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HCV cure: new treatment paradigms for HCV infection

Sanjay BhaganiConsultant Physician/Senior Lecturer

Royal Free Hospital/UCL

London

www.aids2014.org

HCV/HIV co-infection – ‘shades of grey’

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Outline

• Impact of HCV in the HIV-infected patient– The importance of treating HCV

• PegIFN/ribavirin – a bygone era• DAAs for HCV and HCV/HIV

– IFN ‘sparing’ and IFN-free regimens

• Is this still a ‘Special Population’?• New Guidelines

D:A:D: Liver-related death is a frequent cause of non-AIDS death in HIV-infected

patients

Weber R, et al. AIDS 2012. Washington USA. Oral presentation THAB0304.

0

20

40

60

80

100

29

13 11 14

33Death

s (

%)

Liver-related disease

Cardio-vascular or other

heart disease

OtherAIDS Non-AIDS malignancie

s

D:A:D Study: Causes of death in n=49,734 HIV-infected patients followed 1999–2011

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HIV/HCV – double-trouble for the liver

Chen J Nat Rev Gastroenterol Hep 2014 doi:10.1038/nrgastro.2014.17

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Faster progression even when controlling for alcohol and other co-morbidities

Kirk D, et al. Ann Intern Med 2013; 158: 658

HIV/HCV – a contribution to multiple organ dysfunction

Adapted from Operskalski EA and Kovacs A. Curr HIV/AIDS Rep 2011;8:12–22.

Immuneactivation

Immunedysfunction

HIV/HCVLiver

diseaseHIV disease progression

Metabolicdisorders

GI tract

Neurologicdisease

Cardio-vascular

Kidneydisease

Bonedisorders

• CD4 apoptosis• Abnormal T-cell responses and cytokine production• Cytotoxic T-cell accumulation in liver• Impaired CD4 recovery post-HAART• Severe immunodeficiency

• Diabetes mellitus• Insulin resistance

• Microbial translocation

• Steatosis• Fibrosis• Cirrhosis• End-stage liver

disease• Liver-related death

• Global cognitive impairment• Cognitive-motor impairment• Dementia• Peripheral neuropathy

• Cerebrovascular disease

• Acute myocardial infarction

• Opportunistic infections

• Wasting syndrome

• Proteinuria• Acute renal failure• Chronic kidney

disease

• Osteonecrosis• Osteoporosis• Bone fracture

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A) Overall-Mortality

Observation time[days]]

500040003000200010000

Cu

mu

lati

ve s

urv

ival

1,1

,9

,7

,5

,3

P<0.0001

Patients with HAART

Patients with dual ARvs untreated Patients

6000

Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 13794 49 37 32 27

6000500040003000200010000

1,1

,9

,7

,5

,3

B) Liver-related-Mortality

P<0.018

Patients with HAART

Patients with dual ARvs untreated Patients

Overall and Liver-related Mortality - effect of HAART

Qurishi N et al. Lancet, 2004

Cu

mu

lati

ve s

urv

ival

Observation time[days]]

Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-group: 13794 49 37 32 27

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‘Hepatotoxcity’ commoner in co-infected patients

Vispo, et al. AIDS 2013:27: 1187

HCV/HIV SVR24 with pegIFN and RIBAVIRIN

0

25

50

75

100

G1 G2/3

Monoinfection

APRICOTACTGRIBAVICLaguno et al.PRESCO

Genotype 1SVR 14–38%

Genotype 3SVR 44–73%

Genotype

SVR

(%)

Adapted from: Fried et al, NEJM 2002;347:975-982, Torriani et al, NEJM 2004;351:438-50, Chung R, et al, NEJM 2004;351:451-9 Carrat F, et al, JAMA 2004;292:2839-42, Laguno et al, AIDS 2004;18:F27-F36, Nunez et al, JAIDS 2007;45:439-44

HCV Life Cycle and DAA Targets – drug classes and nomenclature

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors NS5B polymerase inhibitors

Nucleoside/nucleotideNonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors

..PREVIR

..ASVIR …UVIR

HCV Life Cycle and DAA Targets – drugs

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors NS5B polymerase inhibitors

Nucleoside/nucleotideNonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors

TelaprevirBoceprevirFaldaprevirSimeprevirABT 450/rAsunaprevirMK-5172

DaclatasvirLedipasvirOmbitasvirMK-8742GS-5816

Sofosbuvir

DasabuvirBMS-791325

ALL

Relapsers

Breakth

rough

Partial R

esponse

Null Resp

onseF0

–F2F3

/F4ATV/r

Raltegra

vir0

20

40

60

80

100

53

90

0

61

24

56

4841

70

ANRS studies TelapreVIH and BocepreVIH inTE HCV GT 1 HIV/HCV co-infected patients

