Optimal therapy in genotype 2 and 3 patients Antonio Craxì Liver & GI Unit, Di.Bi.M.I.S.,...

Optimal therapy in genotype 2 and 3 patients

Antonio Craxì

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

University of Palermo, Italy

[email protected]

Treatment for patients infected with Treatment for patients infected with HCV genotype 2 or 3HCV genotype 2 or 3: the current SOC: the current SOC

End-of-treatment virological responseEnd-of-treatment virological responseSustained virological responseSustained virological response

End-of-treatment virological responseEnd-of-treatment virological responseSustained virological responseSustained virological response

HCV RNA detection at end ofHCV RNA detection at end oftreatment and 24 weeks latertreatment and 24 weeks laterHCV RNA detection at end ofHCV RNA detection at end oftreatment and 24 weeks latertreatment and 24 weeks later

Pegylated interferon + ribavirinPegylated interferon + ribavirin0.8 g per day x 24 weeks0.8 g per day x 24 weeks

Pegylated interferon + ribavirinPegylated interferon + ribavirin0.8 g per day x 24 weeks0.8 g per day x 24 weeks

No liver biopsy or serologicalmarkers of disease severity

No liver biopsy or serologicalmarkers of disease severity

Optimising treatment based on genotype: Optimising treatment based on genotype: 48 weeks for G1, 24 weeks for G2/348 weeks for G1, 24 weeks for G2/3

84%79%

0

20

40

60

SV

R (

%)

Genotype 1

8081% 80%

100

Genotype 2/3

24-LD

24-SD

48-LD

48-SD

96 144 99 153

LD = RBV 800 mg/day SD = RBV 1000/1200 mg/day

Hadziyannis S, et al. Ann Intern Med 2004; 140: 346

PEG IFN alfa2a 180 g plus Ribavirin

29%

41%42%

52%

n= 101 118 250 271

0 2 4 6 8 10 12 14–5

–4

–3

–2

–1

0

Mea

n d

eclin

e in

HC

V R

NA

(lo

g10

co

pie

s/m

L)

Days

Genotype 2 Genotype 1

Neumann A et al. J Infect Dis 2000; 182: 28

HCV RNA kinetics during antiviral treatment: importance of HCV genotype

Pooled analysis of genotype 2 and 3 Pooled analysis of genotype 2 and 3 patients treated with antivirals for 24 weekspatients treated with antivirals for 24 weeks

Andriulli, APT 2008, 28:397

AuthorAuthor YearYear Genotype 3Genotype 3 Genotype 2Genotype 2

Working groupWorking group 20052005 110/171110/171 94/14794/147

BrownBrown 20062006 151/251151/251 213/298213/298

MangiaMangia 20052005 13/1713/17 40/5340/53

Meyer-WyssMeyer-Wyss 20062006 47/6747/67 21/2421/24

RizzettoRizzetto 20052005 118/148118/148 80/9280/92

ShiffmanShiffman 20072007 244/369244/369 268/356268/356

ZeuzemZeuzem 20042004 143/182143/182 39/4239/42

ZeuzemZeuzem 20042004 15/2015/20 27/3827/38

PooledPooled(fixed effect)(fixed effect)

841/1225841/1225 782/1050782/1050

1/64 1/16 1/4 1 4 16 64

Better Genotype 3 Better Genotype 2

1.489 (1.233/1.798)

HCV G2: SVR 74% (782/1050) irrespective of viral load

HCV G3: •LVL: SVR 75% (405/737)•HVL: SVR 58% (298/500)

Response rates in genotype 2/3 patients(pooled analysis of Fried, Hadzyiannis, Shiffman)

G2(n=395)

G3(426)

