hiv/hcv co-infection: the journey of a special population
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Susanna Naggie, M.D., M.H.S., of Duke Clinical Research Center, presents "HIV/HCV Co-Infection: The Journey of a Special Population" at AIDS Clinical RoundsTRANSCRIPT
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AIDS CLINICAL ROUNDS
HIV/HCV Co-infection: The Journey of a Special Population
Susanna Naggie, MD, MHS Assistant Professor of Medicine
Director, Infectious Diseases Research Duke Clinical Research Institute
Disclosure
Commercial Research support: AbbVie Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, and Vertex Pharmaceuticals
Scientific advisor/consultant: AbbVie Pharmaceuticals, Bristol Myers Squibb. (Updated 12/11/14) **Off label use of FDA approved medications
Mr. KB 34 y/o man with HIV/HCV co-infection Diagnosed with HIV in his 20s, quite ill at the time with disseminated MAC and PCP, CD4 count was 9 He was simultaneously diagnosed with HCV Since diagnosis, he has had excellent control of his HIV
PMHx ►HIV dx 1990s
– Nadir CD4 9 – + history of OI: PCP, MAC
►HCV dx 1990s – GT1b, VL 1.2 million IU/mL – Cirrhosis dx by liver biopsy 2009 – No history of decompensation – Portal HTN with thrombocytopenia, splenomegaly and
portal gastropathy (last EGD 3/2014) – HAV and HBV immune
►AVN ►Nephrolithiasis ►Atopic Dermatitis ►Lumbar DDD
Clinical Questions to Address
►What is his prognosis? ►Why does a 34 y/o who does not drink have
cirrhosis? ►What treatment options do we have?
– Can we cure him? – What does that mean?
What is his prognosis? HIV/HCV: Natural History
D:A:D Study: Liver-Related Deaths in Persons with HIV
DAD Study Group, Arch Intern Med 2006; Lancet 2014
Mor
talit
y
31
14.5
11 9.4
34
0
5
10
15
20
25
30
35
40
AIDS Liver Cardiovascular non-AIDS cancer Other
29%
13%
15%
32%
HAART Era: Cirrhosis Risk
►Overall RR 2.11 ►Pre-HAART era
– RR 2.49
►HAART era – RR 1.72
►20-year, 30-year rates – 25%, 54%
Thein et al. AIDS 2008; 22:1979
HCV monoinfection
HIV/HCV coinfection
0.01 0.1 1 10 100
Accelerated Liver Disease in HIV
Massard et al. J Hepatol 2006; 44:S19-24 Kirk et al. Ann Intern Med 2013; 158:658-666
Hepatic Decompensation
Lo Re et al. Ann Intern Med 2014; 160
HIV-associated Non-AIDS related: “Diseases of Aging”
►Liver Fibrosis ►Cardiovascular disease ►Diabetes ►Chronic kidney disease ►Non-AIDS malignancy ►Bone disease/fractures
Why would a 34 y/o who does not drink have cirrhosis? HIV/HCV: Mechanisms of Liver Disease
Mechanisms of Fibrosis Progression
Naggie, Sulkowski. Gastroenterology 2012
The site of fibrogenesis
http://www.hindawi.com/journals/grp/2010/453563/fig1/
Gastroenterology 2008 134, 1655-1669DOI: (10.1053/j.gastro.2008.03.003) Copyright © 2008 AGA Institute Terms and Conditions
Cellular Players in Fibrogenesis
Gastroenterology 2008 134, 1655-1669DOI: (10.1053/j.gastro.2008.03.003) Copyright © 2008 AGA Institute Terms and Conditions
Pathways of hepatic stellate cell activation
HSC have HIV co-receptors
Bruno et al. Gut 2010
gp120 induces HSC cellular signaling
Bruno et al. Gut 2010
HSC may be permissive to HIV infection
Tuyama et al. Hepatology 2010
The role of a fetal morphogen
Choi et al. Intern J Biochem Cell Biol 2011
Hedgehog Signaling Pathway
Amakye et al. Nature Med 2013
Hedgehog pathway signaling following liver injury (BDL)
Omenetti et al. Lab Investigiation 2007
Hedgehog pathway signaling in HCV infection
Omenetti et al. Lab Investigiation 2007
Immunohistochemistry HIV/HCV: Immunology and Fibrosis
►Pathology specimens from liver biopsy ►Healthy controls, HIV, HCV, HIV/HCV ►Matching age, gender, race/ethnicity, fibrosis
stage, CD4 at time of biopsy, HIV suppression ►Staining: hedgehog pathway (SHH, Gli2, Ptch),
T-cell markers including CD3, CD8, CD56, CD57, CXCL16, ASMA, P16Ink4a
Hedgehog Signaling in HIV and HCV
HC HIV HCV HIV/HCV
p=0.236
p=0.007
p=0.011
Hedgehog Signaling in HIV and HCV
HC HIV HCV HIV/HCV
p=0.182
p=0.006
p<0.0001
Hedgehog Signaling in HIV/HCV
Healthy Control
HIV/HCV Infected Gli2
Targeting Hh signaling for therapy
Amakye et al. Nature Med 2013
Are Pericytes Stem Cells?
