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AIDS CLINICAL ROUNDS

Interferon-free HCV therapy for those with HIV: Ready for Prime Time?

David L. Wyles, MD

Associate Professor of Medicine

USPHTF update

Burden of liver disease in the US

US Burden of Disease Collaborators. JAMA 2013.

Benefits of SVR in HIV/HCV cirrhotics

Mira JA. CID 2013.

Hepatic Decompensation

All-cause Mortality

Wait, what about telaprevir and boceprevir?

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

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)

TVR in prior IFN failures - ANRS HC 26

• Prior failures with >12 weeks Peg/RBV

• Null cirrhotics excluded

Cotte L. CROI 2013.

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.

• 63% HCV RNA <15 IU/mL at week 16

BOC in prior IFN failures - ANRS HC 27

Poizot-Martin I. CROI 2013.

NEW AGENTS IN COMBINATION WITH IFN FOR CO-INFECTION

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.

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

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.

UCSD experience

Cachay E. AIDS 2013.

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

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

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.

SVR

12

(%) RGT eligible:

• 85% QUEST1: 91% SVR • 93% PROMISE: 83% SVR

Good safety profile: • 3% discontinuation due to AE • 9% elevated bilirubin

• 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

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

SVR

12 (

%)

2% stopped due to AEs

Lawitz E. NEJM 2013.

FISSION: Treatment naïve genotype 2/3

• IFN naïve

– 73% gt3

– 20% cirrhosis

SOF 400 QD + RBV 1000/1200

24 weeks

SVR 12 N=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

FUSION: Treatment experienced GT 2/3 SOF 400 QD + RBV

1000/1200

12/16 weeks

SVR 12 N=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

SVR

12

(%

) – 75% relapsers

– 34% cirrhosis

Jacobson I. NEJM 2013.

SOF 12wk: 1 subject discontinued 12wk: 5% SAEs; 16 wk: 3% SAEs

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

IFN-free: boosted PI based

Kowdley K. EASL 2013.

SVR

12

(IT

T)

96 87 89 83

24 week duration did not improve response for naïve or experienced.

How short is too short?

King M. CROI 2013.

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)

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.

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.

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?!

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

Sofosbuvir and HIV ARVs

Kirby B. #1877. AASLD 2012.

Sofosbuvir monotherapy in HCV/HIV

clinicaltrials.gov Rodriguez-Torres M. ICAAC 2012.

SOF/RBV GT 2/3 studies underway

Simeprevir drug interactions

• CYP3A4 substrate

– Mild intestinal CYP3A4 inhibitor

• No significant interaction: TDF, RAL, RPV

Ouwerkerk-Mahadevan S. IDSA 2012.

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.

OFF LABEL IFN-FREE PRESCRIBING IN 2014?

HCV Therapeutics Timeline

1995 2000 2010 2005 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

(%

) R

elative mise

ry

Boceprevir Telaprevir IFN-free DAA

regimens

New DAAs (w/ Peg/RBV)

You are here

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.

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

Un

det

ecta

ble

HC

V R

NA

(%

) 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

Sofosbuvir plus Daclatasvir

0

20

40

60

80

100

EOT SVR12 SVR24

GT1 +

GT1 -

GT2/3 +

GT2/3 -

GT1 PI +

GT1 PI -

20 55 56 20 21

Sulkowski M. EASL 2013.

14 14

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

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

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