Management of the treatment-naïve patient with HCV infection

Paul DesmondGreg 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

• 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 62 U/L- Albumin 40 g/L- Platelets 247 x 109/L

- HCV PCR Positive- HCV VL 4,730,000 IU/mL- Genotype 1a

Questions

• Genotype 1a vs 1b?• Viral load?

• Influence on response to treatment?

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

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)

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)

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

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

Mrs LF

Entered a clinical trial:

• Telaprevir BD vs Telaprevir TID

Transfusion

RBV dose 1000 mg 600 mg

End of treatment

Mrs LF – Haemoglobin during treatment

• Anaemia management on telaprevir

• Ribavirin dose reduction

• Transfusion

• EPO

Mrs LF – Telaprevir side effect (rash)

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

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

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)

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

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-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

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

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

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

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

Issue 3:

Role of EPO vs RBV dose reduction?

Role for monitoring of serum RBV concentration?

　 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

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

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%

CHARIOT study: RBV conc and SVR (n=210)

Ali R, et al. EASL 2011

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)

Issue 4:

Duration of treatment?

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

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

Genotype 1a

Viral load 2,230,000 IU/mL

IL28B C/T

Fibroscan 42.2 KPa

Mr MD

Question

Mr MD: • Severe cirrhosis• Portal hypertension• Very active inflammation

What can we offer him?