CARE AND TREATMENT OF CHRONIC HBV AND HCV€¦ · CARE AND TREATMENT OF CHRONIC HBV AND HCV...

CARE AND TREATMENT

OF CHRONIC HBV AND HCV - D e c e m b e r 20 1 8 -

GEORGE PAPATHEODORIDIS, MD

PROFESSOR IN MEDICINE AND GASTROENTEROLOGY ATHENS UNIVERSITY MEDICAL SCHOOL

HARRY JANSSEN, MD PROFESSOR OF MEDICINE, TORONTO WESTERN AND TORONTO GENERAL HOSPITAL,

UNIVERSITY HEALTH NETWORK, TORONTO, CANADA

ANGELOS HATZAKIS, MD PROFESSOR OF EPIDEMIOLOGY AND PREVENTIVE MEDICINE

ATHENS UNIVERSITY MEDICAL SCHOOL

Contents

Care and Treatment of Chronic Hepatitis B

Care and Treatment of Chronic Hepatitis C

Chronic HBV and HCV are treatable or curable

Current HBV treatment options Current HCV treatment options

Lamivudine Ribavirin

Adefovir dipivoxil Sofosbuvir

Peginterferon alfa-2a Simeprevir

Peginterferon alfa-2b Daclatasvir

Entecavir Sofosbuvir/Ledipasvir

Telbivudine Paritaprevir/ritonavir/Ombitasvir ± Dasabuvir

Tenofovir disoproxil fumarate Sofosbuvir/Velpatasvir

Tenofovir alafenamide Elbasvir/Grazoprevir

Glecaprevir/Pibrentasvir

Sofosbuvir/Velpatasvir/Voxilaprevir

Agents in bold are those mostly used

CARE AND TREATMENT OF CHRONIC HEPATITIS B

• Induction of long-term suppression of HBV DNA:

the main endpoint of all current treatment strategies.

• Induction of HBeAg loss, with or without anti-HBe seroconversion,

in HBeAg-positive CHB patients: valuable endpoint, often

representing partial immune control of the chronic HBV infection.

• Biochemical response (ALT normalization): additional endpoint

achieved in most patients with long-term suppression of HBV

replication.

• HBsAg loss, with or without anti-HBs seroconversion:

optimal endpoint indicating profound suppression of HBV

replication and viral protein expression.

End-points of therapy

EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.

Indications for treatment

• Patients should be considered for treatment if

– HBV DNA >2,000 IU/ml and

– ALT >ULN (40 IU/L) and/or

– At least moderate necroinflammation and/or at least moderate

fibrosis by liver biopsy [or liver stiffness >9 or >12 kPa if ALT ≤ULN or

>ULN (<5xULN)]

• Patients with compensated or decompensated cirrhosis need treatment, with any detectable HBV DNA level and regardless of ALT levels

• Indications for treatment may also take into account

age, health status, comorbidities, family history of HCC or cirrhosis and

extrahepatic manifestations


Treatment indications/Management in HBeAg-pos. CHB patients

ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2

A. HBeAg-pos. chronic HBV infection (previously immunotolerant phase):

Persistently ALT ≤ULN

• No Biopsy – No therapy – Follow-up if age ≤30

• Treatment if age >30 or family history of HCC, cirrhosis, stiffness >9 kPa

B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000 IU/ml

• Therapy – Biopsy optional


ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2

A. HBeAg-ve patients with persistently ALT ≤ULN

(ALT every 3 months for at least 12 months) &

- HBV DNA <2000: No biopsy, No therapy, Follow-up

- HBV DNA 2,000-20,000 & no evidence of advanced liver disease:

No Biopsy, No therapy, Follow-up (close for another 2 years)

- HBV DNA >20,000 & no evidence of advanced liver disease: individualize

- HBV DNA >2000 & evidence of advanced liver disease

(including stiffness >9 kPa): therapy

B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000

• Therapy – Biopsy optional

Treatment indications/Management in HBeAg-neg. CHB patients


HBeAg-negative patient with normal ALT at baseline

ALT every 2-4 months for 12 months

ALT >ULN and/or Persistently ALT<ULN and Persistently ALT<ULN and HBV DNA >20,000 or HBV DNA >2,000 (≤20,000) HBV DNA <2,000 IU/mL signs of advanced disease or liver stiffness >12 kPa Elastography Liver stiffness >9 Stiffness ≤9 kPa ALT every 6 mos, periodical HBV DNA, & elastography Liver biopsy and/or ALT every 3-4 mos, Treatment HBV DNA every 12 mos for two years

ALT<ULN and HBV DNA 2,000-20,000 IU/mL ALT every 6 mos, periodical HBV DNA

ALT >ULN and/or

HBV DNA >20,000

Liver biopsy or Elastography

HBsAg<1000 ALT every 12 mos

Modified from

Vlachogiannakos & Papatheodoridis.

Liver Intern 2018;38(Suppl. 1):71-78.

