Clinical management of Hepatitis C...

Clinical management of

Hepatitis C infection

1st Asian Conference on Hepatitis B and C, HIV and Influenza, 18-19 May 2012,

Beijing, China

Jürgen K. Rockstroh Department of Internal Medicine I

University Hospital Bonn Germany

Natural History of HCV Liver Disease

~55-85%

25-30 yrs

2 - 4% / yr

Liver failure

(2 – 5% / yr)

Chronic Hepatitis C: Therapy

HCV therapy is worthwhile…..

GT3 without SVR

GT1 without SVR

GT2 without SVR

GT1, 2 & 3 with SVR

Backus et al., Clin Gastroenterol Hepatol 2011

Cum

ulat

ive

Mor

talit

y Effective HCV therapy prolongs

survival

Van der Meer al., AASLD 2011

Sustained virological response improves overall survival in chronic hepatitis C patients with advanced fibrosis

529 patients followed for up to 20.2 years (median 7.7 years)

Recommendations

(1) The goal of therapy is to eradicate HCV infection (A1). (2) The endpoint of therapy is sustained virological response (A1). Once obtained, SVR usually equates to cure of infection in more than 99% of patients (A1). (3) Intermediate endpoints to assess the likelihood of an SVR are HCV RNA levels at 4, 12, and 24 weeks of therapy (B2).

EASL Clinical Practice Guidelines: Management of hepatitis C virus infectionJournal of Hepatology 2011;245–264

Definitions of virological response at week 4 and week 12 H

CV

RN

A d

ecre

ase

(IU

/mL

)

EOTR SVR

72 4 48 Weeks of therapy

0 12

Undetectable HCV RNA

(<50 IU/mL)

0 RVR = undetectable HCV RNA at week 4 cEVR = no RVR but undetectable HCV RNA at week 12

>2 log10

pEVR = no RVR and detectable HCV RNA, but >2 log10 drop at week 12

24

RVR - Rapid virological response; cEVR – complete Early virological response; pEVR - partial Early virological response; SVR – Sustained virologic response

Recommendations (1) Liver disease severity should be assessed prior to therapy (B1). (2) Identifying patients with cirrhosis is of particular importance, as their prognosis and likelihood to respond to therapy are altered, and they require surveillance for HCC (A1). (3) As liver disease can progress in patients with repeatedly normal ALT levels, disease severity evaluation should be performed regardless of ALT levels (B2). (4) Assessment of the severity of liver fibrosis is important in decision making in patients with chronic hepatitis C (A1). (5) Liver biopsy is still regarded as the reference method to assess the grade of inflammation and the stage of fibrosis (A2). (6) Transient elastography (TE) can be used to assess liver fibrosis in patients with chronic hepatitis C (A2). (7) Non-invasive serum makers can be recommended for the detection of significant fibrosis (METAVIR score F2–F4) (A2).

Chronic Hepatitis C: Improvement by trial and error

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996

IFN 24 weeks IFN 48 weeks

Sus

tain

ed v

irolo

gica

l res

pons

e

Optimization of dose and duration

IFN & Ribavirin 48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998


Sus

tain

ed v

irolo

gica

l res

pons

e One unspecific drug plus another unspecific drug = highly effective therapy

O N

O H H O

H O

N

N H 2 N

O

Chronic Hepatitis C: Improvement by trial and error

IFN & Ribavirin 48 weeks

0%

20%

40%

60%

80%

1988 1990 1992 1994 1996 1998


Sus

tain

ed v

irolo

gica

l res

pons

e

>50% cure of chronic Hepatitis C

2001

PEG IFN & Ribavirin

PEG - IFN 48 weeks

40 kDa PEG - - IFN alfa - 2a

12 kDa PEG - IFN alfa - - 2b

Negative Prognostic

Factors

Not all patients have the same likelihood of achieving an SVR

Age

Cirrhosis

Race

Diabetes

High Viral load

Gender

HIV Co-infection

HCV genotype 1 and 4

Obesity

IL28B T allele

ESRD

Alcohol

SVR – Sustained virologic response, ESRD – End-stage renal disease, IL28B – Interleukin 28B

The error bars correspond to the 95% confidence intervals Virological response defined as: HCV RNA <50 IU/mL

Marcellin P et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 73

PROPHESYS Study: Virological Response Varied by Genotype: G1 and G4

n= 287 1200 2769 1891 n= 287 1200 2769 1891

PROPHESYS Study: Virological Response Varied by Genotype: G2 and G3

The error bars correspond to the 95% confidence intervals Virological response defined as: HCV RNA <50 IU/mL

Marcellin P et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 73

n= 261 868 973 732 n= 251 932 1161 763

Impact of fibrosis on treatment outcome (PROPHESYS study)

Ferenci P, et al. AASLD.2011

Ge DL, et al. Nature. 2009; 461;399-401; Thomas DL, et al. Nature. 2009;461:798-801

Percentage of SVR by genotypes of rs12979860.

