Treatment of chronic hepatitis C in drug-na¯ve patients - Virology

Treatment of chronic hepatitis C in drug-naïve patients

8th International Workshop on HIV & Hepatitis Co-infectionMadrid, 31. May 2012

Christoph SarrazinJ. W. Goethe-University Hospital

Medizinische Klinik IFrankfurt am Main, Germany

Hepatitis C: New treatment era with approval of NS3 protease-inhibitors

EMA Market Authorisation European Union18.7.2011

HCV NS3 Protease-InhibitorTelaprevir

Triple-TherapyHCV Genotype 1

HCV NS3 Protease-InhibitorBoceprevir

Triple-TherapyHCV Genotype 1

EMA Market Authorisation European Union19.9.2011

Triple-Therapies: Improved SVR ratesTreatment-naïve Genotype 1 pts.ADVANCE

RGT, TVR 12 vs. 8 wksSPRINT-2

Lead-in(LI), RGT vs. non-RGT

Jacobson et al. NEJM 2011

0

10

20

30

40

50

60

70

80

Sust

aine

d vi

rolo

gic

resp

onse

Response guided

TVR 12 wks+ PEG2a+ Riba

75%69%

44%

PEG2a + Riba

(48 wks)

Response guided

TVR 8 wks+ PEG2a

+ Riba

Poordad et al. NEJM 2011

0

10

20

30

40

50

60

70

80

Response guidedLI BOC+ PEG2b+ Riba

63% 66%

38%

PEG2b+ Riba

(48 wks)

LI BOC+ PEG2b

+ Riba(48 wks)

TVR TVR SOC BOC BOC SOC

Triple-Therapies: Improved SVR ratesTreatment-experienced Genotype 1 pts.

REALIZE(+/- Lead-in) TVR 12 wks + PEG2a + Riba

48 weeks

RESPOND-2/PROVIDE*Lead-in (+/-RGT) BOC + PEG2b + Riba

36 / 48 weeks

0

20

40

60

80

100

Sust

aine

d vi

rolo

gic

resp

onse

15%24%

REL

57%

31%

86%

TVR SOC

5%

P-NR NULL

Relapser (REL): negative at end-of-treatment but relapse thereafterPartial Non-Responder (P-NR): ≥2log wk12 but pos HCV RNA wk 24Null-Responder (NULL): <2log wk 12

TVR SOC TVR SOC 0

20

40

60

80

100

7%

29%

REL

BOC SOC

P-NR NULL

BOC SOC

75%

52%

Bacon et al., NEJM 2011*PROVIDE study, Vierling et al., AASLD 2011Zeuzem et al., NEJM 2011

36%*

0

1

2

3

4

5

6

GT 1 GT 2 GT 3 GT 4 GT 5 GT 6

Antiviral activities of Telaprevir / Boceprevir in other HCV genotypes

Mean maximum log10 HCV RNA decline during mono-therapies 7-14 days

Telaprevr 750mg TID; Reesink et al., Gastro 2006, Foster et al., Gastro 2011, Benhamou et al., EASL 2009

HC

V R

NA

log1

0 de

clin

e

4,43,9

0,5 0,9

Boceprevir 400mg TID (current dose 800mg TID); Sarrazin et al., Gastroenterology 2007; Silva et al., APASL 2011

2,11,4

1,7no data

Triple-Therapies: HIV co-infectionLimited efficacy and long duration of PEG/R

Characteristic APRICOT1 ACTG 50712 RIBAVIC3 Barcelona4

Number enrolled 868 133 412 95

PEG-IFN 2a 2a 2b 2b

RBV 800mg 600mg up to 1g 800mg 800mg up to 1.2g

HIV and CD4 status

>200/mm3 or 100–200/mm3

if HIV-RNA <5,000

copies/mL

>100/mm3 + HIV-RNA <10,000

copies/mLor >300/mm3, tx

naïve + not starting ART during trial

>200/mm3>250/mm3 and

HIV-RNA <10,000 copies/mL

ALT “elevated” NA NA >1.5 ULN

Genotype 1, % 60–61 77–78 48 49

Bridging fibrosis or cirrhosis, % 15–16 9–11 (cirrhosis) 39 30

SVR, n/N (%) Genotype 1 51/176 (29) 7/51 (14) 21/123 (17)* 22/59 (38)*

1.Torriani FJ, et al. N Engl J Med 2004;351:438–450 2. Chung RT, et al. N Engl J Med 2004;351:451–459

