The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.

AIDS CLINICAL ROUNDS

On#again,#off#again…on#again?##Resistance#tes1ng#for#the#management#

of#HCV#infec1on.#

David#L.#Wyles,#M.D.#Associate#Professor#of#Medicine#University#of#California#San#Diego#

#

Outline#

#1.  HCV#virology,#resistance,#and#assays#2.  What#do#the#clinical#trials#tell#us?#3.  Op1mizing#therapy#and#the#role#of#RAVs#4.  What#does#the#future#hold?#

Case#62#WM#with#HCV#GT1b#and#cirrhosis#(CPT#A5);#prior#breakthrough#on#PEG/RBV+TVR.#Treatment#complicated#by#severe#anemia#and#neutropenia: ##

–  Week#8:#Required#transfusion,#RBV#dose#reduc1on#–  Week#12:#PEG#dose#reduc1on,#GCSF#–  HCV#RNA#127#IU/ml#at#week#4;#viral#BT#at#week#26#

•  Treatment#discon1nued#–  Followbup#HCV#RNA#2.7#million#

Rebtreated#in#a#study#(12#weeks#of#SOF/LDV).#•  #Week#4:#HCV#RNA#<25#IU/mL#(detected)#•  All#subsequent#HCV#RNA#TND#(week#6#and#on)#•  SVR4#f/u:#HCV#RNA#+#

Case#Rebrebtreated#in#the#1118#study#[SOF/LDV#for#24wks#(no#RBV)]#Again#viral#relapse#by#week#4#postbtreatment.##•  HCV#RNA#UD#at#week#4;#undetectable#for#remainder#of#course#•  SVR4#f/u:#AST/ALT#45/67….#

–  HCV#RNA:#253,000#IU/mL#What#to#do#now?#•  Updated#labs:#

–  PLT#61,#Hgb#13.8#g/dL#–  AST/ALT:#59/59,#TB#0.7,#DB#0.3,#ALB#4.1,#INR#1.0#–  Cr#1.29#(prior#1.08)#–  HCV#RNA#1.2#million#

•  U/S:#Nodular#liver,#no#lesions.#12mm#PV,#15cm#spleen.#No#ascites.#Nonbocclusive#R#PVT.#

•  EGD:#grade#1#esophageal#varices##

HCV#Genotypic#Resistance#Sequencing#

The#HCV#lifecycle#favors#resistance#development…but#not#persistence.#

Favors'Resistance'1.  High#viral#turnover#rate#

–  1012#virions/day#

2.  Errorbprone#RNA#polymerase#–  ~1#error#per#10,000#bases#–  Involved#twice#in#replica1on#

3.  No#overlapping#reading#frames#

4.  Moderate#rate#of#infected#hepatocyte#turnover#

Lack'of'Persistence'1.  No#DNA#intermediate#

–  Contrast#to#integrated#HIV#–  Contrast#to#HBV#cccDNA#

2.  No#longblived#cellular#reservoir#known#–  Contrast#latently#infected#

HIV#+#CD4#cells#–  Contrast#to#transfer#of#HBV#

cccDNA#in#dividing#cells#

3.  There#are#excep1ons!#

Resistant#variants#prebexist#in#all#pa1ents#

Modeling#the#resistance#barrier#

•  Prebexistence#of#resistant#variant#explains#their#rapid#emergence##•  Not#all#variants#will#be#“fit”#enough#to#persist#unless#there#is#drug#

selec1ve#pressure#

Rong#L#et#al.#Science#Transl#Med#2010.#

Available#Resistance#Tes1ng#(US)#

•  Ultrabdeep#(or#NGS)#vs#popula1on#(Sanger)#– What#is#available:#1.  LabCorp/Monogram#Biosciences#

•  NGS#with#10%#detec1on#level#reported#

2.  Quest#Diagnos1cs#•  RTbPCR#with#DNA#sequencing##

– Both#assays#now#available#for#GT1#and#GT3##

hpp://www.monogrambio.com/content/hcvbns5abtes1ng##hpp://www.questdiagnos1cs.com/testcenter/testguide.ac1on?dc=TS_HCV_NS5A_Genotype&tabview=true#

#

Examples:#NS3#resistance#genotyping#

Examples:#NS5A#resistance#genotyping#

Characteris1cs#of#HCV#an1viral#classes#Class' An5viral'