Sampling locations, allele frequencies and degree of regional differentiation of the

rs12979860 C allele.

IL28B polymorphism and treatment outcome

SVR – Sustained virologic response

Stättermayer AF, et al. Clin Gastroenterol Hepatol. 2011;9:344-350

SVR in relation to IL28B (rs12979860), fibrosis grade and baseline viral load (GT1)

RVR - Rapid virological response; cEVR – complete Early virological response; SVR – Sustained virologic response

Treatment start HCV-RNA-level

Standard therapy in HCV genotyp 2/3

Week 4 HCV-RNA-determination


Treatment discontinuation

HCV-RNA < 12-15 IU/ml


∆ HCV-RNA > 12-15 IU/ml

∆ HCV RNA*

< 2 log

Initial HCV-RNA

< 8x 105 IU/ml

+

16 weeks of therapy

24 weeks of therapy

48 weeks of therapy

Consensus: 100%

No shortened duration for F3/F4 Metabolic Syndrom No data for normal transaminases

*extended therapy in case of slow response is currently studied

Z Gastroenterol 2010; 48:289–351

Treatment start HCV-RNA-level

Standard therapy in HCV genotyp 1/4




Treatment discontinuation




HCV RNA > 2 log or

> 3x104 IU/ml

HCV RNA pos

Initial HCV-RNA *

< 6-8x 105 IU/ml

+

24 weeks of therapy

48 weeks of therapy

72 weeks of therapy

RVR cEVR Slow Responder

* 6x105 IU/ml pegIFN α2b 8x105 IU/ml pegIFN α2a No shortened duration for F3/F4 Metabolic Syndrom No data for normal transaminases

Consensus: 98%

Z Gastroenterol 2010; 48:289–351

The new DAAs……………..

Protease- Inhibitors Polymeraseinhibitors

NI NNI

NS5A-Inhibitors

TLR-Agonists Therapeutic Vaccine

Other IFNs PEG-IFN lambda

Entry-Inhibitors

Cyclophillin Inhibitors

Ribavirin

Boceprevir (Victrelis) FDA approval 13.5.2011

Europe: 18.7.2011

Telaprevir (Incivek) FDA approval 23.5.2011

Europe: 20.9.2011

4x200 mg every 7-9h With a meal (3X4 tablets)

2x325 mg alle 7-9h With a fatty meal

(3X2 tablets)

SVR

(%)

PRESCO HIV/HCV

Peg2a/RBV

0 10 20 30 40 50 60 70 80 90

100

Núñez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-82 Poordad et al. , NEJM 2011;364:1195-1206 Jacobson IM, et al, NEJM 2011;364:2405-16

ADVANCE HCV mono

Telaprevir12

SPRINT-2 HCV mono

Boceprevir44

ADVANCE HCV mono Peg2a/RBV

35%

44%

75% 66

%

n= 191 361 363 366

Improved SVR rates for GT1 patients with Triple Therapy

Tolerability

Jacobson I. AASLD 2010. Poordad F. AASLD 2010.

• Discontinuation rates higher in PI arms • Telaprevir

– Pruritus, nausea, rash, anemia, and diarrhea – Severe rash in 3-6% (1% PEG/RBV)

• 5-7% stop TVR; 1% stop treatment – Hgb <10g/dl: 35-45% vs. 14% [ESA use not allowed]

• Boceprevir – Anemia, dysgeusia – Hgb <10g/dl: 50% vs. 18%

• Erythropoietin use: 43% vs. 24%

Hezode C et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 8.

CUPIC: Preliminary Safety Findings (1)

Patients, n (% patients with at least one event)

Telaprevir n=296

Boceprevir n=159

Serious adverse events (%) 48.6 38.4 Premature discontinuation Due to SAEs (%)

26.0 14.5

23.9 7.4

Death (%) 2.0 1.3

Infection (Grade 3/4) (%) 8.8 2.5

Asthenia (Grade 3/4) (%) 4.7 5.7 Rash Grade 3 (%) Grade 4 (SCAR) (%)

6.8 0.7

0 0

Pruritus (Grade 3/4) (%) 3.7 0.6

Hepatic decompensation (%) 4.4 4.4


CUPIC: Preliminary Safety Findings

Patients, n (% patients with at least one event)

Telaprevir (n=296)

Boceprevir (n=159)