3. Carrat F, et al. JAMA 2004;292:2839–2484 4. Laguno M, et al. AIDS 2004;18:F27–36

*Genotype 1 or 4IFN: interferon; RBV: ribavirin; ALT: alanine aminotransferaseULN: upper limit of normal; SVR: sustained virologic response

Triple-Therapies: HIV co-infectionPotential of DDIs with Telaprevir/Boceprevir

Telaprevir Boceprevir

RTV1,2 ↓ TVR ↑ RTV ↓ BOC

Peg-IFN2 n/a ↔ BOC

EFV2,3 ↓ TVR ↓ EFV ↓ BOC ↑ EFV

TDF2,3 ↓ TVR ↑ TDF ↑ BOC ↑ TDF

ATV/r3 ↓ TVR ↑ ATV n/a

DRV/r3 ↓ TVR ↓ DRV n/a

FPV/r3 ↓ TVR ↓ FPV n/a

LPV/r3 ↓ TVR ↔ LPV n/a

Methadone4 ↔ TVR ↓ R-methadone (↑ free fraction) n/a

Cyclosporine5 ↔ TVR ↑ cyclosporine n/a

Tacrolimus5 ↔ TVR ↑ tacrolimus n/a

Midazolam2 n/a ↑ MDZ

Diflunisal2 n/a ↔ BOC

Clarithromycin2 n/a ↔ BOC

Ketoconazole2,6 ↑ TVR ↑ KET ↑ BOC

Oral contraceptives2,6 ↓ EE ↔ NOR ↑ DRSP ↓ EE

Renal impairment7 ↔ TVR n/a

1. Garg V, et al. CROI 2011. Abstract 629; 2. Kassera C, et al. CROI 2011. Abstract 118; 3. van Heeswijk R, et al. CROI 2011. Abstract 1194. van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1): S491; 5. Garg V, et al. ATC 2011. Abstract 65; 6. Telaprevir French cohort

ATU Protocol. Available at http://www.afssaps.fr; 7. van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1): S492

Triple-Therapies: HIV co-infectionTelaprevir Triple-Therapy Study

Dieterich et al., CROI 2012

Part A: no ART

Follow-upPR48 (control) PR

SVRPbo + PR

T/PR TVR + PR Follow-upSVR

PR

Follow-upPR48 (control) PR

SVRPbo + PR

T/PR TVR + PR Follow-upSVR

PR

Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)

(EFV)=efavirenz; (TDF)=tenofovir; (FTC)=emtricitabine; (ATV/r)=ritonavir-boosted atazanavir; (3TC)=lamivudine; (T) TVR=telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; (P) Peg-IFN=pegylated interferon alfa-2a (40 kD) 180 µg/wk; (R) RBV=ribavirin 800 mg/day or weight-based (1000 mg/day if weight <75 kg, 1200 mg/day for if weight ≥75 kg; France, Germany, n=5 patients)Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL, LOD of <10 IU/mL

240 48 72Weeks 12 36 60

SVR12

SVR12

SVR12

SVR121:1

2:1

Triple-Therapies: HIV co-infectionTelaprevir Triple-Therapy Study

Dieterich et al., CROI 2012

Pat

ient

s w

ith S

VR

(%)

No ART EFV/TDF/FTC ATV/r/TDF/FTC Total

n/N = 5/7 11/16 12/15 28/38

T/PR PR2/6 4/8 4/8 10/22

71

33

69

50

80

50

74

45

0

10

20

30

40

50

60

70

80

90

100

*Patient was defined as SVR12 if HCV RNA was < LLOQ in the visit window

Triple-Therapies: HIV co-infectionBoceprevir Triple-Therapy

Mallolas et al., EASL 2012





Telaprevir / Boceprevir Triple-TherapiesAdverse events

Bacon et al. NEJM 2011, Poordad et al. NEJM 2011, Jacobson et al. NEJM 2011, Zeuzem et al. NEJM 2011, Sherman et al. NEJM 2011

