The document summarizes a presentation about HIV/HCV co-infection given by Dr. Susanna Naggie. It discusses the case of a 34-year-old man with HIV/HCV co-infection and cirrhosis. It reviews the accelerated progression of liver disease seen in HIV/HCV patients and potential mechanisms including the role of hedgehog signaling and immune activation. Treatment options for co-infected patients have advanced significantly in recent years with highly effective all-oral regimens that achieve cure rates over 90% with minimal side effects.

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. 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

3. 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

4. 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

5. 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

6. 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?

7. What is his prognosis? HIV/HCV: Natural History

8. D:A:D Study: Liver-Related Deaths in Persons with HIV
DAD Study Group, Arch Intern Med 2006; Lancet 2014
Mortality
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%

9. 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

10. Accelerated Liver Disease in HIV
Massard et al. J Hepatol 2006; 44:S19-24
Kirk et al. Ann Intern Med 2013; 158:658-666

11. Hepatic Decompensation
Lo Re et al. Ann Intern Med 2014; 160

12. HIV-associated Non-AIDS related: “Diseases of Aging”
►
Liver Fibrosis
►
Cardiovascular disease
►
Diabetes
►
Chronic kidney disease
►
Non-AIDS malignancy
►
Bone disease/fractures

13. Why would a 34 y/o who does not drink have cirrhosis? HIV/HCV: Mechanisms of Liver Disease

14. Mechanisms of Fibrosis Progression
Naggie, Sulkowski. Gastroenterology 2012

15. The site of fibrogenesis
http://www.hindawi.com/journals/grp/2010/453563/fig1/

16. Gastroenterology 2008 134, 1655-1669DOI: (10.1053/j.gastro.2008.03.003)
Copyright © 2008 AGA Institute Terms and Conditions
Cellular Players in Fibrogenesis

17. 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

18. HSC have HIV co-receptors
Bruno et al. Gut 2010

19. gp120 induces HSC cellular signaling
Bruno et al. Gut 2010

20. HSC may be permissive to HIV infection
Tuyama et al. Hepatology 2010

21. The role of a fetal morphogen
Choi et al. Intern J Biochem Cell Biol 2011

22. Hedgehog Signaling Pathway
Amakye et al. Nature Med 2013

23. Hedgehog pathway signaling following liver injury (BDL)
Omenetti et al. Lab Investigiation 2007

24. Hedgehog pathway signaling in HCV infection
Omenetti et al. Lab Investigiation 2007

25. 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

26. Hedgehog Signaling in HIV and HCV
HC HIV HCV HIV/HCV
p=0.236
p=0.007
p=0.011

27. Hedgehog Signaling in HIV and HCV
HC HIV HCV HIV/HCV
p=0.182
p=0.006
p<0.0001

28. Hedgehog Signaling in HIV/HCV
Healthy Control
HIV/HCV Infected
Gli2

29. Targeting Hh signaling for therapy
Amakye et al. Nature Med 2013

30. Are Pericytes Stem Cells?
Kramann et al. Cell Stem Cell 2014

31. T cell presence in HIV and HCV
HC HIV HCV HIV/HCV
p<0.0001
p=0.028
p=0.001

32. Cytotoxic CD8 T cells
p=0.034
HC HIV HCV HIV/HCV

33. NK(T) cell presence in HIV and HCV
HC HIV HCV HIV/HCV
p=0.004
p=<0.0001

34. NKT cytokine CXCL16
HC HIV HCV HIV/HCV
p=0.026
p=0.0002
p=0.165

35. T cell terminal differentiation
HC HIV HCV HIV/HCV
p=0.002
p=0.017
p<0.0001

36. p16Ink4a aging and senescence
HC HIV HCV HIV/HCV
p<0.0001
p=0.096
p<0.0001

37. 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

38. What treatment options do we have?

39. 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

40. HIV/HCV: a “Special Population”

41. 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

42. 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

43. 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

44. SMV: HCV versus HIV/HCV, genotype 1 in Clinical Trials Not head to head comparison
80
77
65
53
79
87
70
57
0
10
20
30
40
50
60
70
80
90
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

45. 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 2
experienced
GT 3 naïve**
GT 3
experienced
HCV
HIV/HCV
Sustained Virologic Response
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)

46. COSMOS: SOF/SMV no longer off label
90
94
89
81
97
94
95
94
96
95
95
92
88
94
0
10
20
30
40
50
60
70
80
90
100
Overall
GT1b
GT1a
GT1a+Q80K
GT1a-Q80K
Cohort 1
Cohort 2
Pooled
Lawitz et al. Lancet July 28 2014

47. 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%)

48. 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 ↔
Slide courtesy of Jennifer Kiser

49. The new treatment paradigm
Nuc-NS5B
NS5A
NS5A
nonNuc- NS5B
NS3/4A
Nuc-NS5B
NS3/4A
RBV

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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
Slide courtesy of Jennifer Kiser

56. 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

57. 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

58. 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

59. Questions

60. α–smooth muscle actin
HC HIV HCV HIV/HCV

61. 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

62. 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

63. 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

64. Bourliere et al AASLD 2014 ABST 83
SOF/LDV in >500 patients with Compensated Cirrhosis