RVR (<50 IU/mL) 71% 60%

cEVR (<50 IU/mL) 24% 29%

pEVR (≥ 2log drop) 1% 3%

SVR 77% 68%

SVR in pts with RVR 86% 86%

SVR in pts with cEVR * 61% 54%

SVR in pts with pEVR ** - -

* Not including RVR; ** not including RVR or cEVR

Fried MW, et al. J Hepatol 2008; 48 (Suppl 2); Abstract 7

The Good, the Bad and the Ugly The Good, the Bad and the Ugly

March 2006March 2006:: Female, 38 yrs, HCV known since 1999 (surgery 1977)Female, 38 yrs, HCV known since 1999 (surgery 1977) No alcohol, BW 61 kg, BMI 22No alcohol, BW 61 kg, BMI 22 ALT ALT 3 3 8 unl 8 unl HCV G2, HCV RNA 6.5 x 10HCV G2, HCV RNA 6.5 x 1066 IU/ml IU/ml FibroscanFibroscan 4.3 KPa, no liver biopsy 4.3 KPa, no liver biopsy

April to October 2006April to October 2006:: PEG IFN PEG IFN -2a 180 -2a 180 g/wk + RBV 800 mg, ITT 2g/wk + RBV 800 mg, ITT 24 weeks4 weeks Excellent tolerance and adherenceExcellent tolerance and adherence RVR at 4 weeks, EVR at 12, ETR at 24RVR at 4 weeks, EVR at 12, ETR at 24

March 2007March 2007:: SVR confirmed SVR confirmed

The Good

Overtreatment? YES NO


May 2007May 2007:: Male, 46 yrs, HCV known since 2004 (no risk factors)Male, 46 yrs, HCV known since 2004 (no risk factors) Alcohol 50 gm/day up to 2004, BW 86 kg, BMI 29Alcohol 50 gm/day up to 2004, BW 86 kg, BMI 29 ALT 2ALT 2 4 4 unlunl HCV G2, HCV RNA 4.3 x 10HCV G2, HCV RNA 4.3 x 1066 IU/ml IU/ml FibroscanFibroscan 8.1 KPa, biopsy: stage 3 grade 2 Metavir 8.1 KPa, biopsy: stage 3 grade 2 Metavir

July 2007July 2007:: Starts PEG IFN Starts PEG IFN -2b 1.5 -2b 1.5 g/Kg/wk + RBV 1200 mg, ITT 2g/Kg/wk + RBV 1200 mg, ITT 24 weeks4 weeks Modest tolerability, adherence >80/80/80Modest tolerability, adherence >80/80/80 No RVR at 4 weeks, EVR at 12No RVR at 4 weeks, EVR at 12

October 2007October 2007:: Patient decides to stop at 15 weeks, while HCV RNA negative (work problems, Patient decides to stop at 15 weeks, while HCV RNA negative (work problems,

tolerability, has heard about short treatments)tolerability, has heard about short treatments) December 2007December 2007::

HCV RNA positive, ALT flareHCV RNA positive, ALT flare

The Bad

Undertreatment (too short)? YES NO


October 2003October 2003:: Male, 39 yrs, HCV known since early ’90s (IVDU in the ’80s)Male, 39 yrs, HCV known since early ’90s (IVDU in the ’80s) Alcohol 80 gm/day up to 2003, “stopped?”; BW 102 kg, BMI 34Alcohol 80 gm/day up to 2003, “stopped?”; BW 102 kg, BMI 34 ALT 2ALT 2 5 5 unl, PLT 104.000/mmunl, PLT 104.000/mm33

HCV G3, HCV RNA 1.8 x 10HCV G3, HCV RNA 1.8 x 1066 IU/ml; HBV and HOV negative IU/ml; HBV and HOV negative FibroscanFibroscan 16.5 KPa, biopsy: stage 4 grade 2 Metavir 16.5 KPa, biopsy: stage 4 grade 2 Metavir F1 esophageal varicesF1 esophageal varices

December 2003 December 2003 May 2004 May 2004:: Starts PEG IFN Starts PEG IFN -2a 180 -2a 180 g + RBV 800 mg, ITT 2g + RBV 800 mg, ITT 24 weeks4 weeks Good tolerability, PEG IFN 135 Good tolerability, PEG IFN 135 g since week 8 due to cytopeniag since week 8 due to cytopenia No RVR at 4 weeks, EVR at 12, ETR at 24 weeksNo RVR at 4 weeks, EVR at 12, ETR at 24 weeks

October 2004October 2004:: HCV RNA positive, ALT flareHCV RNA positive, ALT flare

The Ugly

Undertreatment (not enough)? YES NO

Optimization of treatment for HCV Optimization of treatment for HCV genotype 2 or 3genotype 2 or 3: 2009: 2009

Extended treatment (48 weeks)?Extended treatment (48 weeks)?Extended treatment (48 weeks)?Extended treatment (48 weeks)?

