Management of the treatment-naïve
patient with HCV infection
Paul Desmond
Greg Dore
Learning objectives
1. Patient factors involved in treatment decisions
2. Viral factors in treatment decisions
3. Logistics in using DAAs
4. Management of side-effects of DAAs
5. Role of IL-28B testing
6. Role of ribavirin monitoring
Mrs LF
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57-year-old housewife
Presents to GP with tiredness
ALT 65 U/L
HCV antibody positive
Otherwise well
On examination NAD
Mrs LF
Risk factors for HCV
• Husband had liver transplant in 2007 for
decompensated HCV/alcohol-related
cirrhosis
• NO IV drug use or blood transfusion
Question
What other investigations
would you order?
Mrs LF
- ALT
- Albumin
- Platelets
62 U/L
40 g/L
247 x 109/L
- HCV PCR
- HCV VL
- Genotype
Positive
4,730,000 IU/mL
1a
Questions
• Genotype 1a vs 1b?
• Viral load?
• Influence on response to treatment?
Telaprevir in G1 patients:
Impact of host and viral factors
100
79
Patients Achieving SVR (%)
78
75
74
71
Results represent telaprevir (T12PR) populations
Treatment-naïve GT1 patients
78
75
62
62
50
25
0
Viral load
LVL HVL
Genotype
1b
1a
Race
Non-Black Black
Fibrosis
F0-2 F3-F4
Marcellin P, et al. Poster 451; Dusheiko GM, et al. Poster 415. Posters presented at: EASL: The International Liver Congress 2011; March
30-April 3, 2011; Berlin, Germany. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
HCV Genotype 1b has a higher genetic
barrier than Genotype 1a
ATC
(V36)
ATG
(V36M)
2 steps
GTG
(V36)
ATG
(V36M)
Subtype 1a
1 step
GTC
(V36)
ATC
(V36)
Subtype 1b
www.hivforum.org
Question
Any further investigations?
Mrs LF
• Fibroscan
Liver stiffness 7.9 KPa
• IL28B
C/T
Question
What should we do now?
- Genotype 1a
- High viral load
- F2-F3 fibrosis
- IL28B C/T
Ge*, Fellay*, Thompson* et al. Nature 2009
Multivariate analysis of baseline predictors
of SVR (genotype 1 HCV)
• ITT analysis of patients from IDEAL study who consented to
genetic testing, regardless of adherence level (n=1604),
plus 67 patients from another trial
(race based on self-report, similar to clinical practice setting)
Adjusted Odds Ratio (95% CI)
P Value
rs12979860 CC
5.2 (4.1-6.7)
< 0.0001
HCV RNA level ≤ 600,000 IU/mL
3.1 (2.3-4.1)
< 0.0001
White vs black
2.8 (2.0-4.0)
< 0.0001
Hispanic vs black
2.1 (1.3-3.6)
0.0041
METAVIR F0-F2
2.7 (1.8-4.0)
< 0.0001
Fasting blood sugar < 5.6 mmol/L
1.7 (1.3-2.2)
< 0.0001
Predictor
Thompson AJ, et al. Gastroenterology. 2010;139:120-129.
HCV-1 Rx-naïve (ADVANCE/SPRINT-2)
100
Patients (%)
80
TVR 8 + PR
BOC 44
TVR 12 + PR
BOC RGT
PR 48
PR 48
Telaprevir
69%
Boceprevir
75%
63%
66%
60
44%
38%
40
20
0
SVR
SVR
Mrs LF
Entered a clinical trial:
• Telaprevir BD vs Telaprevir TID
Mrs LF – Haemoglobin during treatment
End of treatment
Transfusion
RBV dose 1000 mg
600 mg
• Anaemia management on telaprevir
• Ribavirin dose reduction
• Transfusion
• EPO
Mrs LF – Telaprevir side effect (rash)
TVR & BOC: Adverse events
SIDE EFFECT
T12
T8
PR (T)
Fatigue
57%
58%
57%
Pruritus
50%
45%
36%
Headache
41%
43%
Nausea
43%
Rash
Anaemia
BOC 44 BOC RGT
PR (B)
57%
53%
60%
39%
46%
46%
42%
40%
31%
43%
48%
42%
37%
35%
24%
37%
39%
19%
49%
49%
29%
43%
43%
24%
33%
32%
33%
EPO Use
Insomnia
32%
32%
31%
Diarrhoea
28%
32%
22%
Flu Sx
28%
29%
28%
33%
36%
28%