Potency'Genotype'Ac5vity'

Resistance'barrier'

FDA'Approved'

NS3#Protease#Inhibitors# +++#to#++++# 1#(and#4)# Low#to#

moderate#

Simeprevir'(2013)#

Paritaprevir'(2014)#

Grazoprevir#(2016)#

NS5B#Nucleoside/1de# ++#to#++++# 1b6# Very#High# Sofosbuvir'

(2013)#

NS5B#Nonbnucleoside# ++#to#+++# 1# Very#low# Dasabuvir'

(2014)#

NS5A#Inhibitors# ++++# 1,#4b6#(+/b#2,3)#

Low#

Ledipasvir'Ombitasvir'

(2014)#Elbasvir#(2016)#

NS3'PI'RESISTANCE'

The#saving#grace#with#PI#resistance?#

Lenz'O.'EASL'2014.'

91%'of'nonSVR'with'resistance'1a:'R155K#+/b#Q80K#1b:'D168V#

Real#World#Data:#Impact#of#prior#PI#therapy?#

•  PI#failure=#PEG/RBV#+#PI#•  Resistance#tes1ng#results#not#available#– Majority#did#not#have#baseline#tes1ng#

•  Prior#PI#failure#was#associated#with#a#decreased#SVR#rate#–  OR:#0.4#(0.2b0.9)#

Nelson#D.#ISVHLD#2015.#Jensen#D.##45#AASLD#2014.#

78#

90#

0#

20#

40#

60#

80#

100#

PI#failure# No#PI#

SVR1

2'(%

)'623#92#

SOF'+'SMV'(±"#$)'

Gane%EJ.%#38%AASLD%2015.%

Lack#of#Q80K#impact#with#the#“appropriate”#dura1on#of#therapy#

97#

84#

96#

73#

0#

20#

40#

60#

80#

100#

12#weeks# 8#weeks#

Q80Q# Q80K#

SVR1

2#(%

)#

Kwo#P.##14##EASL#2015.#Lawitz#E.##LP04#EASL#2015##

92#

74#

0#

20#

40#

60#

80#

100#

12#weeks#

Q80Q# Q80K#

OPTIMISTU1' OPTIMISTU2'

Data#are#lacking#with#24#weeks#of#SOF/SMV#therapy.#

NS3#Resistance#tes1ngb#where#does#it#fit?#

•  Significant#baseline#NS3#RAVs#are#rare#–  Rou1ne#baseline#tes1ng#not#needed#

•  There#is#no#clear#impact#of#Q80K#on#SOF+SMV#when#using#approved#dura1ons#–  Data#are#lacking#with#24#weeks#in#cirrho1cs#

•  Well#studied#nonbPI#containing#op1ons#are#available#

•  If#you#need#to#use#an#NS3#PI#soon#axer#PI#failure#–  NS3#resistance#tes1ng#should#be#done#Marks%K.%#644%CROI%2015.%–  Determine#dura1on#in#retreament#with#triple#DAA#regimens?#

NS5A'RESISTANCE'

NS5A#Virology#

•  Mul1func1onal#phosphoprotein#–  Replica1on#complex/membranous#

web#forma1on#–  RNA#binding/replica1on#–  Virion#assembly/secre1on#

•  Homodimer#–  Mul1meric#form?#

•  Resistant#variants#impact#inhibitor#binding#–  Y93H#(Kwon%HJ.%PlosONE%2015)%

Rupp#D.#Seminars#in#Liver#Disease#2014.#

NS5A#structure#and#RAV#posi1ons#

Zeuzem#S.##91#AASLD#2015.#

NS5A#Resistance#Overview#

•  Baseline#polymorphisms#associated#with#resistance#are#rela1vely#prevalent#(~10%)#– They#impact#responses#in#select&se'ngs&

•  Currently#available#NS5A#inhibitors#suffer#from#broad#crossbresistance#at#key#posi1ons#– Q30R,#L31M/V,#Y93H/N#

•  NS5A#variants#persist#for#prolonged#periods#•  Selected#NS5A#RAVs#impact#rebtreatment#responses#

Broad#crossbresistance#with#“early#genera1on”#NS5As#

FoldUchange' 1a' 1b'

