Richard Haubrich, M.D., and David Wyles, M.D. of UC San Diego Antiviral Research Center, presents "Update from the American Association for the Study of Liver Diseases Meeting" 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. UPDATE'FROM'AASLD'
Presented'by'Laurel'and'Hardy'

3. • we'talk'about'our'pt'and'both'his'ini@al'treatment'op@ons'for'a'guy'on'
TDF/FTC/RAL/DRV/rit'and'how'we'are'trying'to'accommodate'SOF/SMV'
now'with'his'HIV'regimen…'
'
• Drug'interac@ons'with'ARVs''(Richard):'
• Mdrug'interac@on'data'
• MHIV'data'with'SOF/NS5a'regimen'(NIH'study'presented'at'AASLD'with'
SOF/LDV)'
• Mother'HIV'data'(AbbVie'data'Turquoise'I)'
• Retreatment'of'SOF'and/or'other'HCV'failures/resistance'(David):'
• M'retereatment'data'(Gilead'1118'study;'data'from'real'world'cohorts)'
• M'resistance'issues'(NS5A'impact'focus)'
• Mfuture'regimens'that'might'address'resistance'if'needed.'

4. GJ'
• 57'AA'yo'male'
• HCV'
– Genotype'1a'
– Cirrhosis'F5/6'(bx'3/2014);'no'decompensa@on'
– U/S'nega@ve'1/2014;'EGD'w/o'varicies''
– Null'responder'to'PEG/'RBV'
– Relapse'a`er'12'weeks'SOF/'DVC'
• PMH'
– DMII;'HTN'
– HBV'and'HAA'immune'

5. HIV'Treatment'Hx'
• 5/13M9/14:'DRVr'(BID)/'RAL/'TDF/'FTC'
– 1/09M5/13:'SQV(BID)/'RAL/'TDF/FTC'2004M'09:'TDF/CBV/
SQV(1000)'BID/RTV(100)'BID'
– 2000M04:'D4T/3TC/IDV/RTV''
– Late'1990s'x'2'weeks:'ZDV'+'2'others?''
• Phenotype'2004:''
– NRTI'M'Sensi@ve'to'ABC,'ddI,'d4T,'TDF,'ZDV.'Reduced'
suscep@bility'to'FTC,'3TC''
– NNRTI'M'Sensi@ve'to'EFV,'NVP,'DLV''
– PI'M'Sensi@ve'to'SQV.'Reduced'suscep@bility'to'ATV,'FPV,'
IDV,'LPV,'NFV,'RTV'

6. What'HCV'regimen'can'be'given'with'
his'current'ARV'regimen?'
• SOF/'LDV'
• SIM/'SOF'
• SIM/'SOF'RBV'
• IFN/'RBV/'SOF'
• none'

7. Labs'10/2014'
• Chemistry:''
– Cr.'1.3;'AST'39;'ALT'25;'TB'0.5'
• CBC:'
– Hg'14.3;'plt'107;'INR'1.0'
• HCV'RNA:'3,457,502'
• APRI'='0.91'(cutoff'1.0);'Fib'4'='4.2'(cutoff'1.45)'
• CD4:'509'(33%)'
• HIV'RNA:'25'(<20'on'9/19/14)'

8. Significant'drug'interac@ons'of'ARV'
and'SOF'include?'
1. TDF'
2. All'PIs'
3. All'NNRTIs'
4. RAL'but'not'other'INSTI'
5. none'

9. Significant'drug'interac@ons'of'ARV'
and'SIM'include?'
1. All'NRTI'
2. Some'NNRTI'
3. All'PI'boosted'with'RTV'or'cobi'
4. 2'and'3'
5. none'

10. Significant'drug'interac@ons'of'ARV'
and'SOF/LDV'include?'
1. All'NRTI'
2. TDF'when'given'with'EFV'or'ETR'
3. TDF'when'given'with'a'PIr'
4. All'PI'
5. 2'M'4'
'

12. SIM'Metabolism'
• SIM'metabolized'by'CYP'3A'
– CYP3A'inhibitors'increase'SIM'
– CYP3A'inducers'decrease'SIM'
• SIM'inhibits'intes@nal'CYP3A'but'not'hepa@c'
• SIM'inhibits'OATP1B1/3'and'PGP'

