Treatment of HCV in Patients with Cirrhosis -...

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Treatment of HCV in Patients with Cirrhosis Norah Terrault, MD, MPH Professor of Medicine and Transplant Surgery University of California San Francisco

Transcript of Treatment of HCV in Patients with Cirrhosis -...

Treatment of HCV in Patients with Cirrhosis

Norah Terrault, MD, MPH

Professor of Medicine and Transplant Surgery

University of California San Francisco

SVR and All-Cause Mortality Benefits in Cirrhotics Treated With IFN-Based Therapy

van der Meer AJ et al. JAMA. 2012;308(24):2584-2593.

0 1 2 3 4 5 6 7 8 9 10

10

20

30

With SVR

Without SVR

P < 0.001

All-cause Mortality

Time (years)

All-

cau

se M

ort

alit

y (%

)

0 1 2 3 4 5 6 7 8 9 10

10

20

30

Time (years)

With SVR

Without SVR P < 0.001

0

Hepatocellular Carcinoma

Hep

ato

cellu

lar

Car

cin

om

a (%

)

0 1 2 3 4 5 6 7 8 9 10

10

20

30

Time (years)

With SVR

Without SVR

P < 0.001

Liver Failure

Live

r Fa

ilure

(%

)

0

0 1 2 3 4 5 6 7 8 9 10

10

20

30

Time (years)

P < 0.001

With SVR

Without SVR

Liver-related Mortality or Liver Transplantation

Live

r-re

late

d M

ort

alit

y o

r Li

ver

Tran

spla

nta

tio

n (

%)

0

75% Reduction in Mortality in Treated Patients with Cirrhosis

Meta-Analysis of those with SVR vs Non-SVR

Simmons B, CID 2015;61; September 1 IFN-based therapy

Unique Aspects of Treating Patients with Cirrhosis

Need for treatment is more urgent, especially if decompensated

Treatment options become more limited as patient transitions from compensated decompensated cirrhosis

SVR rates influenced by cirrhosis severity

CP-A > CP-B >> CP-C

Tolerability and safety need closer scrutiny

Concurrent liver and renal dysfunction may be present

Consequences of treatment failure may be greater

DAA Primary Metabolic Pathway

Suitable in Patients With Cirrhosis CP-A CP-B CP-C

Suitable if Renal Impairment

Sofosbuvir ± Ledipasvir

Renal Yes Yes

Yes

Not if CrCl < 30 mL/min

Daclatasvir Hepatic Yes Yes Yes Yes, but not studied in dialysis

Simeprevir Hepatic Yes (Yes) No Not if CrCl < 15 mL/min

Ombitasvir/Paritaprevir/r

Hepatic Yes No No Yes but not if dialysis

Dasabuvir Hepatic Yes No No Yes but not if dialysis

Elbasvir/grazoprevir

Hepatic Yes No No Yes

Ribavirin Renal Yes Yes Yes Yes, adjusted

Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clin Pharm 2014. P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German et al. AASLD 2013. Abstract 467. Kirby R, et al. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy PO20

Drug Options in Patients with Cirrhosis

General Themes in the Treatment of Patients with Cirrhosis

More frequent need for:

Use of ribavirin and/or

Extension of therapy

Important modifiers of SVR in this population

Presence of baseline RAVs

Severity of portal hypertension

Concurrent renal dysfunction reduces treatment options further

If decompensated cirrhosis with CrCl <30 mL/min no treatment options

Genotype 1 populations

Daclatasvir +

sofosbuvir

Ledipasvir +

sofosbuvir

Paritaprevir/r +

ombitasvir +

dasabuvir

Simeprevir +

sofosbuvir

Elbasvir +

grazoprevir

No prior treatment

Alternative +/-RBV 24 wks

Recommended, 12 wks

Alternative + RBV 24 wks

Alternative +/-RBV 24 wks

Recommended if no RAVs, 12 wks

Alternative if RAVs,16 wks+RBV

PEG/RBV failures

Alternative +/-RBV 24 wks

Recommended No RBV, 24 wks + RBV, 12 wks

Alternative + RBV 24 wks

Alternative +/-RBV 24 wks

Recommended if no RAVs, 12 wks

Alternative if RAVs,16 wks+RBV

SOF/RBV or SOF/PEG/RBV failures

Recommended + RBV 24 wks

PEG/RBV + PI failures

Recommended +/-RBV 24 wks

Recommended No RBV, 24 wks + RBV, 12 wks

Recommended No RAV, 12wk+RBV RAVs,16 wks+RBV

www.hcvguidelines.org

Genotype 1A with Compensated Cirrhosis

Genotype 1 populations

Daclatasvir +

sofosbuvir

Ledipasvir +

sofosbuvir

Paritaprevir/r +

ombitasvir +

dasabuvir

Simeprevir +

sofosbuvir

Elbasvir +

grazoprevir

No prior treatment or PEG/RBV failures

Alternative +/-RBV 24 wks

Recommended No RBV, 24 wks + RBV, 12 wks

Recommended 12 wks

Alternative +/-RBV 24 wks

Recommended 12 wks

SOF/RBV or SOF/PEG/RBV failures

Recommended + RBV, 24 wks

PEG/RBV + PI failures

Recommended +/-RBV 24 wks

Recommended No RBV, 24 wks + RBV, 12 wks

Recommended 12 wks + RBV

www.hcvguidelines.org

Genotype 1B with Compensated Cirrhosis

Total

Treatment

Naïve

Treatment

Experienced

Overall SVR12

Duration 12 wk

24 wk

Regimen LDV/SOF

LDV/SOF + RBV

Duration/

± RBV

LDV/SOF 12 wk

LDV/SOF + RBV 12 wk

LDV/SOF 24 wk

LDV/SOF + RBV 24 wk

96% 98% 95%

95% 97% 94%

98% 99% 98%

95% 96% 95%

97% 99% 96%

92% 96% 90%

96% 98% 96%

98% 97% 98%

100% 100% 100%

SVR12, %

LDV/SOF ± RBV for 12 vs 24 Weeks in Compensated Cirrhotics: Pooled Analysis

Reddy R et al, Hepatology. 2015 Jul;62(1):79-86

Total

Treatment

Naïve

Treatment

Experienced

Overall SVR12

Albumin

(g/dL)

<3.5

≥3.5

Platelets

(x 103/µL)

<75

≥75 – <100

≥100 – <125

≥125

FibroScan >12.5 – ≤20

>20

Is SVR12 Influenced by Severity of Portal Hypertension?

96% 98% 95%

99%

96%

10

98%

95%

99%

84% 90%

100%

98%

98%

100%

100%

82%

98%

93%

98%

99%

95%

SVR12, %

96%

97% 95%

98%

98%

95%

Reddy R et al, Hepatology. 2015 Jul;62(1):79-86

11

26/27 65/68

12 weeks 24 weeks

SVR

12 (

%)

10/10 27/27 8/9 19/19

Studies included for analysis: LDV/SOF 12 Wks: GS-US-334-1274 (Bleeding Disorder), GS-US-337-0102 (ION-1), GS-US-337-0113 (Japan 1), GS-US-337-0115 (ION-4), GS-US-337-0122 (ELECTRON-2), GS-US-337-0131(China), GS-US-337-1406; LDV/SOF+RBV 12 Wks: GS-US-337-0102 (ION-1), GS-US-337-0113 (Japan 1), GS-US-337-0122 (ELECTRON-2); LDV/SOF 24 Wks: GS-US-337-0102 (ION-1), GS-US-334-1274 (Bleeding Disorder)

Treatment Naive Treatment Experienced

12 weeks 24 weeks

The largest impact of RAVs on treatment outcome was observed in

patients with cirrhosis treated for 24 weeks of LDV/SOF (and no ribavirin)

Zeuzem S, Abstract 91

Efficacy of LDV-SOF in Patients with and without NS5A RAVs at Baseline

With cirrhosis

LDV-SOF in Patients with Cirrhosis

LDV-SOF for 12 weeks suitable for treatment naïve group

LDV-SOF plus RBV for 12 weeks if:

Treatment experienced

Other potential groups to consider:

Baseline RAVs present

Platelet count <75K

LDV-SOF for 24 weeks if:

Above groups but ribavirin ineligible

Summary

Efficacy of EBR-GZR in Treatment of Patients with Cirrhosis (N=402)

HCV genotype 1, 4 and 6, compensated CP-A cirrhosis Cirrhosis defined by biopsy, Fibroscan, or APRI + Fibrotest Included treatment duration of 12, 16, 18 weeks