M28T# Q30R# L31M/V# Y93H/N# L31V# Y93H/N#

LDV# 20x# >100x# >100x/#>100x#

>1,000x/#>10,000# >100x/bb#

Ombitasvir# >1000x# >100x#<3x# >10,000x/#

>10,000x# <10x# 20x/50x#>100x#

DCV# >100x# >1000x# >100x/#>1000x#

>1,000x/#>10,000x# <10x# 20x/50x#

Elbasvir# 20x# >100x#>10x# >1,000x/##

>1,000x# <10x# >100x/bb#>100x#

Velpatasvir# <10x# <3x# 20x/50x# >100x/#>1000x# <3x/bb#

ACHb3102# 30x# 20x# <10x# >100x/>100x# <3x/<3x#

ABTb530# <3x# <3x# <3x# <10x/<10x# <3x# <3x/<3x#

MKb8408# <10x# <10x# <10x# <10x# <10x# <10x#

Wang#C.#AAC#2012.#Cheng#G.##1172.#EASL#2012.##Zhao#Y.##A845#EASL#2012.#Yang#G.#EASL#2013.#Ng#T.##639#CROI#2014.#AsantebAppiah#E.#AASLD#2014.#

A#word#on#NS5A#resistance#terminology#

The#prevalence#of#baseline#NS5A#resistance#varies#widely#in#the#literature.#•  RAPs:#Resistance#associated#polymorphisms#

–  ANY#nonbconsensus#amino#acid#at#a#site#associated#with#resistance#to#ANY#NS5A#inhibitor#

•  Class#RAVs:#Resistance#associated#variants#–  Specific#amino#acid#subs1tu1ons#associated#with#resistance#to#ANY#NS5A#inhibitor#

•  Drugbspecific#RAVs:#–  Specific#amino#acid#subs1tu1ons#associated#with#resistance#to#a#par1cular#NS5A#inhibitor#

•  Different#foldbchange#cutboffs#have#been#used#(2x,#5x,#10x#etc)#

Baseline#NS5A#RAVs:#A#moving#target#

Sarrazin#C.##1926#AASLD#2014.#

Baseline#NS5A#RAVs:#A#moving#target#

1a#

1b#

Jacobson#I.##LBb22#AASLD#2015.#

Baseline#NS5A#resistance#and#SOF/LDV#•  Deep#sequencing#analysis#of#baseline#samples#(n=1904)#in#phase#2/3#SOF/LDV#studies#

Sarrazin#C.##1926#AASLD#2014.#

No#RAVs#

NS5A#RAVs#

GT1'(n=2137)'

84%#16%#

GT'1b'(n='529)'

84%#16%#

GT'1a'(n=1602)'97%#SVR12#

93%#SVR12#

96%#SVR12#

98%#SVR12#

92%#SVR12#

95%#SVR12#

Baseline#NS5A#resistance#and#SOF/LDV#

Sarrazin#C.##1926#AASLD#2014.#

<100X#

>100X#

No#RAVs#

Impact#of#baseline#NS5A#RAVs#in#pa1ents#with#cirrhosis#treated#with#SOF/LDV#

Impact#of#subtype#and#foldbchange#

98# 97#

85#96#

0#

20#

40#

60#

80#

100#

1a# 1b#

No#RAVs# RAVs#

40# 52#263# 154#

100# 100#92#

97#100#

67#

0#

20#

40#

60#

80#

100#

None# <100x# >100x#

Naïve# Experienced#

70# 193# 3# 11# 12# 15#

Sarrazin#C.##P0773.#EASL#2015.#

SVR1

2#(%

)#

SVR12#combined:#98%#no#RAVs#vs#89%#RAVs#[@15%#level]#

Impact#of#baseline#NS5A#RAVs#in#pa1ents#with#cirrhosis#treated#with#SOF/LDV#

Impact#of#dura1on#and#RBV#

Sarrazin#C.##P0773.#EASL#2015.#

Expanded#analysis:#5,937#subjects#across#the#globe#treated#with#SOF/LDV#

90# 89# 87#

99# 96#100#

0'

20'

40'

60'

80'

100'

TE#NC:#12wks# TE#Cirr:#12wks#+#R# TE#Cirr:#24wks#

Impact'of'NS5A'RAVs*'with'select'SOF/LDV'regimens'

