David L. Wyles, M.D., of UCSD, presents "On again, off again... on again? Resistance testing for the management of HCV infection" at AIDS Clinical Rounds

1. 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

2. 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#
#

3. 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?#

4. 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#+#

5. 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#
#

6. HCV#Genotypic#Resistance#Sequencing#

7. 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#

8. 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.#

9. 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#
#

10. Examples:#NS3#resistance#genotyping#

11. Examples:#NS5A#resistance#genotyping#

12. 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)#

13. NS3'PI'RESISTANCE'

14. The#saving#grace#with#PI#resistance?#
Lenz'O.'EASL'2014.'
91%'of'nonSVR'with'resistance'
1a:'R155K#+/b#Q80K#
1b:'D168V#

15. 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#
SVR12'(%)' 623#92#
SOF'+'SMV'(±"#$)'
Gane%EJ.%#38%AASLD%2015.%

16. 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#
SVR12#(%)#
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.#

17. 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?#

18. NS5A'RESISTANCE'

19. 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.#

20. NS5A#structure#and#RAV#posi1ons#
Zeuzem#S.##91#AASLD#2015.#

21. 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#

22. 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.#

23. 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)#

24. Baseline#NS5A#RAVs:#A#moving#target#
Sarrazin#C.##1926#AASLD#2014.#

25. Baseline#NS5A#RAVs:#A#moving#target#
1a#
1b#
Jacobson#I.##LBb22#AASLD#2015.#

26. 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#

27. Baseline#NS5A#resistance#and#SOF/LDV#
Sarrazin#C.##1926#AASLD#2014.#
<100X#
>100X#
No#RAVs#

28. 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.#
SVR12#(%)#
SVR12#combined:#98%#no#RAVs#vs#89%#RAVs#[@15%#level]#

29. Impact#of#baseline#NS5A#RAVs#in#pa1ents#
with#cirrhosis#treated#with#SOF/LDV#
Impact#of#dura1on#and#RBV#
Sarrazin#C.##P0773.#EASL#2015.#

30. 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.#
SVR12#(%)#
88# 300# 214#66# 84#15#
*LDV#RAVs#@1%#cutoff#

31. 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'
SVR12#(%)#
SVR12#(%)#
Integrated%phase%2/3%analysis:%Baseline%NS5A%RAVs%(>5xEC50)%
predicVve%of%nonYSVR%with%12%weeks%of%treatment.%
Zeuzem%S.%#700.%AASLD%2015.%

32. 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#
SVR12'(%)'
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.#

33. 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.#

34. GZP/EBR#efficacy#in#GT1a:#Resistance#is#
all#that#mapers!?#
Zeuzem#S.##700#AASLD#2015.#
p#value#eOR#(95%#CI)#
GT#1a##
TNbPEP#

35. Same#story#with#GT1a#treatment#
experienced#pa1ents#
Zeuzem#S.##700#AASLD#2015.#

36. 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#

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

38. 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.#

39. Durability#of#treatment#emergent#NS5A#
RAVs#
Wyles#D,#DvorybSobol#H.#EASL#2015#

40. 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%)#

41. 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'
SVR12(%)

42. 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.#

43. 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?#

44. 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#

45. 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#

46. 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.%
%

47. 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.#

48. 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#Fixedb
Dose#Combina1on#for12#Weeks#in#DirectbAc1ng#An1viralb
Experienced#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#

49. A5348##
# '
Phase'II'Trial'of'Retreatment'Strategies'for'
DifficultUtoUTreat'Hepa55s'C'Virus'(HCV)U
infected'Individuals'Who'Have'Failed'Prior'
Direct'Ac5ng'An5viral'(DAA)Ubased'Regimens'
'
'
Protocol#Cobchairs:# #Annie#Luetkemeyer,#MD#
# # #Jennifer#Kiser,#PharmD#
&
#

50. A5348 Study Design
12 24Study Weeks
n= 20
SVR12SOF/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'

51. 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%#

52. 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##

53. ASTRALb1:#SOF/VEL#for#12#weeks#
No#“room”#for#resistance#impact?#
99' 98' 99' 100' 100' 97' 100'
0#
20#
40#
60#
80#
100#
SVR12#(%)#
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''

54. 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#

55. hpp://www.nature.com/ki/journal/v62/n5/fig_tab/4493262f1.html#
UDS!#
Sanger!#
NS5A!#
NS3#+#
NS5A!#
Cirrhosis!#
DAA#
failures!#
THE#HCV#RESISTANCE#
ELEPHANT#