hcv treatment in the era of daa - prof. gamal esmatgamalesmat.com/admin/uploads/hcv...

Prof. Gamal Esmat Prof. Hepatology &Ex. Vice President of Cairo University, Egypt

Member of WHO Strategic Committee for Viral Hepatitis

www.gamalesmat.com

HCV Treatment in the Era of DAA

Ribavirin

Pegylated interferons

Suppression of HCV with DAA combination

(PI + NI)

Curability of HCV without

interferon

Frequent curability of

diverse populations without IFN

Simeprevir or sofosbuvir with IFN (GT1)

HCV therapy: past, present and future

2015+ 1990 2000 2005 2010 2011 2012 2013 2014

Interferon Proof

of concept for DAA (PI)

Telaprevir and

boceprevir

Daclatasvir (Japan and

Europe)

Daclatasvir+ sofosbuvir (GT1b)

Ledipasvir + sofosbuvir

Paritaprevir/RTV/ ombitasvir +

dasabuvir ± RBV

Simeprevir + sofosbuvir

First approved IFN-free therapy: Sofosbuvir +

RBV (GT2,3)

Simeprevir + sofosbuvir (off label use in US and

EU)

6–19 11–19 10–22

31–44 33–36

61–79

18–39 42–46

76–82 66–79

80–90 85–97

0

20

40

60

80

100

24 48 78

IFN monotherapy (weeks)

IFN + ribavirin PegIFN PegIFN + ribavirin PegIFN + ribavirin + BOC/TVR SMV or SOF + PegIFN + RBV

SOF + RBV

All genotypes Genotype 1 Genotype 2/genotype 3

Evolution of HCV treatment and SVR

rates

Davis GL, et al. N Engl J Med 1989; 321:1501–1506; Poynard T, et al. N Engl J Med 1995; 332:1457–1462; McHutchison JG, et al. N Engl J Med 1998; 339:1485–1492; Poynard T, et al. Lancet 1998; 352: 1426–1432; Zeuzem S, et al. N Engl J Med 2000;

343:1666–1672; Linsay KL, et al. Hepatology 2001; 34:395–403; Pockros PJ, et al. Am J Gastroenterol 2004; 99:1298–1305;

Manns MP, et al. Lancet 2001; 358:958–965; Fried MW, et al. N Engl J Med 2002; 347:975–982; Poordad F, et al. N Engl J Med 2011;

364:1195–1206; Jacobson IM, et al. N Engl J Med 2011; 364:2405–2416; Simeprevir prescribing information, November 2013;

Lawitz E, et al. N Engl J Med 2013; 368:1878–1887; Zeuzem S, et al. Hepatology 2013; 58(Suppl 1):733A; AbbVie press release

2014 [Accessed 25-02-14]; Gilead press release 2013 [Accessed 25-02-14]; Sulkowski MS, et al. N Engl J Med 2014; 370:211–221.

1989 2011 2013 2014/15

SV

R (

%)

DAA

comb

os

95–100

We now have highly efficacious DAAs that target

different stages in the HCV lifecycle

Lindenbach BD, Rice CM. Nature 2005;436(Suppl):933–8; Liang J, Ghany MG. N Engl J Med 2014;370:2043–7.

DAA: direct-acting antiviral agent; ER: endoplasmic reticulum; GT: genotype; IFN: interferon; LD: luminal domain; NA: nucleos(t)ide analogue;

NS: non-structural protein; SVR: sustained virological response

Receptor binding and endocytosis

Fusion and uncoating

Transport and release

(+) RNA Translation and polyprotein processing

RNA replication

Virion assembly

ER lumen

LD

LD

ER lumen

LD

NS3 protease

inhibitors

Non-NA NS5B inhibitors

NA NS5B inhibitors

NS5A inhibitors

Membranous web

96%

SVR

Summary of New England Journal

of Medicine studies on IFN-free therapy

in GT 1 patients published in 2014

3680/

3826

Non-Nucs

NS5A inhibitors ‘…asvirs’

Sofosbuvir Ledipasvir

Sofosbuvir Daclatasvir

Sofosbuvir Simeprevir

Protease inhibitors ‘…previrs’

Polymerase inhibitors ‘…buvirs’

Nucleos(t)ide

Paritaprevir/r Ombitasvir +/-Dasabuvir

Sofosbuvir + RBV

IFN-free regimens available in 2016

EASL Recommendations 2015, DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.025. Accessed April 2015.

