Reaching the Unreachable: Strategies for HCV Eradication in Patients With Refractory Opioid Addiction-A Real-world Experience.

BRIEF REPORT Open Fo um In ec ious Diseases BRIEF REPORT • o id • 1 Recei ed 28 Ap il 2021; edi o ial decision 14 June 2021; accep ed 16 June 2021. Co espondence: Benjamin Maasoumy, MD, Hanno e Medical School, Ca l-Neube g-S . 1, 30625 Hanno e , Ge many (maasoumy.benjamin@mh-hanno e .de). Open Fo um In ec ious Diseases®2021 © The Au ho (s) 2021. Published by Ox o d Uni e si y P ess on behal o In ec ious Diseases Socie y o Ame ica.This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s licence (h p://c ea i ecommons.o g/licenses/ by-nc-nd/4.0/), which pe mi s non-comme cial ep oduc ion and dis ibu ion o he wo k, in any medium, p o ided he o iginal wo k is no al e ed o ans o med in any way, and ha he wo k is p ope ly ci ed. Fo comme cial e-use, please con ac [email p o ec ed] h ps://doi.o g/10.1093/o id/o ab325 Reaching he Un eachable: S a egies o HCV E adica ion in Pa ien s Wi h Re ac o y Opioid Addic ion—A Real- wo ld Expe ience LisaSandmann,1, JulianDeppe,2,3 Ch is ophBeie ,1 Vale ieOhlendo ,1 JuliaSchneide ,1 Heine Wedemeye ,1,4 FelixWedegä ne ,2 Ma kusCo nbe g,1,4,5 and BenjaminMaasoumy1,4,5 1Depa men o Gas oen e ology, Hepa ology and Endoc inology, Hanno e Medical School, Hanno e , Ge many, 2Depa men o Psychia y, Social Psychia y and Psycho he apy, Hanno e Medical School, Hanno e , Ge many, 3Pa ida Medizinisches Ve so gungszen um, Hanno e , Ge many, 4Ge man Cen e o In ec ion Resea ch (DZIF), Pa ne Si e Hanno e - B aunschweig, Hanno e , Ge many, and 5Cen e o Indi idualised In ec ion Medicine (CiiM), Helmhol z Cen e o In ec ion Resea ch, Hanno e , Ge many To achie e global hepa i is C i us (HCV) e adica ion, ba - ie s p ohibi ing ea men access need o be o e come. We es ablished a s a egy o ini ia e an i i al he apy in pa- ien s wi h se e e, e ac o y he oin addic ion. All pa ien s achie ed sus ained i ological esponse. Ou each p og ams o hepa ologis s migh be a easonable way o o e come ba - ie s o HCV ea men . Keywo ds. ac i e d ug use; DAA; diamo phine; HCV; he oin. Since he in oduc ion o di ec -ac ing an i i als (DAAs), ea men o ch onic hepa i is C i us (HCV) in ec ion has been well ole a ed and highly e ec i e. The e o e, he Wo ld Heal h O ganiza ion (WHO) has se he goal o e adica ing HCV in ec ion by 2030 [1]. To achie e his aim, ea ing ch onic HCV in ec ion in popula ions wi h a high p e a- lence o HCV is essen ial. People who injec d ugs (PWID) a e highly a ec ed by ch onic HCV in ec ion. In his popula- ion, an i-HCV p e alence is es ima ed o be 52.3% globally [2]. In Ge many, an i-HCV p e alence in he PWID popula- ion anges om 63% o 68% [3]. I has been shown ha an i- i al ea men is sa e and e ec i e o PWID wi h mode a e addic ion diso de who can be managed wi h opioid agonis main enance he apy (OAT) [4–6]. Howe e , pa ien s wi h documen ed ac i e d ug use ha e a ely been included in such ials [5, 7, 8]. Mo eo e , da a on hose wi h se e e, e ac o y addic ion a e sca ce. People wi h ongoing in a enous d ug use su e om mul iple como bidi ies and di icul ies wi h ega d o in eg a ion in o he egula heal h ca e sys em. A he same ime, a es o ch onic HCV in ec ion a e high and an i i al ea men is u gen ly needed, o bo h indi idual [9] and public heal h bene i [10]. Howe e , ini ia ion o an i i al ea men has been shown o be hinde ed a mul iple le els. Implemen a ion o HCV es ing, linkage o hepa ologis ca e, lack o on-si e deli e y o HCV ea men , and comple ion o he apy a e examples o gaps ha ha e been iden i ied by se - e al s udies [11, 12]. To o e come hese ba ie s, no el ea - men app oaches a e needed. The e o e, we de eloped a local ea men s a egy in coope a ion wi h he ou pa ien clinic o he oin-assis ed ea men (HAT) o deli e HCV ea men o pa ien s wi h se e e opioid dependency. METHODS The ou pa ien clinic