1. Dr. Afzal Haq Asif
Associate Professor
Pharmacology & Therapeutics
Nov
Dr. Afzal Haq Asif

2. Clinical Case
 A 45-year-old woman with a history of blood transfusion is
seen in the clinic for complaints of tiredness, fatigue,
anorexia, and weakness.
 On Physical examination, nothing was remarkable
 Laboratory values reported today include AST 150 IU/mL,
ALT 250 IU/mL , SCr 0.9 mg/dL,
 Bilirubin: 2.0 mg/dL, albumin 2.5 g/dL.
 Serum Anti HCV : +
HCV RNA level: 1, 220200 IU/mL
 A liver biopsy has revealed severe necro-inflammation and
bridging fibrosis.
 What is diagnosis ?
 What is the best course of action?
Nov
Dr. Afzal Haq Asif

3. ILO’s
 At the end of the session, the attendee will be able to
 Define the acute and chronic viral hepatitis C
 Diagnose based upon clinical and lab data
 Design therapeutic objectives
 Design therapeutic and follow up evaluation plan for
patient
 Resolve drug related problems of patient
 Educate the patient to improve therapeutic outcome
Nov
Dr. Afzal Haq Asif

4. Introduction
 In 60’s only A & B
 In 70’s, it was found that neither agent is found
responsible for post trans fusion Hepatitis, So
Hepatitis caused by NANB was introduce
 The major cause of parenterally transmitted NANB
hepatitis. In 1989, the genome was cloned from the
serum of an infected chimpanzee.
Nov
Dr. Afzal Haq Asif

5. Introduction: fact sheet
 An estimated 130–170 million people are infected with
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Nov
hepatitis C worldwide
Out of 100 people who contract the infection, 75–85% will
develop chronic infection,
60–70% develop chronic liver disease,
5–20% develop cirrhosis over the course of their chronic
infection,
1–5% will die of complications including hepatocellular
carcinoma (HCC)
7.3 % individuals were found seropositive for Anti-HCV
antibodies in a study carried out on 15323 Saudi patients
Dr. Afzal Haq Asif

6. Figure 1. Seroprevalence of anti-HCV antibodies using chemiluminescent microparticle
immunoassay.
The total seroprevalence among the 15323 tested individuals. B. HCV
seroprevalence in males in comparison to females
Abdel-Moneim AS, Bamaga MS, Shehab GMG, Abu-Elsaad A-ASA, et al. (2012) HCV Infection among Saudi Population: High
Prevalence of Genotype 4 and Increased Viral Clearance Rate. PLoS ONE 7(1): e29781. doi:10.1371/journal.pone.0029781
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029781
Nov
Dr. Afzal Haq Asif

7. HCV
 HCV is a single stranded RNA virus
 Genus Hepa-civirus, (HCV)
 Family Flavi-viridae
 Characterized by a high spontaneous mutation rate
 11 genotypes (90 sub-types) , (1a, 1,b, 2a, 3b etc)
 USA:
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Genotype 1 (subtypes 1a, 1b, and 1c) 70%–75%.
Genotypes 2 (subtypes 2a, 2b, and 2c) and 3 (3a and 3b) are less
common
 KSA:
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Nov
Genotype helps determine therapy
duration and likelihood of responding to
therapy
Genotype 4 is common
Ia And Ib less common
Genotype 2, 3, 5 and 6 are least common
Dr. Afzal Haq Asif

8. Epidemiology
 Worldwide seroprevalence 3% based upon anti- HCV) up to 180
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Nov
million people infected chronically.
Variation in distribution 0.4% to 1.1% in North America to 9.6% to
13.6% in North Africa.
A primary cause of death from liver disease
The leading indication for liver transplantation in the United States
Deaths as a result of liver failure or HCC) will continue to rise in the
next two decades
Responsible for 85% of cases associated with posttransfusional NANB
hepatitis
Occurs among persons of all ages, highest between 20 to 39 years, with
a male predominance.
Blacks have a substantially higher prevalence of chronic HCV infection
than do whites.
Dr. Afzal Haq Asif