Grazoprevir Elbasvir

Currently approved IFN-free treatment choices

in the International label for patients with HCV GT-4

DCV + SOF1,2

SOF/LDV (FDC)3

SOF2 + Riba

AASLD

x

Duration (weeks)

EASL WHO

x x

SIM + SOF1,2 x

SOF/PEG/RBV x

PARr/OMB

*Consideration should be given to potentially extending treatment duration, up to 24 weeks, especially for those subgroups with one or more factors historically associated with lower response rates to IFN-based therapies. 1. Daklinza (Daclatasvir) SmPC, Bristol-Myers Squibb Pharmaceutical Limited, October 2014. 2. Sovaldi (Sofosbuvir) SmPC, Gilead Sciences Ltd, March 2015. 3. Harvoni (LDV/SOF FDC) SmPC, Gilead Sciences Ltd, November 2014.

Graz/Elba x x

Guidelines of the National Treatment Program in Egypt

• Easy to treat group: • Treatment naïve • Total serum bilirubin ≤ 1.2 mg/dl. • Serum albumin ≥ 3.5 g/dl. • INR≤ 1.2. • Platelet count≥ 150.000/mm3.

• Easy to treat group are eligible to be treated by any of the following regimens for 12 weeks:

• Sofosbuvir + daclatasvir • Sofosbuvir + simeprevir • Sofosbuvir + ledipasvir • Paritaprevir-r/ombitasvir +ribavirin


• Not easy to treat group: • Peg-IFN treatment experienced • Total serum bilirubin ≥1.2 mg/dl. • Serum albumin ≤3.5 g/dl. • INR≥1.2. • Platelet count <150.000/mm3.

• These patients are eligible to be treated by any of the following regimens for 12 weeks:

• Sofosbuvir +daclatasvir +ribavirin • Sofosbuvir + simeprevir • Sofosbuvir + ledipasvir +ribavirin • Paritaprevir-r/Ombitasvir +ribavirin

• *The dose of ribavirin is 600 mg/day. A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability.

• *Neither paritaprevir-r/ombitasvir or sofosbuvir-simeprevir is given to patients with Child B or C cirrhosis.


Patients with advanced liver disease(Child B)

• Treatment only in one of several assigned specialized centers.

• One of the following regimens is used for 12 weeks :

• Sofosbuvir + Daclatasvir + Ribavirin

• Sofosbuvir + Ledipasvir + Ribavirin

• The dose of ribavirin is 600 mg/day. A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability

• Treatment of patients with post organ transplantation:

• Treatment will be with Sofosbuvir + Daclatasvir or Sofosbuvir + Ledipasvir for 24 weeks

Unique Patient Populations Decompensated Cirrhosis

Genotype Recommended Rating

1 and 4

DCV + SOF + RBV** x 12 weeks

OR

SOF/LDV + RBV** x 12 weeks

Class II, Level A

Class IIb, Level C

2 and 3

DCV + SOF + RBV** x 12 weeks

OR

SOF + RBV x up to 48 weeks

Class II, Level A

Class IIb, Level B

RBV intolerant/ineligible

1 and 4 DCV + SOF x 24 weeks Class IIb, Level C

Prior SOF-based regimen failure

1 and 4 SOF/LDV + RBV** x 24 weeks Class IIb, Level C

* Decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C) who may or may not be candidates for liver transplantation,

including those with hepatocellular carcinoma

**initial RBV dose of 600 mg, increased as tolerated

PEG: Pegylated interferon, RBV: Ribavirin, SMV: Simeprevir, SOF: Sofosbuvir, LDV: Ledipasvir, DCV: Daclatasvir, PrOD: Paritaprevir + Ritonavir + Ombitasvir, + Dasabuvir

AASLD Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: http://www.hcvguidelines.org. Last accessed: Aug 8, 2015. AASLD Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: http://www.hcvguidelines.org. Last accessed: Aug 8, 2015.

In subgroup analysis of pts in the advanced cirrhosis cohort, those who

were Child-Pugh class C (n = 16) or had albumin < 2.8 g/dL (n = 18)

had SVR12 rates of 56%

ALLY-1: SVR12 by HCV Genotype

76

97 100 90

80 83 91

100 100

0

20

40

60

80

100

SV

R12, %

1a 1b 2 3 4 6

Genotype

1a 1b 2 3 4 6

Advanced cirrhosis cohort N = 60

Post-transplant cohort N = 53

Child-Pugh Class

11/12

92

A B C

30/ 32

94

9/ 16

56

87 87 8689 89 90

0

20

40

60

80

100

Overall ChildPughB ChildPughC

LDV/SOF+RBV12weeks LDV/SOF+RBV24weeks

SV

R 1

2 (

%)

45/52 42/47 26/30 24/27 19/22 18/20

3 relapses

1 death

1 relapses 2 deaths

1 relapses 1 death 1 LFU

1 relapses 1 death

6 patients were transplanted and excluded from analysis

3 patients did not reach SVR12

108 patients randomized 12 vs 24 weeks

Rbv: escalating dose staring at 600 mg/day

Deaths (n=3), D/S for AE (n=3), OLT (n=4)

Flam et al., AASLD 2014

SOLAR1: LDV-SOF in Decompensated Cirrhosis

AASLD 2015

Patients with HCV who have decompensated cirrhosis (moderate or severe hepatic impairment; Child Turcotte Pugh [CTP] class B or C) should be referred to a medical practitioner who is highly experienced in the management of advanced liver disease and HCV treatment (ideally in a liver transplant center).