o HAT in Hanno e o e s ea men wi h in a enous diamo phine o pa ien s wi h se e e, e- ac o y he oin addic ion who ha e p e iously ailed con- en ional subs i u ion ea men . Pa ien s isi he ou pa ien clinic on a daily basis o ecei e diamo phine ea men man- aged by psychia is s who specialize in addic ion medicine. In coope a ion wi h he psychia is s, we es ablished a s a egy o ini ia e an i i al he apy in hese pa ien s: An i-HCV and HCV-RNA-posi i e pa ien s we e iden i ied by he psychia - is s du ing ou ine assessmen . The hepa ologis eam isi ed he ou pa ien clinic o baseline isi . Decompensa ed li e ci hosis was excluded based on clinical and basic labo a- o y alues. Due o he use o pangeno ypic DAA ea men wi h so osbu i / elpa as i , HCV geno yping was abdicable. Labo a o y es s we e educed o a minimum o minimize blood wi hd awal p ocedu es and we e only pe o med be o e baseline o e i y ongoing i al in ec ion and 12 and 96 weeks a e he end o ea men o assess SVR and e-in ec ion (all on-si e). An i i al ea men was ca ied ou on-si e by he psychia is s, and he hepa ologis eam p o ided consul a- ion i needed. No addi ional medical appoin men s we e nec- essa y o he pa ien s. I was he pa ien ’s choice whe he o manage hei DAA ea men independen ly o wi h he sup- po o he HAT eam. Heal h- ela ed quali y o li e (HRQOL) was assessed by he SF-36 ques ionnai e be o e and a e he end o DAA ea men (Figu e 1A). S a is ical analyses we e pe o med using Excel ( e sion 16.37 o Windows, Mic oso , Redmond, WA, USA), G aphPad P ism ( e sion 7.05 o Windows, G aphPad So wa e, La Jolla, CA, USA), and SPSS ( e sion 26, SPSS Inc, Chicago, IL, USA). applypa as yle “ ig//cap ion/p[1]” pa as yle “FigCap ” Downloaded om h ps://academic.oup.com/o id/a icle/8/8/o ab325/6303541 by Ges Bio echnologische use on 06 Sep embe 2021 2 • o id • BRIEF REPORT RESULTS Fo y- i e pa ien s wi h e ac o y he oin addic ion we e ea ed in he HAT clinic. An i-HCV an ibody was de ec ed in mo e han one- hi d o he pa ien s (n = 17/45), and he as majo i y had ch onic HCV in ec ion (82%, 14/17). An i i al ea men was o e ed o all i emic pa ien s. Howe e , 5 pa ien s did no s a DAA he apy o a ious nonhepa ic easons: 2 ex- pe ienced imp isonmen , 2 discon inued HAT, and 1 decided agains DAA ea men (Figu e 1B). Pa ien s we e p edomi- nan ly male (89%). Six pa ien s (70%) we e an i-HBc posi i e, bu HBsAg was nega i e in all pa ien s. Fou pa ien s (44%) we e a isk o li e ci hosis based on aspa a e ansaminase o pla ele a io index (APRI) sco e, bu li e disease was compen- sa ed in all pa ien s (Table 1). In pa ien s s a ing an i i al ea men , in ec ion had been known o a median o 11yea s (min 4, max 30). All pa ien s we e awa e o hei in ec ion, bu only 1 pa ien had p e i- ously been ea ed wi h an in e e on-based egimen. “Fea o in e e on side e ec s” was he mos p e alen eason o no commencing an i i al ea men be o e (n = 5/9, 56%). The a ailabili y o DAA he apy was al eady known by 78% (n = 7/9) o he pa ien s. All pa ien s epo ed pa allel consump ion o addi ional d ugs including alcohol (44% wi h ha m ul use), and all bu 2 pa ien s named he HAT ou pa ien clinic as hei p ima y medical con ac (no addi ional p ima y ca e physi- cian). The a e o psychia ic como bidi ies was 100% (n = 9/9). All bu 1 pa ien decided o ake he daily DAA dose du ing hei isi o he ou pa ien clinic. Du ing DAA he apy, no side e ec s we e epo ed. All pa ien s who s a ed ea men Psychia is s: Pa ien s: On-si e ea men managemen On-si e ea men No addi ional appoin men s (Di ec ly obse ed he apy) Blood wi hd awal (minimum) HAT ou pa ien clinic On-si e isi A C B Clinical exclusion o decompensa ed ci hosis Pangeno ypic, p o ease- ee ea men egimen Consul a ion i needed Hepa ologis : 7 pa ien s did no s a ea men : 1 pa ien decided agains s a ing he apy To al n = 45 an i-HCV posi i e n = 17 Baseline isi n = 10 S a o ea men n = 9 HCV RNA neg. EOT