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5/17/2019 Curre nt He pa titis C T re a tme nt a nd Vira l Re sista nc e Co nc e rns CHRI ST OPHE R PACK , PHARM.D., AE -C CL I NI CAL PHARMACI ST & RE SI DE NCY DI RE CT OR, CHOCT AW NAT I ON OF OK L AHOMA WE ST

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5/17/2019 1

Curre nt He pa titis C T re a tme nt a nd Vira l Re sista nc e Co nc e rns

CHRI ST OPHE R PACK , PHARM.D., AE

  • C

CL I NI CAL PHARMACI ST & RE SI DE NCY DI RE CT OR, CHOCT AW NAT I ON OF OK L AHOMA WE ST ON L OVE L L , PHARM.D., MHA CL I NI CAL PHARMACI ST , CHOCT AW NAT I ON HE AL T H CE NT E R

Disc lo sure

 Unde r g uide line s e sta b lishe d b y the

Ac c re dita tio n Co unc il fo r Pha rma c y E duc a tio n, disc lo sure must b e ma de re g a rding fina nc ia l re la tio nships with c o mme rc ia l inte re sts within the la st 12 mo nths.

 T

he a utho rs o f this pre se nta tio n ha ve no re le va nt fina nc ia l re la tio nships o r a ffilia tio ns with c o mme rc ia l inte re sts to disc lo se .

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L e a rning Ob je c tive s

At the c o mple tio n o f this a c tivity, pha rma c ists will b e a b le to :

 De fine a tre a tme nt a lg o rithm fo r He pa titis C fro m re a dily a va ila b le

re so urc e s.

 Se le c t a g e ne tic va ria nt a sso c ia te d with tre a tme nt re sista nc e o f

He pa titis C.

 De fine a me tho d fo r a ddre ssing tre a tme nt re sista nc e in pa tie nts with

He pa titis C.

Pre -Asse ssme nt Que stio n # 1

Wha t is the le a ding c a use o f ne wly dia g no se d HCV infe c tio ns tripling fro m 2011-2016?

  • A. I

nc a rc e ra tio n

  • B. Opio id Crisis
  • C. Mo re Ba b y-b o o me rs re q ue sting sc re e ning
  • D. No n-pro fe ssio na l ta tto o
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Pre -Asse ssme nt Que stio n # 2

 A 60 y/ o 80kg ma le HCV pa tie nt ha s la b o ra to ry sc re e ning do ne

prio r to the ra py. T he pa tie nt ha s g e no type 1a a nd c a nno t re me mb e r the re g ime nt tha t the y we re o n b ut b e lie ve it mig ht ha ve b e e n rib a virin. T he physic ia n e le c ts to ha ve NS5a re sista nc e te sting do ne . I t sho ws pro b a b le L e dipa svir re sista nc e . Upo n furthe r re vie w, a Q30R muta tio n with >100 fo ld c ha ng e is sho wn. Wha t is the b e st tre a tme nt c o urse fo r this pa tie nt pe r g uide line s?

  • A. Ha rvo ni (L

e dipa svir/ So fo sb uvir) 1ta b le t da ily fo r 12 we e ks

  • B. Wa it fo r a fe w mo nths, the n tre a t a s this type o f re sista nc e will

fa de in tha t time .

  • C. Ha rvo ni (L

e dipa svir/ So fo sb uvir) 1ta b le t da ily + Rib a virin 600mg BI D fo r 24 we e ks

  • D. E

pc lusa (Ve lpa ta svir/ So fo sb uvir) 1 ta b le t da ily fo r 12 we e ks

HCV Re vie w

 He pa titis C (HCV) is the mo st c o mmo n b lo o d-b o rne pa tho g e n

 5 time s mo re c o mmo n tha n HI

V

 T

  • ta l c o sts e xc e e ding $10 b illio n do lla rs fro m 2010-2019 with o ve r 190,000

re la te d de a ths

 E

stima te d 2.4 millio n pe o ple a re c hro nic a lly infe c te d in the US ~ 1% o f US po pula tio n

 Ove r ha lf o f tho se infe c te d do no t kno w the y ha ve HCV  Risk fa c to rs inc lude : I

VDU (b ig g e st risk fa c to r), Othe r illic it drug s (due to c o nta mina tio n o f pa ra phe rna lia ), he a lthc a re a sso c ia te d tra nsmissio n (ra re ), ta tto o s, tra nsfusio ns (ra re ), Birth to HCV po sitive mo the r, se xua l a c tivity with HCV-infe c te d pe rso n (ine ffic ie nt me a ns)