Additional indications of treatment/prophylaxis

for chronic HBV patients

• Liver transplantation

• HBV-HIV co-infection

• HDV-HBV co-infection with ongoing HBV replication

• HBV-HCV co-infection during and for 12 weeks after DAAs

• Last trimester of pregnancy and up to 12 weeks after delivery if HBV DNA

>200,000 IU/ml or HBsAg >4 log10 IU/ml

• During and for 12 months after immunosuppressive therapy or

chemotherapy

• Healthcare workers performing exposure prone procedures with serum HBV

DNA >200 IU/ml

• Extrahepatic manifestations and replicative HBV infection


HBV-RELATED CHRONIC LIVER DISEASE

Groups of treatment options

Peg-interferon-alfa

(PegIFNa)

(antiviral+

immunomodulator)

Entecavir (ETV)1, Tenofovir disoproxil

fumarate (TDF)1, tenofovir alafenamide (TAF)1

Telbivudine (TBV)2, Lamivudine (LAM)2,

Adefovir (ADV)2 (pure antivirals)

Subcutaneous injections (one weekly) Tablets (one daily)

1High barrier to resistance 2Low barrier to resistance

EFFICACY OF 48-WEEKS OF PegIFNa IN CHB: End of therapy (EOT) & Sustained off-therapy responses

Pts, %

Lau G et al, NEJM 2005; Marcellin P et al, NEJM 2004

HBeAg(+)CHB HBeAg(-)CHB

EOT 6-mos FUP EOT 6-mos FUP HBeAg to anti-HBe seroconversion HBV DNA <400 cp/ml

Cumulative incidence of HBV resistance for NA in

pivotal trials in nucleos(t)ide-naïve patients with CHB

Collation of currently available data – not from head-to head studies

Note: No evidence of resistance has been shown after 8 years of TDF treatment.

Preferred regimens

EASL 2017 CPG HBV, J Hepatol 2017;67:370-398. NA: nucleos(t)ide analogue(s)

Resistance to ETV or TDF in CHB with LAM resistance P

atie

nts

wit

h r

esi

stan

ce (

%)

6 0 0 0 0

Years 1 2 3 4 5 6 1 2 3 4

Entecavir (ETV) Tenofovir (TDF)

These trials included different populations, different exclusion criteria and different endpoints

15

31

47 51

Although licensed, ETV (1.0 mg) is not recommended for patients with LAM resistance by almost all guidelines

57

Tenney D et al. EASL 2009, Abstr. 20; Van Bommel F et al. Hepatology 2010, 51: 73-80

Indications for selecting ETV or TAF over TDF*

* TAF should be preferred to ETV in patients with previous exposure to nucleoside analogues.

** ETV dose needs to be adjusted if eGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged at least 12 years and of ≥35 kg body weight) with estimated creatinine clearance (CrCl) ≥15 ml/min or in patients with CrCl <15 ml/min receiving haemodialysis.


Han S et al. AASLD 2008. Shouval et al. AASLD 2008.

Pat

ien

ts w

ith

HB

V D

NA

<3

00

cp

/mL

(%)

55%

Year 1

83%

Year 2

89%

Year 3

67%

n/ N

236/ 354

Year 4

91%

80/ 146

116/ 140

116/ 131

98/ 108

Year 5

88/ 94

94%

Year 1

ETV-022

0

20

40

60

80

100

ETV-901

Long-term ETV therapy in naive HBeAg(+)/(-) CHB

HBeAg(+) HBeAg(-)

Year 1

91%

Year 2 95%

Year 3

94%

93/99 84/90

67/74 54/57

93%

Year 1

ETV-027

0

20

40

60

80

100

ETV-901

Marcellin P et al. AASLD 2011, 2012

HBeAg(-): 5 year - 6 years

ΙΤΤ: 83%- 81%

Per protocol*: 99%- 100%

HBeAg(+): 5 years - 6 years

ΙΤΤ: 65%- 62%

Per protocol*: 97%- 99%

Patients with HBV DNA <400 cp/mL at 5-6 years under TDF

*missing = exclusion

Antiviral Efficacy of TAF and TDF at Week 96

Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF

*Adjusted for baseline HBV DNA level and oral antiviral treatment status strata M=F: Missing =Failure

Agarwal K et al. J Hepatol 2018;68:672-81.

HBeAg+

Rates of Viral Suppression (ITT; M=F) HBV DNA <29 IU/mL

No resistance was detected through 96 weeks Similar HBV DNA suppression rates for TAF compared to TDF through

Week 96

HBeAg-

73%

75%

P=0.47*

90%

91%

P=0.84*

TAF

TDF

94%

93% 64%

67%

Changes in Renal Markers During Treatment with TAF or TDF

Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF

Changes in Quantitative Proteinuria at Week 96

Significantly smaller changes in renal tubular markers with TAF vs TDF

UPCR, urine protein-to-creatinine ratio; UACR, urine albumin-to-creatinine ratio; RBP:Cr, retinol binding protein-to-creatinine ratio; B2M:Cr, β2 microglobulin-to-creatinine ratio * p-values from 2-sided Wilcoxon rank-sum test

Chuang, EASL 2017, SAT-171

Glomerular Proteinuria

Tubular Proteinuria

UPCR UACR

RBP:Cr β2m:Cr

Med

ian

% C

han

ge

(Q1

, Q3

) M

edia

n %

Ch

ange

(Q

1, Q

3)

100

50

0

-50

0 4 12 24 48 72 96

100

50

0

-50

100

50

0

-50

100

50

0

-50

0 4 12 24 48 72 96

0 4 12 24 48 72 96 0 4 12 24 48 72 96

P=0.07

P=0.20

P<0.001 P<0.001

Week Week

TAF

TDF

107

108.5 126.7 221.3 199.6 153.1

Monitoring of patients treated with ETV, TDF or TAF

1) All patients treated with NA should be followed with periodical assessments

including ALT (every 3-4 months during year 1 & then every 6 months) and

serum HBV DNA (every 3-4 months during year 1 & then every 6-12

months) (and HBeAg/anti-HBe every 6 months for HBeAg-pos. patients


2) Patients at risk of renal disease treated with any NA should undergo

periodical* renal monitoring with eGFR and all patients regardless of

renal risk treated with TDF should undergo periodical* renal monitoring

with at least eGFR and serum phosphate levels.

