Abacavir-induced liver toxicity

(1)

braz j infect dis 2 0 1 6;20(5):502–504

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

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Case

report

Abacavir-induced

liver

toxicity

Maria

Diletta

Pezzani

a

_,

_Chiara

_Resnati

a

_,

_Valentina

_Di

_Cristo

a

_,

Agostino

Riva

b

_,

_Cristina

_Gervasoni

b,∗

a_Università_di_Milano,_Luigi_Sacco_University_Hospital,_Department_of_Biomedical_and_Clinical_Sciences_L._Sacco,_Milan,_Italy b_Università_di_Milano,_Luigi_Sacco_University_Hospital,_Department_of_Infectious_Diseases,_Milan,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received10January2016 Accepted13March2016 Availableonline4April2016

Keywords:

HIV Abacavir Livertoxicity

a

b

s

t

r

a

c

t

Abacavir-inducedlivertoxicityisarareeventalmostexclusivelyoccurringinHLA B*5701-positivepatients.Herein,wereportonecaseofabnormalliverfunctiontestsoccurringin ayoungHLAB*5701-negativewomanonastablenevirapine-basedregimenwithno his-toryofliverproblemsoralcoholabuseafterswitchingtoabacavirfromtenofovir.Wealso investigatedthereasonsforabacavirdiscontinuationinacohortofpatientstreatedwith abacavir-lamivudine-nevirapine.

Introduction

Drug-induced hepatotoxicity represents an important side effectofhighlyactiveantiretroviral therapy(HAART), com-plicates the management of HIV-infected patients and, althoughinfrequently,mayhaveseriousconsequences.1

Pos-siblepathogenicmechanismsinvolvedinhepatotoxicityare multiple,including directdrugtoxicity,immune reconstitu-tion inthe presence ofhepatitis C (HCV) and/or hepatitis B (HBV) co-infections, hypersensitivity reactions with liver involvement,andmitochondrialtoxicity.1

Abacavir(ABC)-inducedlivertoxicityisarareeventalmost exclusivelyoccurringinHLAB*5701-positivepatients,2 _with

ahandfulofcasesreportedinnoncarriersoftheHLAallele risk.3,4 _All_cases_happened_in_patients _on_a_stable

nevirap-ine(NVP)-basedregimenafterswitchingtoABCfromanother nucleosideanalog. Herein,wereportonecaseofabnormal

∗ _{Corresponding}_author_.

E-mailaddress:[email protected](C.Gervasoni).

liverfunctiontestsoccurringinayoungHLAB*5701-negative womanonastableNVP-basedregimenwithnohistoryofliver problemsor alcoholabuseafterswitchingtoABC. Inorder toassesstheincidenceofABClivertoxicityintheHIV pop-ulation treatedwithABC,lamivudine, andNVP, whichisa poorlyinvestigatedbutcurrentlyusedcombinationinclinical practice,mainlyincountrieswitheconomicconstraints,we investigatedthereasonsforABCdiscontinuationinpatients onNVP-basedregimensfromourclinicaldatabase.

Case

report

A 33-year-old woman was switched from tenofovir/ emtricitabine/NVP to ABC/lamivudine/NVP after seven yearsoninitialtreatmenttoavoidtenofovirrelatedlong-term toxicity.Ourchoicewasbasedonthelowbodyweightofthe patient–whichisriskfactorforthedevelopmentoflong-term

http://dx.doi.org/10.1016/j.bjid.2016.03.002

(2)

brazj infect dis.2016;20(5):502–504

503

tenofovir complications5 _– _and _the _observed _mild_increase

inserum creatinineconcentrations.Shetestednegativefor HLAB*5701andhepatitisviruses. Hertransaminaseslevels hadalways beennormalalong herantiretroviraltreatment but eight weeks after switching to ABC aspartate amino-transferase(AST) andalanineaminotransferase (ALT)levels progressivelyincreasedto222and518UI/mL,respectively.The patienthasalwaysbeenasymptomatic.Serologyforhepatitis A(HAV IgM), hepatitisB(HBsAg, HBcAbIgM), and hepatitis C (HCVAb) were negative, as were hepatitis C viral load (HCVRNAundetectable).Autoantibodyscreeningtestswere negative.Thepatientdidnottakeconcomitantmedications afterswitchingtoABCandwasnotgivenacetaminophen,a drugknown toinducelivertoxicity eventuallyexacerbated byABC.6 _Given_the _previous _long _term _tolerability_to _NVP,

ABCwas discontinued and the patient was switchedback totenofovirwithsubsequentnormalizationofASTandALT withinsixweeks.