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HCV Ove rvie w

 Sing le -stra nde d RNA virus o f the

F la vivirid a e fa mily

 Do e s no t ha ve pro o fre a ding

po lyme ra se

 E

na b le s fre q ue nt vira l muta tio ns

 Co pio us re plic a tio n po se s pro b le ms

fo r ho st immune c o ntro l

https:/ / e n.wikipe dia .o rg / wiki/ He pa titis_C_virus

HCV Ove rvie w

 T

he re a re c urre ntly 6 g e no type s o f He pa titis C

 I

n the US, g e no type s 1-3 a re mo st c o mmo n

 Ge no type 1a a nd1b is b y fa r the mo st c o mmo n, fo llo we d b y 2 a nd

3, re spe c tive ly

 Ge no type s 4-6 c o ntinue to po se a the ra pe utic c ha lle ng e  I

n mo st insta nc e s a c ute infe c tio n le a ds to c hro nic infe c tio n, sinc e immune syste m fo r mo st insta nc e s is insuffic ie nt to c le a r virus

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HCV Ac ute I nfe c tio n

 Up to 85% o f a c ute HCV infe c tio ns will le a d to c hro nic infe c tio ns  HCV RNA le ve ls a re de te c ta b le a fte r 1-2 we e ks o f e xpo sure  Pa tie nts a re la rg e ly a sympto ma tic a t this time  AL

T c a n rise up to 10 time s UL N during e nsuing we e ks

 Afte r 7 we e ks, 1/ 3 c a n e xpe rie nc e sympto ms inc lude fa tig ue (mo st

c o mmo n), a no re xia , we a kne ss, ja undic e , a b do mina l pa in, o r da rk urine .

HCV I nfe c tio n pro g re ss

Once exposed to HCV:

 75-85% will g o o n to de ve lo p c hro nic infe c tio n  10-20% will g o o n to de ve lo p c irrho sis o ve r a pe rio d o f 20-30 ye a rs

Among patients with cir r hosis, ther e is:

 1-2% a nnua l risk o f he pa to c e llula r c a rc ino ma  3-6% a nnua l risk o f he pa tic de c o mpe nsa tio n, fo r whic h the risk o f

de a th in the fo llo wing ye a r is 15-20%

 Pro g re ssio n to c irrho sis o c c urs a fte r 20+ ye a rs o f infe c tio n

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Who sho uld b e te ste d fo r HCV?

CDC r ecommends HCV testing for :

 Curre nt o r fo rme r inje c tio n drug use rs, inc luding tho se who inje c te d

  • nly o nc e ma ny ye a rs a g o

 A multi-sta te syste ma tic re vie w o f g lo b a l HCV infe c tio n pre va le nc e

a mo ng PWI D pub lishe d in 2017 pro vide d a po int e stima te o f 53.1% in the Unite d Sta te s, with a ra ng e o f 38.1% to 68.0%

 E

ve ryo ne b o rn fro m 1945 thro ug h 1965

 Re c ipie nts o f c lo tting fa c to r c o nc e ntra te s ma de b e fo re 1987, whe n

le ss a dva nc e d me tho ds fo r ma nufa c turing tho se pro duc ts we re use d

Who sho uld b e te ste d fo r HCV?

 Re c ipie nts o f b lo o d tra nsfusio ns o r so lid o rg a n tra nspla nts prio r to

July 1992, b e fo re b e tte r te sting o f b lo o d do na tio ns b e c a me a va ila b le

 Chro nic he mo dia lysis pa tie nts  Pe o ple with kno wn e xpo sure s to HCV, suc h a s

 he a lth c a re wo rke rs a fte r ne e dle stic ks invo lving HCV-po sitive b lo o d  re c ipie nts o f b lo o d o r o rg a ns fro m a do no r who te ste d HCV-po sitive

 Pe o ple with HI

V infe c tio n

 Childre n b o rn to HCV-po sitive mo the rs

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Curre nt HCV Co nc e rns

 Ne w HCV I

nfe c tio n dia g no sis mo re tha n triple d fro m 2011-2016

 Pe r CDC E

xpa nde d te sting , tre a tme nt, a nd pre ve ntio n se rvic e s a re urg e ntly ne e de d, e spe c ia lly in lig ht o f the surg e in ne w infe c tio ns linke d to the o pio id c risis.

