1. HCV, Difficult groups to be treated Medhat Elhosary, MPH, MTM, TQM Manager of Kafr elsheikh Liver Research Center (KLRC) 6th Conference of Cardiology Shebeen , September, 26th 2012

2. Objectives BY the end of this brief talk, everybody ISA will be able to mention how to deal with these special groups of patients of HCV infection: Acute HCV infection HCV with thalassemia & Sickle cell disease HCV in dialysis patients HCV in patients with a renal transplant HCV with psychiatric comorbidity HCV and Morbid Obesity HCV and Injecting drug users HCV with autoimmune features HCV in LT recipients HCV with advanced liver disease HCV in Children HCV & HBV Co-infection Non-responders & relapsers

3. HCV- Burden of the disease WHO estimates that about 170 million people, 3% of the worlds population, are infected with HCV and are at risk of developing liver cirrhosis and/or liver cancer. It is estimated that 3 to 4 million people are newly infected each year. HCV is responsible for 5076% of all liver cancer cases, and two thirds of all liver transplants in the developed world.

4. HCV- Burden of the disease HCV-associated cirrhosis leads to liver failure and death in about 20%-25% of cirrhotic cases. Egypt still has the highest prevalence all over the world.

5. Over Half of Patients with HCC are Positivefor Hepatitis C Neither 33% HBV and HCV 5% HCV 47% HBV 15%El-Serag HB. Hepatocellular Carcinoma: Recent Trends in the United States. Gastroenterology.2004;127(Suppl 1):S27-S34.

6. Acute HCV Infection Acute HCV infection is an under-recognized clinical entity due to its mostly asymptomatic nature and variable rates of spontaneous resolution. Symptomatic patients are more likely to spontaneously clear the virus, although approximately 70% of patients will develop chronic HCV infection (1).(1) Maheshwari A, et al Acute hepatitis C. Lancet 2008;372:321332.

7. Acute HCV Infection Antiviral therapy can be delayed for at least 12 weeks, possibly up to 24 weeks, from the date of exposure or onset of symptoms to allow for spontaneous resolution. Antiviral therapy with peginterferon monotherapy (for 1224 weeks depending on genotype) achieves SVR rates over 80% in this setting (1).(1) Kamal S, Moustafa K, Chen H et al. Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology 2006;43:923931.

8. HCV with thalassemia and sickle cell disease Chronic HCV infection is common in patients with blood diseases and should be managed jointly by specialists in hepatology and haematology (1). Liver biopsy is needed for histological assessment and chemical quantitation of liver iron content. Patients with thalassemia major should be optimally chelated before starting antiviral therapy, with liver iron maintained in the range 27 mg/g dry weight. Patients with sickle cell disease may require regular transfusion during anti-viral therapy to reduce the risk of severe haemolysis and acute sickle crisis.(1) Lai ME, et al. Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet 1994;343:388390.

9. HCV with thalassemia and sickle cell disease Combination therapy with peginterferon and ribavirin induces SVR in about 50% of patients with thalassemia and should be considered if there is evidence of active inflammation or fibrosis on biopsy (1). During treatment, careful monitoring of side effects, transfusion frequency and iron chelation is required.(1) Angelucci E, Pilo F. Treatment of hepatitis C in patients with thalassemia. Haematologica 2008;93:11211123 .

10. HCV in dialysis patients HCV infection remains frequent in patients on maintenance haemodialysis (1). HCV infection plays a detrimental role on survival in haemodialysis patients and renal transplant recipients (2). No optimal antiviral therapy of chronic HCV infection in dialysis populations exists.(1) Fabrizi F, et al. Hepatitis C virus infection and the dialysis patient. Seminars in Dialysis 2007;20:416422.(2) Fabrizi F, et al. The impact of hepatitis C virus infection on survival in dialysis patients: meta-analysis of observational studies. Journal of Viral Hepatitis 2007;14:697703.

11. HCV in patients with a renal transplant HCV infection reduces both graft and patient survival in recipients of renal transplants (1). New-onset diabetes and renal lesions are both common after transplantation in patients infected with HCV (2). Historically, antiviral therapy has been avoided after renal transplantation due to risks of precipitating graft rejection. Recent small studies have challenged this issue.(1) Dominguez-Gil B, Morales JM. Transplantation in the patient with hepatitis C. Transplant International 2009(2) Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation and treatment of hepatitis C in chronic kidney disease. Kidney International Supplement 2008;109;S1S99.

12. HCV with psychiatric comorbidity Psychiatric comorbidity is common in patients with chronic HCV infection (1). Psychiatric side effects are common following treatment with interferon alfa therapy (2). Treatment of patients with HCV infection and psychiatric comorbidity requires an interdisciplinary team approach including hepatologists and psychiatrists.(1) El-Serag HB, Kunik M, Richardson P et al. Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology 2002;123:476482.(2) Hosoda S, et al. Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis. Psychiatry and Clinical Neurosciences 2000;54:565572.

