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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
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