Hepatitis C Treatment Update A/Prof Josh Davis

Infectious Diseases Physician John Hunter Hospital, NSW Principal Research Fellow

Menzies School of Health Research, NT, Australia August 2016

• Currently approved drug regimens

• Uptake of new regimens nationally and at JHH

• Remaining questions/problems

Evolution of HCV treatment

IFN 6 mos

PegIFN/ RBV

12 mos

IFN 12 mos

IFN/RBV 12 mos

PegIFN 12 mos

2001

1998 Standard

IFN

RBV

PegIFN

1991

2011

PegIFN/ RBV +

Protease Inhibitors

IFN/RBV 6 mos

6

16

34

42 39

55

70+

0

20

40

60

80

100

DAAs

Adapted from the US FDA, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

Evolution of HCV treatment

IFN 6 mos

PegIFN/ RBV

12 mos

IFN 12 mos

IFN/RBV 12 mos

PegIFN 12 mos

2001

1998 Standard

IFN

RBV

PegIFN

1991

2011

PegIFN/ RBV +

Protease Inhibitors

IFN/RBV 6 mos

6

16

34

42 39

55

70+

0

20

40

60

80

100

DAAs

95+

All oral DAAs

2014

Adapted from the US FDA, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

TOLERABILITY

EF

FIC

AC

Y

IFN

IFN/RBV

PEG-IFN/RBV

PEG-IFN/RBV/TVR PEG-IFN/RBV/BOC

PEG-IFN/RBV/SMV

PEG-IFN/RBV/SOF

SOF/SMV SOF/LDV PTV/OBV/DSV/RBV SOF/DCV

48 WEEKS

24-48 WEEKS

24 WEEKS

12 WEEKS

Dore GJ & Feld J. CID 2015

20 years

3 years

Protease

inhibitor

Nucleotide

analogue

Non-

nucleoside

analogue

NS5A

inhibitor Other Duration

Total

tablets/

dosing

Phase

Janssen/

Gilead Simeprevir Sofosbuvir

+/-

Ribavirin

12-24

weeks

2-8

daily/b

d

TGA

approved

Gilead Sofosbuvir Ledipasvir 8-24 wks 1

daily

TGA

approved

Abbvie Paritaprevir/r Dasabuvir Ombitasvir +/-

Ribavirin 12-24 wks

4-10

bd

TGA

approved

BMS Asunaprevir Beclabuvir Daclatasvir +/-

Ribavirin 12 wks

2-8

bd FDA

Merck Grazoprevir Elbasvir +/-

Ribavirin 12-16 wks

1-7

daily/b

d

FDA

BMS/

Gilead* Sofosbuvir Daclatasvir 12 wks

2

daily

TGA

approved

Gilead* Sofosbuvir Velpatasvir 12 wks 1

daily FDA

IFN-free Regimens in 2016DAA development: GT1

* Pangenotypic regimens

)

Current PBS-funded regimens

• Genotype 1

– Sofosbuvir/Ledipasvir “Harvoni”

• 8-12 weeks

• 24 weeks for Rx experienced cirrhotic

– Paritapreivr/ritonavir, Ombitasvir, Dasabuvir “Vikeira Pak”

• GT1b non-cirrhotic - 12 weeks

• GT1a non-cirrhotic - 12 weeks + ribavirin

• GT 1 with cirrhosis – 12 weeks plus ribavirin

• GT1a Rx experienced cirrhotic – 24 weeks plis ribavirin

Current PBS-funded regimens

• Genotype 3

– Sofosbuvir plus Daclatasvir

• 12 weeks non-cirrhotic

• 24 weeks cirrhotic

• Genotype 2

– Sofosbuvir plus ribavirin

• 12 weeks non-cirrhotic

• 24 weeks cirrhotic

National HCV Rx uptake

• ~2,000 people Rx per year pre 2016

• PBS listing on 1st March

• 17,870 people started DAA Rx March to May 2016

HCV elimination

• Pre-2016: 230,000 infected, 1.5% Rx annually, 10,000 new infections annually

• Number of infected people would triple by 2030

BUT . . . .in the new world

• WHO: HCV elimination by 2030

• Australia: HCV elimination within 10 years (2026)

HCV Rx uptake at JHH

• 2012-2014: ~100 patients treated per year

– JHH, Cessnock, RT, Taree

• March-June 2016

– 353 patients commenced on Rx

– A 1000% increase!

– Not sustainable without more resources and different models

How much monitoring is needed?

In adults treated with 12 weeks of Sofosbuvir/Ledipasvir for Genotype 1 hepatitis C virus infection, or Sofosbuvir/Daclatasvir for genotype 3 hepatitis C, does minimal monitoring lead to a similar chance of cure with reduced staff time and good patient acceptability compared to a current standard monitoring regimen?

How to diagnose cirrhosis?

• Fibroscan is the current most accepted method

• 4 machines in HNE health, but difficult for GPs to access

• APRI (AST:Plt ratio index) – insufficient sensitivity and specificity

• Private radiology: US-based SWE yet to be validated

How to increase GP prescribing?

• GPs allowed to prescribe “in consultation with a specialist”

• Multiple education sessions delivered

• 1-page consultation form developed

• Wall chart/guidelines available

• More staff time needed for “ECHO” like telehealth project and outreach clinics

How to treat GT 4,5,6?

