Update from the American Association for the Study of Liver Diseases Meeting

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AIDS CLINICAL ROUNDS

UPDATE'FROM'AASLD'

Presented'by'Laurel'and'Hardy'

•  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.'

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'

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'

What'HCV'regimen'can'be'given'with'his'current'ARV'regimen?'

•  SOF/'LDV'•  SIM/'SOF'•  SIM/'SOF'RBV'•  IFN/'RBV/'SOF'•  none'

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)'

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'

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'

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''

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'

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'

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'

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.'

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'

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'

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'

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'

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'

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'

ARV'Regimen'

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

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'

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

GENOSURE'ARCHIVE'11/7/14'

GENOSURE'ARCHIVE'11/7/14'

ARV'Regimen'

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

•  11/21/2014'MVC'added'

Other'than'DDI,'does'HIV'coMinfec@on'change'HCV'DAA'selec@on/'outcome?'

1.  Yes'2.  No'

Osinusi A. AASLD 2014; 84

CharacterisKc$

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'

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'

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

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

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

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'

Retreatment'of'SOF'failure'with'SOF/LDV'+'RBV:'GSMUSM342M1118'

Wk 0 Wk 12 Wk 36 Wk 24

LDV/SOF + RBV SVR12 SOF failures (n=51)

LDV/SOF SVR12 LDV/SOF failures

LDV/SOF + RBV SVR12 SOF failures (advanced liver disease)

Wyles D. AASLD 2014.

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.

24

98 100 100 98 98 98

0

20

40

60

80

100

Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12 SVR24

HC

V R

NA

<LLO

Q, %

Error'bars'represent'95%'CIs.'EOT,'end'of'treatment.'

51/51 12/51$ 51/51$

HC

V R

NA

<LLO

Q, %

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.&

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?'

'

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$2014.$

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: [email protected].

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'

Long'term'DCV'followMup'from'AASLD'

Reddy'KR.'AASLD'2014.'

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.'

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)'

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'(%)'

Baseline'NS5A'resistance'and'SOF/LDV'

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

<100X'

>100X'

No'RAVs'

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*'

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…'

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?'

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.'

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).'

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.'

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'

TRIO'network'realMworld'experience'

65%'of'GT1'received'SOF/SIM'+/M'RBV;'~50%'treatment'experienced.'

Flamm'S.'#983'AASLD'2014.'

TRIO'network'realMworld'experience'

No'data'on'Q80K'presented.'

Flamm'S.'#983''AASLD'2014.'

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.'

SIRIUS'Study'

Bourliere'M.'#LBM6'AASLD'2014.'Bourliere'M.'#82'AASLD'2014'

HCV'regimen'

•  SIM/'SOF/'RBV'10/10/14'– Week'2'10/24'– Week'4'11/07'

HCV'RNA'

BACKUP'

•  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

HIV'RNA'

HCV'RNA'

GENOSURE'ARCHIVE'11/7/14'