13. DDI'between'NRTI'and'HCV'Agents'
ARV$ SOF$ LDS/$SOF$ SIM$
FTC/$3TC$ 00$ 00$ 00$
ABC$ 00$ 00$ 00$
TDF$ 00$ ✖ PIr$$
! TDF$
00$
ZDV$ 00$ 00$ 00$
MM'='no'significant'effect'
✖''='do'not'use'
AASLD/IDSA/IAS–USA.'hpp://www.hcvguidelines.org.'hpp://aidsinfo.nih.gov/contenqiles/lvguidelines/AdultandAdolescentGL.pdf'

14. DDI'between'TDF'and'LDV/'SOF'
• C24'geometric'mean'ra@o:'2.6'(90%'CI:'2.4M'3.0)'
• no'effect'='1.0'
• TFV'levels'similar'to'dosing'with'DRVr'+'TDF'
Similar'data'with'RPV'
as'EFV'
German'et'al.'15th'Clinical'Pharmacology'Workshop'of'HIV'&'HCV;'2014:'OM06'

15. DDI'between'TDF'and'LDV/'SOF'
• Drug'interac@on'data'with'PIr'+'TDF'+'
LDV/SOF'is'not'available'
• DRVr'increases'LDV'(GMR'='1.39)'
• TFV'levels'are'expected'to'be'higher'with'
PIr'and'LDV/SOF'
AASLD/IDSA/IAS–USA.'hpp://www.hcvguidelines.org.'

16. DDI'between'NNRTI'and'HCV'Agents'
ARV$ SOF$ LDS/$SOF$ SIM$
EFV$ 00$ 00$
(TDF$!)$
✖
EFV00$
SIM$"$
ETR$ 00$ 00$ ✖
EFV00$
SIM$"$
RPV$ 00$ 00$
(TDF$!)$
00$
MM'='no'significant'effect'
✖''='do'not'use'
AASLD/IDSA/IAS–USA.'hpp://www.hcvguidelines.org.'hpp://aidsinfo.nih.gov/contenqiles/lvguidelines/AdultandAdolescentGL.pdf'

17. No'DDI'between'EFV'and'LDV/'SOF'
• C24'geometric'
mean'ra@o:'
0.91'(90%'CI:'
0.83M'0.91)'
• no'effect'='1.0'
• RPV'less'effect'
German'et'al.'15th'Clinical'Pharmacology'Workshop'of'HIV'&'HCV;'2014:'OM06'

18. DDI'between'PIr''and'HCV'Agents'
ARV$ SOF$ LDS/$SOF$ SIM$
ATVr$or$
ATV/$cobi$
00$ 00$
(TDF$!)$
✖
SIM$!$
DRVr$or$
DRV/$cobi$
00$ 00$
(TDF$!)$
✖
SIM$!$
MM'='no'significant'effect'
✖ ='do'not'use'
“Monitor'for'TFVMassociated'adverse'events'
in'EFV/FTC/TDF,'or'RTVMboosted'ATV'or'DRV+'
TDF/FTC”'
AASLD/IDSA/IAS–USA.'hpp://www.hcvguidelines.org.'hpp://aidsinfo.nih.gov/contenqiles/lvguidelines/AdultandAdolescentGL.pdf;''German'et'al.'
AASLD'2014'

19. DDI'between'INSTI'and'MVC'and'HCV'
Agents'
ARV$ SOF$ LDS/$SOF$ SIM$
DTG$ 00$ 00$ 00$
RAL$ 00$ 00$ 00$
EVG/cobi/
TDF/FTC$
00$ ✖$ ✖$
MVC$ 00$ 00$ 00$
MM'='no'significant'effect'
✖''='do'not'use'
AASLD/IDSA/IAS–USA.'hpp://www.hcvguidelines.org.'hpp://aidsinfo.nih.gov/contenqiles/lvguidelines/AdultandAdolescentGL.pdf'

20. No'effect'of'RAL'on'LDV/'SOF'
• C24'geometric'
mean'ra@o:'
0.89'(90%'CI:'
0.81M'0.98)'
• no'effect'='1.0'
• No'effect'SOF'
on'RAL'
German'et'al.'15th'Clinical'Pharmacology'Workshop'of'HIV'&'HCV;'2014:'OM06'

21. To$be$able$to$use$all$HCV$DAA,$what$ARV$regimen?$
1. DRVr/RAL/'ABC/3TC'
2. RAL/'ETR/'TDF/FTC'
3. 'DTG/ETR/TDF/FTC'
4. DTG/RPV/TDF/FTC'
5. Other'
Current:'DRVr'(BID)/'RAL/'TDF/'FTC;'Phenotype:''
– NRTI'–'Sensi@ve:'ABC,'TDF,'ZDV.'ResistantM'FTC,'3TC''
– NNRTI'Sensi@ve:'EFV,'NVP'
– PI'–'Sensi@ve:'SQV.'Reduced'suscep@bility'to'ATV,'FPV,'RTV'