(*periodical: every 3 months during year 1 & then every 6 months)

3) Patients on TDF at risk of development and/or with underlying renal or

bone disease should be considered for a switch to ETV or TAF, depending

on previous LAM exposure.

Ishak Fibrosis Scores

Pe

rce

nta

ge o

f p

atie

nts

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 5

39%

38%

12%

P < 0.001

P < 0.001

63%

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 5

39%

38%

12%

P < 0.001

P < 0.001

63%

6

5

4

3

2

1

0

6

5

4

3

2

1

0

Patients with cirrhosis (Ishak score ≥5): 28% at baseline, 8% at year 5

Fibrosis Is Reversible Liver Fibrosis Regression over 5 Yrs of Tenofovir Therapy

Marcellin P et al. Lancet 2013

348 patients with paired biopsies at baseline & year 5

Long-term outcome during NA therapy

1) Patients under effective long-term NA therapy should

remain under surveillance for HCC.

(Evidence level II-2, grade of recommendation 1)

2) HCC surveillance is mandatory for all patients with

cirrhosis as well as those with moderate or high HCC

risk scores at the onset of NA therapy.

(Evidence level II-2, grade of recommendation 1)


HCC in CHB patients under LAM

Patients with HCC,

%

LAM Untreated

Patients n: 779 534

HBeAg(-) 49% 54%

Comp. Ci: 29% 39%

FUP (mos): 32-90 32-108

• Liaw et al, NEJM 2004

• Papatheodoridis et al, HEP 2005

• Yuen et al, AVT 2007

P=0.003

P=0.015

P=0.016

All VR BR/BTH Untreated pts LAM treated pts N 779 353 426 534

Papatheodoridis GV et al. J Hepatol 2010;53:348-56

0,5%

1,0%

0,7%

0,1%

0,5%

0,0%

0,5%

1,0%

1,5%

2,0%

Tx-naive Tx-naive and/or tx-experienced Tx-naive

Papathe- odoridis N=212

Yang N=202

Wong N=984

Wong N=813

Yang N=314

Hosaka N=237

Lampe- rtico

N=213

Arends N=580

An

nu

al H

CC

In

cid

en

ce

Lim N=878

Cho N=933

Wu N=18748

Lampe- rtico

N=243

Papathe- odoridis N=1231

ETV TDF ETV or TDF

Yamada N=402

Prior exposure

NR

Tx-naive and/or tx-experienced

Asians Caucasians

ETV or TDF for non-cirrhotic CHB patients

HCC rates per year


1,4%

2,8%

5,4%

2,0%

4,1%

3,3%

0,9%

5,4%

2,6%

5,1%

2,2%

4,5%

3,9%

0,0%

1,0%

2,0%

3,0%

4,0%

5,0%

6,0%

Yang N=121

Wong N=482

Wong

N=247

Hosaka N=79

Chen

N=239

Kim

N=324

Yang

N=152

Chen N=143

Papa theo- dori dis

N=69

Lamp- etico

N=155

Are- nds

N=164

Koklü N=77

2,8%

4,2%

1,8%

3,3%

2,5%

5,2%

1,5%

0,0%

1,0%

2,0%

3,0%

4,0%

5,0%

6,0%

Lim N=860

Cho

N=445

Su N=666

Wu N=2847

Lamp- ertico

N=131

Papa theo- dori dis

N=1231

Koklü N=72

Yama- da

N=94

ETV or TDF for cirrhotic CHB patients HCC rates per year

ETV TDF ETV or TDF

Tx-naive Tx-naive and/or tx-experienced Tx-naive

Prior exposure

NR

Tx-naive and/or tx-experienced

Asians Caucasians


PAGE-B represents a simple to use HCC risk score for the first 5 years of ETV/TDF in Caucasian CHB patients

Construction of the PAGE-B risk score for HCC

Age (years) Gender Platelets

(/mm3)

16–29: 0 Female:

0 ≥200,000: 0

30–39: 2 Male: 6 100,000–

199,999: 6

40–49: 4 <100,000: 9

50–59: 6

60–69: 8

≥70: 10


HCC risk in 1946 ETV/TDF treated CHB patients beyond year 5

GV Papatheodoridis et al. Hepatology 2017;66:1444-1453.

Ci

No Ci

All patients Patients with & without Ci

Yearly HCC incidence

1.22% 0.63%

P=0.086

Yearly HCC incidence

3.27% 1.07%

P=0.046

0.45% 0.51%

Cumu-

lative

HCC

incide-

nce,

%

Pts at risk-1946 1670 1088 498 169 56 No Ci-1346 1156 734 329 127 45

Ci-518 444 304 145 34 6

1) NAs should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion. (Evidence level II-2, grade of recommendation 1).

2) NAs can be discontinued in non-cirrhotic HBeAg positive CHB

patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy. Close post-NA monitoring is warranted. (Evidence level II-2, grade of recommendation 2)

3) Discontinuation of NAs in selected non-cirrhotic HBeAg-

negative patients who have achieved long-term (3 years) virological suppression under NA(s) may be considered if close post-NA monitoring can be guaranteed. (Evidence level II-2, grade of recommendation 2)

NA discontinuation


Patients with

durable HBeAg

seroconversion,

%

At 6 12 24 months after NA(s) discontinuation

GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.