 Opio id c risis puts ne w g e ne ra tio ns a t risk o f he pa titis C infe c tio ns  Re sista nc e -a sso c ia te d sub stitutio ns

HCV T re a tme nt

Sc re e n Pa tie nts

 HCV a ntib o dy  Co nfirm with PCR  Ob ta in Vira l L

  • a d

 Ge no type  With Co mpe nsa te d Cirrho sis o r witho ut c irrho sis  Cho o se the mo st a ppro pria te the ra py fo r pa tie nt  Pro vide the ra py fo r the pa tie nt

 E

va lua tio n fo r re tre a tme nt is re c o mme nde d a s e ffe c tive a lte rna tive tre a tme nts b e c o me a va ila b le if tre a tme nt fa ile d to a c hie ve Susta ine d Viro lo g ic Re spo nse

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Vira l Re sista nc e

 He pa titis C, muc h like HI

V, is a n RNA virus tha t re plic a te s c o pio usly (Billio ns o f c o pie s da ily)

 Re plic a tio n o f the virus will re sult in a n a ppro xima te e rro r ra te o f 33%  T

he re sult o f the se e rro rs will e ithe r b e no disc e rna b le c ha ng e , no n- func tio na l (o r de a d viruse s), o r vira l muta tio ns le a d to vira l re sista nc e

 Re g a rding muta te d viruse s, sub the ra pe utic a ntivira l the ra py a llo ws

fo r se le c tive pre ssure tha t pro mo te s the se va ria nts to pro spe r

 T

he mo st c o mmo n a re a s o f muta tio n a re to NS5A a nd NS3 site s

 T

he se a re mo re pre va le nt in pa tie nt who ha ve fa ile d a ntivira l the ra py

 NS5B Re sista nc e a sso c ia te d sub stitutio ns (RASs) a re ra re due to the

c o nse rve d c a ta lytic site a nd a c c o unt fo r <1% o f RASs.

Vira l Re sista nc e

 NS5A RASs ma inta in hig h re plic a tio n c o mpe te nc e in the a b se nc e o f

c o ntinue d drug pre ssure (fo r ye a rs) re la tive to NS3 a nd NS5B RASs (whic h to b e o ve rta ke n b y wild type virus within mo nths).

I t is impo rta nt to re me mb e r tha t the impa c t o f RASs o n tre a tme nt

  • utc o me s will va ry due to a multitude o f fa c to rs inc luding :

 Co -Administe re d Drug s  Pa tie nt F

a c to rs (c irrho sis)

 Cha ng e in po te nc y c o nfe rre d b y e a c h RASs

 I

t is impo rta nt to c o nside r tha t te sting a lo ne will no t dic ta te o ptima l the ra py no r will the pre se nc e o f a RASs e limina te a the ra py o ptio n in a ll pa tie nts.

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Vira l Re sista nc e

 Ce rta in vira l muta tio ns c a n le a d to tre a tme nt fa ilure , b ut the impa c t

va rie s b y g e no type .

 Ge no type 1a a nd 3 ha ve the mo st c linic a lly sig nific a nt Re sista nc e

a sso c ia te d sub stitutio ns (RAS)

 NS5A inhib ito rs a re the mo st c linic a lly sig nific a nt vira l va ria nts  NS3/ 4A Pro te a se I

nhib ito rs se e m to b e le ss sig nific a nt

 At le a st 15% o f the to ta l virus lo a d sho uld c a rry the RAS in o rde r to e ffe c t

e ffic a c y

 RAS te sting is re c o mme nde d with Ze pa tie r(E

lb a svir/ Gra zo pre vir), Ha rvo ni (L e dipa svir/ So fo sb uvir), E pc lusa (So fo sb uvir/ Ve lpa ta svir), a nd Da c la ta svirplus So fo sb uvir

Vira l Re sista nc e in L ite ra ture

 F

  • r Da c la ta svir+So fo sb uvir,in the AL

L Y-3 study, in pa tie nts with g e no type 3 a nd the Y93H muta tio n: 67%a c hie ve d SVR w/ o c irrho sis vs 25% with c irrho sis. No te : All pa tie nts a na lyze d sho we d SVRs o f 97% in tho se witho ut c irrho sis vs 58% with c irrho sis.

 F

  • r E

lb a svir/ Gra zo pre vir, tre a tme nt-na ïve o r prio r re la pse pa tie nts tre a te d fo r 12 we e ks w/ o rib a virin with NS5A RASs sho we d a n SVR o f 58% ve rsus 98% fo r tho se witho ut. T re a tme nt e xpe rie nc e d pa tie nts with NS5A RASs sho we d a n SVR o f 29% ve rsus 97%.

