

Pimentel

Mota,

Patricia

da

Silva

Fucuta,

Maria

Lucia

Cardoso

Gomes

Ferraz

UniversidadeFederaldeSãoPaulo(UNIFESP)SãoPaulo,SP,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received9January2014 Accepted11March2014 Availableonline13May2014

Keywords:

HepatitisC Proteaseinhibitor Sideeffect

a

b

s

t

r

a

c

t

Approximately170millionpeopleareinfectedwithhepatitisC,andthesustainedvirological responseratetotreatmentwithpegylatedinterferonandribavirinis30–50%.Inanattempt toimprovethechancesofcure,boceprevirisbeingaddedtotherapy,butitisassociatedwith anincreasedincidenceofadverseevents.Wehereinreportacaseofacutepancreatitis devel-opedduringtreatmentwithpegylatedinterferon,ribavirinandboceprevir.Boceprevirwas themostlikelycauseofdrug-associatedpancreatitisafterthemostcommoncauseswere ruledout,sincethisadverseeventhadnotoccurredwhenthepatienthadpreviouslybeen exposedtopegylatedinterferonandribavirinandtherewasnorecurrenceoftheepisodeof pancreatitiswhenthesetwodrugswerereintroduced.Acutepancreatitisisarareadverse eventassociatedwithboceprevirtherapy,butapotentiallyfatalevent.Sequential deter-minationofpancreaticenzymesshouldbeconsideredduringhepatitisCtreatmentwith boceprevir.

Introduction

Anestimated170millionpeople worldwidearechronically infectedwith hepatitisC virus (HCV).1 _The_sustained

viro-logical response (RVS) rate to combination treatment with pegylatedinterferonandribavirinforHCVgenotype1ranges from 30 to 50%.2 _In _an _attempt _to _improve _the _chances

ofcure, new drugs were developedand used in combina-tionwithpegylatedinterferonandribavirin.Oneofthetwo recentlyapproveddirect-actingantiviralagentsisboceprevir,

∗ _{Corresponding}_author_at_:_Rua_Izabel_Gimenez_Fante,_51,_Quinta_do_Golfe,_15093-307,_São_José_do_Rio_Preto,_São_Paulo,_SP,_Brazil.

E-mailaddress:jmbilar@gmail.com(J.M.Bilar).

aprotease inhibitorthat blocksviralreplicationbybinding reversiblytotheviralproteaseNS3.3

The addition of boceprevir to pegylated interferon and ribavirinincreasedthechanceofaSVR(63–66%in treatment-naivepatientsand52–75%inpreviouslytreatedpatients),4,5

but it also was associated with an increased incidenceof adverse events during treatment, especially anemia and dysgeusia.4,5

Wereportthecaseofapatientwithacutepancreatitis asso-ciatedwithboceprevir therapy. Informedconsenthasbeen obtained.

http://dx.doi.org/10.1016/j.bjid.2014.03.008

(2)

b r a z j i n f e c t d i s . 2014;18(4):454–456

455 Case

report

A43-year-oldwhitemanwasadmittedtotheHepatitisUnit ofthe Federal University ofSão Paulo, Brazil,in May 1995 forthe investigation ofliver disease dueto the finding of “chronichepatitiscausedbyHCV”inanintraoperativeliver biopsyobtainedonemonthearlier.Thepatienthadundergone cholecystectomy for symptomatic gallstones and reported no other comorbidities or surgeries. Thepatient had used illicit drugs in the past, has been smoking since he was 20 years old, and reported no alcohol abuse. The diagno-sis of chronic hepatitis C was confirmed by the detection ofHCV RNA. Re-examination ofthe liver biopsy classified the specimen as F1A2 according to the METAVIR scoring system. The patient received conventional interferon for sixmonths untilOctober 1996and was considered a non-responder.

In2006,genotype1wasdetectedandanalysisofanew percutaneousliverbiopsyrevealedF2A3.Thepatientreceived a second course of pegylated interferon alfa 2a (180␮g, subcutaneously, once a week) and ribavirin (1.0g per day, orally) for 48 weeks and again did not respond to treat-ment.

In 2012,noninvasive examinations showed noevidence ofadvancedfibrosisandthepatientstartedthethird treat-mentwithpegylatedinterferonalfa2b(1.5␮g,subcutaneously, onceaweek),ribavirin(1.250gperday,orally),and bocepre-vir (800mg, orally, three times per day). The viral load at thebeginningoftreatmentwas2,200,000IU/mL(6.34log)and boceprevirwas administeredaftera4-week lead-inperiod. Theviralloadremainedat2,360,000IU/mL(6.37log)afterthe lead-inperiodbutwasundetectableafter8and12weeksof treatmentandthepatientpresentedonlymildflu-like symp-toms.