13. HCV in patients with psychiatric comorbidity Prospective clinical trials suggest that within an interdisciplinary team approach, patients with HCV infection and psychiatric comorbidity can be safely and effectively treated with antiviral regimens including interferon alfa (1). Early intervention with antidepressant therapy may attenuate/prevent major depressive episodes in those patients at risk of worsening depressive symptoms.(1) Knott A, et al. Integrated psychiatric/medical care in a chronic hepatitis C clinic: effect on antiviral treatment evaluation and outcomes. American Journal of Gastroenterology 2006;101:22542262.

14. HCV and Morbid Obesity Obesity is common in patients with chronic HCV infection (1). Obesity is associated with a reduced chance of viral clearance with antiviral therapy (2). Insulin resistance, the severity of which correlates with BMI in chronic HCV infection, is one mechanism by which response to antiviral therapy is reduced.(1) Chen W et al Prevalence and predictors of obesity among individuals with positive hepatitis C antibody in a tertiary referral clinic. Journal of Hepatology 2008;49:711717.(2) Bresler BL et al High body mass index is an independent risk factor for on response to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639644.

15. HCV and Morbid Obesity Interventions targeted at reducing obesity and/or insulin resistance may improve treatment outcome (1). Antiviral therapy tailored to body weight improves rates of SVR (2).(1) Overbeck K, et al. Pioglitazone in chronic hepatitis C not responding to pegylated interferonalpha and ribavirin. Journal of Hepatology 2008;49:295 298.(2) Jacobson IM, et al. Peginterferon alfa- 2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology 2007;46:971981.

16. HCV and injecting drug users Chronic infection with HCV is common in those who use illicit drugs (1). Illicit drug users may be categorized as regular users, those who are stable on opiate replacement therapy, or as past injectors. Each phase of activity is unstable and many drug users oscillate between the different stages (2).(1) Roy K, et al Monitoring hepatitis C virus infection among injecting drug users in the European Union: a review of the literature. Epidemiology and Infection 2002;129:577585.(2) Hser YI, et al. A 33-year follow-up of narcotics addicts. Archives of General Psychiatry 2001;58:503508.

17. HCV and injecting drug users Uptake of antiviral therapy is low in active injectors and in those who are stable on opiate replacement therapy. However, successful therapy has been achieved, particularly in the latter group, and case- by-case assessment is required. Treatment in past injectors is common and usually associated with excellent compliance and success rates.Backmund M, et al. Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users. Clinical Infectious Diseases 2004;39:15401543.

18. HCV with autoimmune features Antiviral therapy for HCV comprises peginterferon alfa and ribavirin, which are thought to have immunostimulatory activities. Medical therapy of autoimmune hepatitis includes immunosuppressive medications. Autoantibody positivity (ANA, SMA, anti-LKM1), which is central to the diagnosis of autoimmune hepatitis, is also common in the setting of chronic HCV (1).(1) Narciso-Schiavon JL, et al. Antinuclear antibody positivity in patients with chronic hepatitis C: clinically relevant or an epiphenomenon? European Journal of Gastroenterology and Hepatology 2009;21:440446.

19. HCV with autoimmune features In general, ANA or SMA positivity in the setting of HCV does not affect disease progression or response to antiviral therapy (1). Since antiviral therapy with immunostimulatory medications can exacerbate underlying immune processes, it is important to identify these patients. High-titre ANA or SMA positivity, unusually highly elevated liver enzymes and liver biopsy suggestive of autoimmune hepatitis should heighten suspicion of chronic HCV with autoimmune features.(1) Williams MJ, et al. Autoantibodies in chronic hepatitis C virus infection and their association with disease profile. Journal of Viral Hepatitis 2009;16:325 331.

20. HCV with autoimmune features In general, antiviral therapy of HCV should proceed in the usual fashion in the setting of ANA or SMA positivity; however, if HCV with autoimmune features is suspected, antiviral therapy with interferon alfa-based medical regimens should be deferred (1).(1) Ferri S, et al. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C. Journal of Hepatology 2009;50:10931101.

21. HCV & Heart Diseases It has been found that having Hepatitis C was associated with an approximately 25 percent higher risk of coronary artery disease. This elevated cardiovascular risk could be due to increased inflammation, immune activation and blood clotting in people with Hepatitis C.Butt AA, et al Hepatitis C virus infection and the risk of coronary disease, Clinical Infectious Diseases, July 2009

22. HCV & Heart Diseases Treatment with pegylated interferon/ribavirin may be safely offered to carefully selected chronic hepatitis C patients with coexisting, clinically significant heart disease (1)(1) Butt Durante-Mangoni et al , Dig Liver Dis. 2011 May;43(5):411-5

23. HCV in liver transplant recipients HCV-infected patients have lower survival rates than non-HCV-infected patients after liver transplantation (1). Consider treatment of recurrent HCV in patients with biopsy-proven advanced fibrosis and/or increased hepatic venous pressure gradient (2).(1) Gane EJ, et al. Long-term outcome of hepatitis C infection after liver transplantation.New England Journal of Medicine 1996;334:815820 .(2) Wiesner RH, et al, International Liver Transplant Society Expert Panel. Report of the first International Liver Transplant Society expert panel consensus conference on liver transplantation and hepatic C. Liver Transplantation 2003;9:S1S9.