Rates of durable HBeAg seroconversion after NAs discontinuation Systematic review: 6 studies, 289 initially HBeAg+ patients

Patients with

HBV DNA <20,000 IU/mL,

%

At 6 12 24 36 months after NA(s) discontinuation

Rates of virological remission after NAs discontinuation 14 studies, 733 initially HBeAg+ patients

Pooled HBsAg loss: 1%; Durable biochemical remission: 76%


Patients with

HBV DNA <20,000 IU/mL,

%

At 6 12 24 36 months after NA(s) discontinuation

Rates of virological remission after NAs discontinuation 17 studies, 967 HBeAg- patients

Pooled HBsAg loss: 1.7%; Durable biochemical remission: 57%


Patients with VR

at 12 mos after NAs

discontin., %

Rates of virological remission at 12 mos after NAs discontinuation in HBeAg-neg. CHB patients in relation to several factors

VR: virological remission

HBV DNA (IU/mL) <200 <2,000 <20,000 <12 12-24 >24 mos

VR definition Duration of on-NAs VR

P=0.513 P=0.017


HBV treatment modifies the outcome of the disease

Sustained response after pegIFNa or long-term ETV/TDF/TAF monotherapy

Improvement/Stabilization of liver disease in practically all patients

Often regression of histological cirrhosis

Improvement/Disappearance of portal hypertension and liver decompensation

No need for liver transplantation due to liver failure

Reduction but not elimination of HCC risk

Improved survival

CARE AND TREATMENT OF CHRONIC HEPATITIS C

1992 1996 1998 2001 2011 2013 2014

SVR, %

>

Standard IFNa

RBV

PegIFNa

BOC/TPV

New DAAs

Evolution in efficacy of CHC treatment

IFN: interferon-alfa, R: ribavirin, PR: pegylated IFN+R, PI: protease inhibitor, BOC:boceprevir, TPV: telaprevir, DAA(s): direcr acting antiviral(s)

SOVALDI®

Sofosbuvir NS5B polymerase

Inhibitor Gilead

OLYSIO® Simeprevir

NS3/4A protease Inhibitor Janssen

DAKLINZA® Daclatasvir

NS5A Inhibitor

BMS

400 mg/24h

Genotypes 1-6

High genetic barrier

150 mg/24h with food

Genotypes 1,4

Low genetic barrier

60 mg/24h

Genotypes 1,2,3,4

Low genetic barrier

January 17, 2014 May 16, 2014 August 28, 2014 November 18, 2014

90+400 mg/24h

Genotypes 1,3,4


HARVONI® Ledipasvir

NS5A inhibitor +Sofosbuvir

NS5B polymerase Inhibitor Gilead

Anti-HCV agents approved by ΕMA in 2014

VIEKIRAX® Ombitasvir

NS5A inhibitor +Paritaprevir

NS3/4A protease inhibitor/ Ritonavir

EXVIERA® Dasabuvir

Non-nucleos(t)ide NS5B polymerase

inhibitor

[75/50+12.5 mg] x2 /24h with food

Genotypes 1, 4

Genetic barrier dependent on genotype

250 mg/12h

Genotype 1

Low genetic barrier

January 16, 2015


Abbvie

EPCLUSA® Velpatasvir


NS5B polymerase Inhibitor Gilead

100+400 mg/24h

Genotypes 1-6


July 8, 2016

ZEPATIER®

Elbasvir NS5A inhibitor +Grazoprevir

NS3/4A protease inhibitor

MSD

50+100 mg /24h

Genotypes 1, 4

Genetic barrier dependent on genotype

July 28, 2016


VOSEVI® Velpatasvir


NS5B polymerase Inhibitor

+Voxilaprevir NS3/4A protease

inhibitor Gilead

MAVIRET® Glecaprevir

NS3/4A protease inhibitor

+Pibrentasvir NS5A inhibitor

Abbvie

• [100/40 mg] x3 /24h with food

Genotypes 1-6

High genetic barrierγμός

• 100/400/100 mg /24h

Genotypes 1-6



July 26, 2017 July 26, 2017

Sofosbuvir + Daclatasvir (±Ribavirin)

Current IFNa-free regimens for genotype 1,4

Sofosbuvir/Ledipasvir* (±Ribavirin)

Paritaprevir/r/Ombitasvir + Dasabuvir (±Ribavirin)

Sofosbuvir/Velpatasvir*

Grazoprevir/Elbasvir (±Ribavirin)

Glecaprevir/Pibrentasvir*

Sofosbuvir/Velpatasvir/Voxilaprevir*

Sofosbuvir + Daclatasvir, Paritaprevir/r/Ombitasvir + Dasabuvir: not used in most countries; Sofosbuvir/Velpatasvir/Voxilaprevir: mostly used in DAA failures

*Also for GT5,6

Sofosbuvir + Daclatasvir +/- RBV for G1 patients (phase IIb study)

100

80

60

40

20

0

SVR12 (%)

100

29/ 29

100

14/ 15

S/D S/D/R

24 wks

100

21/ 21

S/D

19/ 20

95

S/D/R

24 wks

100

41/ 41

95

39/ 41

12 wks S/D S/D/R

Naive Prior PI (BOC/TPV) failures

• 20% cirrhotics • Almost all cured – 12 weeks adequate, RBV unnecessary

Sulkowski M et al. N Engl J Med 2014;370:211-21

ALLY-1: Advanced cirrhosis cohort

Total: n = 60; any GT; Baseline MELD score range 8–27 GT-1: n=45; GT-1/CP-B: 53%, GT-1/CP-C: 22%

Safety: Discontinuations due to adverse events, n = 1

SVR rates with SOF+DCV+RBV x12 weeks in HCV GT1 patients with advanced cirrhosis

Poordad F et al. Hepatology 2016;63:1493-505.