% of patients (Phase II / III-studies) Telaprevir/PRN = 1.346

Placebo/PRN = 764

Discont. Telaprevir / Placebo due to AEs 14 4Pruritus 51 26Rash 55 33Nausea 39 29Diarrhea 26 19Anorectal symptoms 26 6Anemia 29 12

% of patients (Phase III-studies) Boceprevir/PR N = 1.057

Placebo/PR N = 443

Discont. entire treatment due to AEs 8-16 2-16Anemia 43-49 20-29Dysgeusia 37-45 11-18Neutropenia (500 to < 750/mm3) 19-25 9-14

Dry skin 21 8

Triple-TherapyPredictors of response

Predictors for lower SVR

• Non-Response PEG-IFN / Ribavirin pre-treatment

• Non-CC IL28B-Genotype (rs12979860)

• High HCV-RNA baseline level (> 8 x 105 IU/ml)

• Advanced Fibrosis (F3 / F4)

• Low LDL

• HCV-Subtype 1a (approx. 10% lower SVR rate)

Importance for treatment algorithm in mono-infected pts. Poordad et al. NEJM 2011 Zeuzem et al. NEJM 2011

Bacon et al. NEJM 2011Berg et al., AASLD 2011

Jacobson et al. NEJM 2011

IL28B (rs12979860)Correlation with SVR / Importance for treatment

algorithm?

Treatment-naive pts. without cirrhosis: Shortening of Triple-Therapy in patients

with IL28B CC-genotype ?

Therapy Boceprevir(SVR)

Telaprevir (SVR)

PEG/R (SVR)

Tx naive(RGT-arms)

CC 82% 90% 64 − 78%CT/TT 62% 72% 25 − 27%

Tx experienced(48 weeks)

CC 77% 79% 29 − 46%CT/TT 73% 61% 15 − 26%

Poordad et al. EASL 2011, Pol et al. EASL 2011

Hézode C, et al. N Engl J Med 2009;360:1839–50

T12P12 (n=78)(no RBV)

PR48 (n=82)

T12PR12 (n=82)

0Weeks

24 4812 36

TVR + Peg-IFN

Peg-IFN + RBV Placebo

+ Peg-IFN + RBV

TVR + Peg-IFN +

RBV Peg-IFN + RBV

TVR + Peg-IFN

+ RBV

T12PR24 (n=81)

46%

69%

60%

36%

SVR rate

Telaprevir Phase 2 Study (PROVE2)SVR Rates

T12P12 (n=78)(no RBV)

PR48 (n=82)

T12PR12 (n=82)

0Weeks

24 4812 36

TVR + Peg-IFN


+ Peg-IFN + RBV

TVR + Peg-IFN +

RBV Peg-IFN + RBV

TVR + Peg-IFN

+ RBV

T12PR24 (n=81)

46%

69%

60%

36%

SVR rate

Bronowicki et al, EASL 2012, poster (1094)

The IL28B genotype (rs12979860) was determined in specimens at the PROVE2 French sites

Telaprevir Phase 2 Study (PROVE2)SVR Rates

Short treatment in IL28B CC patients

T12P12 (n=78)(no RBV)

PR48 (n=82)

T12PR12 (n=82)

0Weeks

24 4812 36

TVR + Peg-IFN


+ Peg-IFN + RBV

TVR + Peg-IFN +

RBV Peg-IFN + RBV

TVR + Peg-IFN

+ RBV

T12PR24 (n=81)

46%

69%

36%

SVR rate

SVR: 100% for 12/12 patients with IL28B CC2

Bronowicki et al, EASL 2012, poster (1094)

Prospective ongoing study (CONCISE) for 12 weeks triple therapy with TVR BID in treatment naïve genotype 1, CC patients

