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Management of the treatment-naïve patient with HCV infection
Paul DesmondGreg Dore
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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
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Mrs LF
• 57-year-old housewife • Presents to GP with tiredness• ALT 65 U/L• HCV antibody positive• Otherwise well• On examination NAD
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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
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Question
What other investigations would you order?
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Mrs LF
- ALT 62 U/L- Albumin 40 g/L- Platelets 247 x 109/L
- HCV PCR Positive- HCV VL 4,730,000 IU/mL- Genotype 1a
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Questions
• Genotype 1a vs 1b?• Viral load?
• Influence on response to treatment?
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Telaprevir in G1 patients: Impact of host and viral factors
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.
100
0
50
Genotype
79
71
Race
75
62
Fibrosis F0-2 F3-F4
62
78
Patie
nts
Achi
evin
g SV
R (%
)
Results represent telaprevir (T12PR) populationsTreatment-naïve GT1 patients
75
25
Non-Black Black 1b 1aViral load
LVL HVL
7874
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GTG(V36)
HCV Genotype 1b has a higher genetic barrier than Genotype 1a
Subtype 1a Subtype 1b
GTG(V36)
ATG(V36M)
GTC ATC(V36) (V36)
ATC ATG(V36) (V36M)
www.hivforum.org
1 step
2 steps
GTC(V36)
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Question
Any further investigations?
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Mrs LF
• Fibroscan Liver stiffness 7.9 KPa
• IL28B C/T
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Question
What should we do now?- Genotype 1a- High viral load- F2-F3 fibrosis- IL28B C/T
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Ge*, Fellay*, Thompson* et al. Nature 2009
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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)
Thompson AJ, et al. Gastroenterology. 2010;139:120-129.
Predictor 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
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0
20
40
60
80
100
Patie
nts
(%) 69%
SVR
75%
44%
TVR 12 + PR
PR 48
TVR 8 + PR
63%66%
38%
SVR
BOC RGT
PR 48
BOC 44
HCV-1 Rx-naïve (ADVANCE/SPRINT-2)
Telaprevir Boceprevir
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Mrs LF
Entered a clinical trial:
• Telaprevir BD vs Telaprevir TID
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Transfusion
RBV dose 1000 mg 600 mg
End of treatment
Mrs LF – Haemoglobin during treatment
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• Anaemia management on telaprevir
• Ribavirin dose reduction
• Transfusion
• EPO
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Mrs LF – Telaprevir side effect (rash)
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SIDE EFFECT T12 T8 PR (T) BOC 44 BOC RGT PR (B)
Fatigue 57% 58% 57% 57% 53% 60%
Pruritus 50% 45% 36%
Headache 41% 43% 39% 46% 46% 42%
Nausea 43% 40% 31% 43% 48% 42%
Rash 37% 35% 24%
Anaemia 37% 39% 19% 49% 49% 29%
EPO Use 43% 43% 24%
Insomnia 32% 32% 31% 33% 32% 33%
Diarrhoea 28% 32% 22%
Flu Sx 28% 29% 28% 33% 36% 28%
Pyrexia 26% 30% 24% 33% 33% 32%
Anorectal Sx 13% 8% 4%
Dysgeusia 43% 37% 18%
TVR & BOC: Adverse events
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Treatment of TVR rash
RASH
Mild
Moderate
Severe
SCAR
Emollients, topical corticosteroids, antihistamines, limit sun exposure, loose fitting clothes
? Derm R/VIf progresses, cease TVRIf no improvement in 7 days, stop RBV
Permanently cease TVRMonitor for progression/systemic symptomsIf no improvement in 7 days, stop RBV+/- peg-IFN
Permanent and immediate cessation of TVRDerm R/V
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SCAR (Severe Cutaneous Adverse Reaction)
Cacoub P et al. J Hepatol 2012;56:455-463
SCAR encompasses
several conditions
Acute generalised exanthematous pustulosis
(AGEP) and Erythema Multiforme Major (EMM)
Drug rash/reaction with eosinophilia and systemic
symptoms (DRESS)
Toxic epidermal necrolysis (TEN) and Stevens-
Johnson Syndrome (SJS)
11 cases suggestive of DRESS
3 cases suggestive of SJS
(1 case considered not related to telaprevir, onset 11 weeks after telaprevir discontinuation)
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Mrs LF – Results on treatmentWeek Hb Neutrophils Platelets ALT PCR
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 Neg
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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
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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
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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
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Ms CB – Follow-upJanuary 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
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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
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Issue 1:
Would result of IL28B testing (if available) have influenced choice of treatment
regimen?
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SPRINT-2: IL28B and DAA response
Poordad F, et al. J Hepatol 2011;54(Suppl.):S6
SVR
(%)
50/64n/N=
CC TT
44/55
CT
63/77 33/116 82/11567/103 10/37 26/4423/42
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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)
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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
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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?
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SPRINT-2: SVR by lead-in viral decline
5
39
29
52
82 82
0
10
20
30
40
50
60
70
80
90
100
PEG/RBV48 BOC/PR48 BOC/RGT
SVR%
>1 log decline
<1 log decline
HCV RNA week 0-4 (Non-black)
Poordad F, et al. NEJM 2011;364:1195-1206
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Issue 3:
Role of EPO vs RBV dose reduction?
Role for monitoring of serum RBV concentration?
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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%
Haematologic parameters
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%
Mean (median) days of use 121 (109) 94 (85) 156 (149)
Poordad F, et al. NEJM 2011;364:1195-1206
SPRINT-2: Adverse events
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After completion of 4 week peg-IFN/RBV lead In, all patients initiated boceprevir
Haemoglobin≤10 g/dL
RBV DR(200-400 mg)
EPO (40,000 IU/wk SC)
RHaemoglobin ≤8.5 g/dL:
Secondary Strategy (EPO, RBV DR, transfusion)
R = randomisation
DR, dose reduction; EPO, erythropoietin; peg-IFN, peg-interferon; RBV, ribavirin; SC, subcutaneously.
EPO vs ribavirin dose reduction in peg-IFN/RBV/BOC
• HCV treatment naïve, genotype 1 (n=687)
Poordad F, et al. EASL 2012
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Enrolled
n=687
SVR=62.7% (431/687)Met protocol-defined
anaemia criteria
n=500
SVR=71.2% (356/500)RBV DR and continued
peg-IFN/RBV+BOC
n=249
SVR=71.5% (178/249)
EPO added and continued peg-IFN/RBV+BOC
n=251
SVR=70.9% (178/251)
Did not meet protocol-defined anaemia criteria
(pending randomisation arm)
n=187
SVR=40.1% (75/187)Did not meet anaemia criteria;
completed peg-IFN/RBV+BOC treatment
n=64
SVR=89.1% (57/64)
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
73% 27%
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CHARIOT study: RBV conc and SVR (n=210)
Ali R, et al. EASL 2011
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HCV treatment: peg-IFN/RBV/BOCMay 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)
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Issue 4:
Duration of treatment?
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23
53
4240
68 67
0
10
20
30
40
50
60
70
80
90
100
PEG/RBV48 BOC/PR48 BOC/PR28-48
SVR%
SPRINT-2: SVR by treatment arm
Non-black(n=938)
Black(n=159)
Poordad F, et al. NEJM 2011;364:1195-1206
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Mr MD
• 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
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Genotype 1a
Viral load 2,230,000 IU/mL
IL28B C/T
Fibroscan 42.2 KPa
Mr MD
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Question
Mr MD: • Severe cirrhosis• Portal hypertension• Very active inflammation
What can we offer him?
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