8291

76

92100

50

0

20

40

60

80

100

N=45 N=34 N=11 N=11 N=24 N=10

All GT1a GT1b CP-A CP-B CP-C

SVR12, %

CP: Child-Pugh

HEPATHER: SOF+DCV ±RBV x12 or 24 wks in GT1 pts

SVR4, %

SOF+DCV SOF+DCV+RBV SOF+DCV SOF+DCV+RBV x12 wks x12 wks x24 wks x24 wks

409 patients, 318 cirrhotics, 306 failures to PR±TPV/BOC

No cirrhosis Cirrhosis

S Pol et al. EASL 2015, Abstr. LB 03

SVR

12

(%

)

n N

141 142

143 143

143 143

211 212

66 66

211 211

67 67

212 214

66 68

Overall GT1a GT1b

141 141

215 215

71 71

Subgroup results do not include patients who withdrew consent or who were lost to follow-up.

Error bars: 95% CI.

ION-1: SOF/LDV ± RBV in GT1 treatment-naive patients – SVR12

Afdhal N et al. New Engl J Med 2014;70:1889-98.

ION-1: SVR rates* in GT1 treatment-naive cirrhotic patients (subgroup analysis)

* Subgroup results do not include patients who withdrew consent or were lost to follow-up.


179 179

32 33

178 178

33 33

181 182

31 32

179 179

36 36

n N

SVR

12

(%

)


One patient achieved SVR12, but was not subgenotyped.

Error bars: 95% CI.

SVR

12

(%

)

n N

159 171

159 172

163 172

202 215

42 43

201 216

42 44

206 216

43 44

Overall GT1a GT1b

ION-3: Phase III SOF/LDV ± RBV in GT1 naive, non-cirrhotic patients – SVR12

Kowdley KV et al. New Engl J Med 2014;370:1879-88.

Predictors of relapse in ION-3 trial: SOF/LDV±RBV for 8 vs 12 wks in GT1 naive, non-cirrhotic patients

Patients with

relapse*, %

*Patients lost to follow-up or who withdraw

consent excluded CC non-CC <6 ≥6 MIU/ml IL28B genotype Baseline HCV RNA n/N 2/56 0/57 0/54 9/157 9/153 3/157 2/121 3/136 2/128 9/92 6/74 1/83

SOF/LDV x8wks SOF/LDV+RBV x8wks SOF/LDV x12wks

P=0.034

P=0.088

P=0.141

Kowdley KV et al. New Engl J Med 2014;370:1879-88.

SVR

12

(%

)

n N

82 86

84 88

84 85

102 109

20 23

107 111

23 23

108 109

24 24

Overall GT1a GT1b

87 88

110 111

23 23

Error bars: 95% CI.

One patient achieved SVR12, but was not subgenotyped.

ION-2: SOF/LDV ± RBV in GT1 treatment-experienced patients


ION-2: SVR rates in GT1 treatment-experienced cirrhotic patients (subgroup analysis)


83 87

19 22

89 89

18 22

86 87

22 22

88 89

22 22

n N

Error bars: 95% CI.

SVR

12

(%

)


LDV/SOF Efficacy in Cirrhotics According to Treatment Experience, Duration, RBV

100

80

60

40

20

0

Total Treatment Naive

92 96 98 100

SV

R1

2 (

%)

118 204 133 58

96 98 97

47 45 33 36

100

Treatment Experienced

90

96 98

71 159 100 22

100

12 wks of LDV/SOF

12 wks of LDV/SOF + RBV

24 wks of LDV/SOF

24 wks of LDV/SOF + RBV

n =

Reddy KR et al. Hepatology 2015;62:79-86.

SYNERGY Trial: LDV/SOF for 12 wks in patients with G4

• Single-center, open-label phase 2a trial

• 38% of patients were TE; all were naive to DAAs; 33% had cirrhosis

• No deaths, SAEs, or grade 4 laboratory events; 1 D/C

GT4 HCV (N=21)

SOF/LDV

12 wks SVR12, %

95

Kapoor R et al. AASLD 2014, Abstract #240

French cohort

GT4 HCV (N=44)

SOF/LDV

12 wks SVR12, %

93

Abergel A et al. EASL 2015, Abstr. O56

Experienced: 22 (50%), Cirrhosis: 10 (23%)

ASTRAL-1: SOF/VEL STR for 12 Weeks in GT1 Patients

Feld JJ et al. N Engl J Med. 2015;373:2599-607.

323/328 206/210 117/118

SVR12, %

ASTRAL-1: SOF/VEL STR for 12 Weeks in GT4, GT5, GT6 Patients


116/116 34/35 41/41

SVR12, %

SV

R1

2 (

%)

299/316 144/157 129/131 n/N =

Overall GT1a GT1b

95 92 99 100

75

50

25

0

SV

R1

2 (

%)

356/370 89/94 92/92 n/N =

Overall 12 weeks 16 weeks + RBV

96 95 100 100

75

50

25

0

Naive

Treatment experienced

Elbasvir/Grazoprevir for GT1 patients

Zeuzem Z et al. Ann Intern Med 2015;163:1-13. Kwo P et al. Gastroenterology 2016.

SV

R1

2 (

%)

18/18 n/N =

GT 4

100% 100

75

50

25

0

SV

R1

2 (

%)

32/37 7/9 8/8 n/N =

Overall 12 weeks 16 weeks + RBV

87 79 100 100

75

50

25

0

Elbasvir/Grazoprevir for GT4 patients

Zeuzem Z et al. Ann Intern Med 2015;163:1-13. Kwo P et al. Gastroenterology 2016.