Triple TherapyNew response definitions

Abbreviation Meaning Comment

SVR Sustained virologic response HCV-RNA undetectable 24 weeks after end of treatment

Relapse Relapse after end of treatment

Partial Non-Response

Week 12 ≥ 2 log-decline of HCV-RNA but HCV RNA detectable at week 24

Null-Response < 2 log-decline of HCV-RNA at week 12

RVR rapid virologic response HCV-RNA negative at week 4

eRVR (TVR) extended RVR Telaprevir HCV-RNA negative at week 4 and 12

eRVR (BOC) extended RVR Boceprevir HCV-RNA negative at week 8 and 24

Breakthrough Virologic breakthorough HCV-RNA positive after undetectability orincrease of > 1 log step

= undetectable HCV RNA

Boceprevir Telaprevir

TW8 TW28 TW48TW24TW4 TW36TW0

32W‐BOC4W‐LI 12W PR

Naive24W‐BOC4W‐LI

Part.Resp.Relapser

Null Resp.F4 Fibrosis

44W‐BOC4W‐LI

NaiveRelapser

Part.Resp.Null Resp.

F4 Fibrosis


TW24 TW48TW12TW4TW0

36W PR

12W‐TVR 12W PR

12W‐TVR

+/-

36W PR12W‐TVR

36W PR12W‐TVR

Treatment algorithms for HCV mono-infected patients: Lead-in

Lead-in versus no Lead-inIndividual decision

Individual decision on

further treatment

Tolerability ofPEG-IFN /

Ribavirin aloneduring Lead-in

Adherenceon PEG-IFN /

Ribavirin alone during Lead-in

Treatment experienced patient with Null-

Response, F4 and < 1 log-decline during

Lead-in

Treatment-naive patient with RVR

during Lead-in and possibility of 24 weeks PEG/Riba

TVR/BOC sparing treatmentRVR during lead-in with PEG/Riba

Rates of RVR (HCV RNA undetectable / <12-50 IU/ml at week 4) in treatment-naive patients with chronic hepatitis

genotype 1 infection and treatment with PEG-IFN / Ribavirin alone range from 12-65% in different studies from the U.S.,

Europe and Asia

Response group

INDIV-2 Study (genotype 1, treatment-naïve)PEG-Interferon alfa 2b plus Ribavirin

Treatment duration (weeks)

ITT population (n=398) PP population (n=346)

HCV RNA negative* at

Baseline viral load

n (%) SVR (%) n SVR (%)

week 4 <800.000 IU/ml

24 41 (10) 36 (88) 36 36 (100)

week 4 ≥800.000 IU/ml

30 7 (2) 6 (86) 6 6 (100)

* HCV RNA undetectable by TMA Assay (<5-10 IU/ml)

Sarrazin et al. Gastroenterology 2011

Fried et al., J Hepatol 2011, McHutchison et al., NEJM 2009, Ferenci et al., Gastroenterology 2008, Mangia et al., Hepatology 2008, Berg et al., Gastroenterology 2006, Sarrazin et al., Gastroenterology 2011, Sanchez-Tapias et al., Gastroenterology 2006,

Bronowicki et al., Gastroenterology 2006, Buti et al., Hepatology 2010, Yu et al., Hepatology 2008, Liu et al., Clin Infect Dis 2008

Boceprevir – Stopping rulesBoceprevir

Stopping rules for Boceprevir :HCV RNA > 100 IU/ml at TW12HCV RNA detectable at TW24

TW28TW24TW4 TW36TW0



Part.Resp.Relapser


44W‐BOC4W‐LI


TW12

Stopping rules Boceprevir Triple

Jacobson et al. AASLD 2011

Treatment naive: SPRINT-2-Study, n = 734 Entire treatment was discontinued within the study if HCV RNA was detectable at week 24

Week 8 Week 12Rate of pts.

with stopmissed SVR

Rate of pts.with stop

missed SVR

≥ 50 IU/ml 147 (20%) 26 78 (11%) 4≥ 100 IU/ml 120 (16%) 16 65 (9%) 0< 3 log-decline 34 (5%) 1 34 (5%) 0

