HCV EASL CPG 2011: what is (still) new? Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S. University of...

HCV EASL CPG 2011: what is (still) new?

Antonio Craxì

GI & Liver Unit, Di.Bi.M.I.S.

University of Palermo, Italy

[email protected]

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Goal of HCV management:

To improve quality of life and survival in patients with chronic hepatitis C by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death

HCV Clinical Practice GuidelinesHCV Clinical Practice Guidelines


This goal can be achieved only if HCV is eradicated. After sustained HCV RNA clearance:

• Necroinflammatory activity of chronic hepatitis ceases.• Progression of fibrosis and development of cirrhosis (in

non-cirrhotic patients) are blocked. Non-cirrhotic fibrosis (METAVIR F3) may regress.

• The risk of development of HCC: • is eliminated in non-cirrhotic patients.• Is reduced, but not canceled altogether, in patients with

cirrhosis.


End-points of therapy

• The only endpoint of therapy is the sustained virological response (SVR), defined by an undetectable HCV RNA 24 weeks after the end of therapy, as assessed by a sensitive molecular method with a lower limit of detection ≤50 IU/mL, ideally a real-time PCR-based assay.

• Long-term follow-up studies have shown that SVR corresponds to a definitive cure of HCV infection in more than 99% of cases.

≤25

Durability of SVR after TVR-based Therapy

SVR was durable in 222/223 patients (>99%)– Median time to follow-up: 21 months after SVR (range 4-45)

– One previously described patient experienced late relapse in parent study 48 weeks after prematurely discontinuing treatment after 10 weeks

Keet al, AASLD 2011, oral presentation

Viral load was determined by Roche Taqman® v2 LLOQ of 25 IU/mL

Months after SVRMonths after SVR

0

5

10

15

20

25

30

0 to 5 6 to 11 12 to 17 18 to 23 24 to 29 30 to 35 36 to 45

Per

cen

t o

f p

atie

nts

Per

cen

t o

f p

atie

nts

56

19 17

3027

3440


Evaluation of patients for treatment

- The causal relationship between HCV infection and liver disease must be established

- Liver disease severity must be assessed prior to therapy. - Baseline virological parameters that will be useful to tailor therapy

should be determined. - Identifying patients with cirrhosis is of particular importance, as their

prognosis and likelihood to respond to therapy are altered. - As liver disease can progress in patients with repeatedly normal

ALT levels, disease severity evaluation should be performed regardless of ALT.

• Liver biopsy remains the reference method. • The risk of severe complications is very low

(1/4,000-10,000), but it remains an invasive procedure. As such, biopsy is more and more hardly accepted by patients as part of their pre-treatment evaluation.

• Alternative, non-invasive methods can now be safely used in patients with chronic hepatitis C to assess liver disease severity prior to therapy.


Assessment of liver disease severity: biopsy

• Both transient elastography and biomarkers have been shown to accurately identify patients with mild fibrosis or cirrhosis. They are less discriminant for moderate to severe fibrosis.

• The combination of blood tests or the combination of transient elastography and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty. However, they increase the cost.

• Assessment of fibrosis may become less relevant as the efficacy of treatments increases.

HCV Clinical Practice GuidelinesHCV Clinical Practice Guidelines Assessment of liver disease severity:

non-invasive vs. invasive


Indications for treatment : who should be treated ?

• All treatment-naïve patients with compensated chronic liver disease related to HCV who are willing to be treated and have no contra-indication to pegylated IFN- or ribavirin should be considered for therapy, whatever their baseline ALT level.

• Treatment should be initiated rapidly in patients with significant fibrosis (METAVIR score F2-F4). In the patients with less severe disease, a balance between the benefit and risk related to therapy must be struck. If treatment is decided, there is no reason to wait for the advent of new HCV therapies, as these patients have a good chance of achieving a sustained virological response with current therapy for a reasonable cost.