Naive

Treatment experienced

SOF/VEL for 12 Weeks in GT 1, 2, 4, 5 and 6 HCV: SVR by Genotype

ASTRAL-1 (SOF/VEL x 12 weeks)

618/624

Total

206/210 117/118 104/104 116/116 34/35 41/41

GT 1a GT 1b GT 2 GT 4 GT 5 GT 6

Genotype LTFU=lost to follow up; WC=withdrew consent

1 death 1 relapse 1 relapse

2 LTFU 1 WC

Feld JJ, et al. N Engl J Med 2015;373:2599–2607.

ENDURANCE-1: 8- vs 12-week treatment with G/P in non-cirrhotic naive or PR/SOF experienced patients with GT1

(Primary Efficacy)

Zeuzem S, et al. NEJM 2018;378:354-369.

PR: Peginterferon+Ribavirin; SOF: sofosbuvir; VF, virologic failure; ITT, all patients receiving study drug.

331

332

332

335 332

332

8 weeks

12 weeks

1 LTFU

331

331

ITT population, excluding

HIV co-infected and SOF-

experienced patients

ITT-PS population excluding patients

with premature D/C or virologic failure

prior to week 8, and missing data in the

SVR12 window

1 d/c

1 VF

1 LTFU

ENDURANCE-4: 12-week G/P in naive or PR/SOF experienced HCV patients with GT4–6 (Efficacy)

mITT population is ITT population excluding patients who did not achieve SVR12 for non-virologic reasons.

120

121

75

76

26

26 19

19

120

120

75

75

26

26 19

19

The patient who did not achieve SVR12 discontinued on day 12 due to a SAE (transient ischemic attack with a reasonable possibility of being related to study drug)

1 D/C

Overall GT4 GT5 GT6

1 D/C

Asselah T, et al. Clin Gastroenterol Hepatol 2018;16:417-426

PR: Peginterferon+Ribavirin; SOF: sofosbuvir.

SURVEYOR-II (Part 4): 8-week G/P in Naive or PR/SOF-Experienced Patients with GT2, 4–6 without Cirrhosis (Efficacy – ITT)

LLOQ, lower limit of quantification; TE, treatment emergent; * All patients had HCV RNA <LLOQ at last visit; † Patient had a medical history of gastric bypass. Exposure of GLE on Day 1 and Week 4 was >75% lower than the mean in patients in the same treatment arm; exposure of PIB was comparable to the other patients in the cohort.

97% (196/203, ITT) of GT2, 4, 5, or 6-infected patients without cirrhosis

achieved SVR12 following 8 weeks of G/P

In DAA-naive patients with GT2 infection, 8-week treatment was non-inferior to the historical 95%

SVR12 rate achieved with 12 weeks SOF + RBV

2 relapses

2 D/C

3 missing

SVR12 data*

196

203

2 relapses

1 D/C

1 D/C

2 missing

SVR12 data

1 missing

SVR12 data

142

145

43

46

2

2

9

10

Sequence Analysis

Patient A† Non-cirrhotic

(relapse)

Patient B Non-cirrhotic

(relapse))

NS3 Baseline None None

TE substitutions at failure None None

NS5A Baseline L31M L31M

TE substitutions at failure None None

GT2-infected patients

Asselah T, et al. Clin Gastroenterol Hepatol 2018;16:417-426

EXPEDITION-I: 12-week G/P for of Chronic HCV GT1, 2, 4, 5 or 6 Infection in Adults with Compensated Cirrhosis (Efficacy)

Forns X, et al. Lancet ID 2017; 17:1062–1068.

d/c, discontinuation; PTW, post-treatment Week; RAS, resistance-associated substitution. * SVR12 ITT and mITT are the same.

145

146

89

90

31

31

16

16

2

2

7

7

1 GT1a patient

relapsed at PTW8

n

N

G/P treatment achieved high SVR rates regardless of baseline patient or viral characteristics

Sofosbuvir + Ribavirin (only for genotype 2)

IFNa free regimens for genotype 2, 3

Sofosbuvir + Daclatasvir ± Ribavirin

Sofosbuvir /Velpatasvir ± Ribavirin

Glecaprevir/Pibrentasvir*

Sofosbuvir + Ribavirin, Sofosbuvir + Daclatasvir: not used in most countries anymore; Sofosbuvir/Velpatasvir/Voxilaprevir in genotype 2: mostly used in DAA failures

Sofosbuvir/Velpatasvir/Voxilaprevir*

ASTRAL-2: SOF/VEL STR for 12 Weeks in GT2 Patients

133/134 124/132

SOF/VEL SOF + RBV P=0.018*

Foster GR et al. N Engl J Med 2015;373:2608-17.

104/104


SVR

12

(%

)

264/277 221/275

P<0.001*

12 Weeks 24 Weeks

ASTRAL-3: Open-Label Trial - SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV


100

ASTRAL-3: Open-Label Trial - SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV


n/N =

SVR

12

(%

)

80

60

40

20

0

264/277

221/275

191/197

163/187

73/ 80

55/ 83

200/ 206

176/ 204

64/ 71

45/ 71

95

80

63

90 97 97 87

91

66

86

All Pts No Yes Naive Experienced

Cirrhosis

P < .001 (superiority)

SOF/VEL 12 wks

SOF + RBV 24 wks

Treatment History

SV

R1

2, %

29/32 72/75 76/77

SOF/VEL

12 weeks

SOF/VEL/VOX 8 weeks

34/35

Treatment-

Naive

Treatment-

Experienced

Treatment-

Naive

Treatment-

Experienced

SV

R1

2, %

POLARIS-3: SOF/VEL/VOX x8 wks or SOF/VEL x12 wks in DAA-Naive HCV GT3 Cirrhotics

Jacobson IM, et al. Gastroenterology 2017;153:113-122

ENDURANCE-3: 8- or 12-week G/P vs 12-week SOF+DCV in naive non-cirrhotic HCV patients with GT3 (Efficacy)

BT, breakthrough; non-VF, non-virologic failure; RAS, resistance-associated substitution.