24. HCV in liver transplant recipients Treatment using combination of peginterferon and ribavirin in patients with confirmed HCV recurrence can improve allograft and patient survival (1). Barriers to treatment include patient tolerance due to adverse effects of antiviral therapy, risk of cellular rejection, and risk of alloimmune hepatitis (2).(1) Bizollon T, et al. Histological benefit of retreatment by pegylated interferon alpha-2b and ribavirin in patients with recurrent hepatitis C virus infection post-transplantation. American Journal of Transplantation 2007;7:448453.(2) Berardi S, et al. High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis? Gut 2007;56:237242.

25. HCV in patients with advanced disease An increasing number of patients with advanced hepatitis C are presenting to clinics for treatment of chronic hepatitis C. The clinician must characterize the severity of the underlying liver disease before recommending a course of antiviral therapy. In general, the ChildPugh classification is useful for defining compensated (class A) and decompensated (class B or C) cirrhosis.

26. HCV in patients with advanced disease Compensated patients have reasonably good chances for SVR and are less prone to severe adverse events or complications (1) . Decompensated patients are difficult to treat and difficult to cure and should be managed primarily by physicians experienced in the treatment of HCV and management of cirrhosis (1) . Rendering blood free of HCV RNA prior to liver transplantation reduces the rate of post-transplant recurrence of hepatitis C.(1) Everson GT, et al. Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: lessons from the HALT-C Trial. Hepatology 2006;44:16751684.

27. HCV in patients with advanced disease These patients are prone to cytopenias, which worsen with treatment: growth factors such as G-CSF and erythropoietin analogue are often required (1) . The clinician has to monitor these patients carefully to detect and manage treatment-emergent adverse events or complications.(1) Dietrich DT, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving ribavirin plus interferon alfa. American Journal of Gastroenterology 2003;98:24912499.

28. HCV in children A minority of individuals with chronic HCV are children, and liver disease is generally mild and slowly progressive in this population. However, some children have advanced liver disease, and others are at risk for future complications such as cirrhosis and HCC (1). The majority of new cases of HCV infection in children are due to perinatal transmission. The likelihood of perinatal transmission is about 5% with each pregnancy (1).(1) Resti M, et al. Clinical features and progression of perinatally acquired hepatitis C virus infection. Journal of Medical Virology 2003;70:373377.

29. HCV in children Children as young as 3 years of age with chronic HCV may be candidates for treatment. The recommended therapy is the combination of peginterferon and ribavirin (1) . The success of treatment for chronic HCV in children and adolescents depends on multiple factors such as genotype, viral level, side effects, adherence, close monitoring, and the availability of a supportive and involved family(1) PegIntron package insert. Available at Drugs@FDA.gov (accessed 6/2/09; access approved 3/10/09).

30. HCV & HBV Co-infection HBV/HCV co-infection is a common phenomenon, particularly in areas where both infections are endemic. Viral interaction may result in fluctuating HBV/HCV dominance and frequently leads to apparent suppression of HBV replication. Peginterferon and ribavirin combination therapy for HCV is as efficacious and safe in HBV/HCV co-infection as in monoinfection.

31. HCV & HBV Co-infection The risk for hepatocarcinogenesis increased twofold in those with anti-HBs and anti-HBc, compared to those who were only anti-HCV- positive (1) Few data are available to guide therapy in patients with dually active co-infection, although addition of a nucleos(t)ide may be appropriate.(1) Chiba T et al. Role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 1996; 91: 11951203.

32. HCV Non-responders & relapsers Non-sustained responses to peginterferon and ribavirin comprise a heterogeneous group of antiviral responses (non-responders and relapsers). Numerous fixed and correctable factors identified during the previous course of treatment must be considered when counselling about retreatment. Patients with correctable factors, such as extreme dose reductions or discontinuation of ribavirin, may be most likely to benefit from retreatment if these issues can be better managed.

33. HCV Non-responders & relapsers The change in HCV RNA during a prior course of therapy has important implications for the likelihood of response to retreatment. Optimized dosages of ribavirin and extending duration of therapy for slow virological responders may modestly improve rates of sustained virological response during retreatment. Preliminary data of triple combination regimens including a direct antiviral agent, such as telaprevir or boceprevir, are promising for the treatment of prior non-sustained responders.

34. Thank You 4 your attention