Monitoring of on-therapy response to PEG IFN/RBV

DVR, delayed virological response; EVR, early virological response; RVR, rapid virological response.

RVR EVR DVR

Clearance of infected cells

Phase 1 (24–48 hours)

Phase 2

HCV RNA

4

Limit of Detection(50 IU/ml)

Likelihood of SVRLikelihood of SVR

weeks 12 24 48 0 1 72

Likelihood of SVR according to viral response Likelihood of SVR according to viral response in the first weeks of therapyin the first weeks of therapy

Viral Genotype Determines the Approach to HCV Therapy

• Genotypes 2, 3, 4,5,6

– Therapy today and in the near future remains pegIFN/RBV

• Genotype 1

– Additional option of an HCV protease inhibitor combined with pegIFN/RBV

– Boceprevir and telaprevir approved in Europe in July-September 2011

• Both indicated for untreated and previously treated HCV

• Different regimen formats

• Different criteria for shortening therapy

HCV-RNA

24124Week 0

72 weeks of therapy

Neg(DVR)Neg(DVR)

pos <2 log drop (NR)pos <2 log drop (NR)

24 weeks of therapy,

only if LVL* at baseline

Neg(RVR)Neg(RVR) stop Tx

pos(PR) pos(PR)

pospos

48 weeks of therapy

Neg(EVR)Neg

(EVR)

pos >2 log droppos >2 log drop

*LVL: < 400,000-800,000 IU/ml*LVL: < 400,000-800,000 IU/ml

Response-guided therapy in patients with genotype 1 (applies also to genotype 4 at a B2 grade of evidence)

CMS

pos <2log drop = null-responder (NR)pos >2log drop at week 12 followed by pos at week 24 = partial non-responder (PR)pos >2log drop at week 12 followed by neg at week 24 = delayed virologic responder (DVR)

Phase III virological efficacy Boceprevir ( Victrelis®) or Telaprevir ( Incivo®)

BoceprevirSVR increases from 38% to

63/66%

Naive patients Increased SVR compared to Peg-IFN/RBV

TelaprevirSVR increases from 44% to

72/75%

RBV is needed

Poordad F et al. N Engl J Med 2011: 364: 1195-1206Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.

INCIVO EMA approval September 2011.

Noncirrhotic patients can be considered for response-guided therapy with TVR

TVR + PegIFN + RBV

480 24124

eRVR; stop at Wk 24, f/u 24 wks

PegIFN + RBV

TVR + PegIFN + RBV

480 24124

PegIFN + RBV

HCV RNAUndetectable

Undetectable

Detectable (≤ 1000 IU/mL)

Undetectable or detectable (≤ 1000 IU/mL)

No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks

HCV RNA

Response-guided therapy with TVR + PegIFN/RBV in naive patients: EU/EMA

Treatment-naivepatients

Cirrhoticpatients and/or Null-Responders

Stopping rules: discontinuation of entire therapy

HCV-RNA measurement

PegIFN + RBV

PegIFN + RBV + Boceprevir

4 8 12 28 480 3624

STOP if HCV-RNA ≥ 100 IE/ml

STOP if HCV-RNAdetectable

Week

HCV-RNA HCV-RNA

32 wks

24 wks

44 wks

4 wks

4 wks

4 wks

12 wks

VICTRELIS® EMA approval July 2011

Treatment-naive patients

Response-guided therapy with BOC + PegIFN/RBV in naive patients: EU/EMA

124Week 0

pos, <2 log drop and positive thereafter

(NR or PR)

pos, <2 log drop and positive thereafter

(NR or PR)

stop Tx

pos >2 log drop but negative thereafter

(DVR)

pos >2 log drop but negative thereafter

(DVR)

48 weeks of therapy

Neg(EVR)Neg

(EVR)

Response-guided therapy in patients with genotypes 2 and 3 (applies also to genotypes 5 and 6, excluding 12-16 weeks, at a C2 grade of evidence)

pospos

*marginally less effective due to higher relapse rates, especially for G3 with high viral load

24 weeks of therapy

Neg(RVR)Neg(RVR)

Risk factors (fibrosis, IR)

12-16 weeks of therapy*

HCV-RNA

The strongest predictors of an SVR are – the HCV genotype – the genetic polymorphisms located in chromosome 19, close to

the region coding for IL28B (or IFN 3), which are associated with the ability of IFN to induce an antiviral response in liver cells.