Standard treatment (24 weeks)?Standard treatment (24 weeks)?Standard treatment (24 weeks)?Standard treatment (24 weeks)?

Short treatment (12-16 weeks)?Short treatment (12-16 weeks)?Short treatment (12-16 weeks)?Short treatment (12-16 weeks)?

HCV genotype 2 or 3patients - Who needs:HCV genotype 2 or 3

patients - Who needs:

Shortening Therapy: Study DesignsShortening Therapy: Study Designs

Week 0

Shiffman Gt 2/3PEG-IFNα-2a 180 µg qwk, RBV 800 mg

Mangia Gt 2/3PEG-IFNα-2b 1.0 µg/kg qwk, RBV 1000/1200 mg2

16 weeks

24 weeks

1. Shiffman ML, et al. N Engl J Med. 2007;357:124-134. 2. Mangia A, et al. N Engl J Med. 2005;352:2609-2017.

24 weeks

Week 4

12 weeks

24 weeks

24-wk Follow-up

24-wk Follow-up

24-wk Follow-up

24-wk Follow-up

24-wk Follow-up+

–

n = 732

n = 731

n = 133

n = 80

n = 70

Shorter Treatment Duration?Shorter Treatment Duration?

Shiffman ML, et al. N Engl J Med. 2007;357:124-134; Mangia A, et al. N Engl J Med. 2005;352:2609-2017.

Standard duration regimen (24 wk)

Variable duration (12 or 24 wk)

0

20

40

60

80

100

AnyHCV Gt

HCVGt 2

HCVGt 3

76 7676

7782

62SV

R,

%

Shiffman et al: Lower SVR ratesat 16 vs 24 wk (Gt 2/3)*

Mangia et al: SVR rates comparableat 12 vs 24 wk (Gt 2/3)*

0

20

40

60

80

100

AnyHCV Gt

HCVGt 2

HCVGt 3

SV

R,

%

HCVGt 3

6270

62

75

6266

P <.001P <.001

P = .23

Standard duration (24 wk)

Shorter duration (16 wk)

* LOD <50 IU/mL

(70)(213) (53)(160) (17)(53)(732) (731) (356)(372) (369)(358)

Relapse rates in Genotype 2 and 3Relapse rates in Genotype 2 and 3

12 – 16 wks 24 wks

0

5

10

15

20

25

30

35

Shiffman 2007

%

All patients

%

0

5

10

15

20

25

30

35

Mangia 2005 Dalgard 2008

RVR patients

Shiffman ML, et al. N Engl J Med. 2007;357:124-134.

Patients infected with HCV genotype 2/3

(N = 1291)

RVR: 67%(871 / 1291)

SVR

378/461 370/410

55/205 105/215

0%

20%

40%

60%

80%

100%

0%

20%

40%

60%

80%

100%

SVR

ACCELERATE Trial: SVR in Patients With and Without an RVR

82%

27% 49%

90%

16 wks24 wks

16 wks24 wks

No RVR: 33%(420 / 1291)

SVR rate with 16 vs.24 weeks of treatment in G2/3 patients with an RVR and LVL

16 weeks PEG IFN alfa 2a plus RBV 800 mg/day

n=123 n=101 n=295 n=260 n=49n=43

≤400 000 IU/mL 400–800 000 IU/mL >800 000 IU/mL

90%84%

78%

95%92% 88%

SV

R (

%)

0

20

40

60

80

100

Standard analysis

24 weeks PEG IFN alfa 2a plus RBV 800 mg/day

Shiffman ML, et al. N Engl J Med. 2007;357:124-134.

