HCV Diagnosis and Treatment

George Ostapowicz

Department of Gastroenterology Gold Coast Hospital

Screening is critical to identifying all patients infected with HCV

• Diagnosis rate in Australia is estimated to be 85% 1 – Compared with rates as low as  17% in some countries 2 • The role of GPs in maintaining high diagnosis rates is crucial • GPs are in the best position to: – Test for HCV – Assess risk factors – Refer to treatment centres 1. Hepatitis C Virus Projections Working Group 2006. Available at: http://www.nchecr.unsw.edu.au

2. UK Health Protection Agency. The Health Protection Agency Annual Report 2008. Available at: http://www.hpa.org.uk

HCV antibody test (EIA) is cheap, reproducible and specific • Exposure to HCV is determined by testing for HCV antibodies (anti-HCV) in serum or plasma • Cheap, reproducible, very high sensitivity (>99%) and specificity (99%) 1 • A positive test indicates exposure to HCV, but does not prove active infection 2 • 65–85% of patients with positive tests have chronic infections (HCV persists for  6 months) 3 – Remaining patients are either in acute phase or have spontaneously cleared the virus 1. NIH. Hepatology 2002; 36: S3 2. Australasian Society for HIV Medicine 2008. Available at: http://www.ashm.org.au 3. Australian Government National Hepatitis C Testing Policy 2007. Available at: http://www.health.gov.au

EIA = Enzyme Immune Assay

A positive antibody test must be confirmed by PCR • An HCV RNA test, such as a PCR test, documents viraemia, and thus active infection 1 • All positive HCV antibody tests must be confirmed by PCR • In a 12-month period, the Medicare Benefits Schedule allows: – One PCR test for HCV genotype – A maximum of 4 HCV RNA assays for patients receiving treatment – Quantification of HCV RNA load in plasma or serum • Pre-treatment evaluation • Assessment of efficacy of antiviral therapy PCR = Polymerase Chain Reaction 1. Australasian Society for HIV Medicine 2008. Available at: http://www.ashm.org.au

2. Medicare Benefits Schedule. Available at: http://www.health.gov.au

The role of testing in diagnosis and treatment

Method HCV antibody test (EIA) PCR: HCV genotype PCR: HCV RNA qualitative assay PCR: HCV RNA quantitative assay Screen X Confirm Duration of therapy Predicting sustained response Assessing treatment response X X X X

Australian Government National Hepatitis C Testing Policy 2007. Available at: http://www.health.gov.au

Referring patients who test positive for HCV infection

Positive HCV antibody test (EIA) Confirmation by PCR assay Refer for appropriate specialist care

Tests: Exclusion of other pathology • FBC, INR, U&E,LFTs – baseline prior to considering antiviral treatment • Non-alcoholic fatty liver disease (Ultrasound, fasting glucose, lipids) • Genetic disorders: haemochromatosis, alpha-1-antitrypsin deficiency (Fe studies, A1antitrypsin level) • Autoimmune liver disease (ANA, anti-SMA, anti-LKM) • Wilson disease (caeruloplasmin, copper) • Thyroid function (TFT) – other cause of similar symptoms, antiviral therapy may cause thyroid toxicity • Hepatitis B, HIV • Hepatitis A

Tests asessing liver damage • Noninvasive tests of fibrosis and activity – Panel of biochemical markers, e.g. FibroTest – Ultrasonography, e.g. FibroScan • Liver biopsy – Gold standard for grading inflammation and disease stage

Role of liver biopsy in HCV infection

Confirm clinical diagnosis Assess severity of fibrosis and necroinflammation 1 Associated risks: bleeding <1% death 0.1–0.01% 2

Role of liver biopsy in HCV infection

Evaluate possible concomitant disease processes (e.g., alcoholic liver disease, NASH) 1 Can aid decision making Assess therapeutic intervention 1

1. NIH Consensus Statement Online. Management of hepatitis C 2. Canadian Liver Foundation. Available at: www.liver.ca

• Individuals who test positive for HCV should be advised to: – Not drink alcohol (or at least limit their consumption) 1 – Not begin any new medication, including over the-counter and herbal medicines, without checking with their doctor 1 – Get vaccinated against hepatitis A and B if liver disease is found to be present 1 Protecting the liver from further harm 1. CDC. MMWR Recommend Rep 1998; 47: 1