Kramann et al. Cell Stem Cell 2014
T cell presence in HIV and HCV
HC HIV HCV HIV/HCV
p<0.0001
p=0.028
p=0.001
Cytotoxic CD8 T cells
p=0.034
HC HIV HCV HIV/HCV
NK(T) cell presence in HIV and HCV
HC HIV HCV HIV/HCV
p=0.004
p=<0.0001
NKT cytokine CXCL16
HC HIV HCV HIV/HCV
p=0.026 p=0.0002
p=0.165
T cell terminal differentiation
HC HIV HCV HIV/HCV
p=0.002
p=0.017
p<0.0001
p16Ink4a aging and senescence
HC HIV HCV HIV/HCV
p<0.0001
p=0.096
p<0.0001
Take home/Future work
►Hh pathway is active in HIV mono-infection, with additive effect in co-infection
►HIV/HCV co-infection increases T cell recruitment, terminal differentiation and immunologic aging/senescence
►Peripheral (NK)T cell subsets and responsiveness to Hh signaling
►Relationship of (NK)T cell activity, dysregulation and markers of aging
►Assess Hh activity in other end organ tissue in HIV-infected patients
What treatment options do we have?
5′ UTR region
3′ UTR region 9.6 kb RNA
C A NS2 NS4B A NS5 B E2 NS3
Polyprotein IRES-mediated translation
p7 C
E1
E1 E2 NS2 NS3 NS4B 4A
Polyprotein Processing
NS5B NS5A
Core Envelope glycoproteins
Serine Protease
Serine Protease Cofactor
RNA dependent RNA polymerase
NS3-4A Protease Inhibitors
NS5B Polymerase Inhibitors
HCV Genome
Hepatitis C Virus
NS5A Inhibitors
Adapted from Naggie et al. J Antimicrob Chemother 2010
HIV/HCV: a “Special Population”
HCV Therapeutic Timeline from Interferon Approval in 1991
0
20
40
60
80
100
1991 1996 2001 2011 2013 2014
Interferon 48W
Interferon + RBV
Telaprevir & Boceprevir
Sofosbuvir & Simeprevir
Ledipasvir* Paritaprevir Ombitasvir Dasabuvir Daclatasvir
First all oral GT 2 & 3
First all oral GT 1
Issues with first wave HCV PIs
►Complex regimens ►Still require pegylated interferon and ribavirin ►~50% still require 48 weeks of treatment ►Worsened safety profile ►SVR = cure only 70% ►Significant drug interactions ►Phase II in HIV/HCV delayed by 3 years
– Still not FDA approved in HIV – Limited access in many states
New Kids on the Block in 2013
►Multi-genotypic NS3/4A PI
►QD dosing ►Second Wave PI ►Low barrier to
resistance ►+ DDI with ARVs ►Rash, photosensitivity ►HIV not a special pop
Simeprevir (TMC-435) Sofosbuvir (GS-7977) ►Pan-genotypic NS5B ►QD dosing ►Nucleotide analogue ►Exceptional barrier to
resistance ►No significant DDI ►No AE ►Approved for HIV/HCV as
special population
SMV: HCV versus HIV/HCV, genotype 1 in Clinical Trials Not head to head comparison
80 77
65
53
79 87
70
57
0102030405060708090
100
Tx Naïve Prior Partial
HCV HIV/HCV
Prior Relapse Prior Null 7/10 13/15 16/28 419/521
Antiviral Drugs Advisory Committee Meeting, FDA review, 10/24/13 C208, C216, C206, C212, HPC3007, Dieterich, 14th European AIDS Conference, 2013; Lawitz et al. NEJM 2013
SVR
Rate
42/53 206/260 15/23 9/17
SOF: HCV versus HIV/HCV in GT 1, 2, 3
89
68
95 94 93
79
89 81
89 90 91 88
0
10
20
30
40
50
60
70
80
90
100
SOF/P/R SOF/R GT 2 naïve GT 2experienced
GT 3 naïve** GT 3experienced
HCV HIV/HCV
Sust
aine
d Vi
rolo
gic R
espo
nse