RAVs# No#RAVs#

Zeuzem#S.##91#AASLD#2015.#

SVR1

2#(%

)#

88# 300# 214#66# 84#15#

*LDV#RAVs#@1%#cutoff#

Impact#of#NS5A#RAVs#on#PI/NS5A#

77#

58#

94#

0#

20#

40#

60#

80#

100#

No#RAVs# RAVs#

All# 1a# 1b#

37# 19# 18#

76#

68#

89#

0#

20#

40#

60#

80#

100#

No#RAVs# RAVs#

All# 1a# 1b#

50# 31# 18#

Zeuzem#S.#Annals#Intern#Med.#2015.#Kwo#P.##P0886#EASL#2015.#

Treatment'naïve:'GZP/EBR'x'12'wks'

Treatment'experienced:'12U16'wks'±&"#$''

Grazoprevir/Elbasvir'

SVR1

2#(%

)#

SVR1

2#(%

)#

Integrated%phase%2/3%analysis:%Baseline%NS5A%RAVs%(>5xEC50)%predicVve%of%nonYSVR%with%12%weeks%of%treatment.%Zeuzem%S.%#700.%AASLD%2015.%

Impact#of#baseline#NS5A#RAVs#in#GT1a#pa1ents#treated#with#GZP/EBR#

EBR#RAVs# NS5A#Class#RAVs# EBR#RAVs# NS5A#Class#RAVs#Popula5on'Sequencing' Next'Genera5on'Sequencing'(1%'level)'

No#RAVS:#414/438#(95%)#

No#RAVS:#432/438#(80%)#

No#RAVS:#396/439#(90%)#

No#RAVS:#289/439#(65%)#

5%# 20%# 10%# 35%#

98# 98# 98# 98#

58#

86#72#

91#

0#

20#

40#

60#

80#

100#

Pa1ents#without#RAVs#

Pa1ents#with#RAVs#

SVR1

2'(%

)'

EBR#RAVs# NS5A#Class#RAVs# EBR#RAVs# NS5A#Class#RAVs#

405/ 414

14/ 24

345/ 352

74/ 86

389/ 396

31/ 43

284/ 289

136/ 150

Popula5on'Sequencing' Next'Genera5on'Sequencing'

EBR#RAVs#=#RAVs#with#>5x#fold#shix#in#EBR#EC50#

Regimen:#GZP/EBR#x#12#weeks #GT1a#naïve/relapsers#

Jacobson#I.##LBb22#AASLD#2015.#

Impact#of#baseline#NS5A#RAVs#in#pa1ents#treated#with#GZP/EBR#

•  Impact#of#NS5A#RAVs#on#TE#(nonbresponder)#GT1a#treated#with#GZP/EBR#x#12#wks#–  EBR#RAVs#(popula1on):#97%#vs.#29%#(No#RAVs#vs.#RAVs)#

#•  Extension#to#16b18#weeks#with#RBV#appears#to#negate#the#impact#of#NS5A#RAVs#

#•  Baseline#RAVs#have#no#significant#impact#in#GT#1b##•  Popula1on#sequencing#iden1fies#the#vast#majority#of#significant#RAVs#

Jacobson#I.##LBb22#AASLD#2015.#

GZP/EBR#efficacy#in#GT1a:#Resistance#is#all#that#mapers!?#

Zeuzem#S.##700#AASLD#2015.#

p#value#eOR#(95%#CI)#

GT#1a##TNbPEP#

Same#story#with#GT1a#treatment#experienced#pa1ents#

Zeuzem#S.##700#AASLD#2015.#

Considera1ons#for#NS5A#resistance#tes1ng#in#DAA#naïve#pa1entsb#GT1a#only#•  SOF/LDV#

–  No#apparent#role#in#treatment#naïve#pa1ents#–  Could#baseline#tes1ng#be#used#to#“op1mize”#therapy#in#TE#pa1ents,#par1cularly#those#with#cirrho1cs?##

•  24#wks#+#RBV#for#all#TE#cirrho1cs#with#baseline#NS5A?#–  Zeuzem%S.%#91%AASLD%2015.#