• Currently no PBS-approved Rx except PEG-IFN and ribavirin

• Sof/Led and Viekira Pak are both effective for these genotypes but not funded

• Elbasvir/Grazoprevir (“Zapateir”) currently before TGA for GTs 1,4,5,6

• Sofosbuvir/Velpatastir FDA approved for GTs 1 to 6.

HCV and Renal Disease

• HCV infection may lead to renal disease or be associated with renal disease

– Mixed cryoglobulinemia (type II cryoglobulins, or + RF)[1]

– Membranoproliferative glomerulonephritis (MPGN)[1]

– Polyarteritis nodosa[2]

• Less clearly related to HCV[1]

– Focal segmental glomerulosclerosis

– Proliferative glomerulonephritis

– Membranous glomerulonephritis

– Fibrillary and immunotactoid glomerulopathies

• Diabetes (direct link to HCV) and hypertension common in HCV infection[3]

1. Ozkok A, et al. World J Gastroenterol. 2014;20:7544-7554. 2. Saadoun D, et al. Arthritis Care Res

(Hoboken). 2011;63:427-435. 3. Satapathy SK, et al. J Clin Exp Hepatol. 2014;4:8-13.

HCV Infection in Pts With End-Stage Renal Disease

• HCV in pts on hemodialysis: – Estimated US prevalence ~ 8% (of 400,000 on HD)[1]

• 5 x greater than general US population

– In industrialized populations HCV prevalence ranges from 2.6% to 23.0% in ESRD pts (mean: 13.5%)[2]

– Number of yrs on dialysis independent risk factor for HCV infection[2]

• HCV: natural history – HCV infection independently associated with

increased mortality in hemodialysis pts[3]

– Increased rates of cirrhosis and hepatocellular cancer

1. Finelli L, et al. Semin Dial. 2005;18:52-61. 2. Fissell RB, et al. Kidney Int. 2004;65:2335-2342. 3. Kamar

N, et al. Transplantation. 2006;82:853-856.

• 362 of 23,046 dialysis patients HCV +ve (1.6%)

• 140 of 7,572 renal transplant patients HCV +ve (1.8%)

• aHR for death in HCV +ve= 1.25 in the dialysis group and 2.38 in the transplant group

HCV TARGET: Safety Outcomes With SOF Regimens by Baseline eGFR

• Rates of anemia AEs, worsening renal function, and renal and urinary AEs increased across decreasing eGFR strata Safety Outcome in Pts Who Completed

SOF-Containing Therapy, n (%)

eGFR ≤ 30

(n = 17)

eGFR 31-45

(n = 56)

eGFR 46-60

(n = 157)

eGFR > 60

(n = 1559)

Anemia AEs 6 (35) 16 (29) 37 (24) 246 (16)

Transfusions 2 (12) 5 (9) 3 (2) 31 (2)

Erythropoietin 1 (6) 8 (14) 14 (9) 50 (3)

Reduction in RBV dose 3 (38) 8 (30) 33 (42) 185 (19)

RBV discontinuation 0 4 (15) 1 (1) 12 (1)

Worsening renal function 5 (29) 6 (11) 4 (3) 14 (1)

Renal or urinary system AEs 5 (29) 6 (11) 13 (8) 84 (5)

Serious AEs 3 (18) 13 (23) 8 (5) 100 (6)

Cardiac AEs 1 (6) 2 (4) 8 (5) 53 (3)

Saxena V, et al. EASL 2015. Abstract LP08.

C-SURFER: Efficacy and Safety Results

Roth D, et al. EASL 2015. Abstract LP02.

AE, %

Grazoprevir/

Elbasvir

(Randomized Tx)

(n = 111)

Placebo

(n = 113)

Serious AEs 14.4 16.8

D/c due to

AE 0 4.4

Death 0.9 2.7

Hb decr from

BL

1 grade 24.3 26.5

2 grades 12.6 7.1

3 grades 3.6 1.8

4 grades 0 0.9

20

Full Set

n/N =

SV

R1

2 (

%)

94

115/ 122

100

6/ 6

100

61/ 61

98.2

54/ 55

98.9

86/ 87

97.6

40/ 41

GT1a HCV

GT1b HCV

Diabetic On HD

100

80

60

40

0

Cirrhosis

GZR/EBV for 12 wks

RUBY-I, Cohort 2: Virologic Response

*one patient withdrew consent; resulted in confirmed virologic failure

†one patient d/c study drug on day 4 due to SAE (volvulus) unrelated to study drug

Options for patients with renal failure

• Viekira Pak (PrOD) – GT1b

– GT1a plus ribavirin

• Elbasvir/Grazoprevir – GT1,4,5,6

• GT2,3 – No good options

– Can use sofosbuvir off label, or

– PEG-IFN + ribavirin

Summary

• The HCV treatment landscape is rapidly changing

• Key unresolved questions include – How to upscale roll out to GPs

– How much monitoring is needed with DAAs

– How to treat “special populations” • Renal disease

• Children

• Decompensated cirrhosis

• Pregnancy

• ?Role of DAAs in PEP and prevention of MTCT