David Wyles, MD, of UC San Diego AntiViral Research Center, presents "Interferon-free HCV Therapy for Those with HIV: Ready for Prime Time?"

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AIDS CLINICAL ROUNDS

2. Interferon-free HCV therapy for those
with HIV: Ready for Prime Time?
David L. Wyles, MD
Associate Professor of Medicine

3. USPHTF update

4. Burden of liver disease in the US
US Burden of Disease Collaborators. JAMA 2013.

5. Benefits of SVR in HIV/HCV cirrhotics
Mira JA. CID 2013.
Hepatic Decompensation
All-cause Mortality

6. Wait, what about telaprevir and
boceprevir?

7. Wait, what about telaprevir and
boceprevir?
• Approved for HCV monoinfection May 2011
– Off label use in co-infection
• Issues:
– Tolerability
– Drug-drug interactions
– Dosing
– Potency

8. 74 75
0
20
40
60
80
100
HIV/HCV ADVANCE
TVR
P/R
Phase2 studies of TVR and BOC in HCV/HIV
• Adverse events consist with mono-infected studies
• Ongoing Phase 3 Studies: VX11-950-115 and ACTG 5294
Sulkowski MS. Annals Int Med 2013. Jacobson IM. NEJM 2011.
Sulkowski MS. Lancet ID 2013. Poordad F. NEJM 2011.
28/38
63
68
0
20
40
60
80
100
HIV/HCV SPRINT-2
BOC
P/R
40/64
SVR24(ITT)

9. TVR in prior IFN failures - ANRS HC 26
• Prior failures with >12 weeks Peg/RBV
• Null cirrhotics excluded
Cotte L. CROI 2013.

10. TVR in prior IFN failures - ANRS HC 26
• 88% HCV RNA undetectable at week 16
61% with grade 3/4 anemia, epo use, transfusion or RBV
dose reduction
Cotte L. CROI 2013.

11. • 63% HCV RNA <15 IU/mL at week 16
BOC in prior IFN failures - ANRS HC 27
Poizot-Martin I. CROI 2013.

12. NEW AGENTS IN COMBINATION
WITH IFN FOR CO-INFECTION

13. New agents with PEG/RBV for HCV/HIV
Simeprevir- study C212
HAART: RAL, RPV, MVC, or T-20 (no PIs or EFV)
HCV: 82% 1a, F3-F4: 21%
Dieterich D. CROI 2013.

14. New agents with PEG/RBV for HCV/HIV
Faldaprevir: phase III STARTVerso 4
HCV gt1, treatment naïve or relapse
– 78% 1a; 17% F4
– 47% RAL-based HAART
Dieterich D. CROI 2013.
EFV
DRV/r
ATV/r
RAL
MVC

15. LESSON: IFN-BASED DAA HCV
THERAPIES LEVEL THE PLAYING
FIELD FOR CO-INFECTED PATIENTS
But…tolerability is an issue in the real-world, at
least for telaprevir based regimens.

16. UCSD experience
Cachay E. AIDS 2013.

17. 50% SVR4 rate with 9/12 having attained SVR12
Cachay E. AIDS 2013.

18. Anticipated DAA approvals in 2013
• Simeprevir November 2013
– NS3 Protease Inhibitor
• Potent but relatively low barrier to resistance
– 150mg PO QD
• Well tolerated
• CYP3A4 substrate
– Likely indication:
• Combination with PEG/RBV for GT1 HCV
– 12 weeks SMV with 24-48 weeks of PEG/RBV (RGT)
– Treatment naïve and experienced

19. Simeprevir phase 3 data
80 79
50
37
0
20
40
60
80
100
QUEST1 PROMISE
All P/R/pbo 1a 1b F4
Jacobson I. EASL 2013. Lawitz E. EASL 2013.
SVR12(%)
RGT eligible:
• 85% QUEST1: 91% SVR
• 93% PROMISE: 83% SVR
Good safety profile:
• 3% discontinuation due to AE
• 9% elevated bilirubin

20. • Sofosbuvir December 2013
– NS5B nucleotide polymerase inhibitor
• Very potent and extremely high barrier to resistance
– 400mg PO QD
• Well tolerated
• Low drug-drug interaction potential
– Not a CYP450 substrate or inhibitor
– Likely indications:
• Combination with PEG/RBV for GT1 (?4-6) HCV
– 12 weeks SOF/P/R
– Naïve only??
• SOF/RBV for GT2 and ?GT3?
– 12 weeks for GT2 naïve or non-responders
» Cirrhosis?
– ?16 or 24 weeks for GT3
Anticipated DAA approvals in 2013

21. Neutrino study: Sofosbuvir + PEG/RBV
• IFN naïve
• 89% gt1
• 17% cirrhosis
SOF 400 QD + Peg2a + RBV
12 weeks SVR 12
N=327
GT 1,4,5,6
90
80
87 87
0
20
40
60
80
100
Combined
gt1
gt 4, 5, 6
Cirrhosis
AA
IL28 T
SVR12(%)
2% stopped due to AEs
Lawitz E. NEJM 2013.