1. Cotte L, et al. CROI 2014; Oral #668; 2. Poizot Martin I, et al. CROI 2014. Oral #659.

SVR24 in HIV/HCV PEG-IFN/RBV experienced treated with PEG-IFN/RBV + TVR (69) or BOC (64); 4 weeks lead in + 44 weeks standard +

24 additional weeks if HCV RNA at Week 8 >15IU/mL. ATV/r: ritonavir boosted atazanavir; TE: treatment-experienced

TVR BOC

SV

R24

(%

)

SV

R12

(%

)

ALL

Relapsers

Breakth

rough

Partial R

esponse

Null Resp

onseF0

–F2F3

/F4ATV/r

Raltegra

vir0

20

40

60

80

100

8074

83

100

71

81 78 81

71

www.aids2014.org

‘Real-life’ experience PegIFN/R + TVR/BOC – pan-European data

Rx discontinuation Rx response ITT and OT

8

36

50

0

20

40

60

80

100

platelets ≥100/µL +albumin ≥3.5 g/dL

platelets ≥100/µL +albumin <3.5 g/dL orplatelets <100/µL +albumin ≥3.5 g/dL

platelets <100/µL +albumin <3.5 g/dL%

of pa

tient

s who

disc

ontin

ued a

ll the

rapy

Neukam K, Munteanu D, et al. CROI 2014

Second generation DAAs + PEG-IFN/RBV in HIV/HCV co-infected patients

1. Dieterich D, et al. EACS 2013. PS9/5; 2. Rockstroh J, et al. EACS 2013 .PS9/7; 3. Rodriguez-Torres M, et al. ID Week 2013. Poster #714.

Follow-up

SMV + PR

Week 12 36 60

SMV + PR (RGT)

Follow-up

Follow-up

48 72

PR

PR

PR

24

Partial response Null response Cirrhotic patients (F4)

Genotype 1a/b• HCV treatment-naïve Prior PR relapsers

FDV 120 mg + PR PR or follow up (RGT)

FDV 240 mg + PR

FDV 240 mg + PR

PR

PR or follow up (RGT)

SOF + PR

SVR4 SVR12 SVR24

Follow-up

C2121

STARTVerso42

SOF + PR3

DAA: direct-acting antiviral agents; FDV: faldaprevir; PR: PEG-IFN/RBV; RGT: response guided therapy; SMV: simeprevir

Protease inhibitors

Nucleoside polymerase inhibitor

Genotype 1a/b Treatment Naïve Relapse 15% Compensated

Cirrhotic patients (F4)

Genotype 1-4• HCV treatment-naïve

C212: SVR12 by concomitant ART use(ITT population)

*0/1 patients; SVR12, sustained virologic response 12 weeks after end of treatment; n/a, not applicable

Overall Naïves Relapsers Partial Null0

20

40

60

80

100 On ARTNot on ART

81

70

62

75

87

78

70/93 8/13 7/10 1/215/267/913/1535/43 n/a 0*

58

50

SV

R12

(%

)

www.aids2014.org

STARTVerso4: SVR12 overall population

87/123 134/185 221/308Pro

port

ion

of p

atie

nts

with

SV

R12

(%

)

www.aids2014.org

Study 1910: SVR12

Rodriguez-Torres M et al. IDWeek 2013, poster 714

100

80

60

40

20

0

HC

V R

NA

<LL

OQ

(%

)

89%

17/19

GT1

1/1

GT2

2/2

GT3

1/1

GT4

LLOQ: lower level of quantification

PHOTON-1 studyNaggie S, et al. CROI 2014. Oral #26

C-WORTHY studySulkowski M, et al. EASL 2014. Oral #63

LDV/SOF STRERADICATE studyOsinusi A, et al. EASL 2014. Oral #14

IFN-free DAA regimens in HIV/HCV co-infected patients

PHOTON-1: Virological response

Naggie S, et al. CROI 2014. Oral #26.