Other predictors of response include: • baseline HCV RNA levels• dose and duration of therapy• stage of fibrosis• host factors (body mass index, age, insulin resistance,

gender)• coinfection with another hepatotropic virus or with HIV.


Predictors of response to SoC

IL28B genotype and response to TPV in naïve patients

1. Jacobson IM, et al. EASL 2011. Abstract 1369.

ADVANCE: T12PR*[]

Eli

gib

ilit

y fo

r R

GT

(%

)39/50

39/68

10/22

78

100

80

60

40

20

0

57

45

n/N =

*IL28B testing in ADVANCE was in whites only.

CC CT TT

ADVANCE: T12PR48*[2]

SV

R (

%)

45/50

48/68

16/22

CC CT TT

90100

80

60

40

20

0

71 73

n/N =

Likelihood of Achieving SVR Likelihood of Shortened Therapy

IL28B genotype and response to BOCin naïve patients

Likelihood of Achieving SVR Likelihood of Shortened Therapy

SPRINT-2: BOC + PR48[1]

SV

R (

%)

44/55

82/115

26/44

80

100

80

60

40

20

0

71

59

n/N =

SPRINT-2: BOC + PR[1]

Eli

gib

ilit

y fo

r R

GT

(%

)

118/132

158/304

CC CT/TT

89100

80

60

40

20

0

52

n/N =

1. Jacobson IM, et al. EASL 2011. Abstract 1369.

HCV-AIFA Italian study: RVR and SRV to PR in genotype 1 patients according to baseline factors

MALES

Variables N. of patients RVR SVR

No favorable factors 21/179 (11.7%) 1/19 (5.2%) 3/21 (14.3%)

1 favorable factor 82/179 (45.8%) 17/80 (21.2%) 25/82 (30.5%)

2 favorable factors 62/179 (34.6%) 25/58 (43.1%) 37/62 (59.6%)


FEMALES

Variables N. of patients RVR SVR

No favorable factors 58/152 (38.1%) 8/57 (14.1%) 16/58 (27.6%)

1 favorable factor 75/152 (49.4%) 20/70 (28.6%) 26/75 (48.0%)


Favorable factors: HCV-RNA < 400,000 UI/mlC/C genotype of rs12979860 SNPNo visceral obesity (VOB)

Favorable factors: Age < 50 years C/C genotype of rs12979860 SNP


Indications for treatment : who should be re-treated ?

• Patients infected with HCV genotype 1 who failed to eradicate HCV on prior therapy with pegylated IFN- and ribavirin should not be retreated with the same drug regimen, as the SVR rates were reported to be low (of the order of 15%). These patients should wait for the approval of new combination therapies, which have been shown to yield high SVR rates, of the order of 50%-60%, in this particular group.

• Patients infected with HCV genotypes other than 1 who failed on prior therapy with IFN- with or without ribavirin can be retreated with pegylated IFN- and ribavirin.