22. FISSION: Treatment naïve genotype 2/3
• IFN naïve
– 73% gt3
– 20% cirrhosis
SOF 400 QD + RBV
1000/1200
24 weeks
SVR 12N=256
N=243 Peg2a + RBV 800 SVR 12
67
97
56
47
67
78
63
38
0
20
40
60
80
100
Combined gt2 gt3 cirrhosis
SOF/RBV P/R
Lawitz E. NEJM 2013.
SOF arm: 1% discontinued due to AEs
P/R: 11% discontinued due to AEs

23. FUSION: Treatment experienced GT 2/3
SOF 400 QD + RBV
1000/1200
12/16 weeks
SVR 12N=103
N=98 SOF 400 QD + RBV 1000/1200 SVR 12
50
86
30
60
19
73
94
62
78
61
0
20
40
60
80
100
GT2 GT3 F4 GT2 F4 GT3
SVR12(%)– 75% relapsers
– 34% cirrhosis
Jacobson I. NEJM 2013.
SOF 12wk: 1 subject discontinued
12wk: 5% SAEs; 16 wk: 3% SAEs

24. Status of IFN-free Therapies for GT1
• Key players
– Sofosbuvir + NS5A
• FDC: SOF/Ledipasvir- phase 3
• SOF + Daclatasvir
– ABT-450/r + ABT-267 + ABT-333 +/- RBV- phase 3
– ASN + DCV + BMS-325 for 12 or 24 weeks
• GT1 naïve: 94% SVR12 Everson G. AASLD 2012.
• Limited data or applications
– ASU + DCV – 1b only
• Proof of concept for IFN free. Lok A. NEJM 2011.
• 77% SVR24 1b null or IFN ineligible. Suzuki F. EASL 2012
– FDV + BI-7027 (deleobuvir) – 1b only
• SOUNDC-2: 1b- 85% SVR12 1a- 43% SVR12 Zeuzem S. EASL 2012
• SOUNDC-3: 1b- 95% SVR12 1a/CC- 17% SVR12 Zeuzem S. APASL 2013.
– Many others with more limited data

25. IFN-free: boosted PI based
Kowdley K. EASL 2013.
SVR12(ITT)
96
878983
24 week duration did not improve response for naïve or experienced.

26. How short is too short?
King M. CROI 2013.

27. ELECTRON: Sofosbuvir/Ledipasvir plus
Ribavirin
SOF + RBV (Null)
SOF + RBV (Naïve)
n=10
n=25
Wk 0 4 8 12
10%
84%
Genotype 1 SVR12
Add second potent DAA Ledipasvir: NS5A antagonist
SOF + LDV + RBV (Null)
SOF + LDV + RBV (Naïve)
n=9
n=25
Wk 0 4 8 12
100%
100%
Gane E. CROI 2013. Sulkowski M. AASLD 2012.
Results replicated with SOF + DCV +/- RBV for 12-24 weeks : 100% SVR12 (N=112)

28. How short can you go: LONESTAR
• Being evaluated in the phase 3 ION-3 study
– SOF/LDV 8 weeks
– SOF/LDV + RBV 8 weeks
– SOF/LDV 12 weeks
Gilead press release May 2, 2013. Clinicaltrials.gov: NCT01851330.

29. Initial lessons from IFN-sparing treatment
1. Cure happens
2. Interferon sensitivity still matters
3. Genotype/subtype matters
4. Ribavirin matters
5. Resistance happens
6. Duration matters
7. Potency/resistance threshold trumps 2-6
Dave Thomas. CROI 2013.

30. Key questions for IFN-free DAA therapies
in those with HIV
• Will efficacy mirror HCV moninfection?
– As it has with IFN + DAAs
• How limiting with drug-drug interactions be?
– Particularly for those with long-standing HIV
• Complex HAART regimens
• More likely to have advanced liver fibrosis and/or prior
treatment failure
• Will tolerability be equally good?
• When can we use them?!