Torres-Rodriguez et al., IDSA 2013 Osinusi et al., JAMA 2013;310(8):804-11; Sulkowski et al. JAMA 2014 (PHOTON-1), Lawitz et al. NEJM April 2013; Zeuzem et al NEJM May 2014, Rockstroh et al, AASLD 2014 (pooled PHOTON 1 and 2)
COSMOS: SOF/SMV no longer off label
90 94 89
81
97 94 95 94 96 95 95 92 88 94
0102030405060708090
100
Overall GT1b GT1a GT1a+Q80K GT1a-Q80KCohort 1 Cohort 2 Pooled
Lawitz et al. Lancet July 28 2014
HCV-TARGET 2.0
Jensen et al. AASLD 2014 ABST 45
SOF/P/R (N=164) SOF/SMV±RBV (N=303)
SVR4 Overall No Cirrhosis Cirrhosis GT 1a GT 1b
140 (85%)
114/127 (90%) 26/37 (70%)
-- --
269 (89%)
113/123 (92%) 156/180 (87%)* 189/222 (89%) 218/222 (95%)
Viral breakthrough 2 (1.5%) 2 (0.9%)
Relapse 21 (15.6%) 21 (9.5%)
Non-responder 1 (0.7%) 2 (0.9%)
ARV Interaction Score Card Simeprevir Sofosbuvir
ATV/r No data No data DRV/r SIM ↑; DRV ↔ SOF ↑; DRV ↔ LPV/r No data No data TPV/r No data No data EFV SIM ↓; EFV ↔ SOF ↔; EFV ↔ RPV SIM ↔; RPV ↔ SOF ↔; RPV ↔ ETV No data No data RAL SIM ↔; RAL ↔ SOF ↔; RAL ↔ ELV/cobi No data No data DLG No data No data MVC No data No data TDF SIM ↔; TFV ↔ SOF ↔; TFV ↔ Sl
ide
cour
tesy
of J
enni
fer K
iser
The new treatment paradigm
Nuc-NS5B
NS5A NS5A
nonNuc-NS5B
NS3/4A
Nuc-NS5B NS3/4A
RBV
Paritaprevir/r/Ombitasvir + Dasabuvir + RBV
Week 0 12 24 60 72
3D + WBR, N=473 SVR12
SVR12 Placebo, N=158 3D + WBR
SAPPHIRE-I: Treatment Naïve, Noncirrhotic
SAPPHIRE-II: PEG/RBV Treatment Experienced, Noncirrhotic
3D + WBR, N=297 SVR12
SVR12 Placebo, N=97 3D + WBR TURQOISE-II: Treatment Naïve and PEG/RBV Experienced, Child-Pugh A Cirrhotics
3D + WBR, N=208 SVR12
SVR12 3D + WBR, N=172
Summary SVR12: 3D+RBV 96 96 94 94 95 95
92 91 98 95 96
0
10
20
30
40
50
60
70
80
90
100
SAPPHIRE-I SAPPHIRE-II TURQUOISE-II TURQUOISE-I*
All GT1a GT1b All Rel NuR All 12W24W
No cirrhosis Tx naive
No cirrhosis NuR 55%
CP-A Cirrhosis
SAPPHIRE-I Feld et al. NEJM 2014, SAPPHIRE-II Zeuzem et al. NEJM 2014, TURQOISE-II Poordad et al. NEJM 2014; Wyles et al. AASLD 2014 Poster 1939
HIV (16% Cirrhosis) Naïve and Exp
12W 24W
Sofosbuvir/Ledipasvir ± RBV
Week 0 8 12 24 60 72
SOF/LDV ± WBR, N=431 SVR12
SVR12 SOF/LDV ± WBR, N=431
ION-1: Treatment Naïve, 16% cirrhotic
ION-2: Treatment Experienced (including triple) 20% cirrhotic
SOF/LDV ± WBR, N=220 SVR12
SVR12
ION-3: Treatment Naïve, noncirrhotic
SOF/LDV±WBR SVR12
SVR12 SOF/LDV, N=216
SOF/LDV ± WBR, N=220
N=431
Summary SVR12: SOF/LDV 99
94 94 98 98 99
93 97
86
95 100 100
0
10
20
30
40
50
60
70
80
90
100
ION-1 ION-2 ION-3 ERADICATE
12W 24W 8W -RBV +RBV
16% cirrhosis Tx naive
20% cirrhosis Triple failure 54%
Naive Non-cirrhotic
ION-1 Afdhal et al. NEJM 2014, ION-2 Afdhal et al. NEJM 2014; 370(16):1483, ION-3 Kowdley et al. NEJM; Osinusi et al. AASLD 2014, Abstract 84
Cirrhosis* -RBV +RBV 12W 24W
Cirrhosis 12W 24W 12W
HIV Naive Non-cirrhotic
Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 HCV and HIV-1 Co-infection (ION-4)
ClinicalTrials.gov Identifier: NCT02073656
100 95 95 100 100
0
10
20
30
40
50
60
70
80
90
100