Preventing the transmission of HCV to others • Avoid sharing toothbrushes and dental or shaving equipment • Cover any bleeding wound • Stop using illicit drugs – Those who continue to inject drugs should be counselled to: • Avoid reusing or sharing syringes, needles, other paraphernalia • To clean the injection site with a new alcohol swab • Dispose safely of syringes and needles after one use • Do not donate blood, body organs, other tissues, or semen • Although the risk of sexual transmission is low, “safer” sex should be practised 1. Ghany MG, et al. Hepatology 2009; 49: 1337 2. CDC. MMWR Recommend Rep 1998; 47: 1

The primary goal of HCV treatment is viral eradication

Primary objectives

• Viral eradication – SVR = cure • Arrest progression of necrosis/fibrosis

Secondary objectives

• Reduce progression of fibrosis/cirrhosis • Prevent decompensation • Prevent HCC SVR = sustained virological response = undetectable serum HCV RNA 24 weeks after cessation of therapy; HCC = hepatocellular carcinoma.

Ghany MG, et al. Hepatology 2009; 49: 1337

HCV infection is considered cured when an SVR is achieved • SVR is defined as absence of HCV RNA in the serum at the end of treatment and 6 months later 1 • Patients who achieve an SVR may be deemed clinically cured of chronic HCV – An SVR achieved with PEGIFN plus ribavirin is durable 2 – 99.2% of patients who achieved an SVR remained HCV RNA undetectable at mean 4.1 (0.4–7) years follow-up SVR = sustained virological response = undetectable serum HCV RNA 24 weeks after cessation of therapy 1. Ghany MG, et al. Hepatology 2009; 49: 1337 2. Swain M, et al. EASL 2007; Abstract 1

Contraindications to treatment

• Patients in whom HCV therapy is currently contraindicated include: – Pregnant patients – Patients unwilling or unable to comply with adequate contraception – Patients with severe uncontrolled systemic diseases – Patients with known hypersensitivity to drugs used to treat HCV Ghany MG, et al. Hepatology 2009; 49: 1347

1989

Evolution of hepatitis C treatment

Discovery of HCV genome Treatment with IFN alfa for 24 or 48 weeks – 3x weekly dosing – Poor outcomes Addition of RBV to IFN alfa improved outcomes Peg-IFN mono – once-weekly dosing Peg-IFN alfa plus RBV becomes gold standard Response-guided therapy emerging New antivirals enter development 2010

Generic Brand Manufacturer Molecular weight of PEG Mode of administration Dosing Presentation

Two types of pegylated interferon are currently available

Peginterferon alfa-2a (40 KD) PEGASYS Roche 40 KD Pegylated interferon alfa-2b (12 KD) Pegatron Schering-Plough 12 KD Subcutaneous injection Fixed dose, 180



g once weekly Pre-filled syringe ready to inject Subcutaneous injection Weight-based dosing, 1.5



g/kg once weekly Powder requiring reconstitution with water

1. PEGASYS Prescribing Information 2. Pegatron Prescribing Information 3. Grace M, et al. J Interferon Cytokine Res 2001; 21: 1103 PEG = polyethylene glycol

Pegylated interferon and ribavirin

Peginterferon alfa-2a (40KD) PEGASYS Ribavirin Subcutaneous injection, once weekly By mouth, twice daily

100 80 60 40 20 0

PEGIFN and ribavirin: SVR rates across genotypes

PEGIFN plus ribavirin: Treatment-naive patients 70-84% 60-66% 48-60% 24-48 wks Overall 48 wks Genotype 1 24 wks Genotype 2/3

Patients who achieve an RVR have high rates of SVR: Genotype 1

PEGASYS 180



g/wk plus RBV 1000/1200 mg/day for 48 weeks; n=569 SVR: 5%

(5/111)

SVR: 27%

(34/128)

No EVR 20%

(111/569)

RVR 16%

(90/569)

pEVR 22%

(128/569)

cEVR 42%

(240/569)

SVR: 87%

(78/90)

SVR: 68%

(162/240) Marcellin P, et al. 18th APASL 2008; Abstract FP022

Optimising outcomes in genotype 1/4 • Patients with a LVL who achieve an RVR may be candidates for shorter treatment duration (24 wks) • Patients with a cEVR achieve high SVR rates with 48 weeks ’ therapy • Slow responders who do not achieve HCV RNA negativity by week 4 or 12, but achieve a pEVR may be candidates for treatment intensification (longer duration eg 72 wks)

1. PEGASYS ® Summary of Product Information, revised 2007

Patients who achieve an RVR have high rates of SVR: Genotype 2/3

PEGASYS 180



g/wk plus RBV 800 mg/day for 24 weeks: ACCELERATE SVR: 49%

(108/220)