9. Transmission
 Mainly blood-borne (transfusion, intravenous
drug abuse)
 High risk: Transfusion, intravenous drug abuse
 Low risk:
 Snorting cocaine or other drugs
 Occupational exposure needle stick , health workers
 Body piercing and acupuncture with unsterilized needle
 Tattooing
 From pregnant mother to child
 Nonsexual household contacts (rare)
 Sharing razors and/or toothbrushes
Nov
 Sexual transmission
Dr. Afzal Haq Asif

10. Pathogenesis: replication in Liver cells
Nov
Dr. Afzal Haq Asif

11. Pathogenesis
 Direct cell injury due to viral replication
 Genotype 1 is associated with higher viral replication,
and infection with the type 1b genotype is associated
with more progressive liver disease
 Immune mediated cell injury:
 CD8+ and CD4+ lymphocytes in portal, peri-portal, and
lobular areas in patients with HCV infection
Nov
Dr. Afzal Haq Asif

12. Course of disease
 Associated with Acute and Chronic Infections
Nov
Dr. Afzal Haq Asif

13. Course of the Disease
 Asymptomatic: 30%
 Moderate to severe hepatitis in 30% <20 years of age
 70-80% develop chronic infection
 Presence of viral RNA in serum for 6 months or more
 Evidence of viral replication: viral load
 10-30% of develop cirrhosis
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Nov
Factors promoting cirrhosis:
 Alcohol use,
 Male sex,
 Age over 40 years at the time of infection
 Co-infection with HIV and/or HBV
 The 5-year mortality with compensated cirrhosis 9%,
 Decompensated cirrhosis had a 5-year mortality of 50%
Dr. Afzal Haq Asif

14. Course of the Disease, contd;
 Hepatocellular Carcinoma in HCV infection
 1% to 4% of patients per year during the first 5
years after cirrhosis develop hepatocellular
carcinoma
 7% after 5 years of cirrhosis
 14% at 10 years;
 Higher in men
 Higher in older patients
NIH Consensus Program. National Institutes of Health consensus development conference panel
statement: management of hepatitis C. Hepatology. 1997;26:2S-10S.
Nov
Dr. Afzal Haq Asif

15. Extra-hepatic manifestations
 Rheumatoid arthritis
 Glomerulonephritis
 Cryo-globenemia
Nov
Dr. Afzal Haq Asif

16. Spontaneous resolution
 Early studies
 15–25% of persons who developed transfusion-
associated acute hepatitis C,
 14–29% HCV-infected blood donors, persons with
‘community-acquired’ infection, IV drug abusers and
children with leukemia
 Later studies:
 42 and 45%. among
infected children (21, 29), young
women (20, 22) and even some persons with
community-acquired hepatitis C
 Young age at the time of infection is an important
determinant of the likelihood of spontaneous
recovery.
The historyof the‘‘natural history’’of hepatitisC(1968-2009): Liver International 2009; 29(s1): 89–99
Nov
Dr. Afzal Haq Asif

17. Diagnosis
 Clinical Signs and symptoms: not suggestive, unless
thorough history and Labs
 Serum anti-HCV antibodies: 99% sensitivity and
specificity
 Serum HCV RNA: “Viral Load”
 Quantitative: used for
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Confirmation of Diagnosis
Monitoring response to therapy
 Qualitative:
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50 IU/ml: 100 copies/mL to confirm diagnosis 98% specificity
AASLD does not recommend qualitative
 Liver biopsy: for cirrhosis, prognosis
 ALT: Non specific
 Genotype: forDr. Afzal Haq Asif duration and response
treatment
Nov

18. AASLD, (American Association for the Study of Liver Diseases)
guidelines-2009
Nov
Dr. Afzal Haq Asif

19. Who should be screened
 Persons who have injected illicit drugs in the recent and remote past
 Persons with conditions of a high prevalence of HCV infection including:
 With HIV infection
 With hemophilia who received clotting factor prior to 1987
 Who have ever been on hemodialysis
 With unexplained abnormal aminotransferase levels
 Immigrants from countries with a high prevalence of HCV infection
 Prior recipients of transfusions or organ transplants prior to July 1992:
 Persons who were notified that they had received blood from a donor who
later tested positive for HCV infection
 Persons who received a transfusion of blood or blood products
 Persons who received an organ transplant
 Children born to HCV-infected mothers
 Health care, emergency medical and public safety workers after a needle stick
injury or mucosal exposure to HCV-positive blood
 Current sexual partners of HCV-infected persons
Nov
Dr. Afzal Haq Asif