Pyrexia
26%
30%
24%
33%
33%
32%
Anorectal Sx
13%
8%
4%
43%
37%
18%
Dysgeusia
Treatment of TVR rash
Mild
Moderate
RASH
Severe
SCAR
Emollients, topical corticosteroids,
antihistamines, limit sun exposure, loose
fitting clothes
? Derm R/V
If progresses, cease TVR
If no improvement in 7 days, stop RBV
Permanently cease TVR
Monitor for progression/systemic symptoms
If no improvement in 7 days, stop RBV+/- peg-IFN
Permanent and immediate cessation of TVR
Derm R/V
SCAR (Severe Cutaneous Adverse Reaction)
Acute generalised
exanthematous
pustulosis (AGEP) and
Erythema Multiforme
Major (EMM)
SCAR
encompasses
several
conditions
Drug rash/reaction with
eosinophilia and systemic
symptoms (DRESS)
Toxic epidermal necrolysis
(TEN) and StevensJohnson Syndrome (SJS)
3 cases suggestive of SJS
(1 case considered not related to telaprevir,
onset 11 weeks after telaprevir discontinuation)
11 cases suggestive of DRESS
Cacoub P et al. J Hepatol 2012;56:455-463
Mrs LF – Results on treatment
Week
Hb
Neutrophils
Platelets
ALT
0
135
4.33
304
50
4
119
1.2
119
17
Neg
8
84
1.23
99
18
Neg
12
87
1
137
27
Neg
16
91
1.6
139
14
Neg
24
92
0.87
113
15
Neg
48
PCR
Neg
Ms CB – Presentation (July 2008)
• 52-year-old, retired
• De facto male partner (HCV +ve)
• 2 children (18, 26 years: HCV –ve)
• Lives in Far South Coast NSW
• Smoker: 20 cigarettes/day
• Alcohol: 40 – 60 grams/day
• Medications: Nil
Ms CB – Presentation (July 2008)
• HCV diagnosis: 1995
• Risk factors: IDU 1979 – late 2007
• Symptoms: mild lethargy
• Past medical Hx: chronic anxiety
• Clinical exam: NAD
Ms CB – Baseline investigations (July 2008)
• LFTs:
Alb 44, Bil 8, AST 49, ALT 44, GGT 127
• FBC:
Hb 153, Neut 3.3, Plats 275
• Genotype: 1 (no subtype)
• HCV RNA:
>700,000 IU/ml
• Fibroscan: 8.1 (November 2008)
Management Plan:
• Alcohol reduction; defer HCV treatment
Ms CB – Follow-up
January 2010:
• Continued alcohol intake 40-60 g/day
• No repeat Fibroscan performed
October 2011:
• Continued alcohol intake 40-60 grams/day
• Fibroscan:
12.0 kPa
• Genotype :
1a, HCV viral load 2 million IU/mL
• LFTS:
Alb 44, Bil 7, AST 67, ALT 82, GGT 134
• FBC:
Hb 148, Neut 2.1, Plats 229
• AFP:
26.1
Ms CB – Follow-up
February 2012:
• No further alcohol intake
• Fibroscan: 13.1 kPa
• Preparation for HCV treatment
• Abdominal U/S: NAD
• No features of cirrhosis/portal H/T
• No IL28B testing available
Issue 1:
Would result of IL28B testing (if available)
have influenced choice of treatment
regimen?
SPRINT-2: IL28B and DAA response
CT
TT
SVR (%)
CC
n/N=
50/64
63/77
44/55
33/116
67/103
82/115
10/37
23/42
Poordad F, et al. J Hepatol 2011;54(Suppl.):S6
26/44
HCV treatment: peg-IFN/RBV(BOC)
April 2012 (baseline):
• Peg-IFN-alfa-2a (180 mcg/week) + RBV 1000 mg/day
• LFTs:
Alb 41, Bil 7, AST 63, ALT 83, GGT 87
• HCV VL: 2.08 million (6.3 log)
HCV treatment: peg-IFN/RBV(BOC)
May 2012 (week 4):
• Peg-IFN-alfa-2a (180 mcg/week) + RBV 1000 mg/day
• AEs:
Lethargy, dyspnoea on exertion, insomnia
• LFTs:
Alb 40, Bil 12, AST 43 (63), ALT 44 (83), GGT 124 (87)
• FBC:
Hb 96 (142), Neut 1.4 (2.3), Plats 218 (213)
• HCV VL:
203,400 (5.3) (2,086,900 (6.3) )
• RBV conc: 2.96
Issue 2:
Given the decline in HCV VL over weeks
0 – 4, what is the prospect of SVR?
Would the decline in VL influence
subsequent treatment?