After17weeksoftreatment(13weeksonboceprevir),the patientwashospitalizedwithepigastricpainradiatingtothe back,nausea,andvomiting.Thepatientreportednoalcohol consumptionoruseofothermedications.Laboratorytestsat admissionshowedhemoglobin14g/L,hematocrit43, leuko-cytes5700mm3_,_platelets _163,000_mm3_,_amylase₁₂₀₉_IU/mL (normal:upto125IU/mL),lipase6462IU/mL(normal:up to 60IU/mL),aspartateaminotransferase 34IU/mL(normal:up to40IU/mL),alanineaminotransferase42IU/mL(normal:up to42IU/mL), total Ca 9.0mg/dL, ionized Ca 4.5mg/dL,and triglycerides195mg/dL.Upperabdominalcomputed tomogra-phyonlyrevealedabsenceofgallbladder(cholecystectomy). Nuclearmagneticresonanceimagingoftheupperabdomen showedapancreasofnormalsize,withazoneofaltered sig-nalin the pancreatichead closeto the papilla, measuring 1.5cm.

The hypothesis of drug-associated pancreatitis was raised after the most common causes had been ruled out. Cholelithiasis and choledocholithiasis were excluded since the patient had undergone cholecystectomy in the past and the upper abdominal computed tomography did not reveal any change in the biliary tree. Alcohol asso-ciated pancreatitis was also ruled out since the patient denied alcohol consumption. Elevated calcium or trigly-cerides were not possible causes of pancreatitis, as both

werewithinthenormalrange.Pegylatedinterferon,ribavirin andboceprevirwereimmediatelydiscontinuedand support-ive care was initiated. The patient was discharged after two dayswith clinical improvementand amylase levelsof 82IU/mL.

Onthe follow-upvisit totheoutpatientcliniconeweek afterdischarge,thepatientwasasymptomaticandpancreatic enzymelevelswerewithinthenormalrange,withamylase levelsof101IU/mLandlipaselevelsof101IU/mL.Onthat occa-sion,pegylatedinterferonandribavirinwerereintroducedat thesame dosesasadministeredpreviouslyand thepatient onlydevelopedmildflu-likesymptoms.Nosymptoms sugges-tiveofpancreatitisornewelevationsofpancreaticenzymes wereobserved.

Treatmentwasdiscontinuedatweek26becauseHCVRNA hadbeendetectedatweek24andthepatientagainwas con-sideredanon-responder.Thepatientremainedasymptomatic sixmonthsaftertheendoftreatment,withoutrecurrenceof pancreatitis.

Conclusion

Thisisthefirstreportdescribingtheassociationofacute pan-creatitisand boceprevir.Recently,thefirstreportdescribing drug-associatedpancreatitisduringtripletherapyfor hepati-tisCwithtelaprevirwaspublished,6_indicating_the_need_for

constantmonitoringofpancreaticenzymesduringtreatment withthesenewdrugs.

Inthepresentcase,thepatientwaseligiblefortriple ther-apysincehehadnotrespondedtotwoprevioustreatments, one consistingofconventional interferon and the other of pegylated interferonplus ribavirin.In bothtreatments, the patient developed flu-like symptoms and mild anemia as adverseevents.

Duringtreatmentwithpegylatedinterferon,ribavirinand boceprevir,thepatientwasdiagnosedwithacutepancreatitis based on the criteria of the American College of Gastro-enterology, which define the condition when two of three criteriaarepresent:(1)abdominalpaincharacteristicof pan-creatitis,(2)serumamylaseand/orlipase≥3×upperlimitof

normal, and (3) computed tomography suggestive of acute pancreatitis.7 _The_most_common_causes_of_acute

pancreati-tis,suchascholelithiasis,alcoholabuse,hypercalcemiaand hypertriglyceridemia,were ruledoutbytestsperformedon admission.

Drugs are less frequent causes of acute pancreatitis, responsiblefor0.1%8_to_5.3%.9_The_diagnosis_of_drug-induced

pancreatitisrequiresthedevelopmentofthecondition dur-ing treatment withthe suspected drug and the resolution ofsymptomsafterdiscontinuationofthedrug,anadequate criterion for the diagnosis of acute pancreatitis, and the absence ofother commoncauses ofpancreatitis.10

Accord-ing to the classification of Karchand Lasagna11 _published

in 1975 and ofMallory and Kern12 _published _in _1980, _the

(3)

456

b r a z j i n f e c t d i s . 2014;18(4):454–456

classified as probable since the symptoms disappear after discontinuation of the drug, as observed in the present case.