In order toproperly address the incidence ofABC liver toxicityinpatientsonstabletreatmentwithNVP,we retro-spectivelysearchedourclinicaldatabaseandidentified1004 maleandfemaleHIV-infectedpatientsreferringtoour Depart-mentbetween2000and2013whobeganreceivingABCaspart oftheirfirstorsubsequentantiretroviraltreatmentregimen. Eighty-threeHIV-infectedpatients(51males,32females),with amedianageof46years(range30–72),receivedastable NVP-containingregimenbeforestartingABC.Themainreasonsfor switchingtoABCwere(a)lipodystrophyandlipid abnormal-itiesinpatientstreatedwithzidovudine(27patients);(b)to avoidtenofovirrelatedtoxicity (38patients);stavudineand didanosinereplacement(10patients).Overall,26out ofthe 83(24%)patientssubsequentlydiscontinuedABCtreatment dueto the followingreasons: virologic failure (n=11), rash (n=5),inthreecasesbeforetheavailabilityofgenetictesting forHLAB*5701,gastrointestinalsideeffects(n=2),pregnancy (n=2),patientrequest(n=2),onepatientdiscontinueddueto change intreatmentstrategy, one patientdue tohigh car-diovascularrisk,andhepatotoxicity(n=2,bothcasestested negativeforHLAB*5701).Ofthetwosuspensionsdueto hepa-totoxicity,onepatienthadnoviralhepatitisco-infectionand presentedclinicalanddemographiccharacteristicssimilarto thosedescribed inprevious reports,3,4 _while_the_other _was

coinfectedwithHCVandhadnothadpreviousraiseinliver enzymes.Interestingly,82%(9outofthe11pts)ofthevirologic failureswereobservedinpatientswithalonghistoryofHIV treatmentincludingantiretroviralregimensthatarenolonger recommended.

Discussion

ABC-inducedliver injury in the context ofa negative HLA B*5701 test is an uncommon event. As a matter of fact, extensiveevidenceisnowavailableshowingthatHLA-B*5701 screeningisaneffective waytopreventhypersensitivity to ABC in susceptible subjects.7,8 _To _the _best _of _our

knowl-edge only three cases of hepatotoxicity occurring in HLA B*5701-negativepatientswithnoviralhepatitisco-infection orhistoryofalcoholabusehavebeenreported;allcaseswere onastableNVP-basedregimenafterswitchingtoABCfrom

anothernucleosideanalog.3,4_Here,_we_confirm_these_findings

bydocumentingthatinourcohortABC-relatedhepatotoxicity was an uncommon, but clinically relevant event. A phar-macokineticdrug-to-druginteractionbetweenABCandNVP isunlikelybecauseABCisnotmetabolizedbycytochromial enzymes.9 _We_have _also_excluded _a _potential _contribution

of acetaminophen on the observed ABC/NVP-related liver toxicity6 _because _this _drug _was _used, _if _any, _in _very _few

patientsfromourcohortsandforshorttimeperiods. Accord-ingly, potential pharmacodynamic mechanisms explaining ABC/NVPlivertoxicitycanbeeventuallyadvocated.Indeed, evidenceisavailableshowingthatbothdrugsseparatelycan favorthebioactivationofreactivemoleculescapableof form-ingproteinproductsultimately leadingtolivertoxicity.10–12

Ontheotherhand,itshouldbeconsideredthatverylimited andscantydataareavailablenotonlyonthesafetybutalso ontheefficacyABC/lamivudine/NVPcombination,13,14_despite

thefactthatthisregimenhasnowbecomeaveryattractive optionfortheverylowcost,limitedmetabolicimpact, and lowpillburden.We,therefore,extendedpreviousfindingsby assessingthefrequencyofABC-relatedhepatotoxicityin HIV-infectedpatientsonNVPbased-regimensandbydescribing theefficacyofthisregimeninareallifescenario.Indeed,a higherincidenceofvirologicfailurewasfoundinourcohort ofpatientscomparedwiththe onlyavailablestudytodate which has formally investigatedABC/lamivudine/NVP as a simplificationstrategyforHIVpatientswithundetectableviral load.13 _The_possibility_that _the_increased_pill_burden_(as_in