22. ARV'Regimen'
• Pa@ent'changed'to'DTG'(50'mg'BID)'+'RPV/
TDF/FTC'(FDC)'9/2014'

23. What'would'you'do'with'the'ARV'
regimen?'
1. Follow'closely,'HIV'RNA's@ll'<200'
2. Add'DRVr'
3. Order'a'resistance'test'
4. pray'

24. Trofile'DNA'(11/7/14)'

25. GENOSURE'ARCHIVE'11/7/14'

26. GENOSURE'ARCHIVE'11/7/14'

27. ARV'Regimen'
• Pa@ent'changed'to'DTG'(50'mg'BID)'+'RPV/
TDF/FTC'(FDC)'9/2014'
• 11/21/2014'MVC'added'

28. Other'than'DDI,'does'HIV'coMinfec@on'
change'HCV'DAA'selec@on/'outcome?'
1. Yes'
2. No'

29. Osinusi A. AASLD 2014; 84

31. Characteris
Kc$
No$ART$$
N$=13$
ART$
N$=$37$
1a$ 75%$ 81%$
HCV$RNA$ 6.1$ 6.0$
Fibrosis$
stage$3$
38%$ 22%$
CD4$ 687$ 576$
Baseline'Characteris@cs'
• Regimen:'EFV'(+/M'RAL)'16;'RPV'(+/M'RAL)'11;'
RAL'10'

32. Results'
• SVR12'='98%'(49/50)'
– One'early'HCV'relapse'(wk'2'post'tx)'
– One'late'relapse'HCV'at'week'36'post'tx'
• HIV'safety'
– No'change'HIV'RNA'in'offMART'group'
– One'blip'in'ART'treated,'reMsupressed'
– CD4'stable'
• Crea@nine'stable'to'week'12'post'treatment'
– Mean'week'12:''crea@nine'change'+0.03;'CrCL'M3.8'
– Mean'post'tx'week'12:'crea@nine'change'+0.04;'CrCL'
+0.4'

33. Turquoise'1:'Abbvie'3'DAA'+'RBV'
• HIV/'HCV'
– GT'1,'naïve/'experienced,'cirrhosis'(CP'A)'
– Stable'ART:'ATVr'or'RAL'
• Paritaprevir/r'(PI)'+ombitasvir'+'dasabuvir'+'
RBV'
Wyles D. AASLD 2014; 1939

34. CharacterisKc$ 12$week$
N$=$31$
24$week$
N$=$32$
HCV$genotype$
1a$
97%$ 91%$
HCV$RNA$ 6.5$ 6.6$
Cirrhosis$ 19%$ 19%$
CD4$ 633$ 625$
ARV$=$ATVr$ 52%$ 38%$
Baseline'Characteris@cs'
Wyles D. AASLD 2014; 1939

35. CharacterisKc$ 12$week$
N$=$31$
24$week$
N$=$32$
Overall$SVR$12$ 94%$ 91%$
No$SVR$ 2$ 3$
Relapse$ 1$ 0$
Failure$during$tx$ 0$ 1$
Stopped$tx$ 1$ 0$
HCV$re0infecKon$ 0$ 2$
SVR12'
Wyles D. AASLD 2014; 1939

36. What'HCV'regimen'would'you'select?'
1. SOF/'LDV'
2. SIM/'SOF'
3. SIM/'SOF'RBV'
4. IFN/'RBV/'SOF'
5. Other'
6. Need'more'informa@on'

37. Retreatment'of'SOF'failure'with'SOF/
LDV'+'RBV:'GSMUSM342M1118'
Wk 0 Wk 12 Wk 36Wk 24
LDV/SOF + RBV SVR12
SOF failures
(n=51)
LDV/SOF SVR12LDV/SOF failures
LDV/SOF + RBV SVR12SOF failures
(advanced liver disease)
Wyles D. AASLD 2014.