Retrospective analysis for introduction of early stopping rules

Telaprevir – Stopping rules

Stopping rules for Telaprevir:HCV RNA > 1000 IU/ml at TW4 or TW12HCV RNA detectable at TW24

Telaprevir

NaiveRelapser


F4 Fibrosis

TW24 TW48TW12TW4TW0

36W PR

12W‐TVR 12W PR

12W‐TVR

+/-

36W PR12W‐TVR

36W PR12W‐TVR

Adda et al. HepDart 2011

Stopping rules Telaprevir Triple

Treatment-naive: ADVANCE-Study, n = 903 Telaprevir was discontinued within study if HCV-RNA > 1.000

IU/ml at week 4 and entire treatment was discontinued if < 2 log decline of HCV RNA at week 12 / HCV-RNA positive at week 24

Week 4 Week 12Rate of pts.

with stopmissed

SVRRate of pts.

with stopmissed

SVR

≥ 100 but< 1.000 IU/ml 19 (2%) 5 10 (1%) ?

≥ 1.000 IU/ml 15 (2%) 0 9 (1%) 0

Retrospective analysis for introduction of early stopping rules

Viral kinetics of triple-therapy

Adda et al. HepDart 2011

104

105

106

107

108

1043

102

101

0 2 4 6 8 10 12Weeks /therapy

HC

V-R

NA

IU/m

l

104

105

106

107

108

1043

102

101

0 2 4 6 8 10 12Weeks /Therapy

HC

V-R

NA

IU/m

l

Treatment naive (n = 15) Treatment experienced (n = 15)

= undetectable HCV RNA

Boceprevir Telaprevir

TW8 TW28 TW48TW24TW4 TW36TW0



Part.Resp.Relapser


44W‐BOC4W‐LI

NaiveRelapser


F4 Fibrosis


TW24 TW48TW12TW4TW0

36W PR

12W‐TVR 12W PR

12W‐TVR

+/-

36W PR12W‐TVR

36W PR12W‐TVR

Telaprevir / Boceprevir Treatment algorithmsDetermination of extended rapid virologic response

Response guided Triple-TherapieDefinition of extended RVR

Telaprevir

eRVR HCV RNA undetectable* at week 4 and 12

* Below the limit of detection (approx. 10 IU/ml)

Boceprevir

eRVR HCV RNA undetectable* at week 8 and 24

* Below the limit of detection (approx. 10 IU/ml)

Importance of residual viremia? Differences between different HCV RNA assays?

Boceprevir & Telaprevir Studies: HPS/Cobas TaqMan Assay

Response guided Triple TherapyDefinitions of extended RVR

HCV RNA concentrations <25 IU/ml are frequently observed during TVR/BOC triple-therapies (52-67% in Phase 3 studies with TVR/BOC until week 4/8)

Overall increased probability of treatment failure in patients with residual viremia (<25 IU/ml but detectable HCV RNA) at week 4/8 during Telaprevir / Boceprevir triple-therapies

Harrington et al., Hepatology 2011

Response guided Triple TherapyDefinitions of extended RVR

Higher Relapse-Rates in patients with residual viremia(<25 IU/ml) at week 4 / 12 in patients with shortened treatment duration (24 weeks).

Harrington et al., Hepatology 2011

Study Time Duration SVR RelapseBoceprevirSPRINT-1

<25 IU/ml wk. 8 28 wks 5/13 (38%) 5/10 (50%)48 wks 9/12 (75%) 0/9 (0%)

negative wk. 8 28 wks 53/62 (85%) 4/57 (7%)48 wks 62/66 (94%) 0/62 (9%)

Telaprevir 104 / PROVE1/2

<25 IU/ml wk. 4 24 wks 6/15 (40%) 4/9 (44%)48 wks 4/7 (57%) 2/6 (33%)

negative wk. 4 24 wks 89/120 (74%) 6/88 (7%)48 wks 49/64 (77%) 0/44 (0%)