Tx Naïve Triple Failures
Sofosbuvir plus Daclatasvir: GT1
24W 12W +RBV -RBV
24W +RBV -RBV
Sulkowski et al. NEJM 2014; 370:211-221
N= 44 41 41 20 21
A Phase 3 Evaluation of Daclatasvir Plus Sofosbuvir in Treatment-naïve and Treatment-experienced Chronic Hepatitis C (Genotype 1, 2, 3, 4, 5, or 6) Subjects Coinfected With
Human Immunodeficiency Virus (HIV) (ALLY 2) ClinicalTrials.gov Identifier: NCT02032888
ARV Interaction Score Card Ledipasvir Daclatasvir AbbVie 3D
ATV/r ↑ LDV, ↑ATV** DCV ↑* ATV ↔; ABT450 ↑
DRV/r ↑ LDV, ↔DRV** No data DRV ↓/↑; 3D ↓
LPV/r No data No data LPV ↔; ABT450 ↑
TPV/r No data No data No data
EFV LDV ↓; EFV ↓ DCV ↓* No PK data**
RPV LDV ↔; RPV ↔ No data ABT450 ↑; RPV ↑
ETV No data No data No data
RAL LDV ↔; RAL ↔ No data 3D ↔; ↑ RAL
ELV/cobi No data No data No data
DLG No data No data No data
MVC No data No data No data
TDF LDV ↔; ↑TFV DCV ↔; TFV ↔ 3D ↔; TFV ↔ * Decrease DCV dose to 30mg QD, Increase DCV dose to 90mg QD, ** 3D + EFV led to premature study discontinuation due to toxicities
Slid
e co
urte
sy o
f Jen
nife
r Kis
er
Back to our patient 2012 – enrolled into PHOTON-1 received 6 months of sofosbuvir + WBR -SVR4, relapsed by week-12 off treatment December 2013 – labs remain reassuring with normal synthetic function, renal function, thrombocytyopenia has worsened over time now in 90s, imaging stable -Enrolled into the ION-4 with SOF/LDV X 12W -Achieved SVR12
Where do we go from here?
►Shorten treatment – 4-6 weeks ►True pangenotypic regimens ►Retreatment studies ►Acute HCV infection: ACTG 5327 ►Other Special/Unique populations:
– ESRD – Transplant – ESLD: CP B/C and decompensated – Children – Pregnant women
Acknowledgements Mentors Andrew Muir Ken Schmader Chuck Hicks John McHutchison John Guyton Mariano Garcia-Blanco Keyur Patel Hans Tillmann Leadership Chris Woods Rodger Liddle John Perfect Mary Klotman
Collaborators CHGV: David Goldstein Kevin Shianna NIAID: Shyam Kottilil Anu Osinusi Eric Meissner Diehl Laboratory: Anna Mae Diehl Steve Choi Marzena Swiderska-Syn
Funding: NIAID K23 AI096913 Duke CFAR Duke Department of Medicine AIDS Clinical Trials Group
Questions
α–smooth muscle actin
HC HIV HCV HIV/HCV
3D Phase III Studies – Viral Failure & Resistance
SVR12 Relapse Viral
Failure 2.8%
Viral Failure
VBT 15.6% (0.4%)
RAVs SAPPHIRE-I SAPPHIRE-II TURQUIOSE-II NS3/NS5A/NS5B 5 3 1 NS3/NS5A 3 1 14 NS5A only 1 1 0
87.5% with RAVS
SOF/LDV Phase III Studies – Viral Failure & Resistance
SVR12
Relapse Viral Failure 1.9%
Viral Failure
VBT 2.7% (0.05%)
RAVs ION-1 ION-2 ION-3 NS5B 0 0 0 NS5A 2 11 15 NS5A RAV at BL 2 6 9
75.6% with NS5A RAVS
ION-1 Afdhal et al. NEJM 2014, ION-2 Afdhal et al. NEJM 2014; 370(16):1483, ION-3 Kowdley et al. NEJM; Osinusi et al. AASLD 2014, Abstract 84
SOF/LDV in >500 patients with Compensated Cirrhosis
SOF/LDV, N=118 SVR12
SVR12 SOF/LDV + WBR, N=204
SOF/LDV, N=133 SVR12
SVR12 SOF/LDV + WBR, N=58
Week 0 8 12 24 60 72
Bourliere et al AASLD 2014 ABST 83
SOF/LDV in >500 patients with Compensated Cirrhosis