38. Baseline'Characteris@cs'
LDV/SOF$+$RBV$12$weeks$
n=51$
Mean'age,'y'(range)' 54 (27‒68)
Men,'n'(%)' 31 (61)
Black/African'American,'n'(%)' 8 (16)
Hispanic/La@no,'n'(%)' 4 (8)
Mean'BMI,'kg/m2'(range)' 30.4 (21.1‒47.9)
IL28B'nonMCC,'n'(%)' 47 (92)
GT'1a,'n'(%)' 30 (59)
Mean'HCV'RNA,'log10'IU/mL'(range)' 6.2 (4.4‒7.3)
HCV'RNA'≥800,000'IU/mL,'n'(%)' 38 (75)
Prior'HCV'treatment,'n'(%)'
SOF'+'PEG/RBV' 25 (49)
SOF'±'RBV*$ 21 (41)
SOF'placebo†' 5 (10)
Cirrhosis,'n'(%)' 15 (29)
Wyles D. AASLD 2014.

39. 24
98 100 100 98 98 98
0
20
40
60
80
100
Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12 SVR24
HCVRNA<LLOQ,%
Error'bars'represent'95%'CIs.'
EOT,'end'of'treatment.'
51/5112/51$ 51/51$
HCVRNA<LLOQ,%
50/51$50/51$ 50/51$50/51$
OnMTreatment'Viral'Kine@cs'and'SVR'Rates'
Wyles D. AASLD 2014.
14/14'SOF/RBV'failures'achieved'SVR12'with'SOF/LDV'for'12'weeks.'
Osinusi&A.&EASL&2014.&

41. But'our'pt'failed'SOF'plus'an'NS5A'
(DCV)…'
• What'is'his'resistance'profile'post'failure'likely'
to'look'like?'
– SOF'resistance?'
– DCV'resistance?'
• What'is'the'impact'of'NS5A'resistance'on'
treatment'outcomes?'
• Is'there'any'data'on'reMtreatment'of'these'
pa@ents?'
'

42. SOF'Resistance'
• AASLD'2013:'No'S282T'in'4'phase'3'studies'
– Studies'across'GTs'1M4'(NEUTRINO,'FISSION,'FUSION,'POSITRON)'
– 226'nonMSVRs:'221'UDS'(1%'detec@on'level)'
• No'S282T'iden@fied'
– 1/294'nonMSVRs'with'S282T'(Svarovskaia&E.&CID&2014)&
• AASLD'2014:'No'S282T'in'phase'3'SOF/LDV'
– L159F'+/M'V321A'seen'as'TEVs'
– 15%'L159F'with'SOF;'1%'with'SOF/LDV'
– impact'on'response?'
• 1.6%'at'baseline'w/'L159F:'100%'SVR'in'SOF/LDV'(23/23)'
Svarovskaia$E.$AASLD$2013.$Gane$E.$#43$AASLD$2014.$

43. Evolution of sofosbuvir resistance in the subject with S282T.
Svarovskaia E S et al. Clin Infect Dis. 2014;59:1666-1674
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases
Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.

44. NS5A'Inhibitor'Resistance'
• Similar'resistance'papern'for'1st'gen'NS5A'
with'respect'to'GT'1a'and'1b'
Kitrinos'KM.'#1949'AASLD'2014.'Wang'C.'AAC'2013'

45. Long'term'DCV'followMup'from'AASLD'
Reddy'KR.'AASLD'2014.'

46. Long'term'DCV'followMup'from'AASLD'
• Median'followMup'ranged'from'41M123'weeks'
– Longer'in'pts'treated'with'DCV/P/R'
• Predominant'NS5A'RAVs'
– 1a:'Q30E/K/R,'L31M/V,'Y93H/C'''1b:'L31M/V'+'Y93H'
• Persistence'of'NS5A'RAVs'
– 86%'(63/73'1a)'and'95%'(56/59'1b)'by'popula@on'at'
last'followMup'
– Contrast'to'41%'(1a)'and'29%'(1b)'at'last'followMup'
for'NS3'RAVs'
Reddy'KR.'#1965'AASLD'2014.'Wang'C.'AAC'2013.'

47. Impact'of'NS5A'baseline'resistance'is'
contextual'
• IFN'vs'IFNMfree'
• Strength'of'surrounding'DAAs'
Kitrinos'KM.'#1949'AASLD'2014.'Manns'M.'EASL'2014'
38%'SVR12'in'ASV/DCV'with'baseline'NS5A'RAVs'(compared'to'85%'overall)'

48. Baseline'NS5A'resistance'and'SOF/LDV'
• Deep'sequencing'analysis'of'baseline'samples'
(n=1904)'in'phase'2/3'SOF/LDV'studies'
– ELECTRON,'LONESTAR'and'ION'studies'
Sarrazin'C.'#1926'AASLD'2014.'
97%'
93%'
GT$1$(n=2137)$
98%'
95%'
GT$1b$(n=529)$
96%'
92%'
GT$1a$(n=1602)$
NS5A'RAVs'No'NS5A'RAVs'
SVR12'(%)'

