Pablo BarreiroServicio de Enfermedades InfecciosasHospital Carlos III, Madrid

Predictors of Response toHepatitis C Therapyin the DAA Era

Why Predicting HCV Response?

•Select candidates for therapy

•Prioritizing expensive drugs•Wait for newer compounds

•Determine type of therapy•Dual therapy•Adding DAAs

•Decide duration of therapy•Motivate patients

•In summary, tailor hepatitis C treatment

Main Predictors of Response to Hepatitis C Treatment

•Level of viremia•Genotype / Subtype•Drug resistant polymorphisms

•Race•IFN cascades genotypes•Liver fibrosis stage•Insulin resistance•CD4 counts

•Treatment history•Initial response (RVR)•RBV doses / levels•Type of ARV and DDI

0

10

20

30

40

50

60

70

80

90

100

Total Genotype 1 Genotype 2 or 3

High (>800,000 IU/ml)

Low (<800,000 IU/ml)

0

10

20

30

40

50

60

70

80

90

100

Total Genotype 1 or 4 Genotype 2 or 3

Rate of Sustained Virological Response

PEG-IFN-2b + RBVPEG-IFN-2a + RBV

HCV Genotype and HCV-RNA Level

Torriani et al. NEJM 2004 Crespo et al. J Viral Hep 2007

% %

HCV-RNAat baseline

p<0.0001

p=0.001

p=0.684

p=0.08775%

38%

65%

30%

86%81%

67%

25%

SVR

All HCV-1 HCV-3 HCV-4

CCCT/TT

Rallon et al. AIDS 2011; 15:F23-9

IL28B Polymorphisms & SVR in HIV/HCV Coinfected Patients

Odds ratio (95% confidence interval)

HCV-RNA <600,000 IU/ml

HCV genotype 3

rs12979860 CC genotype

Liver fibrosis stage F0-F2

0 5 10 15 20 25 30 35 40

11.9

8.0

3.7

3.5

p<0.001

p<0.001

p=0.002

p=0.009

Rallon et al. AIDS 2010

Predictors of Response in HIV-HCV Coinfection

http://www.fundacionies/prometheusindex.phpMedrano et al. Clin Infect Dis 2010

Prometheus Index

Viral Factorsin DAAs Era

SVR (%

)

n/N=

BOC RGT41/54

PR

35/55

PR

102/308

BOC 44/PR48197/313

≤800,000 >800,000

Poordad F, et al. N Engl J Med 2011;364:1195–206

SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow‐up Week 24. If there was no such value, the follow‐up Week 12 value was carried forward

BOC RGT192/314

BOC 44/PR4845/53

Baseline Viral Load as a Predictor of SVRBoceprevir for naive (SPRINT-2)

Poordad F, et al. N Engl J Med 2011;364:1195–206

Bacon BR, et al. N Engl J Med. 2011;364:1207-1217

Baseline HCV-RNA Levels as Predictor in Patients with Poor IFN Response before Boceprevir Therapy

Advance Study

Influence of HCV-1 SubtypeTelaprevir

Realize StudyRelapsers Partial responders Null responders

% o

f pat

ient

s w

ith S

VR

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

Influence of HCV-1 SubtypeBoceprevir

20

54

27

43

25

47

0

20

40

60

80

100 % SVR

1154

1935

33124

44178

2661

4596

1a 1b 1a 1b 1a 1b

RESPOND‐2 SPRINT‐2 CombinedStudies

p = 0.001 p = 0.028 p < 0.001

Poordad F, et al. N Engl J Med 2011;364:1195–206

Bacon BR, et al. N Engl J Med. 2011;364:1207-1217

Frequency and Distribution of RAVs by genotype

(Expressed as a percentage of RAVs detected for each genotype)

Lower Genetic Barrier of HCV-1a Subtype

Distribution of RAVs by genotype

Total n=342*

97

43

117

38

32

15

0

50

100

150

200

250

300

Patie

nts, n

G1a Gt1b

Patients with No Sequence Data

Patients with RAVs Detected

Patients with no RAVs Detected

*1 patient excluded due to indeterminate Genotype 1 subtype; Gt = Genotype

3

61

6 0 0

19

3 1

68

8 5 4 07

0 1 1 0 03 3

42

3 3

37

24

0 3 0

26

3 5 5

32

0 0 3 50102030405060708090100

Varia

nts, %

Genotype 1aGenotype 1b

Rallón, AIDS 2011;25:1025-33

Differences in Virological Response to PegIFN plus RBV in HCV/HIV-Coinfected

Patients by HCV Subtype (1a vs 1b)