149

157

111

115

222

233

12 weeks 12 weeks 8 weeks

1 BT 3 relapses 7 non-VF



G/P is non-inferior to 12-week SOF+DCV

G/P 8 weeks is non-inferior to G/P 12 weeks

n

N

149

155

111

112

222

226 n

N

12 weeks 12 weeks 8 weeks

Zeuzem S, et al. NEJM 2018;378:354-369.

SURVEYOR-II (Part 3): Patients with HCV GT3 Infection with Prior Treatment Experience and/or Cirrhosis (Efficacy – ITT)

Wyles DL, et al. Hepatology 2017 Sep 19, [Epub ahead of print]

• Substitutions detected by next- • generation sequencing at 15% • detection threshold

(NS3: 36, 43, 54, 55, 56, 80, • 155, 156, 166, and 168;

NS5A: 24, 28, 29, 30, 31, • 32, 58, 92, and 93)

TE

Non-cirrhotic

12 weeks

TE

Non-cirrhotic

16 weeks

TN

Cirrhotic

12 weeks

TE

Cirrhotic

16 weeks

2 relapses 1 relapse 1 LTFU

1 breakthrough

1 relapse

20

22 21

22

39

40

45

47

Sequence Analysis*

Patient A Non-cirrhotic

12 weeks (relapse)

Patient B Non-cirrhotic

12 weeks (relapse))

Patient C Non-cirrhotic

16 weeks (relapse)

Patient D Cirrhotic 16 weeks (relapse)

Patient E Cirrhotic 16 weeks

(breakthrough)

NS3 Baseline None None None None A166S

Failure None None Y56H, Q168R None A156G, A166S

NS5A Baseline Y93H A30K A30K None None

Failure Y93H A30K, Y93H A30K, Y93H L31F, Y93H A30K, Y93H

4 of 5 patients with virologic failure had treatment-emergent

substitutions

Treatment recommendations for TN and TE* patients without cirrhosis SOF/VEL GLE/PIB

SOF/VEL/ VOX

LDV/SOF GZR/EBR OBV/PTV/r+

DSV

GT1a

TN 12 wk 8 wk No 8-12 wk 12 wk

(HCV RNA ≤800,000 IU/ml) No

TE 12 wk 8 wk No No 12 wk


GT1b TN 12 wk 8 wk No 8-12 wk

8 wk (F0-F2) 12 wk (F3)

8 wk (F0-F2) 12 wk (F3)

TE 12 wk 8 wk No 12 wk 12 wk 12 wk

GT2 TN 12 wk 8 wk No No No No

TE 12 wk 8 wk No No No No



GT4 TN 12 wk 8 wk No 12 wk

12 wk (HCV RNA ≤800,000 IU/ml)

No


GT5 TN 12 wk 8 wk No 12 wk No No




EASL 2018 Recommendations on Treatment of Hepatitis C 2018, J Hepatol 2018

Treatment recommendations for TN and TE patients with compensated cirrhosis

SOF/VEL GLE/PIB SOF/VEL/VOX LDV/SOF GZR/EBR OBV/PTV/r+DSV

GT1a

TN 12 wk 12 wk No 12 wk 12 wk


TE 12 wk 12 wk No No 12 wk


GT1b TN 12 wk 12 wk No 12 wk 12 wk 12 wk

TE 12 wk 12 wk No 12 wk 12 wk 12 wk



GT3 TN No 12 wk 12 wk No No No

TE No 16 wk 12 wk No No No

GT4 TN 12 wk 12 wk No 12 wk

12 wk (HCV RNA ≤800,000 IU/ml)

No







GT

DAA

Naive

no cirrhosis

PR/SOF exper.

no cirrhosis

Naive

cirrhosis

PR/SOF exper.

cirrhosis

1,2,

4,5,

6

SOF/VEL x12 weeks

GLE/PIB x8 weeks x12 weeks

3

SOF/VEL x12 weeks x12 weeks + RBV (or SOF/VEL/VOX)

GLE/PIB x8 weeks x12 weeks x16 weeks

Synopsis of treatment recommendations for pangenotypic regimens for TN and TE patients without or with compensated cirrhosis

PR: PegIFNa+RBV

• Protease inhibitors are contraindicated

• SOF/LDV, SOF/VEL: the only DAA options

• Addition of RBV increases the SVR rates

Treatment recommendations for HCV patients with decompensated cirrhosis


SOLAR-1: SVR12 and safety according to CTP score in decompensated cirrhosis

100

80

60

40

20

0

SVR

12

(%

)

Overall CTP B CTP C

LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks

87 89

45/52 42/47

87 89 86 90

26/30 24/27 19/22 18/20

3 relapses 1 death 1 relapse

2 deaths

1 relapse 1 death 1 LTFU 1 relapse

1 death

Patients n (%)

CTP B CTP C

12 Wks

(n=30)

24 Wks

(n=29)

12 Wks

(n=23)

24 Wks

(n=26)

AE 29 (97) 27 (93) 23 (100) 26 (100)

SAE 3 (10) 10 (34) 6 (26) 11 (42)

Treatment-emergent, -related

SAEs 2 (7) 0 0 2 (8)

Treatment D/C due to AEs 0 1 (3) 0 2 (8)

Charlton M et al. Gastroenterology 2015;149:649-59.