Acute pancreatitis is a rare adverse event in registry studiesofboceprevir.TheSPRINT-2studyevaluatedthe effi-cacy and safety of boceprevir in treatment-naive patients with hepatitis C.4 _Acute _pancreatitis _was _observed _in _one

(<1%) of the 734 subjects exposed to the drug. In the RESPOND-2study,whichevaluatedboceprevirforthe retreat-ment of patients with hepatitis C, acute pancreatitis was observed in 2 (<1%) of the 323 patients who received boceprevir.5

Inthepresent case,pancreatitiswasmostlikely associ-atedwith boceprevir therapy since this adverse event had notoccurredwhenthepatienthadpreviouslybeenexposed to pegylated interferon and ribavirin. Pegylated interferon and ribavirin were reintroduced one week after clinical improvementand there was no recurrence of the episode ofpancreatitis,lendingsupporttothepossibilitythatthese drugswerenotinvolvedinthedevelopmentofpancreatitisin thispatient.

According to the Naranjo algorithm, which is used to estimate the probability ofdrug-induced adverse events,13

boceprevirwasaprobabledrugassociatedwithpancreatitis inthe present case.Another finding supportingthe causal relationship between boceprevir and acute pancreatitis is the factthat the patientdidnot developpancreatitisprior to the use of boceprevir or during the 6-month observa-tionperiodafterthe endoftreatment.Other lesscommon causes of acute pancreatitis, such as biliary microlithia-sisand autoimmune pancreatitis, could therefore be ruled out.

Inconclusion,boceprevirhasrecentlybeenintroducedfor thetreatmentofchronichepatitisC,andwillbeusedinalarge numberofpatients.Oneofthesideeffectsassociatedtothis drugisacutepancreatitiswhich,althoughrare,isapotentially fatalevent.Wesuggestthatthesequentialdeterminationof pancreaticenzymesshouldbeconsideredduringhepatitisC treatmentwithboceprevirinordertoallowforearlydiagnosis ofacutepancreatitis.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1.WorldHealthOrganization.HepatitisC–globalprevalence

(update).WklyEpidemiolRec.2000;75:18–9.

2.MannsMP,McHutchisonJG,GordonSC,etal.Peginterferon

alfa-2bplusribavirincomparedwithinterferonalfa-2bplus

ribavirinforinitialtreatmentofchronichepatitisC:a

randomizedtrial.Lancet.2001;358:958–65.

3.MalcolmBA,LiuR,LahserF,etal.SCH503034,amechanism

basedinhibitorofhepatitisCvirusNS3protease,suppresses

polyproteinmaturationandenhancestheantiviralactivityof

alphainterferonrepliconcells.AntimicrobAgents

Chemother.2006;50:1013–20.

4.PoordadF,McConeJrJ,BaconBR,etal.Boceprevirfor

untreatedchronicHCVgenotype1infection.NEnglJMed.

2011;364:1195–206.

5.BaconBR,GordonSC,LawitzE,etal.Boceprevirforpreviously

treatedchronicHCVgenotype1infection.NEnglJMed.

2011;364:1207–12.

6.VenturaC,UrichR,SkinnerS,etal.Firstreportof

telaprevir-inducedpancreatitis.DigDisSci.2013;58:887–8.

7.BanksPA,FreemanML.Practiceguidelinesinacute

pancreatitis.AmJGastroenterol.2006;101:2379–400.

8.BalaniAR,GrendellJH.Drug-inducedpancreatitis.Incidence,

managementandprevention.DrugSaf.2008;31:823–37.

9.VinklerovaI,ProchazkaM,ProchazkaV,UrbánekK.

Incidence,severityandetiologyofdrug-inducedacute

pancreatitis.DigDisSci.2010;55:2977–81.

10.NitscheC,MaertinS,ScheiberJ,RitterCA,LerchMM,Mayerlel

J.Drug-inducedpancreatitis.CurrGastroenterolRep.

2012;12:128–31.

11.KarchFE,LasagnaL.Adversedrugreactions:acriticalreview.

JAMA.1975;234:1236–41.

12.MalloryA,KernF.Druginducedpancreatitis:acriticalreview.

Gastroenterology.1980;78:813–20.

13.NaranjoCA,BustoU,SellersEM,etal.Amethodfor

estimatingtheprobabilityofadversedrugreaction.Clin