 F

  • r Ha rvo ni, whe n RASs with >100-fo ld re sista nc e we re pre se nt SVR12

ra te s dro ppe d to 64.7% with 12 we e ks o f the ra py ve rsus 100% with 24 we e ks o f the ra py. One sma ll c o ho rt sho we d a dding Rib a virin did no t sho w a s muc h e ffic a c y a s e xte nd ing the inte rva l to 24 we e ks. I n g e ne ra l, tho se with b a se line RASs did no t sho w SVR12 le ss tha n 90%

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Vira l Re sista nc e

 F

  • r Vo se vi, RASs ha ve no t sho wn a n impa c t o n SVR12 ra te s

 F

  • r E

pc lusa , the pre se nc e o f Y93H in g e no type 3 infe c te d pa tie nts de c re a se d the SVR12 ra te s to 84% c o mpa re d to 97%

 T

his wa s mo re impa c tful in tho se with c irrho sis a nd/ o r prio r tre a tme nt

 F

  • r Ma vyre t, the pre se nc e o f RAS ha d minima l impa c t o n SVR ra te s

in no n-c irrho tic pa tie nts. T he re is no t suffic ie nt da ta to sug g e st tha t RAS e ffe c t SVR ra te s in the se pa tie nts.

 F

  • r Pa rita pre vir/ Rito na vir/ Omb ita svir+ Da sa b uvir± Rib a virin, risk o f

tre a tme nt fa ilure ha s no t b e e n e sta b lishe d, b ut use o f Vie kira Pa k witho ut Rib a virin in tho se with a histo ry o f DAA fa ilure is no t re c o mme nde d.

Clinic a lly I mpo rta nt RASs b y Ge no type a nd Re g ime nt

Drug 1a 1b 3 Ha rvo ni (L e dipa svir/ So fo sb uvir) Q30H/ R, L 31M/ V, Y93C/ H/ N L 31V, Y93H N/ A Ze pa tie r (E lb a svir/ g ra zo pre vir) M28A/ T , Q30H/ R, L 31M/ V, Y93C/ H/ N Y93H N/ A E pc lusa (So fo sb uvir/ ve lpa ta svir) N/ A N/ A Y93H Pa rita pre vir/ rito na vir/ o mb ita svir +/ - rib a virin N/ A N/ A N/ A

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NS5a RAS T e sting Re c o mme nda tio ns b e fo re T he ra py

Drug 1b T N o r T E 1a T N 1a T E No Cirrho sis 1a T E Cirrho sis Ha rvo ni (L e dipa svir/ So fo sb uvir) NO NO YE S YE S Ze pa tie r (E lb a svir/ g ra zo pre vir) NO YE S YE S YE S E pc lusa (So fo sb uvir/ ve lpa ta svir) NO NO NO NO Pa rita pre vir/ rito na vir/ o mb ita svir +/ - rib a virin NO NO NO NO

Guide line Re c o mme nda tio ns o n the use o f RAS te sting

Ze pa tie r (E lb a svir/ Gra zo pre vir)

NS5A RAS testing is recommended for genotype 1a-infected, treatment-naive or -experienced patients being considered for elbasvir/grazoprevir. If present, a different regimen should be considered

Harvoni (Ledipasvir/Sofosbuvir)

NS5A RAS testing can be considered for genotype 1a-infected, treatment-experienced patients without cirrhosis being considered for ledipasvir/sofosbuvir. If clinically important resistance is present, a different recommended therapy should be used.NS5A RAS testing can be considered for genotype 1a-infected, treatment-experienced patients with cirrhosis being considered for ledipasvir/sofosbuvir. If clinically important resistance is present, a different recommended therapy should be used.

Epclusa (Sofosbuvir/Velpatasvir)

NS5A RAS testing is recommended for genotype 3-infected, treatment-naive patients with cirrhosis and treatment- experienced patients (with or without cirrhosis) being considered for 12 weeks of sofosbuvir/velpatasvir. If Y93H is present, weight-based ribavirin should be added or sofosbuvir/velpatasvir/voxilaprevir should be used.

Da c la ta svir plus So fo sb uvir

NS5A RAS testing is recommended for genotype 3-infected, treatment-experienced patients without cirrhosis being considered for 12 weeks of daclatasvir plus sofosbuvir. If Y93H is present, weight-based ribavirin should be added.NS5A RAS testing is recommended for genotype 3-infected, treatment-naive patients with cirrhosis being considered for 24 weeks of daclatasvir plus sofosbuvir. If Y93H is present, treatment should include weight-based ribavirin, or a different recommended therapy used.