SOLAR-2: SOF/LDV+RBV in HCV decompensated cirrhotics and transplant patients

M Manns et al. Lancet Infect Dis 2016;16:685-97.

SOLAR-2: SOF/LDV+RBV in HCV decompensated cirrhotics and transplant patients

MELD score change from baseline to follow-up week-4

M Manns et al. Lancet Infect Dis 2016;16:685-97.

ASTRAL-4: SOF/VEL ± RBV in HCV Patients with Decompensated Liver Disease

75/90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4 GT4 4/4

GT2 4/4 GT4 2/2

GT2 3/4 GT4 2/2 GT6 1/1

Curry MP et al. N Engl J Med 2015;373:2618-28.

Drug-Drug interactions (Transplantation & HIV drugs excluded) Co-administration is NOT recommended

Sofosbuvir P-glycoprotein inducers (carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampicin, St. John's wort), modafinil, amiodarone

Simeprevir (Caution: digoxin, amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine, warfarin, calcium channel blockers)

Inhibitors or inducers of CYP3A4 (erythromycin, clarithromycin, antifungals, dexamethasone, cicapride, milk thistle, astemizole, terfenadine)

P-glycoprotein inducers

Daclatasvir (Caution: erythromycin, dabigatran, digoxin, calcium channel blockers, rosuvastatin)

Strong inducers of CYP3A4/P-glycoprotein , amiodarone

(Moderate inducers of CYP3A4: DCV 90 mg/24h)

(Inhibitors of CYP3A4: DCV 30 mg/24h)

Ledipasvir/Sofosbuvir (Caution: amiodarone, antacids, PPIs, digoxin, dabigatran, pravastatin, statins)

P-glycoprotein inducers, rosuvastatin, simeprevir, modafinil , amiodarone

Paritaprevir/r/Ombitasvir ± Dasabuvir (Caution: digoxin, warfarin, calcium channel blockers)

P-glycoprotein inducers, gemfibrozil, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, ethinyl estradiol-containing oral contraceptives, sildenafil for pulmonary hypertension, amiodarone

Drug-Drug interactions (Transplantation & HIV drugs excluded) Co-administration is NOT recommended

Velpatasvir/Sofosbuvir (Caution: antacids, H2RAs, PPIs)

P-glycoprotein inducers (carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampicin, St. John’s

wart), amiodarone

Elbasvir/Grazoprevir (Caution: amiodarone, cyclosporine)

OATP1B1/3 inhibitors, Potent CYP3A4 inducers (carbamazepine, phenytoin, rifampicin, St. John’s wart)

Glecaprevir/Pibrentasvir P glycoprotein and CYP3A inducers (rifampicin, St. John’s wort, carbamazepine, phenobarbital, phenytoin, primidone), atorvastatin, simvastatin, dabigatran, ethinylestradiol-containing products

Sofosbuvir, Sofosbuvir/Ledipasvir, Sofosbuvir/Velpatasvir

Daclatasvir

Paritaprevir/r/Ombitasvir ± Dasabuvir

Drug-Drug interactions

None

None

Increase of TACR>CsA levels TAC: 0.5 mg/wk or 0.2 mg/72h,

CsA: 20% of previous dose Not with everolimus

Not with CsA (increases GZR plasma levels: ALT flares?)

- Close monitoring TACR levels

Not with CsA - Close monitoring TACR levels

Not with CsA


Grazoprevir/Elbasvir

Transplant patients

Sofosbuvir/Velpatasvir /Voxilaprevir

CsA: cyclosporin, TACR: tacrolimus

Drug-Drug interactions with HIV drugs

None

Not with darunavir, lopinavir, etravirine ή nevirapine - DCV 30 mg with atazanavir/r, DCV 90 mg with efavirenz

Not with cobicistat*, tripanavir/r

Not with efavirenz, rilpivirine ή lopinavir

Not with efavirenz (closer follow-up for TDF AEs)

Not with efavirenz (closer ALT fup with atazanavir, darunavir, lopinavir, saquinavir, tripanavir)

Not with atazanavir, darunavir, efavirenz, lopinavir, etravirine, nevirapine

Not with atazanavir, efavirenz, lopinavir, etravirine, nevirapine (closer follow-up for TDF AEs) *cobicistat: elvitegravir + cobicistat + emtricitabine + tenofovir

Sofosbuvir

Daclatasvir

Sofosbuvir/Ledipasvir

Paritaprevir/r/Ombitasvir ± Dasabuvir

Sofosbuvir/Velpatasvir


HCV & HIV coinfection IFNa-free regimens similar efficacy to HCV monoinfected patients


Sofosbuvir/Velpatasvir /Voxilaprevir

Sofosbuvir (/Ledipasvir, /Velpatasvir, /Velpatasvir/Voxilaprevir)

Paritaprevir/r/Ombitasvir, Dasabuvir

HCV in patients with renal impairment

Drug doses in reduced Creatinine Clearance (CrCl)

200/400 mg /24/24h - ClCr 30-50 ml/min 200 mg /24h - ClCr <30 ml/min

No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min

No change

No change

No change

Ribavirin



New DAAs - Conclusions

Increasing number of licensed agents for patients with HCV

-Availability and accessibility vary among countries

Shortening of treatment duration to 8 weeks is possible in some non-cirrhotic

patients, with no loss of efficacy

Treatment options available irrespective of cirrhosis status

The proportion of patients failing to respond to DAAs is small and re-

treatment options are available for most patients

-NS5A inhibitor failures remain a treatment challenge

The availability of DAAs means that HCV cure is now a reality for most patients

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