SOLAR-1: Change in MELD Score From BL

to FU Wk 4 in Decompensated Cirrhosis

n = 5

n = 5

n = 2

n = 3

(-8)

(+10)

CTP B CTP C 12 wks (n = 30)* 24 wks (n = 29)* 12 wks (n = 23)* 24 wks (n = 26)*

*Missing FU-4: n = 2 CTP B 12 wks; n = 4 CTP B 24 wks; n = 2 CTP C 12 wks; n = 7 CTP C 24 wks. Each bar represents 1 pt.

Flamm SL, et al. AASLD 2014. Abstract 239. Reproduced with permission.

4

2

0

-2

-4

-6

4

2

0

-2

-4

-6

Ch

ange

in M

ELD

Sco

re


Patients with chronic kidney disease (CKD):

• In patients having a serum creatinine exceeding the upper normal level, eGFR is calculated, and, accordingly,

• Patients with CKD stage I-II (eGFR> 30 ml/min) are treated by the usual treatment regimens.

• Patients with CKD stage III-V (eGFR≤ 30 ml/min) are treated by Paritaprevir-r/Ombitasvir+ribavirin, provided the following are fulfilled

• Patients have compensated liver (Child A cirrhosis or no cirrhosis) • Hb level is at least 10 g/dL • The patient has no associated uncontrolled co-morbidity (Cardiac, neuro-

psychic,..) • A nephrologist consultation is done. A report determining the treatment

eligibility and necessity, and the exact ribavirin recommended dose (and time of administration in relation to dialysis).

• In case of dialysis, the patient should be aware of the high risk of re-infection by signing a consent form.

Renal Impairment

PEG: Pegylated interferon, RBV: Ribavirin, SMV: Simeprevir, SOF: Sofosbuvir, LDV: Ledipasvir, PTV: Paritaprevir, OBV: Ombitasvir, DSV: Dasabuvir;

Renal

Impairment

eGFR/

CrCl

(ml/mi

n) SOF LDV DCV OBV PTV SMV

Mild 50-80 Standard Standard Standard Standard Standard Standard

Moderate 30-50 Standard Standard Standard Standard Standard Standard

Severe <30 Limited

data

available

Data not

available

Limited

data

available

Standard Standard Standard

ESRD/HD Limited

data

available

Data not

available

Limited

data

available

Limited

data

available

Limited

data

available

Limited

data

available

Abbreviations: CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HD, hemodialysis.

Unique Patient Populations

AASLD Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: http://www.hcvguidelines.org. Last accessed: Aug 8, 2015.


• Patients who failed previous Sofosbuvir containing regimen

• Treatment will be with Sofosbuvir + Daclatasvir + Ribavirin

Or Sofosbuvir + ledipasvir +ribavirin

• for 24 weeks.

• The dose of ribavirin is 600 mg/day. A trial should be done to reach a dose of 1000 mg/day based on the patient tolerability

ATU / AMM project 2014 - 07/12/15 (patients treated with AAD)

18

Cohorte ANRS CO22 HEPATHER

4 978 patients treated with DAA (patients treated in therapeutic trials excluded)

• Combinaisons thérapeutiques

Combination Effective Patients 12 weeks after the DAA initiation

W12 or EOT

Patients 24 weeks after the DAA initiation

SVR12 or EOT

SOF + RBV 463 453 427

SOF + PegIFN + RBV 270 270 268

SOF + DCV 1 487 1 438 1 412

SOF + DCV + RBV 495 472 446

SOF + SMV 793 788 780

SOF + SMV + RBV 88 85 82

SOF + LDV 958 837 711

SOF + LDV + RBV 410 376 319

OBV + PTV+ RTV 123 84 56

OBV + PTV+ RTV + RBV 82 70 55

Figure 8: Real-world experience from the TRIO Network: Patient distribution and SVR rates with all-oral DAA regimens

Figure 9: SVR12 rates by regimen in the TRIO network

AGENDA

• Acute HCV

• Predictors of response

• G3

• Shorten duration of therapy

• Retreatment.

• Future HCV management in Egypt

TREATMENT Of ACUTE HCV

Course of acute, resolving HCV Course of acute HCV evolving into chronicity

Table 2: SOF/LDV vs. SOF + SIM for Acute Hepatitis C: Results