n = 9/9 (100%) SVR 12 n = 9/9 (100%) 1 pa ien swi ched o OAT Rein ec ion a e (FU96) n = 0/8 (0%) lack o ch onici y (<6 mon hs), n = 1 HCV RNA neg., n = 2 P ison, n = 2 Los o FU, n = 2 HAT (baseline) 100 ** 80 60 40 Physical Func io n Role Physical Bodily Pain Gene al Heal h Vi ali y Social Func ion Role Emo ional Men al Heal h Physical Componen Summa y Men al Componen Summa y HAT (FU 24) Ge man popula ion (1994) Addic ion diso de (Ge many, 1998) - - - - Figu e 1. T ea men app oach (A), s udy o e iew (B), and esul s om he SF-36 ques ionnai e be o e an i i al ea men (HAT baseline) and 24 weeks a e he end o ea men (HAT FU24) (C). Values a e compa ed wi h he Ge man no m popula ion (Ge man popula ion 1994)and he Ge man e e ence popula ion wi h addic ion diso de (Addic ion diso de Ge many 1998). *P < .05, calcula ed by pai ed es . Abb e ia ions: EOT, end o ea men ; FU, ollow-up; FU24, ollow-up 24 weeks; HAT, he oin-assis ed ea men ; SVR, sus ained i ological esponse. Table 1. Baseline Cha ac e is ics To al (n = 9) Gende , male 8/9 (89) Age, y 47± 8.6 HCV RNA, log IU/mL 6.16± 0.9 An i-HBc pos. 6/9 (66.7) HBsAg pos. 0/9 (0) An i-HBs pos. 5/9 (55.6)a ALT, U/L 60.4± 25.3 Bili ubin, µmol/L 10.8± 6.1 C ea inine, µmol/L 75± 20.5 Th ombocy es, sd/µL183± 95.6 INR 0.94± 0.08 APRI sco e 0.95± 0.47 APRI >1 4/9 (44.4) Ca ego ical da a a e exp essed as No. (%). Con inuous da a a e exp essed as mean ±SD. Abb e ia ions: ALT, alanine ansaminase; APRI, AST o pla ele a io index; AST, aspa a e ansaminase; HBV, hepa i is B i us; HCV, hepa i is C i us; INR, in e na ional no malized a io. aHBV eac i a ion o he 2 an i-HBc-posi i e, an i-HBs-nega i e pa ien s was excluded by no mal ALT le els and nega i e HBV DNA a he end o ea men . Downloaded om h ps://academic.oup.com/o id/a icle/8/8/o ab325/6303541 by Ges Bio echnologische use on 06 Sep embe 2021 BRIEF REPORT • o id • 3 comple ed he apy and achie ed SVR (mITT: 9/9, 100%; ITT: 9/14, 64%) (Figu e 1B). No e-in ec ion occu ed du ing 96 weeks o ollow-up. HRQOL was assessed by he SF-36 ques ionnai e. Pa ien s’ sco es on he physical and men al subscales we e o e all lowe compa ed wi h he popula ion no m i espec i e o ea men s a us. When compa ed wi h he Ge man no m popula ion wi h addic ion diso de , sco es in all subscales excep “Bodily Pain” we e lowe in ou coho be o e an i- i al ea men . Howe e , 24 weeks a e he end o ea men , all subscale sco es excep o “Role Emo ional” we e highe han o simila o his no m popula ion. O e all, subscales measu ing physical and men al cha ac e is ics imp o ed 24 weeks a e he end o ea men (Figu e 1C). The inc eases exceeded 5% (which is conside ed o be a meaning ul clin- ical change) [13] in 7 o he 8 domains and included a 33% imp o emen on he Vi ali y scale, which has been iden i ied as he HRQOL domain o he SF-36 ha is mos ele an o ch onic HCV in ec ion [14]. DISCUSSION In ou s udy, we es ablished a eal-li e ea men concep o de- li e an i i al ea men o ch onic HCV in ec ion o pa ien s wi h se e e, e ac o y opioid dependency. We showed ha an i i al ea men is easible, well ole a ed, and success ul in pa ien s on HAT. This is in line wi h indings om he in e - e on e a ha showed compa able i al esponse a es be ween se e ely opioid-dependen pa ien s on HAT and non–d ug use s [15]. Mo eo e , he e icacy o DAA in PWID wi h less se e e addic ion diso de , ha is hose s able on OAT, has been demons a ed by mul iple s udies [5, 16, 17]. Vi al e adica ion causes se e al posi i e e ec s: Fi s , he isk o hepa ic de e i- o a ion due o HCV in ec ion is emo ed [9]. Second, pa ien s expe ience imp o emen in HRQOL [18, 19]. Fu he mo e, indi idual i al e adica ion leads o a educ ion o he gene al bu den o HCV in ec ion and educes u he i al sp eading [20, 21]. Despi e i s posi i e e ec s, implemen a ion o an i i al ea men in he PWID popula ion emains insu icien . The easons o his a e mul ilaye ed and include