Dalgard, Hepatology 2008, 47:35

PEG IFN alfa-2b and RBV for 14 vs 24 weeks in patients PEG IFN alfa-2b and RBV for 14 vs 24 weeks in patients with HCV G2 or 3 and rapid virological responsewith HCV G2 or 3 and rapid virological response

PEG IFN alfa 2b 1.5 ug/kg, RBV 800-1400 mg

14 wks14 wks 24 wks24 wksn.n. SVRSVR RelapseRelapse n.n. SVRSVR RelapseRelapse

OverallOverall 139139 120 (86)120 (86) 146146 136136 (93.2)(93.2)

Geno 3Geno 3 110110 93 (84)93 (84) 17 (16)17 (16) 115115 106 (92)106 (92) 9 (8)9 (8)

22 2929 27 (93)27 (93) 2 ( 7)2 ( 7) 3131 30 (97)30 (97) 1 (3)1 (3)

Viral loadViral load

Geno 3Geno 3

≥ ≥ 400,000 IU400,000 IU 6666 57 (86)57 (86) 9 (14)9 (14) 6666 57 ( 86)57 ( 86) 9 (14)9 (14)

< 400,000 IU< 400,000 IU 3636 29 (80)29 (80) 7 (20)7 (20) 4444 44 (100)44 (100) 0 (0)0 (0)

Geno 2Geno 2

≥ ≥ 400,000 IU400,000 IU 2222 20 (90)20 (90) 2 (10)2 (10) 1919 18 (95)18 (95) 1 (5)1 (5)

< 400,000 IU< 400,000 IU 66 6(100)6(100) 0 (0)0 (0) 1111 11 (100)11 (100) 0 (0)0 (0)

56%

38%

Genotype 2 (n=55)

(%

)

0

10

20

30

40

50

60

70

80

90

100

12 weeks of treatment

Genotype 3 (n=137)

Genotype 3 (n=139)

Genotype 2 (n=49)


5%

58%

31%

9%

82%

12%6%

78%

12% 10%

Lagging, Hepatology 2008, 47:1837

SVR Relapse NR

Randomized comparison of 12 or 24 weeks of Randomized comparison of 12 or 24 weeks of PEG IFN alfa-2a and RBV in chronic HCV G2/3 infectionPEG IFN alfa-2a and RBV in chronic HCV G2/3 infection

RBV 800 mg

Meta-analysis of short vs standard therapy Meta-analysis of short vs standard therapy in genotypes 2 and 3 patients with RVRin genotypes 2 and 3 patients with RVR

AuthorAuthor YearYear ShortShort StandardStandard

DalgardDalgard 20082008 120/139120/139 136/146136/146

ShiffmanShiffman 20072007 385/487385/487 397/466397/466

MangiaMangia 20052005 113/153113/153 41/4541/45

BonardiBonardi 20062006 29/3229/32 27/3127/31

YuYu 20072007 43/4343/43 85/8785/87

PooledPooled(fixed effect)(fixed effect)

690/854690/854 686/775686/775

1/64 1/16 1/4 1 4 16 64

Better Short Better Standard

1.629 (1.234/2.152)

Andriulli, APT 2008, 28:397

SVR-Rate (%) Relapse Rate (%)

100

80

60

40

20

0

6565 67677676

n=22/34

n=20/30

n=28/37

6767

PegIFN alfa 2aRiba 1000-120024 weeks

Peg IFN alfa 2aRiba 80048 weeks

PegIFN alfa2aRiba 1000-120048 weeks

2626

n=14/21

n=15/27

PegIFN alfa 2aRiba 80024 weeks

2424n=

7/2091313

3/23n=

1/27

Should Treatment be Intensified in Genotypes 2/3 without RVR ?

Retrospective analysis

1Fried M et al, N Engl J Med al. 2002 2 Hadziyannis el at. Ann Intern Med 2004

4

Willems B et al. EASL 2007

Optimization of treatment for HCV Optimization of treatment for HCV genotype 2 or 3genotype 2 or 3: 2009: 2009

Extended treatment (48 weeks)?Extended treatment (48 weeks)?Extended treatment (48 weeks)?Extended treatment (48 weeks)?

Standard treatement (24 weeks)?Standard treatement (24 weeks)?Standard treatement (24 weeks)?Standard treatement (24 weeks)?