GT 1 GT 2 GT 3 GT 2 GT 30

20

40

60

80

100

76

88

67

92 94

SVR1

2 (%

)

TN TE

12 weeks

24 weeks

SOF + RBV

• No HCV resistance (S282T) observed in virological failures (deep sequencing)– HCV breakthrough in 2 patients due to non-adherence to SOF – HIV breakthrough in 2 patients due to non-adherence to ART

16/17

28/42

22/24

23/26

87/114

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TW4 TW8 TW12 SVR40

102030405060708090

100100 100 100 97100

90 90 90

MK-5172 + MK-8742 + RBV (n=29)

MK-5172 + MK-8742 (No RBV; n=30)

Week

% H

CV

RN

A <

25 I

U/m

LC-Worthy Virologic Response

ITT Population

2929

21

28 29

2929

2929

3030

2629*

2730

2730

Virologic Failures: 1 relapse in +RBV arm; 2 breakthrough and 1 lost to follow up in No

RBV arm* One patient has not yet reached FU4

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The IFN and RBV free regimen of LDV/SOF in HCV/HIV co-infected patients resulted in SVR12 of 100% in ARV untreated patients and SVR4 of 100% in ARV treated patients

LDV/SOF STR was generally well tolerated with no discontinuations Actively enrolling ION-4 (target of 300 GT 1 and GT 4 HCV/HIV patients). NCT 02073656.

ERADICATE - Treatment Response

Week 4 Week 8 EOT SVR4 SVR8 SVR120

20

40

60

80

100100 100 100 100 100 100100 100 100 100

ARV Untreated ARV Treated%

of p

atie

nts

with

HC

V R

NA

<

LL

OQ

13/13

37/37

13/13

37/37

13/13

30/30

12/12

22/22

10/10

10/10

Osinusi A, EASL, 2014, O14

SVR12 - PEG-IFN/RBV + TVR, SMV, FDV and SOF in HCV GT1 TN patients: HIV+ vs HIV–

TVR + PR SMV + PR FDV + PR SOF + PR0

20

40

60

80

100

7479

72

91

79 80 80

91

HIV+HIV-

1. Sulkowski M, et al. AASLD 2012. Oral #54; 2. Janssen Cilag International. INCIVO (Telaprevir), Summary of product characteristics, September 2011; 3. Dieterich D, et al. CROI 2014 Abstract #24; 4. Jacobson I, et al. AASLD 2013. Poster #1122; 5. Dieterich D, et al. APASL 2014. Oral‘#681; 6. Ferenci P, et al. EASL 2013. Abstract #1416; 7. Rodriguez-Torres M, et al. ID week 2013. Poster #714; 8. Lawitz E, et al. APASL 2013. Oral #LB-02.

419/521

42/53

296/327

21/23

285/363

28/38

414/520

221/308

24 or 48 weeks 12 weeks24 or 48 weeks 12 or 24 weeks

SVR1

2 (%

)

Cirrhosis Excluded12%3 9%411%1 6%2 15%5 6%6

5,6 7,8

NOTE: not head-to-head comparisons.

1,2 3,4

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Adjusteda SVR12 (%)

HIV Co-infection

No (reference)

Yes

72.3

85.0

Genotype

1a (reference)

1b

74.2

83.2

FDV dose

120 mg (reference)

240 mg

79.0

78.3

Comparisons of SVR12 rates of interest adjusted for important predictors of response across the STARTVerso studies, excluding PI- and EFV-treated patients

from STARTVerso4

Adjusted difference in SVR12 (95% CI)

-20 -15 -10 0 10 15 20

12.6 (5.7, 19.5)

9.0 (4.2, 13.8)

30

5

-0.7 (-5.0, 3.6)

-5

a Adjusted for IL28B, race, fibrosis stage, baseline HCV RNA, age, baseline GGT and baseline platelet count.

Deitrich, APASL 2014, o681

New online EASL HCV recommendations

Same treatment regimens can be used in HIV/HCV patients as in patients without HIV infection, as the virological results of therapy are identical (A1)

EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf

New EASL HCV recommendations – treatment combination options

EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf

SOF + PEG-IFN/RBV

SMV + PEG-IFN/RBV

Daclatasvir + PEG-IFN/RBV

SOF + SMV (± RBV)

SOF + daclatasvir (± RBV)

12 weeks

12 weeks + RGT 12/36

12 weeks + RGT 12

12 weeks

12–24 weeks

SOF + RBV 12–24 weeks

G1, 3, 4

G1, 4

G1, 2, 3, 4

G4

G1, 4

G1, 2, 3, 4, 5, 6

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S.Khoo, 15th Intl. W’shop, 2014

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Conclusions

• The era of DAA based therapy has arrived– IFN-sparing and IFN-free therapy a reality

• Responses in HIV+ similar to HIV-• Beware DDIs• Still a ‘Special Population’ – aggressive,

multi-system disease, urgent need of Rx• Need for improved cascade of care and

access to Rx

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HCV/HIV co-infection – ‘shades of grey’