Menopause, and not age, is a critical factor associated with a worse response to antiviral therapy in women affected by chronic hepatitis C

Letter

to

the

Editor

Menopause,andnotage,isacriticalfactorassociatedwitha worseresponsetoantiviraltherapyinwomenaffectedby chronichepatitisC

Wereadwithgreatinterestthearticleentitled‘‘Impactofsex on virologic response rates in genotype 1 chronic hepatitis C patientswithpeg-interferonalpha-2aandribavirintreatment’’.1_It wasshown that in women affectedby chronichepatitis Cand treatedwithantiviraltherapy,thesustainedvirologicalresponse (SVR)ratedecreaseswithageasalikelyconsequenceofgradual estrogen decline. Moreover, it was reported that among young patients,SVR ishigherinfemales thaninmales,whilein older subjectstheoppositeoccurs.

Althoughthedatareportedareinteresting,wewouldliketo make somecomments.First of all,thechoicetoselecta priori patientswithgenotype1producesaselectionbias,asgenotype1 infectionisuniversallyknowntobeassociatedwithresistanceto interferon,andthusthepopulationwasnotrepresentativeofall hepatitisCvirus(HCV)females. Moreover,we foundextremely interestingtheclear-cutdifferenceinSVRaccordingtothethree agecategorieschosen(<40years,40–50years,and50–60years), withSVRdecreasinginfemalesfromthefirstcategorytothelast one.Wethinkthatthisfits,withastonishingaccuracy,thedata recentlypublishedbyourgroupon theeffect ofmenopausein HCV-positivewomen.2_{Indeed,thelastcategorydescribedbyYu} et al. (age 50–60 years) most likely includes almost only menopausal women. In this regard, our finding applies to all menopausalwomen,althoughtheeffectismostevidentinthose withgenotype1.

Webelievethat menopauseandnotageis thekey factorin determiningthelackof responsetoantiviral therapy.We have demonstrated that cytokine dosage and immunohistochemical assessmentoftumornecrosisfactoralpha(TNF-

a

)andsuppressor ofcytokinesignaling3(SOCS3),dramaticallyincreaseinwomen afterthemenopauseincomparisonwithwomenofreproductive age. Our data suggest that the early menopause (estrogen deprivation <5 years) is associated with an up-regulation of hepatic TNF-

a

and SOCS3 togetherwith a marked increase in

circulatinginterleukin6(IL-6),whoselevelscorrelatewithhigher necro-inflammation; its postmenopausalrise is associatedwith theprogressionoffibrosisandwithworsenednecro-inflammation. The levels of the analyzed cytokines progressively decrease after the menopauseand, over time, thehepatic expression of TNF-

a

becomes comparable to that of women of reproductive age. Thisalso occursin younger women who undergosurgical menopause.

Thesemodificationsarecausallylinkedwiththeoccurrenceof resistance tothe actionof interferonand therefore explainthe progressivelylowerSVRrateinwomen:menopauseandnotageis thecriticalfactor.

Conflictofinterest:Nonetodeclare. References

1.YuJW,SunLJ,ZhaoYH,KangP,YanBZ.Impactofsexonvirologicresponserates ingenotype1chronichepatitisCpatientswithpeginterferonalpha-2aand ribavirintreatment.IntJInfectDis2011;15:e740–6.

2.VillaE,KarampatouA,Camma` C,DiLeoA,LuongoM,FerrariA,etal.Early menopauseisassociatedwithlackofresponsetoantiviraltherapyinwomen withchronichepatitisC.Gastroenterology2011;140:818–29.

StefanoGittoa AimiliaKarampatoub PietroAndreonea EricaVillab,_*

a_{DepartmentofClinicalMedicine,UniversityofBologna,Bologna,Italy} b_{DepartmentofGastroenterology,UniversityofModenaandReggio}

Emilia,ViadelPozzo71,41124,Modena,Italy CorrespondingEditor:WilliamCameron,Ottawa,Canada

*Correspondingauthor.Tel.:+390594225308;fax:+390594224363 E-mailaddress:erica.villa@unimore.it(E.Villa). 26September2011 27September2011 InternationalJournalofInfectiousDiseases16(2012)e149

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International

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j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d

1201-9712/$36.00–seefrontmatterß2011InternationalSocietyforInfectiousDiseases.PublishedbyElsevierLtd.Allrightsreserved. doi:10.1016/j.ijid.2011.09.025