Date post: | 15-Jul-2015 |
Category: |
Health & Medicine |
Upload: | uc-san-diego-antiviral-research-center |
View: | 99 times |
Download: | 2 times |
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
• 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'
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'
ARV'Regimen'
• Pa@ent'changed'to'DTG'(50'mg'BID)'+'RPV/TDF/FTC'(FDC)'9/2014'
• 11/21/2014'MVC'added'
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'
• 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'(%)'
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.'
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.'
• 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