80%78%76%79%

50%

0%

23%34%

0102030405060708090

100

No RAVs RAVs Hot RAVs Other RAVs

IFN respondersIFN non-responders

% o

f pat

ient

s w

ih S

VR

Brass et al. EASL 2011

PROVIDE Study Interim Results: Boceprevir + PegIFN + RBV

*V36M, R155K, T54S/A and V55A

*

Pretreated patients

Host Factorsin DAAs Era

SVR by Fibrosis Stage in Naïve Patients(SPRINT-2- Boceprevir)

SVR (%

)

PR48

123/328

BOC44/PR48

211/313n/N=

No, minimal or portal fibrosis (F0–F2)

Bridging fibrosisor cirrhosis (F3/F4)

BOC RGT

213/319

BOC44/PR48 

22/42

BOC RGT

14/34

Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206

PR48 

9/24

*p<0.001 for both boceprevir arms vs PR48; ‡p=1.00 for boceprevir vs PR48**p=0.31 for boceprevir vs PR48

*

‡

**

*

SVR by Fibrosis Stage in Pretreated Patients(REALIZE- Telaprevir)

Zeuzem S, et al. EASL 2011. Abstract 5.

Previous Relapsers Previous Partial Responders

Previous Null Responders

2/15n/N= 53/

62144/167

12/38 0/5

10/18

34/47

3/17 0/9

15/38

11/32

1/5

No, minimal, or

portal fibrosis

CirrhosisStage

Pooled T12/PR48Pbo/PR48

2/15

48/57

24/59

1/18 7/50

1/10

Bridgingfibrosis

No, minimal, or

portal fibrosis

CirrhosisBridgingfibrosis

No, minimal, or

portal fibrosis

CirrhosisBridgingfibrosis

100

0

60

SVR

(%)

80

40

20

86

32

85

13

84

13

72

18

56

0

34

20

41

6

39

014 10

SVR rates by IL28B genotypeTelaprevir for naive (ADVANCE)

Samples were available for 454/1088 (42%) patients (Caucasian) enrolled in ADVANCESVR: sustained virologic response, defined as undetectable HCV RNA 24 weeks after last planned dose Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

T8/PRPR T12/PR PR T12/PRT8/PR PR T12/PRT8/PR

n/N= 38/4535/55 45/50 20/80 48/6843/76 6/26 16/2219/32

SVR

(%)

CC TTCT

RVR: rapid viral response (undetectable HCV RNA at Week 4) Jacobson IM, et al. J Hepatol 2011;54(Suppl. 1):S542

Patie

nts

(%)

PR48

RVR

T12PR

SVR in RVR+

PR48 T12PR

78% of CC patients in the T12PR arm were treated with 24 weeks of treatment

9/55n/N= 42/50 9/9 39/42

SVR rates in IL28B CC with RVRTelaprevir for naive (ADVANCE)

68

SOUND-C2: Efficacy According to Study Arm, HCV Subtype, and IL28B

Zeuzem S, et al. EASL 2012. Abstract 101.

SV

R12

(%)

0

40

60

80

100

20

BID28 wksRBV

TID28 wks

TID40 wksRBV

TID28 wksRBV

TID16 wksRBV

32

71

38

71

42

62

32

82

53

0

1a non-CC All 1b and 1a-CC

SVR According to IL28B and HCV Subtype (ITT)

59

All patients

6156

39

Lower SVR in Blacks Regardless of IL28B Genotype

Ge D, et al. Nature. 2009

SPRINT-2: SVR to Boceprevir According to Race

BOC/PR48BOC/PR RGTPR48

0

20

40

60

80

100

SVR

(%)

67

40 42

23

Nonblack Black

P < .0001P = .004

P = .044

Poordad F, et al. AASLD 2010. Abstract LB-4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