No RVR: 35% RVR, LVL*: 24% SVR: 94%

(141/150)

SVR: 88%

(229/260)

RVR, HVL**: 41% SVR: 90%

(370/410)

*LVL:



800 000 IU/mL **HVL: >800 000 IU/mL

Shiffman M et al. 18th APASL 2008; Abstract FP023

Optimal treatment duration in genotype 2 or 3: conclusions • Overall, 24 weeks of treatment is superior to 16 weeks in genotype 2 or 3 patients • Patients with an RVR achieve high SVR rates >90% – Patients with an RVR and a low baseline viral load achieve very high rates of SVR with a shorter duration • Patients without an RVR achieved an SVR of 49% with 24 weeks – The possibility of improving SVR in non-RVR patients by intensifying treatment (longer duration/higher RBV doses) is being explored

Pegylated interferon: Adverse events are common but manageable Side effects 1 • Flu-like symptoms • Weight loss • Depression • Neutropenia • Concentration/memory disturbance • Insomnia • Thrombocytopenia Management includes 1,2 : • Pegylated interferon dose reduction • Antidepressants such as SSRIs NSAIDs = non-steroidal anti-inflammatory drugs SSRIs = selective serotonin reuptake inhibitors 1. Ghany MG, et al. Hepatology 2009; 49: 1346 2. Fried M. Hepatology 2002; 36: S237

Ribavirin: Adverse events are common but manageable Side effects 1 • Haemolytic anaemia • Significant teratogenicity • Rash • Fatigue • Itching • Sinusitis Management includes 1,2 : • Ribavirin dose reduction • Strict contraception (for females) 3 1. Ghany MG, et al. Hepatology 2009; 49: 1346 2. Fried M. Hepatology 2002; 36: S237 3. PEGASYS ® Prescribing Information NSAIDs = non-steroidal anti-inflammatory drugs

Monitoring the patient • Routine on-treatment monitoring is responsibility of specialist – GPs participating in shared-care programmes may also monitor patient • Base frequency of laboratory monitoring on patient’s cytopenias 1 • Check thyroid-stimulating hormone (TSH) every 3 months 1 • Remind patient to use adequate birth control 1 • Review side effects at each visit 1 1. Chronic Liver Disease Foundation: Available at: www.chronicliverdisease.org

5 ’

Potential antiviral targets

C E1 Potential targets and approaches in the next 5 years Antiviral targets E2/NS1 NS2 NS3 NS4A NS4B NS5A NS5B 3 ’ Internal ribosomal entry site RNA binding site Envelope glyco proteins Signal peptide Serine protease/ helicase telaprevir, boceprevir RNA dependent RNA polymerase

Telaprevir with PEGIFN and Ribavirin in treatment naïve patients (HCV G1)

80 70 60 50 40 30 20 10 0 PR48 T12PR12 T12PR24 T12PR48 PROVE 1 (USA) n = 250 PROVE 2 (Europe) n = 334 Key: PR48 (control)

PEGIF/ribavirin 48wks

T12PR12

telaprevir 12 wks PEGIF/ribavirin 12wks

T12PR24

telaprevir 12 wks PEGIF/ribavirin 24wks

T12PR48

telaprevir 12 wks PEGIF/ribavirin 48wks 1. McHutchison et al, NEJM 2009; 2. Hezode et al, NEJM 2009

Telaprevir for previously treated (PEGIFN / ribavirin) HCV G1 patients

80 70 60 50 40 30 20 10 0 PR48 T12PR24 T12PR48 All patients n = 453 Non-responders n = 260 Relapsers n = 162 PROVE 3 (international) Key: PR48 (control)

PEGIF/ribavirin 48wks

T12PR24

telaprevir 12 wks PEGIF/ribavirin 24wks

T12PR48

telaprevir 12 wks PEGIF/ribavirin 48wks McHutchison et al, NEJM 2010

Conclusions • GP diagnosis and referral is critical to help cure HCV infection • Treatment may be successful: – overall, up to 2 out of 3 patients may be cured with PEGIFN and RBV 1–5 – Higher SVR rates (  shorter duration of treatment) especially in Genotype 1 patients will be possible with the addition of new drugs 1. Fried M, et al. N Engl J Med 2002; 347: 975; 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 3. Zeuzem S, et al. J Hepatol 2005; 43: 250 4. Ascione A, et al. J Hepatol 2008; 48(Suppl 2): S370 5. Rumi M, et al. 59th AASLD 2008; Oral 212; 6. Cheng WSC, et al. EASL 2009. Abstract 601