•  Overtreatment#of#many#pa1ents#•  GZP/EBR#

–  Baseline#resistance#tes1ng#accurately#defines#those#who#can#get#12#weeks#without#RBV#

•  Appears#to#apply#across#most#groups#studied#–  Zeuzem%S.%#700.%AASLD%2015.#

•  16#weeks#with#RBV#negates#the#impact#of#baseline#RAVs#–  Jacobson%I.%#LBY22.%AASLD%2015.%

•  3D#+#RBV#–  Baseline#resistance#data#not#available#

Baseline#vs#Selected#RAVs#

•  Is#there#a#difference?#– Propor1on#in#quasispecies#– Compensatory/associated#muta1ons#–  Impact#on#response#– What#role#does#the#host#play?#

Rate#of#selec1on#of#NS5A#resistance#upon#virologic#failure#

•  Varies#by#regimen#and#dura1on#–  PI#based#

•  Vedroprevir#+#tegobuvir#+#LDV:#>99%#•  GZR/EBR:#90%##•  3D:#68%#

– Nucleo1de#based#•  SOF/LDV:#75%#

–  8#weeks:#65%#

– Nucbbased#triple#•  SOF/5816/9857#(≤#6#weeks):#0%#(n=15)#•  SOF#+#GZR/EBR#(≤#8#weeks):#37%#(n=30)#

Kitrinos#K.##AASLD#2014.Sulkowski#M.#Lancet#2014.#Lawitz#E.#Lancet#2014.#Sarrazin#AASLD#2014.#Kowdley#K.#NEJM#2013.#Gane#E.#EASL#2015.#Poordad#F.#EASL#2015.#

Durability#of#treatment#emergent#NS5A#RAVs#

Wyles#D,#DvorybSobol#H.#EASL#2015#

RAV#persistence#axer#3D#treatment#

Krishnan#P.##O057#EASL#2015.#

RAV' FU'week'24' FU'week'48'NS3/4A'(all)' 31/67'(46%)' 5/57'(9%)'##D168# ##21/55#(38%)# ##2/53#(5%)#

##R155K# ##10/13#(77%)# ##2/7#(29%)#

NS5A'(all)' 68/70'(97%)' 49/51'(96%)'##M28V/T# ##32/33#(97%)# ##21/21#(100%)#

##Q30E/K/R# ##38/41#(93%)# ##25/28#(89%)#

NS5B'(all)' '33/44'(75%)' 20/35'(57%)'##S556G# ##27/30#(90%)# ##17/22#(77%)#

NS5A#RAVs#are#associated#with#retreatment#failure#

71'

100'

60'

0#

20#

40#

60#

80#

100#

Combined# No#RAVs#####RAVs#

18/30'11/11'29/41'

SOF/LDV#

12# 24#0#

N=41# SVR12#

weeks#100' 80'

33'

0#

20#

40#

60#

80#

100#

Q30R#or#M28T#

L31M# Y93H/N#

Lawitz E. #O005 EASL 2015.

5/5' 4/5' 2/6'

SV

R12

(%)

Is#resistance#a#unique#considera1on#in#DAA#failures?#YES.#

1.  DAA#resistance#is#frequently#selected#on#failure#2.  Resistance#muta1ons#to#some#DAA#classes#

(NS5A)#persist#for#prolonged#dura1ons#3.  RAVs#are#associated#with#retreatment#failure##What#we#don’t#know#for#sure#is:#Selec1on#of#retreatment#therapy#based#on#resistance#tes1ng#(selec1on#of#nonbcross#resistant#regimens)#will#result#in#improved#treatment#success.#

Considera1ons#in#pa1ents#who#failed#a#DAAbbased#regimen#

•  Was#ini1al#therapy#subbop1mal#(or#subbmaximal)?#–  Dura1on#–  RBV#use#

•  What#specific#medica1on#classes#were#used#– What#role#dose#resistance#play?#

•  Stage#of#liver#disease/host#characteris1cs#•  Indica1ons#of#other#problems#

–  Adherence?#–  Significant#drug#interac1ons?#

•  Terrault%N.%#94%AASLD%2015.%–  Immunosuppression?#

When#to#do#NS5A#resistance#tes1ng?#

DAA#naïve#pa1ents:#•  Baseline#tes1ng#should#be#considered#prior#to#use#of#GZP/EBR#in#GT#1a#pa1ents.#– Alterna1ve#regimens#of#16#weeks#+#RBV#if#EBR#RAVs*#found#at#baseline#