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Stra te g ie s to Ma na g e RASs

 Cha ra c te rize Pa tie nts a t risk fo r tre a tme nt fa ilure

 Suc h a s a c c ura te a sse ssme nt o f live r fib ro sis a nd c la rific a tio n o f prio r the ra py

 Virus

 De te rmine a de q ua te the ra py b a se d o n g e no type , sub type , a nd b a se line

RASs  T

re a tme nt Dura tio n

 Sho rte r the ra pie s a sso c ia te d with hig he r risk o f fa ilure whe re a s lo ng e r

dura tio ns ha ve le a d to inc re a se d ra te s o f SVR  Rib a virin

 Inc re a se s the ra te o f SVR in tho se with inc re a se d risk o f fa ilure , b a se line RASs,

a nd prio r DAA tre a tme nt fa ilure  Multiple Co mb ine d T

he ra pie s

Clinic a lly I mpo rta nt RASs b y Ge no type a nd F

  • ld Cha ng e
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Po st-Asse ssme nt Que stio ns # 1

Wha t is the le a ding c a use o f ne wly dia g no se d HCV infe c tio ns tripling fro m 2011-2016?

  • A. I

nc a rc e ra tio n

  • B. Opio id Crisis
  • C. Mo re Ba b y-b o o me rs re q ue sting sc re e ning
  • D. No n-pro fe ssio na l ta tto o

Pre -Asse ssme nt Que stio n # 2

 A 60 y/ o 80kg ma le HCV pa tie nt ha s la b o ra to ry sc re e ning do ne

prio r to the ra py. T he pa tie nt ha s g e no type 1a a nd c a nno t re me mb e r the re g ime nt tha t the y we re o n b ut b e lie ve it mig ht ha ve b e e n rib a virin. T he physic ia n e le c ts to ha ve NS5a re sista nc e te sting do ne . I t sho ws pro b a b le L e dipa svir re sista nc e . Upo n furthe r re vie w, a Q30R muta tio n with >100 fo ld c ha ng e is sho wn. Wha t is the b e st tre a tme nt c o urse fo r this pa tie nt pe r g uide line s?

  • A. Ha rvo ni (L

e dipa svir/ So fo sb uvir) 1ta b le t da ily fo r 12 we e ks

  • B. Wa it fo r a fe w mo nths, the n tre a t a s this type o f re sista nc e will

fa de in tha t time .

  • C. Ha rvo ni (L

e dipa svir/ So fo sb uvir) 1ta b le t da ily + Rib a virin 600mg BI D fo r 24 we e ks

  • D. E

pc lusa (Ve lpa ta svir/ So fo sb uvir) 1 ta b le t da ily fo r 12 we e ks

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Re fe re nc e s

 Ce nte rs fo r Dise a se Co ntro l a nd Pre ve ntio n (CDC).” He pa titis C

Pre va le nc e E stima te s 2013-2016”. 6 No ve mb e r, 2018 We b . Ac c e sse d 14 Ma y 2019

 Ce nte rs fo r Dise a se Co ntro l a nd Pre ve ntio n (CDC).” Ne w He pa titis C

I nfe c tio ns Ne a rly T riple d o ve r F ive Ye a rs”. 11 Ma y, 2017 We b . Ac c e sse d 14 Ma y 2019

 HCV Guida nc e : Re c o mme nda tio ns fo r T

e sting , Ma na g ing , a nd T re a ting He pa titis C. http:/ / hc vg uide line s.o rg . Ac c e sse d 14 Ma y 2019

 AASL

D-I

  • DSA. HCV Re sista nc e Prime r. Re c o mme nda tio ns fo r te sting ,

ma na g ing , a nd tre a ting he pa titis C. Https:/ / www.hc vg uide line s.o rg / e va lua te / re sista nc e . [Ma y 15, 2019]

Curre nt He pa titis C T re a tme nt a nd Vira l Re sista nc e Co nc e rns

CHRI ST OPHE R PACK , PHARM.D., AE

  • C

CL I NI CAL PHARMACI ST & RE SI DE NCY DI RE CT OR, CHOCT AW NAT I ON OF OK L AHOMA WE ST ON L OVE L L , PHARM.D., MHA CL I NI CAL PHARMACI ST , CHOCT AW NAT I ON HE AL T H CE NT E R