Hepatitis C Treatment

Transcription

1 Hepatitis C Treatment Standard of care & Managing advrse events Mohssen Nassiri Toosi, MD A s s o c i a t e P ro f e s s o r Of Internal M e d i c i n e Te h r a n U n i v e r s i t y O f M e d i c a l S c i e n c e s I m a m K h o m e i n i H o s p i t a l

2 Who should be considered for HCV treatment? All treatment-naïve HCV-RNA positive patients baseline ALT level whatever their Compensated chronic liver disease related to HCV Willing to be treated Have no contraindication to pegylated IFN-a or ribavirin

3 Who should be considered for HCV treatment? All treatment-naïve HCV-RNA positive patients baseline ALT level whatever their compensated chronic liver disease related to HCV willing to be treated have no contraindication to pegylated IFN-a or ribavirin

4 Assessment of liver disease severity Liver disease severity should be assessed prior to therapy (Identifying fibrosis and cirrhosis) Clinical Liver biopsy Transient elastography (Fibroscan) Panels of biomarkers of fibrosis (Fibrotest) To determine: likelihood of responding to therapy post-treatment prognosis surveillance for HCC is required in cirrhotic patients

5 Who should be considered for HCV treatment? All treatment-naïve HCV-RNA positive patients baseline ALT level whatever their compensated chronic liver disease related to HCV willing to be treated have no contraindication to pegylated IFN-a or ribavirin

6 Search systematically for other causes of liver disease The causal relationship between HCV infection and liver disease must be established. Other disease must be ruled out. HIV and/or other hepatotropic viruses Alcoholic liver disease Autoimmune liver disease metabolic liver disease with steatosis or steatohepatitis pre-existing thyroid disease

7 Who should be considered for HCV treatment? All treatment-naïve HCV-RNA positive patients baseline ALT level whatever their compensated chronic liver disease related to HCV willing to be treated have no contraindication to pegylated IFN-a or ribavirin

8 Absolute contra-indication for HCV therapy Uncontrolled Depression Uncontrolled Psychosis Uncontrolled Epilepsy Uncontrolled autoimmune diseases Cirrhosis Child B7 or more Pregnant women or couples unwilling to comply with adequate contraception Severe concurrent medical disease (poorly controlled HTN, heart failure, diabetes, and COPD)

9 Relative contraindications for HCV therapy Abnormal hematological indices (Hb <13 for men and <12 for women, PMN <1500, PLT <90,000) Creatinine >1.5 mg/dl Significant coronary heart disease Untreated thyroid diseases

10 Power of recommendation for HCV treatment! Treatment should be initiated promptly in patients with advanced fibrosis (stage 3-4/6) Treatment strongly considered in patients with moderate fibrosis (stage 2/6) Treatment individualized in patients with mild fibrosis (stage 0-1/6) particularly with longstanding infection Individualized by risk / benefit balance related to therapy, consider new drugs and life expectancy of patient

11 EASL 2011 HCV Guidelines: PegIFN/RBV Regimens Genotype 1/4 PegIFN alfa-2a PegIFN alfa-2b PegIFN dose (weekly) 180 µg 1.5 µg/kg RBV dose (daily) 15 mg/kg 15 mg/kg Planned duration* 48 wks 48 wks Genotype 2/3 PegIFN alfa-2a PegIFN alfa-2b PegIFN dose (weekly) 180 µg 1.5 µg/kg RBV dose (daily) 800 mg 800 mg If low responsiveness anticipated 15 mg/kg 15 mg/kg Planned duration 24 wks 24 wks *24 wks of therapy can be considered in patients with low HCV RNA (< 400, ,000 IU/mL) who achieve RVR wks can be considered in patients who achieve RVR. Craxi A, et al. J Hepatology. 2011

12 What are the endpoints in HCV therapy? The goal of therapy is to eradicate HCV infection. (virologic cure ) The endpoints are defined by virologicl response. Virological responses is defined by negative HCV-RNA PCR by sensitive PCR assay. RVR rapid virological response at week 4 EVR early virological response at week 12 DVR delay virological response at week 24 Intermediate on-treatment endpoints Assess likelihood of receiving final endpoint (SVR) SVR sustained virological response at week 24 after stopping therapy