BoceprevirRelapsers

SVR increases from 29% to 75%

Partial-Responders SVR increases from 7% to 52%

Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV

TelaprevirRelapsers

SVR increases from 24% to 83/88%

Partial-responders SVR increases from 15% to 54-59%

Null-respondersSVR increases from 5% to 29/33%

Phase III virological efficacy Boceprevir ( Victrelis®) and Telaprevir (Incivo ®)

Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3

RBV is needed

Retreatment with TVR + PegIFN/RBV in treatment-experienced patients: EU/EMA

F/u 24 wks

TVR + PegIFN + RBV

480 24124

PegIFN + RBV

No eRVR; PegIFN + RBVTVR + PegIFN + RBV

480 24124

eRVR; stop at Wk 24, f/u 24 wksPegIFN + RBV

F/u 24 wks

Previous relapsers* (same as naives)

Previous partial responders† and null responders

*Response-guided therapy not studied in relapsers in registration trials.†AASLD guidelines say RGT “may be considered” for prior partial responders [1] but package insert recommends 48 weeks of therapy

Undetectable

Undetectable

HCV RNA

HCV RNADetectable (≤ 1000 IU/mL)

Undetectable/detectable (≤ 1000 IU/mL)

No eRVR; extend pegIFN + RBV to Week 48; f/u 24 wks

INCIVO EMA approval September 2011.

Treatment-experiencedpatients

Cirrhoticpatients and/or Null-Responders

Stopping rules: discontinuation of entire therapy

HCV-RNA measurement

PegIFN + RBV

PegIFN + RBV + Boceprevir

4 8 12 28 480 3624

STOP if HCV-RNA ≥ 100 IE/ml

STOP if HCV-RNAdetectable

Week

HCV-RNA HCV-RNA

32 wks

44 wks

4 wks

4 wks

12 wks

VICTRELIS® EMA approval July 2011

Retreatment with BOC + PegIFN/RBV in treatment-experienced patients: EU/EMA

• Patients with compensated cirrhosis must be treated in the absence of contra-indications, in order to prevent the complications of chronic HCV infection that occur exclusively in this group on the short- to mid-term.

• Large cohort studies and meta-analyses have shown that an SVR in patients with advanced fibrosis is associated with a significant decrease of the incidence of clinical decompensation and HCC. However, the SVR rates with pegylated IFN- and ribavirin are lower in patients with advanced fibrosis of cirrhosis than in patients with mild to moderate fibrosis.


Compensated cirrhosis

• Monitoring and management of side-effects should be particularly careful in this group of patients, who are generally older and have worse tolerance than patients with less advanced liver disease.

• Due to portal hypertension and hypersplenism, leucocyte and platelet counts at baseline may be low in cirrhotic patients. They may contra-indicate therapy. As a result, haematological side effects are more frequent in cirrhotic than in non-cirrhotic patients. Growth factors are particularly useful in this group and should be used as described above.

• Irrespective of the achievement of an SVR, patients with cirrhosis should undergo regular surveillance for the occurrence of HCC, as this risk is decreased but not abolished when HCV infection has been eradicated.


Compensated cirrhosis

SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving BOC + PegIFN/RBV

All cirrhotic patients receiving BOC + PR should receive 48 weeks of therapy[1,2]

Subgroup Analysis of SPRINT-2[3]

PR48BOC RGTBOC/PR48

1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Poordad F, et al. NEJM. 2011;364:1195-1206. 4. Bacon BR, et al. NEJM. 2011;364:1207-1217.

F3/4

100

80

60

40

20

0

SV

R (

%)

F0/1/2

38

67

213/319

n/N=

38

9/24

52

22/42

41

14/34

211/313

67

F3/4

100

80

60

40

20

0

SV

R (

%)

F0/1/2

23

66

77/117

132/15

68

21/31

44

14/32

81/119

68

Subgroup Analysis of RESPOND-2[4]

123/328

n/N=

14/61

PR48T12PRT8PR

SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving TVR + PegIFN/RBV

All cirrhotic patients receiving TVR + PR may benefit from 48 weeks of therapy[1,2]

1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Jacobson IM, et al. NEJM. 2011;364:2405-2416.