Anemia (%)

Grade 2 (8.0 – <10.0 g/dL)

Grade 3/4 (<8,0 g/dL)

EPO use

Blood transfusion

19.6

10.1

56.8

15.2

22.6

10.1

66.0

10.7 Neutropenia (%)

Grade 3 (500 – <1000/mm3)

Grade 4 (<500/mm3)

G-CSF use

4.0

0.7

2.4

4.4

0.6

3.8 Thrombopenia (%)

Grade 3 (25 000 – <50 000)

Grade 4 (<25 000)

Thrombopoïetin Use

11.8

1.3

1.7

6.3

0.6

1.9


CUPIC: Telaprevir Preliminary Efficacy Data

% o

f Pat

ient

s w

ith U

ndec

tabl

e H

CV

RN

A

145/276 145/285 224/265 224/282 218/254 219/281 177/205 177/251


CUPIC: Boceprevir Preliminary Efficacy Data

% o

f Pat

ient

s w

ith U

ndec

tabl

e H

CV

RN

A

2/155 2/155 55/149 55/160 88/144 88/151 89/126 89/146

Treatment algorithm for triple HCV therapy with boceprevir (BOC)

LI

0 4 8 12 24 28 36 48 weeks

-

+

+/-

Naive Pat. Without RVR

Naive Pat. with RVR

Previous relapsers

Non-responders + All cirrhosis

12 wks PEG/RBV

12 wks PEG/RBV

24 weeks BOC + PegIFN/RBV




-

-

Treatment algorithm for triple HCV therapy with telaprevir (TVR)

0 4 8 12 24 28 36 48 weeks

-

+ Naive Pat. + relapsers without RVR

Naive Pat. + relapsers with RVR

Previous Partial responders, Null responders All cirrhosis pat.

12 wks PEG/RBV

12 weeks TVR + PegIFN/RBV



-/+

- 12 weeks PEG/RBV

36 weeks PEG/RBV

36 weeks PEG/RBV

Futility rules

W4 W12 W24 W4 W12 W24 W48

HCV - RNA >1000 IU/ml

PEG - IFN+RBV

Stop

Telaprevir


Stop

HCV - RNA >20 IU/ml

Stop

PEG - IFN+RBV Boceprevir


Stop

HCV - RNA >20 IU/ml

Stop

Hivbook 2012 in press; Hivbook.com

Initial HCV RNA decline provides information on treatment prediction outcome

GS-7977 + RBV

GS-7977 + PEG + RBV GS-7977 + RBV

GS-7977 + PEG + RBV

GS-7977 + PEG + RBV

n= 9

n= 10

n= 10

GS-7977

GT 2/3 Treatment-Naïve (GS-7977 + RBV +PEG)

GS-7977 + RBV (GT 1 Null Responders)

GS-7977 + RBV (GT 1 Treatment-Naive)

GS-7977 + RBV (GT 2/3 Treatment-Experienced)

n= 11

n= 10

n= 10

n= 10

n= 25

n= 25

Wk 4 Wk 8 Wk1 2 Wk 0

GT 2/3 Tx-naive

Gane E, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1113.

Electron Study: Treatment with GS-7977

Electron Study: Virologic Response

GT 2/3 Treatment-naïve

8 wks (N=10)

GT 1 Null Responders

12 wks (N=10)

GT 1 Treatment-naïve

12 wks (N=25)

GT 2/3 Treatment- experienced

12 wks (N=25)

Week 1 6/10 (60) 1/10 (10) 7/25 (29) 8/25 (32)

Week 2 10/10 (100) 7/10 (70) 17/24 (71) 21/25 (84)

Week 4 10/10 (100) 10/10 (100) 25/25 (100) 25/25 (100)

EOT 10/10 (100) 9/9 (100) 25/25 (100) 21/21 (100)

SVR 4 10/10 (100) 1/9 (11) 22/25 (88) 12/15 (80)

SVR 8 10/10 (100) 1/9 (11) -

SVR 12 10/10 (100) - - -

Patients with HCV RNA <LOD Over Time, n/N (%)

Gane E, et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1113.

“Individualized” Therapy of Hepatitis C in 2012

Therapy-indication Therapy wish

F0/F1, CI for IFNa Other reasons against therapy

IFN-free Therapy in 2014/5

For now no therapy

Neg. Factors SVR-Chance <10%

continue PEG-IFN/RBV

RG-Triple- Therapy

Therapy 12-48 W

SVR No SVR

PEG_IFNa/RBV Lead-in

Futility rules

Therapy- discontinuation

Wedemeyer et al., DMW 2012

Clinical management of Hepatitis C...

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