International commercially available HCV RNA assays

100

101

102

103

104

105

106

107

108IU/ml

615 5005-10 50 10

TMA bDNA kPCRVersantTM

Siemens(CE/FDA für TMA/bDNA)

qual. quant. real-time AmplicorTM vs2 TaqManTM

Roche Diagnostics(CE/FDA)

real-timeRealTime HCVTM

Abbott(CE/FDA)

101034

HCV RTartusTM

Qiagen(CE)

Response guided Triple TherapyDifferences between assays

Fevery et al., EASL 2012

• Samples obtained from the TMC435 PILLAR study (TMC435-C205)

o Treatment-naïve patients received once-daily TMC435 in combination with PegIFNα-2a/RBV

o 79-86% of TMC435-treated patients were eligible for shortened treatment of 24 weeks, of whom 85-96% achieved SVR24

• In PILLAR, HCV RNA was assessed using Roche High-Pure-System/COBAS® TaqMan assay v2 (HPS)

• A total of 1411 plasma sampleswith sufficient volume were selected from 290 of 309 TMC435-treated patients, and re-analysed in a blinded fashion with the Abbott RealTime(ART) assay

Visit Number of samplesScreening 113Baseline 16Day 3 28Week 1 135Week 2 186Week 3 164Week 4 261Week 6 108Week 8 140Week 12 260Total 1411

Differences between HCV RNA AssaysOverall HCV RNA quantification

Fevery et al.,EASL 2012

1 2 3 4 5 6 7Roche TaqMan (HPS), log10 IU/mL

Abb

ott R

ealT

ime

(AR

T), l

og10

IU/m

L

(r2=0.978)

LLOQ ART

LLO

Q H

PS

N=326

1

2

3

4

5

6

7

*censored values excluded


Abbott RealTime (ART)

<12 IU/mLnot detected

<12 IU/mLdetected

12 IU/mLbut

<25 IU/mL25 IU/mL

Roc

he T

aqM

an(H

PS)

<25 IU/mL not detected 549 181 28 8

<25 IU/mLdetected 35 128 86 65

25 IU/mL 0 5 19 307

217/766 (28.3%)

• 217/766 (28.3%) samples from different time points with HCV RNA undetectable by HPS had detectable/quantifiable HCV RNA by ART

• 35/584 (6.0%) samples undetectable by ART had detectable/quantifiableHCV RNA by RCT

• For both assays, the majority of these discrepant samples had HCV RNA levels <25 IU/mL

35/584 (6.0%)

Differences between HCV RNA AssaysHCV RNA undetectability


Differences between HCV RNA AssaysAssessment of rapid virologic response

At Week 4, 197/261 (75.5%) samples were undetectable by HPS whereas 129/261 (49.4%) were undetectable and 79/261 (30.3%) <12 IU/mL detectable by ART, leading to a different determination of RVR in 68/261 (26.1%) of cases

75,5

16,58,0

0

20

40

60

80

100

Not detected <25 IU/mLdetected

≥25 IU/mL

Abbott RealTime (ART)

49,4

30,3

7,7 12,6

0

20

40

60

80

100

Notdetected

<12 IU/mLdetected

≥12 and<25 IU/mL

≥25 IU/mL

75.5% <25 IU/mL undetectable 49.4% <12 IU/mL

undetectable

79.7% <12 IU/mL

Prop

ortio

n of

pat

ient

s, %

Prop

ortio

n of

pat

ient

s, %

Roche TaqMan (HPS)

Summary

New era with Boceprevir / Telaprevir triple-therapies- significant improvement of SVR rates- genotype 1 only- high efficacy also in HIV co-infected patients- complex management, high pill burden, additionalAEs, DDI and limited efficacy in non-responders

Response guided therapy according to HCV RNA viral kinetics (stopping rules, eRVR)

Lead-in may be used for testing tolerability, PI sparing and prediction of non-response to PIs

IL28B may be used to tailor treatment in the future

Importance of HCV RNA assays

Documents

Treatment of chronic hepatitis C in drug-na¯ve patients - Virology