DAAbexperienced#pa1ents#(IFNbfree#DAA#failures)#•  Resistance#tes1ng#recommended#(my#opinion)#•  Based#on#the#results…#

*#RAVs#at#posi1ons#28,#30,#31,#and#93#

DAA#failure#

No#NS5A#RAVS#

SOF/LDV#+#RBV#

24#weeks#No#Q80K#(or#other#PI#RAVs)#

SOF#+#SMV#+#RBV#24#weeks#

+#NS5A#RAVs#(Q30,#L31,#H58,#Y93)#

SOF#+#SMV#+#RBV#24#weeks#(even#if#Q80K)#

+NS5A#RAVs#+#NS3#RAVs#(R155,#A156,#D168)#

Despera1on#1me#

3D#+#SOF#(LBY20)#SOF#+#SMV#+#DCV#+#RBV#

SOF/LDV#+#RBV#

Inves1ga1onal#Triple#

Regimens#

Genotypic#resistance#tes1ng#

Triple#(or#quad)#therapy#to#the#rescue?#

•  CbSWIFT#Retreatment:#– GZP/EBR#+#SOF#+#RBV#x12wks#(n=23)#–  100%#SVR12#(including#9/9#with#NS3+NS5A#RAVs)#

Lawitz%E.%LBY12%AASLD%2015%

•  3D#+#SOF#(±RBV)#x#12#wks:#–  SVR12#93%#(14/15);#12/13#GT1a,#2/2#GT1b#

Poordad%F.#LBY20%AASLD%2015%

•  SOF/VEL#+#GSb9857:#–  6#wks:#No#apparent#impact#of#baseline#RAVs#on#SVR#–  8#wks:#Decreased#response#with#baseline#RAVs#

Gane%EJ.%#713.%AASLD%2015.%Gane%EJ.%#38.%AASLD%2015.%

%

Role#of#Resistance#in#GT3#Responses#

•  SOF+DCV#x#12#weeks#(ALLYb3)#–  54%#SVR12#with#baseline#Y93H#(7/13)#– ALLYb3+#SVR12:#93%#(38/41)#vs.#88%#(7/8)#(No#RAVs#vs.#RAVs)#

Leroy%V.%LBY3%AASLD%2015%•  SOF+VEL#x#12weeks#(ASTRALb3)#

–  SVR12:#97%#(225/231)#vs.#88%#(38/43)#(No#RAVs#vs.#RAVs)#–  Y93H:#84%#SVR12#(21/25)#

%Mangia%A.%NEJM%2015.%

•  GZP/MKb3682/MKb8408#(CbCREST#1#&#2):#–  45%#(5/11)#vs.#97%#(72/74)#[NS5A#RAVs#vs#not]##

%Gane%EJ.%LBY15.%AASLD%2015%

Nelson#D.#Hepatology#2015.#

Retreatment#study#op1ons#at#UCSD#

•  A5348#•  POLARISb1:#A#Phase#3,#Global,#Mul1center,#Randomized,#

DoublebBlind,#PlacebobControlled#Study#to#Inves1gate#the#Safety#and#Efficacy#of#Sofosbuvir/Velpatasvir/GSb9857#FixedbDose#Combina1on#for12#Weeks#in#DirectbAc1ng#An1viralbExperienced#Subjects#with#Chronic#HCV#Infec1on#

•  MKb021#Study:#A#Phase#II,#Randomized,#OpenbLabel#Clinical#Trial#to#Study#the#Efficacy#and#Safety#of#the#Combina1on#Regimen#of#MKb3682B#(MKb5172#+#MKb3682#+#MKb8408#Fixed#Dose#Combina1on#(FDC))#in#Subjects#with#Chronic#HCV#GT1#or#GT3#Infec1on#who#have#failed#a#Direct#Ac1ng#An1viral#Regimen#

A5348###'

Phase'II'Trial'of'Retreatment'Strategies'for'DifficultUtoUTreat'Hepa55s'C'Virus'(HCV)Uinfected'Individuals'Who'Have'Failed'Prior'