thecaseofswitchingfromzidovudine+lamivudine coformu-lationtoABC/lamivudineassinglecomponents)mighthave contributed,atleastinpart,tothevirologicfailuresobserved inpatientscannotbedefinitivelyruledout.Itshouldbe con-sidered,however,thatlargepartofourfailuresweredriven by events occurring in patients with long term history of antiretroviraltherapywhichincludedmonoordualregimens nolongerrecommended.Asaresult,itcanbereasonably spec-ulatedthatsomeofthevirologicfailuresapparentlyobserved withABCmayhavebeensignificantlyinfluencedbyprevious antiretroviralregimens.

Inconclusion,cliniciansshouldremainalertforsignsof hepatitisinpatientstreatedwithABC,while,atthesametime, considertheefficacyofABC/lamivudine/NVPcombinationas asimplificationoptiononlyinpatientsnotpreviouslytreated withsuboptimalantiretroviralregimens.

Conflicts

of

interest

CGhasreceivededucationalgrantsfromMerckSharp&Dome, Janssen-Cilag, Bristol Myers Squibb, Gilead and Abbvie. AR hasreceivededucationalgrantsfromMerckSharp&Dome, Janssen-Cilag,BristolMyersSquibb,Gilead,ViiVandNovartis.

r

e

f

e

r

e

n

c

e

s

1.Nú ˜nezM.Clinicalsyndromesandconsequencesof antiretroviral-relatedhepatotoxicity.Hepatology. 2010;52:1143–55.

(3)

504

braz j infect dis.2016;20(5):502–504

2. HughesCA,FoisyMM,DewhurstN,etal.Abacavir hypersensitivityreaction:anupdate.AnnPharmacother. 2008;42:387–96.

3. DiFilippoE,RipamontiD,RizziM.Abacavir-inducedliver toxicityinanHIV-infectedpatient.AIDS.2014;28:613. 4. SoniS,ChurchillDR,GilleeceY.Abacavir-induced

hepatotoxicity:areportoftwocases.AIDS.2008;22:2557–8. 5. GervasoniC,MeravigliaP,LandonioS,etal.Lowbodyweight

infemalesisariskfactorforincreasedtenofovirexposure anddrug-relatedadverseevents.PLoSOne.2013;8:e80242. 6. Blas-GarcíaA,Martí-RodrigoA,VíctorVM,etal.Thepurine

analoguesabacaviranddidanosineincrease

acetaminophen-inducedhepatotoxicitybyenhancing mitochondrialdysfunction.JAntimicrobChemother.2016 (epubheadofprint).

7. MaJD,LeeKC,KuoGM.HLA-B*5701testingtopredictabacavir hypersensitivity.PLoSCurr.2010;2:RRN1203.

8. PhillipsE,MallalS.Successfultranslationof

pharmacogeneticsintotheclinic:theabacavirexample.Mol DiagnTher.2009;13:1–9.

9. YuenGJ,WellerS,PakesGE.Areviewofthepharmacokinetics ofabacavir.ClinPharmacokinet.2008;47:351–71.

10.GriloNM,AntunesAM,CaixasU,etal.Monitoringabacavir bioactivationinhumans:screeningforanaldehyde metabolite.ToxicolLett.2013;219:59–64.

11.CaixasU,AntunesAM,MarinhoAT,etal.Evidencefor nevirapinebioactivationinman:searchingforthefirststepin themechanismofnevirapinetoxicity.Toxicology.

2012;301:33–9.

12.JessonJ,DahourouDL,RenaudF,etal.Adverseevents associatedwithabacaviruseinHIV-infectedchildrenand adolescents:asystematicreviewandmeta-analysis.Lancet HIV.2016;3:e64–75.

13.CabelloÚbedaA,SanzMorenoJ,WilliamsF,GórgolasM. Efficacyandsafetyofnevirapine+Kivexa

(abacavir/lamivudine)asasimplificationstrategyforHIV patientswithundetectableviralload.JAcquirImmuneDefic Syndr.2011;58:e95–6.

14.PodzamczerD,RojasJF,NevesI,etal.Effectivenessand tolerabilityofabacavir-lamivudine-nevirapine(ABC/3TC/NVP) inamulticentrecohortofHIV-infected,ARV-naïvepatients.J IntAIDSSoc.2014;17:19773.