Short treatment (12-16 weeks)?Short treatment (12-16 weeks)?Short treatment (12-16 weeks)?Short treatment (12-16 weeks)?

HCV genotype 2 or 3patients - Who needs:HCV genotype 2 or 3

patients - Who needs:

Cofactors?Cofactors?

67%60%

48%

76%

0%

20%

40%

60%

80%

G2/3 for 24 wks G2/3 for 16 wks

SV

R [

%]

F0-F2 fibrosis F3-F4 fibrosis

Bruno et al, EASL 2008, poster

SVR rates in genotype 2/3 patients(pooled analysis of ACCELERATE, Fried, Hadzyiannis)

Lagging, Hepatology 2008, 47:1837

Randomized comparison of 12 or 24 weeks of Randomized comparison of 12 or 24 weeks of PEG IFN alfa-2a and RBV in chronic HCV G2/3 infectionPEG IFN alfa-2a and RBV in chronic HCV G2/3 infection

80%

14%

< 40 years of age (n=76)

(%

)

0

10

20

30

40

50

60

70

80

90

100


≥ 40 years of age (n=118)

≥ 40 years of age (n=112)

< 40 years of age (n=76)


5%

45% 45%

10%

83%

8% 9%

75%

15%9%

SVR Relapse NR

RBV 800 mg

RVR and SVR in patients receiving Peg-IFN 2a 135 g + RBV 11 mg/Kg for 24 Weeks

Weiland O et al J Viral Hep 2008;15:641-645

Ribavirin dosage and Ribavirin dosage and SVR in G2/3 patientsSVR in G2/3 patients

Hadziyannis:Ann Intern Med. 2004;140:346-355.

Willems et al: J Hepatol, 2006 Volume 46, S1, p S6

8481 79 80

67 65 67

76

0

10

20

30

40

50

60

70

80

90

100

24 weeks 800mg

24 weeks 1000/1200 mg

48weeks 800 mg

48weeks1000/1200 mg

% S

VR

All Non RVR

SVR in G2/3 patients according to schedule SVR in G2/3 patients according to schedule and to RBV concentration at 4 weeksand to RBV concentration at 4 weeks

57

74 75

91

0

10

20

30

40

50

60

70

80

90

100

< 2mg/l n =145

≥ 2mg/ln = 34

< 2mg/ln = 131

≥ 2mg/ln =45

% S

VR

p = 0.02

p = 0.12

12 weeks 24 weeksChristensen et al, EASL 2008

WIN-R: impact of weight-based RBV WIN-R: impact of weight-based RBV dosing on SVR in G2/3 patientsdosing on SVR in G2/3 patients

SVR %SVR % 65-85 kg65-85 kg 86-105 kg86-105 kg > 105 kg> 105 kg PP value value

Weight-based RBV dosing,Weight-based RBV dosing,RBV 800-1400 mg (n = 325)RBV 800-1400 mg (n = 325)

Genotype 2/3Genotype 2/3 64.164.1 59.259.2 61.261.2 .356.356

Flat dosing, Flat dosing, RBV 800 mg (n = 333)RBV 800 mg (n = 333)

Genotype 2/3Genotype 2/3 63.663.6 55.455.4 55.255.2 .034.034

Jacobson IM, et al. Hepatology. 2007;46:971-981.

A RCT of RBV 400 mg vs 800 mg/day in combination with PEG IFN -2a

ITT analysis at 24 week

Ribavirin 800 mg Ribavirin 400 mg

HCV G 2 No. of patients =18

SVR = 77.8%

No. of patients = 19

SVR = 63.2%

HCV G 3 No. of patients = 123

SVR = 67.5%

No. of patients = 122

SVR = 63.9%

Ferenci P et al Hepatology 2008;47:1816-1823

Response-guided treatment for Response-guided treatment for HCV GT 2/3 RVR: a meta-analysisHCV GT 2/3 RVR: a meta-analysis

Di Martino V, et al. AASLD 2008. Abstract 213.