78

62

73

5347

33

0

20

40

60

80

100

No, Minimal, or Portal Fibrosis Bridging Fibrosis or Cirrhosis

SV

R (

%)[3

,4]

134/288

n/N =

226/290

205/279

24/73

45/73

45/85

REALIZE: SVR by Fibrosis and Prior Response

Prior relapsers

Prior partial responders

Prior null responders

No, minimal or portal fibrosis

CirrhosisStage

Pooled T12/PR48

Pbo/PR48

Pat

ien

ts w

ith

SV

R (

%)

Bridgingfibrosis


CirrhosisBridgingfibrosis


CirrhosisBridgingfibrosis

2/15

n/N= 53/62

145/167

12/38

0/5

10/18

36/47

3/17

0/9

16/38

11/32

1/5

1/15

48/57

24/59

1/18

7/50

1/10

1. Pol S, et al. AASLD 2011

- Cirrhotic patients receiving TVR + PR need 48 weeks of therapy[1]

- Cirrhotics with previous null response have modest SVR rates

• Non-cirrhotic patients who achieve an SVR should be retested for ALT and HCV RNA at 48 weeks post-treatment and one year later (2 years post-treatment). If ALT levels are still normal and HCV RNA is still not detected, the patient can be discharged.

• As hypothyroidism may occur after stopping therapy, TSH levels should also be assessed 1 and 2 years after treatment.

• Cirrhotic patients who achieve an SVR should undergo surveillance for oesophageal varices and screening for HCC every 3 to 6 months by means of ultrasonography


Post-treatment follow-up of patients who achieve an SVR

• Untreated patients with chronic hepatitis C should be regularly followed.

• Previous guidelines recommended performing a liver biopsy every 3 to 5 years. With non-invasive methods, more frequent screening can be performed.

• Thus, untreated patients should be assessed every 1 to 2 years with a non-invasive method.

• Patients with cirrhosis should undergo screening for HCC every 3 to 6 months.

HCV Clinical Practice GuidelinesHCV Clinical Practice Guidelines Follow-up of untreated patients

Updated AASLD Guidelines on Treatment of HCV Genotype 1 Infection

Optimal treatment is BOC or TVR, each in combination with pegIFN/RBV

– All treatment-naive and experienced patients can be considered for treatment with BOC and TVR

– Caution is advised when using BOC in null responders given lack of definitive information from phase III studies*

– All patients can be considered for shortened duration of therapy except patients with cirrhosis and null responders (who should receive 48 wks of therapy)†

IL28B genotype testing may be considered prior to therapy to inform about probability of response or treatment duration

Ghany MG, et al. Hepatology. 2011;54:1433-1444.

*Package insert says if BOC tx of previous null responders is considered, it should be 48 wks of therapy.†Package insert recommends 48 wks of therapy with TVR for previous partial responders.

What may stay:

• General aims of treatment• Therapeutic approach to non-1 genotypes• PR therapy for selected patients with Gt 1• Criteria to evaluate indications for treatment• Criteria for post-treatment follow-up

Updated EASL HCV CPG 2012: a personal viewUpdated EASL HCV CPG 2012: a personal view

What must be updated:

• Indication to triple therapy with first generation PIs as SoC for most naive patients with Gt 1

• Clearer definition of role of biomarkers (IL28B), of baseline predictors (fibrosis, viral load, IR) and of subgenotypes (1a vs 1b) with triple therapy

• Indications for practical management of triple therapy (also IFN and RBV dosing)

• New stopping/futility rules


Hot topics to be defined:

• Use of triple therapy with first generation PIs for:– non-sustained responders to PR (excluding relapsers)– Patients with mild, slowly progressive disease– Patients with advanced cirrhosis– OLT subjects– HIV/HCV coinfected

• Use of the lead-in phase as “IFN sensitivity testing”• What to do with non-responders to triple therapy?• Who should be treated now? Who can wait?


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HCV EASL CPG 2011: what is (still) new? Antonio Craxì GI & Liver Unit, Di.Bi.M.I.S. University of...

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