SPRINT-2: SVR by lead-in viral decline
100
90
82
82
HCV RNA week
0-4 (Non-black)
80
70
60
SVR
%
>1 log decline
52
50
<1 log decline
39
40
29
30
20
10
5
0
PEG/RBV48
BOC/PR48
BOC/RGT
Poordad F, et al. NEJM 2011;364:1195-1206
Issue 3:
Role of EPO vs RBV dose reduction?
Role for monitoring of serum RBV
concentration?
SPRINT-2: Adverse events
48 PR (n=363)
BOC RGT (n=368)
BOC/PR48 (n=366)
Median treatment duration, days
203
197
335
Deaths
N= 4
N=1
N= 1
Serious AEs
9%
11%
12%
Discontinued due to AEs
16%
12%
16%
Dose modifications due to AEs
26%
40%
35%
Neutrophil count (< 750 to 500/mm3/< 500/mm3)
14%/4%
24%/6%
25%/8%
Haemoglobin (< 10 to 8.5 g/dl/<8.5 g/dL)
26%/4%
45%/5%
41%/9%
Discontinuation due to anaemia
1%
2%
2%
Dose reductions due to anaemia
13%
20%
21%
Erythropoietin use
24%
43%
43%
121 (109)
94 (85)
156 (149)
Haematologic parameters
Mean (median) days of use
Poordad F, et al. NEJM 2011;364:1195-1206
EPO vs ribavirin dose reduction in
peg-IFN/RBV/BOC
• HCV treatment naïve, genotype 1 (n=687)
RBV DR
(200-400 mg)
After completion of 4 week peg-IFN/RBV
lead In, all patients initiated boceprevir
Haemoglobin
≤10 g/dL
Haemoglobin ≤8.5 g/dL:
Secondary Strategy
(EPO, RBV DR, transfusion)
R
EPO
(40,000 IU/wk SC)
R
= randomisation
DR, dose reduction; EPO, erythropoietin; peg-IFN, peg-interferon;
RBV, ribavirin; SC, subcutaneously.
Poordad F, et al. EASL 2012
73%
Enrolled
n=687
SVR=62.7% (431/687)
Met protocol-defined
anaemia criteria
n=500
SVR=71.2% (356/500)
27%
Did not meet protocol-defined
anaemia criteria
(pending randomisation arm)
n=187
SVR=40.1% (75/187)
RBV DR and continued
peg-IFN/RBV+BOC
n=249
SVR=71.5% (178/249)
Did not meet anaemia criteria;
completed peg-IFN/RBV+BOC
treatment
n=64
SVR=89.1% (57/64)
EPO added and continued
peg-IFN/RBV+BOC
n=251
SVR=70.9% (178/251)
Did not meet anaemia criteria;
did not complete treatment
n=92
SVR=19.6% (18/92)
Discontinued
during lead-in
n=31
SVR=0% (0/31)
Poordad F, et al. EASL 2012
CHARIOT study: RBV conc and SVR (n=210)
Ali R, et al. EASL 2011
HCV treatment: peg-IFN/RBV/BOC
May 2012 (week 5):
• RBV reduced from 1000 mg to 600 mg
• Commenced on BOC (800 mg tds)
June 2012 (week 9, (BOC week 4)):
• Peg-IFN-alfa-2a (180 mcg/week) + RBV (600 mg/day) + BOC (800 mg tds)
• LFTs:
AST 26 (63, 43) , ALT 21 (83, 44), GGT 54 (87, 124)
• FBC:
Hb 97 (142, 96) , Neut 0.9 (2.3, 1.4), Plats 146 (213, 218)
• HCV RNA:
Undetectable (<15 IU/ml)
Issue 4:
Duration of treatment?
SPRINT-2: SVR by treatment arm
100
90
80
68
70
60
53
SVR 50
%
Non-black
(n=938)
42
40
40
30
67
23
20
10
0
PEG/RBV48
BOC/PR48
BOC/PR28-48
Poordad F, et al. NEJM 2011;364:1195-1206
Black
(n=159)
Mr MD
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47-year-old owner/operator of a trucking business
HCV diagnosed in 2010 (IV DU 25 years ago)
Moderate alcohol intake until 2010
Working fulltime, few symptoms
Genotype 1a, viral load 2,230,000 IU/mL
ALT 242 U/L
Platelets 56, Albumin 24 g/L
Varices banded 2011
Mr MD
Genotype 1a
Viral load 2,230,000 IU/mL
IL28B
C/T
Fibroscan 42.2 KPa
Question
Mr MD:
• Severe cirrhosis
• Portal hypertension
• Very active inflammation
What can we offer him?