sys em-, p o ide -, and pa ien - ela ed ac o s. In ou coho , pa ien s epo ed ea o ea men - ela ed side e ec s and lack o mo i a ion as he main easons o no ha ing s a ed ea men be o e. Addi ionally, pe cei ed lack o capabili y o ini ia e ea men au onomously, he bu den o addic ion diso de i sel , and s ig- ma iza ion we e named as gene al easons o no s a ing ea - men . Simila aspec s eme ged in he s udy by Skee e al., who addi ionally iden i ied “pe cei ed lack o e e al o ea men ”, “lack o ca e con inui y”, and he pe cei ed need o ea men including “lack o dese ingness o ea men ” as ba ie s o ca e [22]. Despi e being awa e o hei in ec ion, mos pa- ien s do no pe cei e li e disease as he medical p oblem mos u gen ly in need o add essing [22]. This is mainly due o hei immense psychia ic como bidi y and concomi an social di - icul ies, which mo e di ec ly a ec he pa ien s’ e e yday li e. Due o he compounding men al symp om load in pa ien s wi h se e e addic ion diso de , a mul idisciplina y ea men ap- p oach is needed o success ully o e an i i al ea men . The se ing o HAT and OAT allows con ac wi h his di icul - o- each popula ion on a egula basis. S ill, physicians in ol ed in addic ion uni s a e no usually ained in HCV ca e, and suc- cess ul e e al o specialized ou pa ien clinics is no easible in mos cases. The e o e, on-si e an i i al ea men eme ges as he bes op ion o hese pa ien s. In ou coho , he HAT ou pa ien clinic se ed as he main medical con ac o he pa ien s, and on-si e ea men was acili a ed in se e al ways. Appoin men s we e lexible, and pa ien s bene i ed om a- milia clinical s a . An i i al ea men was explained and ini- ia ed by he hepa ologis eam bu conduc ed by he on-si e psychia ic eam. No addi ional appoin men s we e necessa y o he pa ien s. This mul idisciplina y ea men app oach and he con inui y o ca e a e impo an ac o s acili a ing an i i al ea men in his popula ion [7]. Fo ou eal-wo ld s udy, i can be assumed ha wi hou he on-si e ea men app oach, pa ien s would p obably no ha e s a ed an i i al ea men in he medium e m. Despi e he single-cen e expe ience and he o e all low numbe o ea ed pa ien s, ou s udy o e s se e al insigh s: I shows ha by es ablishing a mul ip o essional on-si e ea - men app oach, compa ably high a es o ea men up ake and i al clea ance a e achie ed. Impo an ly, pa ien s a high isk o u he delaying o ne e s a ing an i i al ea men we e linked o ca e. The s udy migh se e as an example no only o mo i a e o he pa ien s o s a an i i al he apy bu also o encou age medical p o essionals o de elop mul idisciplina y s a egies o o e come ea men ba ie s. Acknowledgmen s Financial suppo . No unding was ecei ed o hes udy. Po en ial con lic s o in e es . B.M.has ecei ed consul ing and/o lec- u e ees om AbbVie, B is ol-Mye s Squibb, Me ck/MSD, Roche, Janssen, and Abbo , as well as g an / esea ch suppo om Abbo , Roche, and Fuji ebio. M.C.has ecei ed pe sonal ees om AbbVie, Gilead Sciences, GSK, Janssen-Cilag, MSD Sha p & Dohme, No a is, Roche, Sp ing Bank Pha maceu icals, and Swedish O phan Bio i um AB (SOBI). H.W. has ecei ed g an / esea ch suppo and consul ing and/o lec u e ees om Abbo , AbbVie, Al immune, Bio es , BMS, BTG, Dice na, Gilead, Janssen, Me ck/MSD, MYR GmbH, No a is, Roche, and Siemens. L.S.has ecei ed hono a ia om D Falk Pha ma. J.D., C.B., V.O., F.W., and J.S.ha e no con- lic s o in e es o decla e. All au ho s ha e submi ed he ICMJE Fo m o Disclosu e o Po en ial Con lic s o In e es . Con lic s ha he edi o s con- side ele an o he con en o he manusc ip ha e been disclosed. Pa ien consen . All pa ien s ag eed o he usage o hei da a a e anonymiza ion. Da a analysis o HCV ea men has been app o ed by he e hics commi ee o Hanno e Medical School (No.9227). Re e ences 1. Wo ld Heal h O ganiza ion. Comba ing hepa i is B and C o each elim- ina ion by 2030. 2016. 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