31. Sofosbuvir drug interaction potential
• Low potential for interactions
– Not a CYP450 substrate or inhibitor
– Low protein binding
– Rapid hepatic uptake after oral dosing
– Major metabolite: GS-331007
• ~90% of systemic exposure following SOF dosing
– Substrate for Pgp and BCRP (NOT an inhibitor)
• GS-331007 is not a substrate for Pgp or BCRP

32. Sofosbuvir and HIV ARVs
Kirby B. #1877. AASLD 2012.

33. Sofosbuvir monotherapy in HCV/HIV
clinicaltrials.gov Rodriguez-Torres M. ICAAC 2012.
SOF/RBV GT 2/3 studies underway

34. Simeprevir drug interactions
• CYP3A4 substrate
– Mild intestinal CYP3A4 inhibitor
• No significant interaction: TDF, RAL, RPV
Ouwerkerk-Mahadevan S. IDSA 2012.

35. Daclatasvir drug interactions
• Substrate of Pgp and CYP3A4
– Moderate Pgp inhibitor
• ATV/r- DCV 20mg: AUCt: 0.70, C24: 1.21
– 30mg (est): AUCt: 1.05, C24: 1.83
• EFV- DCV 120mg: AUCt: 1.37, C24: 0.83
– 90mg (est): AUCt: 1.03, C24: 0.62
• TDF- DCV 60mg: AUCt: 01.10, C24: 1.17
Phase3 trial using these adjusted doses ongoing:
NCT01471574
Bifano M. CROI 2012.

36. OFF LABEL IFN-FREE PRESCRIBING
IN 2014?

37. HCV Therapeutics Timeline
1995 2000 20102005
2015
1989
HCV
identified
Consensus IFN
IFN a-2a
IFN a-2b + RBV
Peg-IFNa-2b
Peg-IFNa-2a
HCV replicons
In vitro
HCV replication
Peg-IFNa-2a
in HCV/HIV
IFN a-2b
BILN-2061
Phase 1b
0
20
40
60
80
100
SVR(%)
Relativemisery
Boceprevir Telaprevir IFN-free
DAA
regimens
New DAAs
(w/ Peg/RBV)
You are here

38. COSMOS: Sofosbuvir + Simeprevir
• Gt 1 null responders to PEG/RBV
• Stage F0-F2 liver fibrosis
• SOF 400mg QD, SMV 150mg QD, RBV 1000/1200
Lawitz E. CROI 2013.

39. 12 Week Arms Results
96
93
0
20
40
60
80
100
EOT SVR4 SVR8
SMV+SOF+RBV
SMV+SOF
Lawitz E. CROI 2013.
26/27 13/14
UndetectableHCVRNA(%)
Likely the first IFN-free therapy
you could write for “off-label”
• Limited to genotype 1
• Limited preliminary data
• No data in cirrhotics
• Drug interaction eliminate many
HAART options

40. Sofosbuvir plus Daclatasvir
0
20
40
60
80
100
EOT SVR12 SVR24
GT1 +
GT1 -
GT2/3 +
GT2/3 -
GT1 PI +
GT1 PI -
205556 20 21
Sulkowski M. EASL 2013.
1414
GT1: 12 and 24 weeks. GT2/3: 24 weeks. GT1 PI failures: 24 weeks
The second IFN-free therapy available off-label?
• Pan-genotypic
• Robust preliminary data
• Data in TVR/BOC failures
• Cirrhosis data lacking
• Supporting drug interaction data
• Few, if any, HAART limitations
• FDC of SOF/LDV not far behind

42. Upcoming Studies Co-Infection Studies
• AbbVie M14-004 trial: GT1 naïve or experienced
– ABT-450/r/ABT-267 + ABT-333 + RBV
– ATV or RAL based HAART
– August 2013
• ACTG 5329: GT 1 naïve
– ABT-450/r/ABT-267 + ABT-333 + RBV
– DRV or RAL based HAART
– Fall/Winter 2013
• ACTG 5327
– SOF/RBV for acute HCV infection
• Any genotype
– HIV + or -; any HAART regimen
– Summer/Fall 2013

43. Acknowledgements
Owen Clinic
Lalo Cachay
Francesca Torriani
Jen Lin
Brad Collwell
Craig Ballard
Lucas Hill
Joe Montanez
All the Owen providers/staff
AVRC
Jill Kunkel
Joanne Santangelo
Kathy Nuffer
Julie Hoffman
Alex Kuo
Chip
Bob Gish
Connie Benson
Richard Haubrich
UCSD GI/Hepatology
AVRC Regulatory and Business