Jacobson I, AASLD 2015, Abstract 42

Jacobson I, AASLD 2015, Abstract 42

Patients Treated with EBR-GZR with Cirrhosis: Treatment Naïve: Pooled Analysis

Jacobson I, AASLD 2015, Abstract 42

Patients Treated with EBR-GZR with Cirrhosis: Treatment Experienced

Prevalence and Impact of Baseline NS5A RAVs in Patients Treated with

EBR-GZR Jacobson I, AASLD 2015, LB-22

Prevalence of NS5A RAVs = 20%

EBR RAVs=~5% TN/relapsers

EBR RAVs=~10% if TE non-responders

GT1B: minimal impact of baseline EBR RAVs

GT1A:

12 wks EBR/GZR 16/18 wks EBR/GZR + RBV

Severity of Portal Hypertension Not Associated with SVR in Cirrhotics

Jacobson I, AASLD 2015, Abstract 42

Treatment regimens primarily driven by sub-genotype and presence of baseline RAVs

Cirrhosis and prior treatment experience appear to be less important

Genotype 1B and Genotype 1A without RAVs

12 weeks and no RBV

Genotype 1A with RAVs*

16 weeks plus RBV

EBR-GZP in Patients with Cirrhosis Summary

* baseline high fold-change

NS5A RAVs are M28, L30,

L31, and Y93

PTV/RTV + DSV for 12 Wks in Genotype 1B Patients with Cirrhosis

Characteristic N=60

White race 87%

Age, median 60.5 yrs

IL28B nonCC 83%

Experienced NR Relapser/VBT

55% 30% 8%

Fibroscan >20 49%

Platelets<90K 21%

Albumin<3.5 17%

Varices 12%

Feld J, J Hepatol 2016;64:301-7

TURQUOISE III

Treatment of Genotype 1 Cirrhosis

5 different DAA combos available

2 “recommended” for genotype 1A

3 “recommended” for genotype 1B

Determination of RBV eligibility necessary

RBV increases SVR with shorter duration therapy and in those with baseline RAVs

Presence of renal dysfunction (eGFR <30 min/mL) reduces treatment options

www.hcvguidelines.org

Genotype 3 populations

Daclatasvir +

sofosbuvir

Sofosbuvir + peg-

IFN + Ribavirin

Sofosbuvir +

Ribavirin

Elbasvir +

grazoprevir +

sofosbuvir

No prior treatment Recommended ± RBV for 24

wks

Recommended 12 wks

Alternative 24 wks

Treatment experienced

Recommended + RBV for 24 wks

Recommended 12 wks

Treatment experienced, RBV ineligible

Alternative?

Genotype 3 with Compensated Cirrhosis

www.hcvguidelines.org

SVR Rates of GT3 Regimens - Cirrhotic

82% 77%

58%

69%

91% 86%

100%

86%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Naïve Experienced

SVR

12

Rat

e

SOF/RIBA x 24weeks

SOF/DCV x 12weeks

IFN/SOF/RIBA x 12weeks

SOF/DCV/RIBA x16 weeks

Leroy V, AASLD 2015:LB-3; Nelson DR, et al. Hepatology 2015;61:1127-35; Zeuzem S, et.al. NEJM 2014;370:1993-2001; Foster GR,

et.al.Gastroent.2015;149:1462-70

(Prior IFN/Ribavirin)

Not head-to-head comparisons

European Compassionate Access Program DCV + SOF ± RBV for 24 Weeks

DCV + SOF DCV + SOF + RBV

HC

V R

NA

< L

LOQ

, TD

or

TND

, %

37 42

25 29

19 19

12 15

12 14

16 20

6 8

Child-Pugh Class MELD Score Categoryb

11 13

2 2

4 5

2 2

15 17

8 9

17 17

a Excludes 4 patients with indeterminate cirrhosis status and 5 without cirrhosis; all except 1 (DCV+SOF) achieved SVR12; b Excludes 1 cirrhotic patient with missing baseline MELD data; patient discontinued therapy at Week 4 due to AE (non-SVR12).