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

50. Impact'of'baseline'NS5A'RAVs'on'
outcomes'in'retreatment'
• No'pa@ents'had'SOFMassociated'variant,'S282T,'detected'at'baseline''
– 2'pa@ents'had'NS5B'treatmentMemergent'variant'L159F'at'baseline'and'
achieved'SVR'
'
Wyles'D.'AASLD'2014'*1'pa@ent’s'baseline'results'were'not'available.'
n=6/6$
100%$SVR$98%$SVR$
n=43/44$
12%$
NS5A$RAVs$
n=6/50'
88%$
No$NS5A$RAVs$
at$baseline$
n=44/50*'

51. And'of'course'this'is'the'single'
LONESTAR'pa@ent…'
Lawitz'E.'#215'AASLD'2013.'
So'we'might'be'able'to'get'away'
with'24wks'of'SOF/LDV,'but…'

52. Why'not'just'avoid'the'NS5A'class?'
• This'makes'the'most'sense'intui@vely'
• What'is'the'data'with'SOF'+'SIM'+/M'RBV'
– This'is'an'FDA'approved'regimen'
• What'does'the'label'say?'
• Do'the'Guidelines'help…not'really.'
– RealMworld'data'with'this'regimen?'
• Very'liple'in'HIV+'
• Special'considera@ons'in'a'treatment'
experienced'cirrho@c?'

53. COSMOS:'Data'in'F3/F4'
93' 97'
89'
0'
10'
20'
30'
40'
50'
60'
70'
80'
90'
100'
F3/F4' F3' F4'
Lawitz'E.'Lancet'2014.'
18'23'41'
89' 89'
Naïve' Null'
12'weeks'
24'weeks'
9' 9'
F4'only'
No'conclusion'can'be'drawn'on'the'u@lity'of'RBV.'

54. FDA'label'indica@ons'for'SOF/SIM'
Tes@ng'for'Q80K'“is'not'strongly'recommended'but'may'be'considered.”'
No'guidance'on'RBV'is'offered.'
Olysio'package'insert'(11/2014).'

55. Real'world'data:'HCV'Target'
SOF/SIM'groups:'60%'experienced'(27%'PI'failure),'57%'cirrhosis'(47%'decompensa@on).'
' ' ' ' ' ' '3%'HIV'CoMinfected'
Jensen'D.'#45'AASLD'2014.'

56. Real'world'data:'HCV'Target'
Jensen'D.'#45'AASLD'2014.'
81'
85'
79'
0'
89'
92'
87'
75'
0'
10'
20'
30'
40'
50'
60'
70'
80'
90'
100'
All' NC' Cirr' DC'
PI'failure' No'PI'
No'data'on'Q80K;'vast'majority'did'not'have'it'tested.'
97%'concordance'between'SVR4'and'SVR12.'
SVR4'

57. TRIO'network'realMworld'experience'
65%'of'GT1'received'SOF/SIM'+/M'RBV;'~50%'treatment'experienced.'
Flamm'S.'#983'AASLD'2014.'

58. TRIO'network'realMworld'experience'
No'data'on'Q80K'presented.'
Flamm'S.'#983''AASLD'2014.'

59. SIRIUS'Study'
• DoubleMblind'study'
• Treatment'experienced'cirrho@c'pa@ents'
– All'failed'both'Peg/RBV'then'P/R/PI'
– Groups'were'well'matched'
• Plt'<100k:'18%'vs'17%'
• ALB'<3.5:'8%'vs.'17%'
Bourliere'M.'#LBM6'AASLD'2014.'

60. SIRIUS'Study'
Bourliere'M.'#LBM6'AASLD'2014.'Bourliere'M.'#82'AASLD'2014'

61. HCV'regimen'
• SIM/'SOF/'RBV'10/10/14'
– Week'2'10/24'
– Week'4'11/07'

62. HCV'RNA'

63. BACKUP'

65. • Phenotype 2004:
– NRTI - Sensitive to ABC, ddI, d4T, TDF, ZDV.
Reduced susceptibility to FTC, 3TC
– NNRTI - Sensitive to EFV, NVP, DLV
– PI - Sensitive to SQV. Reduced susceptibility
to ATV, FPV, IDV, LPV, NFV, RTV

66. HIV'RNA'

67. HCV'RNA'

68. GENOSURE'ARCHIVE'11/7/14'