13 What the endpoints mean in HCV therapy?

14 EASL: Response-Guided Therapy in Patients With Genotype 1 HCV RNA Wk Neg (RVR) Pos Pos < 2 log drop (NR) Stop Tx Pos (PR) Pos > 2 log drop Neg (EVR) Neg (DVR) 24 wks of therapy, only if LVL* at baseline *HCV RNA < 400, ,000 IU/mL 48 wks of therapy 72 wks of therapy Craxi A, et al. J Hepatol. 2011

15 EASL: Response-Guided Therapy in Patients With Genotype 2/3 HCV RNA Wk Neg (RVR) Pos Pos < 2 log drop or pos at Wk 24 Stop Tx Risk factors (fibrosis, IR) Pos > 2 log drop but neg thereafter (DVR) Neg (EVR) wks of therapy* 24 wks of therapy 48 wks of therapy *Marginally less effective due to higher relapse rates, especially for genotype 3 with high HCV RNA. Craxi A, et al. J Hepatol. 2011

16 HCV RNA (log 10 IU/mL) Patterns of Virologic Non-Response PegIFN alfa and RBV NullResponse* Partial Non-Response* 3 2 Relapse 1 Undetectable RVR EVR ETR SVR Wks After Start of Therapy *Subset of Nonresponse Ghany MG, et al. Hepatology. 2009;49: Reprinted with permission from the AASLD.

17 Benefits of Sticking to HCV treatment Guidelines Increase viral eradication (higher SVR) Reduce unnecessary exposure to drugs (dose optimization) By shortening therapy in patients likely to achieve SVR without requiring the full duration By terminating therapy early in patients unlikely to achieve SVR Decrease side effect (better tolerance and quality of life)

18 HCV therapy - managing adverse events Importance of keeping patients on treatment: impact on SVR Full treatment ( 80% of dose & duration ) SVR 67% Dose reduction ( < 80% of dose ) SVR 56% Discontinuation ( < 80% of duration ) SVR 7%

19 Better adherence to therapy can be achieved by better management of AEs Anticipating AEs Educating and motivating the patient Initiating appropriate prevention and treatment measures in a timely fashion

20 Severity Appearance of AEs varies over time Flu-like symptoms 3, Duration of interferon therapy (weeks) 1. McHutchison JG, et al. Am J Gastroenterol 2007; 102: 880; 2. Reau N, et al. Am J Gastroenterol 2008; 103: Russo MW & Fried MW. Gastroenterology 2003; 124: 1711; 4. Smith JP. Pharmacotherapy 2008; 28: Kraus MR, et al. World J Gastroenterol 2005; 11: 1769; 6. Fontana RJ, et al. Am J Gastroenterol 2008; 103: 1

21 Severity Appearance of AEs varies over time Flu-like symptoms 3,4 Fatigue Duration of interferon therapy (weeks) 1. McHutchison JG, et al. Am J Gastroenterol 2007; 102: 880; 2. Reau N, et al. Am J Gastroenterol 2008; 103: Russo MW & Fried MW. Gastroenterology 2003; 124: 1711; 4. Smith JP. Pharmacotherapy 2008; 28: Kraus MR, et al. World J Gastroenterol 2005; 11: 1769; 6. Fontana RJ, et al. Am J Gastroenterol 2008; 103: 1

22 Severity Appearance of AEs varies over time Anaemia 1,2 / neutropenia 3 / thrombocytopenia 3 Flu-like symptoms 3,4 Fatigue Duration of interferon therapy (weeks) 1. McHutchison JG, et al. Am J Gastroenterol 2007; 102: 880; 2. Reau N, et al. Am J Gastroenterol 2008; 103: Russo MW & Fried MW. Gastroenterology 2003; 124: 1711; 4. Smith JP. Pharmacotherapy 2008; 28: Kraus MR, et al. World J Gastroenterol 2005; 11: 1769; 6. Fontana RJ, et al. Am J Gastroenterol 2008; 103: 1

23 Severity Appearance of AEs varies over time Anaemia 1,2 / neutropenia 3 / thrombocytopenia 3 Flu-like symptoms 3,4 Fatigue 4 Psychiatric side effects (depression) 5, Duration of interferon therapy (weeks) 1. McHutchison JG, et al. Am J Gastroenterol 2007; 102: 880; 2. Reau N, et al. Am J Gastroenterol 2008; 103: Russo MW & Fried MW. Gastroenterology 2003; 124: 1711; 4. Smith JP. Pharmacotherapy 2008; 28: Kraus MR, et al. World J Gastroenterol 2005; 11: 1769; 6. Fontana RJ, et al. Am J Gastroenterol 2008; 103: 1