Phase III: genotype 1, treatment naive

Race

68

53

311n = 316 311 55 52 52

ADVANCE: SVR to Telaprevir According to Race and Ethnicity

T12PRT8PRPR48

SVR

(%)

Race/EthnicityJacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Phase III: genotype 1, treatment naive

75

62

74 7570

5866 69

46

25

3944

0

20

40

60

80

100

White Black Latino Non-Latino

325n = 315 318 26 40 28 35 44 38 328 320 323

•Expressed in HCV-infected hepatocytes•Role in recruitment of T-lymphocytes?•Inverse association of IP-10 plasma levels with SVR after dual and triple therapy

Casrouge A, et al. J Clin Invest 2011

IFN-gamma Inducible Protein 10 kDa (IP-10)

Vijgen L, et al. EASL 2012 (abstract 1167)

•HCV replication upregulates IP10 levels that tend to normalize after therapy•Baseline IP10 plus IL28B genotype improves prediction of treatment responses•IP-10 not an independent predictor

Rallón et al. AASLD 2011

IP-10 in HIV-HCV Coinfected Patients

%

%

%

%

IFN experience HCV genotype Advanced liver fibrosis

59%41%

47% 53%

22%11%

20%

8%

39%Yes

NoYesNo

G1a

G1b

G4Others

G3

424 HIV/HCV-coinfected patients in 2011

Antiviral Therapy 2012; 17: 571-5.

30%

70%

IL28B

CT/TT

CC

Predicted Effect of DAA in HIV-HCVCoinfected Patients

0 1 2 3 4

% o

f HIV

-HC

V C

oinf

ecte

d P

atie

nts

No. of unfavorable factorsPoveda E et al. Antiviral Therapy 2012;17:571-5

•HCV subtype 1a•IFN exposure•IL28B nonCC•Metavir F3-F4

Jacobson IM, et al. N Engl J Med 2011;364:2405–16Sherman KE, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-8

DT Dieterich et al., CROI 2012Poordad F. N Engl J Med. 2011; 364:1195-1206Mallolas J et al. EASL Barcelona-Spain. April, 2012

Similar Response to DAA in Naïve Patients Despite HIV Infection

% o

f pat

ient

s

Boceprevir Telaprevir

208368

243368

2764

4064

246363

288363

2638

2838

Boceprevir TelaprevirNaive All All

HCV 1a 66% 64%

High HCV-RNA 88% 87%

Cirrhosis 6% 0%

Median CD4 count(cells/uL)

577 535

IL28B nonCC NA NA

Too Favorable Factors in HIV-HCVCoinfected Patients Treated with DAA

Mallolas J, et al. EASL 2012Sulkowski MS, et al. CROI 2012

NaiveRelapsers

Partialresponders

Null respondersCha

nces

of r

epon

seTreatment

history

Yes CC No

Yes CT/TT No

No Any Yes

No Any No

PredictorsRVR IL28B F4

12 weeks?

24 weeks

48 weeks

Defer

Treatmentduration

Opt

imiz

atio

n of

ther

apy

Aproach to DAA Therapy

SummaryHCV-genotype 2 or 3 4 1

Therapy pIFN-RBV pIFN-RBV-PI IFN-Free

HCV-RNA level ++ +++ + +

HCV-1 subtype -- -- ++ ++

IL28B - +++ + ++

RBV doses ++ ++ - ++

Liver fibrosis + ++ +++ -

RVR ++ +++ ++ (R) / ++++ (F) -

LIP - - High VL / Nulls -

RAVs - - IFN resistance ?

Prior pegIFN-RBV failure

Any Any Null / Partial response

?

Molecular Biology Clinicians Computing and Administration

Carmen de Mendoza Pablo Labarga Gustavo ManuzzaEva Poveda Eugenia Vispo Alma GonzálezAna Treviño Francisco Blanco Carmen SoleraNorma Rallón José V Fernández-MonteroJosé Miguel Benito Dolores HerreroMariola López Ivana Maida Lourdes Anta Luz Martín-CarboneroNatalia Zahonero Fernanda RickZulema Plaza Vicente SorianoEduardo Seclén

Acknowledgements

pm.barreiro@gmail.com