Welzel T, AASLD 2015, Abstract 37

14

15

Non-

cirrhotic

Cirrhotic

10

11

14

14

SOF/GRZ/EBV x 8 vs 12 Weeks in GT3

Treatment-Naïve Cirrhotic and Non-Cirrhotic

mITT analysis excluded patients who discontinued early due to reasons other than virologic failure

Poordad et al. Abstract #O006, EASL 2015

Lactic acidosis in Cirrhotics Treated with Ribavirin/Sofosbuvir N=35 patients with advanced fibrosis/cirrhosis treated with

various SOF/RBV containing regimens

16 CP-A, 12 CP-B/C; 8 post-transplant

Pre-treatment During treatment

SAEs 43% 34%

Infectious complications 16% 21%

De novo or worsening decompensation

49% 39%

Renal complications 11% 21%

Lactic acidosis* 0% 14%

*Lactic acidosis more frequent in those with advanced cirrhosis and/or renal

dysfunction

Welker M, J Hepatol 2016, in press

Hepatotoxicity in Patients with Cirrhosis on Elbasvir-Grazoprevir

Antiviral options are more limited

Protease inhibitors contraindicated

Concurrent renal dysfunction may limit use of sofosbuvir

SVR rates with DAA therapy in decompensated cirrhosis (CP-B/C) are generally lower than in compensated cirrhosis (CP-A)

Benefits of therapy are great but competing risk of dying before attaining benefits

Challenges with Treating Decompensated Cirrhosis

DAA Combinations Available for Decompensated Cirrhosis

Sofosbuvir + RBV

Ledipasvir-Sofosbuvir ± RBV

[Simeprevir + Sofosbuvir]

Daclatasvir + Sofosbuvir ± RBV

G2

G1,4

G1,4-6

G1-6

www.Hcvguidelines.org accessed March 1, 2016

SOF/LDV or SOF/DCV plus RBV for Decompensated Cirrhosis

ALLY-1: GT 1

DCV + SOF + RBV 12 weeks

Charlton M, Gastroenterology. 2015 Sep;149(3):649-59 Poordad F. EASL 2015. Abstract LO8. Manns M, EASL 2015

CPT

46 53

46 50

36 42

31 38

8 relapses 3 deaths

4 relapses 7 deaths

1 LTU

Achievable Endpoints with DAA Therapy in Patients with

Decompensated Cirrhosis

Reductions in MELD score

Reversal of symptoms of decompensation

Reduced rates of portal hypertension complications

Lower mortality

Delisting

DCV + SOF + RBV for 12 Wks: ∆MELD in Those with Advanced Disease

Poordad F, Hepatology 2016

SVR Associated with Fewer Cirrhosis-Related Complications

Saxena et al. AASLD 2015, Abstract #1825..

Multicenter study of patients with compensated/decompensated cirrhosis treated with SMV/SOF ±RBV for 12-24 wks; 84% achieved SVR

Compared to 269 untreated/non-SVR matched controls Median MELD=9 and CP score 6

SVR SVR

No-SVR No-SVR

Bivariate Cox Regression Analysis of Factors

Associated with Liver Transplantation / Death

Unique Clinical Issues with Treatment of Patients with Decompensated Disease Recognize the competing risk of progressive disease

and liver-related mortality

Benefits of SVR are more than viral eradication

Improvement in MELD, CP scores in majority, but most in the short term

Reversal of symptoms of decompensation in some

Wait-listed patients present special challenge

Weighing benefits of treatment vs LT

Looking to the New Future?

SOF/VEL

± RBV

Other

Combos

SOF/VEL for 12 weeks: SVR12 Rates in Patients with Cirrhosis

99% 100%

91%

G1-6 G2 G3

120/121

1 relapse

7 relapses

73/80

19/19

Foster G, N Engl J Med, 2015;373:2608-17.

Feld J, N Engl J Med. 2015;31;373:2599-607.

SOF/VEL + RBV for 12 weeks: SVR12 Rates in Patients with Decompensated Cirrhosis

96%

85%

100%

Curry M, N Engl J Med 2015;373(27):2618-28.

65/68

1 relapse 2 deaths

GT 2 (4/4)

GT 4 (2/2)

Treatment of Patients with Cirrhosis Take Home Messages

High priority for treatment

Benefit great if SVR achieved

More limited treatment options if decompensation

Still room for improvement in treatment regimens

Eliminate ribavirin

Options for decompensation plus renal dysfunction

Vigilance regarding safety, especially if concurrent decompensation and renal dysfunction