24 Potential AEs can be anticipated by proper assessment of patients BASELINE Screen Course of therapy Ghany MG, et al. Hepatology 2009; 49: 1335 Craxi A, et al. J Hepatol 2011; 55: 245

25 Potential AEs can be anticipated by proper assessment of patients Liver failure BASELINE Screen Pre-existing medical problems: - anemia, cytopenia - Thyroid disease (hypo-, hyper-) - Diabetes mellitus, Gout - Renal failure - Active autoimmune disease - Depression, Psychosis, Suicide - Hypertension, Underlying heart disease, CVA - Skin disease, anaphylaxia Pregnancy, Willingness to pregnancy Active addiction Course of therapy Ghany MG, et al. Hepatology 2009; 49: 1335 Craxi A, et al. J Hepatol 2011; 55: 245

26 Potential AEs can be anticipated by proper assessment of patients BASELINE Screen: Underlying heart disease Pre-existing medical problems Depression WEEKS 1, 2 AND 4? Assess: AEs Treatment adherence Laboratory tests: CBC creatinine ALT Course of therapy EVERY 4 WEEKS? Pregnancy testing CBC = Complete blood count ALT = Alanine transaminase Ghany MG, et al. Hepatology 2009; 49: 1335 Craxi A, et al. J Hepatol 2011; 55: 245

27 Potential AEs can be anticipated by proper assessment of patients BASELINE Screen: Underlying heart disease Pre-existing medical problems Depression WEEKS 1, 2 AND 4? Assess: AEs Treatment adherence Laboratory tests: CBC creatinine ALT 48 WEEK INTERVALS Repeat assessments Course of therapy EVERY 4 WEEKS? Pregnancy testing EVERY 12 WEEKS Thyroid function Ghany MG, et al. Hepatology 2009; 49: 1335 Craxi A, et al. J Hepatol 2011; 55: 245

28 Better adherence to therapy can be achieved by better management of AEs Anticipating AEs Educating and motivating the patient Initiating appropriate prevention and treatment measures in a timely fashion

29 Severity Patients should be informed that the appearance of AEs varies over time Anaemia 1,2 / neutropenia 3 / thrombocytopenia 3 Flu-like symptoms 3,4 Fatigue 4 Psychiatric side effects (depression) 5, Duration of interferon therapy (weeks) 1. McHutchison JG, et al. Am J Gastroenterol 2007; 102: 880; 2. Reau N, et al. Am J Gastroenterol 2008; 103: Russo MW & Fried MW. Gastroenterology 2003; 124: 1711; 4. Smith JP. Pharmacotherapy 2008; 28: Kraus MR, et al. World J Gastroenterol 2005; 11: 1769; 6. Fontana RJ, et al. Am J Gastroenterol 2008; 103: 1

30 Side effects that need urgent attention Severe depression, suicidal thoughts Chest pain or difficulty breathing Persistent fever Loss of vision or blurry vision Worsenig of psoriasis Bloody diarrhea Unusual bleeding or bruising Severe abdominal or lower back pain Hepatitis C Support Project Available at

31 Side effects that need urgent attention Severe depression Chest pain or difficulty breathing Persistent fever Loss of vision Patients or should blurry understand vision that side Worsening discontinuation of psoriasis and all are reversible Bloody diarrhoea Unusual bleeding or bruising Severe abdominal or lower back pain effects can be treated effectively to avoid treatment Hepatitis C Support Project Available at

32 Better adherence to therapy can be achieved by better management of AEs Anticipating AEs Educating and motivating the patient Initiating appropriate prevention and treatment measures in a timely fashion

33 Common AEs associated with HCV therapy Flu-like symptoms Fatigue, headache, fever, myalgia and rigors 13 Haematological AEs 1,3,4 Anaemia, neutropenia and thrombocytopenia HCV treatment-associated AEs Dermatological AEs 4 Skin rashes and itching, injection site reactions, hair loss and eye problems Neuropsychiatric symptoms 4 Cognitive impairment, anxiety, depression, irritability, insomnia and psychosis (rare) Gastrointestinal AEs 4 Nausea, diarrhea, weight loss, dehydration, taste changes and mouth sores 1. Fried M, et al. NEJM 2002; 347: 975; 2.Hadziyannis S, et al. Ann Intern Med 2004; 140: 346; 3. Russo and Fried. Gastroenterol 2003; 124:1711; 4. Hepatitis C Support Project Available at

