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 world's 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 50–76% 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 Positive
for 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;372:321–332.

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 12–24 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;43:923–931.

9. 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 2–7 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;343:388–390.

10. 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;93:1121–1123 .

11. 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;20:416–422.
(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;14:697–703.

12. 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;S1–S99.

13. 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;123:476–482.
(2) Hosoda S, et al. Psychiatric symptoms related to interferon therapy for chronic
hepatitis C: clinical features and prognosis. Psychiatry and Clinical Neurosciences
2000;54:565–572.

14. 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;101:2254–2262.

15. 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;49:711–717.
(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;38:639–644.

16. 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;46:971–981.

17. 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;129:577–585.
(2) Hser YI, et al. A 33-year follow-up of narcotics addicts. Archives of General
Psychiatry 2001;58:503–508.

18. 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;39:1540–1543.

19. 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;21:440–446.

20. 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.

21. 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;50:1093–1101.

22. 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

23. 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

24. 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;334:815–820 .
(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:S1–S9.

25. 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;7:448–453.
(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;56:237–242.

26. 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 Child–Pugh classification is
useful for defining compensated (class A) and
decompensated (class B or C) cirrhosis.

27. 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;44:1675–1684.

28. 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;98:2491–2499.

29. 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;70:373–377.

30. 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).

32. 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.

33. 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: 1195–1203.

34. 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.

35. 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.

36. Thank You
4 your attention