Direct'Ac5ng'An5viral'(DAA)Ubased'Regimens'''

Protocol#Cobchairs:# #Annie#Luetkemeyer,#MD## # #Jennifer#Kiser,#PharmD#

&#

A5348 Study Design 12 24 Study Weeks

n= 20 SVR12 SOF/LDV +

RBV

0

N = 40 SOF treatment

experienced limited to SOF/SIM, SOF/RBV, SOF/PEG/

RBV

SVR12

36

n = 20

•  Phase II study, evaluating retreatment strategies for SOF-failures •  Genotype 1, HIV/HCV co-infected •  Cirrhotic patient permitted (CPT-A only), no cap on number

participating •  PK evaluation of participants on Tenofovir + ritonavir-boosted PI: TFV

levels off and on SOF/LDV. (DIFFERENT FROM DBS- every visit) •  Low intensity PK at entry and week 4: 3 blood draws (0,1,4

hours)- no need for GCRC •  PK participation required for first 15 on PI/r/tenofovir & 15 spots

reserved for those on PI/r/TDF x 3 months

SOF/LDV

Nested%PK%of%TFV%in%r/PI,%n=15%%

4

PK'

Inclusion#Criteria:#HIV##•  HIV+##•  HIV#Treatment:#

–  On#stable#ART#regimen#x#>8#weeks#with#CD4#>#200#and#HIV#VL#<#50#within#42#days#of#entry#or#

–  No#ART#but#CD4>500#or%–  #Elite#controller#with#CD4#>#200#and#with#all#HIV#RNA#<#500#in#48#weeks#prior#to#study#entry#

•  Most#ART#permiped#–  efavirenz,#rilpivirine,#raltegravir,#dolutegravir,#tenofovir,#abacavir,#3TC/FTC,#RTVbboosted#atazanavir,#RTV#boosted#darunavir#(both#800#mg#QD#and#600#mg#BID#permiped).#

–  NOTE:#PrioriVzing%enrollment%of%parVcipants%on%PI/r/Tenofovir%:%reserving%15%spots%for%the%first%3%months%aeer%study%opens%#

Inclusion#Criteria(2):#HCV#•  HCV#Genotype#1#only#•  Prior#virologic#failure#on#one#of#the#following#

–  Sofosbuvir/Ribavirin#(with#or#without#interferon)#–  Sofosbuvir/Simeprevir#(with#or#without#ribavirin)##

•  Cirrho1cs#permiped#(without#prior#decompensa1on:#ascites,#variceal#bleeding,#encephalopathy)##

•  Cirrhosis#assessment#required#but#biopsy#should#not#be#necessary ##– Algorithm:#Fibrosure/APRI#b>#Fibroscan#bbb#>#biopsy##

ASTRALb1:#SOF/VEL#for#12#weeks#No#“room”#for#resistance#impact?#

99' 98' 99' 100' 100' 97' 100'

0#

20#

40#

60#

80#

100#

SVR1

2#(%

)#

618'624'

206'210'

117'118'

104'104'

116'116'

34'35'

41'41'

Total# 1a# 1b# 2# 4# 5# 6#

Genotype#

32%#treatment#experienced#(99%#SVR12);#19%#cirrhosis#(99%#SVR12)#Feld#JJ.#NEJM#2015.#

Wk'0' Wk'12' Wk'24'

SVR12'#SOF/VEL'N='624'

Placebo# #SOF/VEL'N='116''

Summary#

•  Addi1onal#data#are#needed,#par1cularly#in#the#seÉng#of#DAA#failure,#to#define#the#role#of#resistance#tes1ng#in#deciding#best#therapy.#

•  Most#prominent#roles#currently:%– Deciding#on#immediate#retreatment#approaches#for#pa1ents#failing#NS5Abcontaining#regimens#

– Prior#to#GZP/EBR#to#define#appropriate#course#•  In#the#future#resistance#tes1ng#may#play#a#role#in#deciding#how#long#to#treat#as#well#as#what#to#use#

hpp://www.nature.com/ki/journal/v62/n5/fig_tab/4493262f1.html#

UDS!#

Sanger!#

NS5A!#

NS3#+#NS5A!#

Cirrhosis!#DAA#

failures!#

THE#HCV#RESISTANCE#ELEPHANT#