34 Management of flu-like symptoms Advise patients to anticipate symptoms 1 Use analgesics such as paracetamol or ibuprofen 1,2 Get adequate sleep 2 Management of flu-like symptoms Maintain adequate hydration 1,2 Coincide dosing schedule with days off work 1 Dose reductions are not required or recommended 1 1. Russo MW & Fried MW. Gastroenterol 2003; 124: Hepatitis C Support Project Available at

35 Management of gastrointestinal AEs Nausea/anorexia: (2040%) prokinetic or anti-emetic agents (dopamine antagonist or 5HT4 agonist) 1,2 Diarrhea: (1525%) opioid receptor agonist loperamide 1,2 Dehydration: drink plenty of water 2 Management of gastrointestinal AEs Taste changes: drink plenty of water and eat cold food 2 Weight loss: (2030%) reassurance, check glucose and thyroid function 1,2 Oral ulcers: topical anaesthesia or topical steroid 1,2 1. Sulkowski MS, et al. Nat Rev Gastroenterol Hepatol 2001; 8: Hepatitis C Support Project Available at

36 Management of anaemia (1) Common AE resulting from Peg-IFN (bone marrow suppression) and RBV (extravascular haemolysis) 1 Start with normal Hb, correct anemia, if possible Start appropriate dose of RBV ensures the best chance of a cure 2,3 Maintaining RBV dose is essential for preventing relapse, SVR 2,3 Erythropoietin may allow for a higher RBV starting dose with less anemia and higher SVR, 4 but this needs to be confirmed 1. Sulkowski MS, et al. Nat Rev Gastroenterol Hepatol 2001; 8: Reddy K, et al. Clin Gastroenterol Hepatol 2007; 5: Mac Nicholas R & Norris S. Aliment Pharmacol Ther 2010; 31: Shiffman ML, et al. Hepatology 2007; 46: 371

37 Management of anaemia (2) If dose reductions are required, the smallest reduction should be used (200 mg/day) to maintain exposure Reduce dose to 600 mg if: Hgb < 10 g/dl in patients without cardiac factors Return to the original dosing is not recommended Discontinue if: Hgb < 8.5 g/dl in patients without cardiac factors If abnormality is reversed, RBV may be restarted at 600 mg daily and further increased to 800 mg daily at the discretion of the treating physician

38 Management of neutropenia and thrombocytopenia Neutrophils and platelets decrease after initiation of treatment and generally stabilise after 48 weeks No association between severity of neutropenia and the incidence of infection 14 Consider Peg-IFN dose modifications if: Neutrophils < 750/mm 3 Platelets <50 000/mm 3 Once cell counts have recovered, consideration should be given to restoring the dose of Peg-IFN Discontinuation of Peg-IFN rarely required but consider if: Neutrophils < 500/mm 3 When neutrophils >1000/mm 3, Peg-IFN alfa-2a can be restarted initially at 90 g 5 Platelets < /mm 3 1. Cooper CL, et al. Clin Infect Dis 2006; 42: Antonini MG, et al. Infection 2008; 36: Alvarez-Uria G, et al. Dig Dis Sci 2010; 55: Yang JF, et al. Aliment Pharmacol Ther 2009; 29: PEGASYS SPC

39 Management of depression Pre-treatment with a selective serotonin re-uptake inhibitor (SSRI) may prevent drop-out and increase SVR 1,2 Treat with SSRI after the onset of symptoms 3 Management of depression Non-pharmacological strategies, e.g. counselling, family support Treatment interruption may be required for severe cases 1. Raison CL, et al. Aliment Pharmacol Ther 2007; 25: Morasco BJ, et al. J Affect Disord 2007; 103: Kraus MR, et al. Gut 2008; 57: 531

40 Conclusions All patients treated with Peg-IFN and RBV will experience some AEs during therapy Exposure to treatment is a critical determinant of SVR Adherence can be improved through careful pre-treatment assessment and ontreatment management of AEs Only a minority of patients will require significant dose reduction or premature discontinuation if AEs are managed proactively Educating of patients and caregivers about potential side effects is an integral component of treatment and is important for a successful outcome 1 With the introduction of triple therapy, managing AEs due to Peg-IFN/RBV and AEs due to DAAs will become even more crucial to providing optimal care for patients DAA = Direct-acting antivirals 1. Ghany MG, et al. Hepatology 2009; 49: 1335