Pooled RCTs of GT 2/3 RVRPooled RCTs of GT 2/3 RVR

(7 studies, n=2054)(7 studies, n=2054)SVR increase with 24 WeeksSVR increase with 24 Weeks

vs shorter treatment, % (95% CI)vs shorter treatment, % (95% CI)

16 weeks treatment* (n=1782)16 weeks treatment* (n=1782) 2 (-5 to 8)2 (-5 to 8)

12 or 14 weeks treatment (n=272)12 or 14 weeks treatment (n=272) 11 (5 to 18)11 (5 to 18)

Fixed-dose RBVFixed-dose RBV†† 13 (0 to 25)13 (0 to 25)

Weight-based RBVWeight-based RBV 3 (-2 to 9)3 (-2 to 9)

*Irrespective of RBV regimen.†Irrespective of duration of shorter treatment.

Mangia, Hepatology 2009, in press

Determinants of relapse after 12 weeks of therapy Determinants of relapse after 12 weeks of therapy in 496 patients with HCV G2 or G3 with RVRin 496 patients with HCV G2 or G3 with RVR

PEG IFN alfa 2b 1.5 ug/kg, RBV 800-1200 mg

Predictors of relapsePredictors of relapse pp OR; 95% CIOR; 95% CI

Age >45 yearsAge >45 years 0.0040.004 --

BMI >30 kg / mBMI >30 kg / m22 0.00010.0001 2.5; 1.49 – 4.20*2.5; 1.49 – 4.20*

Platelets <140.000/mmPlatelets <140.000/mm33 0.00010.0001 1.7; 1.03 – 2.70*1.7; 1.03 – 2.70*

*independently associated with SVR

EOT: 96%: SVR: 82%, Relapse: 14%

EOTEOT 33 (76.7%)33 (76.7%)

SVRSVR 30 (70%)30 (70%)

Re-treatment of 43 relapsers after short therapy Re-treatment of 43 relapsers after short therapy with standard (24 wks) treatment durationwith standard (24 wks) treatment duration

Mangia et al, J Hepatol 2008; 48 (Suppl 2): S6

Albinterferon -Albinterferon -IFN Naïve, Gt 2/3 (Achieve 2/3): SVR Rates IFN Naïve, Gt 2/3 (Achieve 2/3): SVR Rates

alb-IFN 1200 µg q2wk

N=311

100

80

60

40

20

0All Pts (933)

79.8 80

alb-IFN 900 µg q2wkN=310

SV

R R

ate,

%

ITT analysis; q2wk, every 2 weeks; ribavirin 800 mg flat dose; G2/3 n=420/513

HGS press release, December 8, 2008

PEG IFN 2a 180 µg wkN=312

84.8P= ns

R7128 in HCV G 2/3 nonrespondersR7128 in HCV G 2/3 nonresponders

Gane E, et al. AASLD 2008. Abstract LB10.

No virologic breakthrough reportedNo virologic breakthrough reported Adverse events similar to previous reportsAdverse events similar to previous reports

GT 2 R7128 + PegIFN/RBVGT 3 R7128 + PegIFN/RBVGT 2 placebo + PegIFN/RBVGT 3 placebo + PegIFN/RBV

Weeks

HC

V R

NA

(lo

g10

IU/m

L)

R7128 treatment period

0 1 8765432

8

7

6

5

4

3

2

1

0

Individual Patient HCV RNA Values Over Time

R7128: nucleoside analogue HCV polymerase inhibitor R7128: nucleoside analogue HCV polymerase inhibitor

HCV GT 2/3 patients with previous

treatment failure

(N = 25)

The G2/G3 RGT algorithm: 2009 on…The G2/G3 RGT algorithm: 2009 on…

G2/3HVL

24 weeks

LVL16 weeks

24 weeks48

weeks?STOP

Week 4

Week 12

Week 24

-

-

-

+

+ ≥2log

-

+

+ <2log

-

+

+

+

STAT-C ?

• Short therapy not to be chosen if F3/F4 fibrosis is present

• Age >40 associated to reduced SVR

Optimal therapy in genotype 2 and 3 patients Antonio Craxì Liver & GI Unit, Di.Bi.M.I.S.,...

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