20. Prevention
 No Vaccine is available
 Risk factor modification
 Intravenous drug abuse: treatment with oral methadone
 Sexual contact: appropriate barrier contraception
 Avoid blood exposure: Occupational (universal
precautions) or other contact
 Avoid sharing toothbrushes or razors or receiving a
tattoo
 HAV and HBV vaccine to prevent further progression
of liver disease
Nov
Dr. Afzal Haq Asif

21. Nov
Dr. Afzal Haq Asif

22. Goals of Therapy
 Eradicate HCV infection in acute
 Decrease HCV associated morbidity and mortality
 Attain Sustained Virologic Response (SVR)
 Undetectable HVC RNA, 24 weeks after therapy
completion
These goals
 Normalize biochemical markers
 Improve clinical symptoms
are partly achieved by
Pharmacotherapy
 Prevent progression to cirrhosis an HCC
 Prevent development of end stage liver disease
 To prevents the development of chronic HCV infection
Nov
Dr. Afzal Haq Asif

23. Acute HCV infection
 PEG- INF α based therapy for 12-24 weeks
 Ribavirin may be added: but no study is available
to favor improve SVR
 Treatment can be delayed for 8-12 weeks for to
assess for spontaneous resolution
 Meta-analysis of 16 trials resulted in a risk
difference of 49% (95% CI 33-65), for developing
chronic infection between treated and untreated
patients
Nov
Dr. Afzal Haq Asif

24. Treatment of Chronic HCV infection
 Indications of therapy:
 Age older than 18 years and positive serum HCV RNA
 On biopsy moderate to severe inflammation/necrosis
 Compensated liver disease, acceptable hemoglobin
(13 g/dL men, 12 g/dL women) and neutrophils (more
than 1500/mm3), SCr less than 1.5 mg/dL
 Willingness to be treated and be adherent
 No contraindications to therapy
Nov
Dr. Afzal Haq Asif

25. Treatment of Chronic HCV infection
 Contraindications to treatment
 Major uncontrolled depressive disorder
 Solid-organ transplantation (renal, heart, lung)
 Autoimmune hepatitis or other autoimmune conditions
 Untreated thyroid disease
 Pregnant or unwilling to adhere to adequate contraception
 Severe concurrent medical disease (hypertension, heart
failure, coronary heart disease, poorly controlled diabetes
mellitus, chronic obstructive pulmonary disease)
 Age younger than 2 years
 Hypersensitivity to IFN or ribavirin
Nov
Dr. Afzal Haq Asif

26. Treatment of Chronic HCV infection
 Difficult patient population: individualized
consideration
 Normal ALT (treatment dependent on genotype, degree of
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fibrosis, symptoms)
Liver biopsy indicating no or mild fibrosis
Advanced liver disease (fibrosis or decompensated cirrhosis)
Recurrence after liver transplantation
Patients younger than 18 years
Co-infection with HIV or HBV
Chronic Kidney Disease
Non responders or relapses
Dr. Afzal Haq Asif

27. Treatment
 First-line treatment for acute HCV includes pegylated interferon plus
ribavirin.
 once-weekly PEG-IFN and a daily oral dose of ribavirin in two divided
doses
Genotype
1
2,3
Pegylated-IFN
Dose
Peginterferon
α2a 180 mcg/wk
Peginterferon α2b
1.5 mcg/wk
Peginterferon á2a
180 mcg/wk
Peginterferon α2b
1.5 mcg/wk
weight
Ribavirin Dose
Duration
Less than 75 Kg
1000 mg
48 weeks
More than 75 kg
1200 mg
800 mg
At week 1, 2, 4 and then interval of 4-8 weeks monitor:
• Symptom of Disease
• Side Effects of therapy
• Blood count
• Aminotransferases
Nov
Dr. Afzal Haq Asif
24 weeks

28. Treatment: Genotype 4
 A meta-analysis leads to recommendations for patients
with genotype 4:
 Combination therapy with Peg IFN plus ribavirin for 48
weeks.
 Combination of Peg IFN-α2b plus a fixed dose of ribavirin
(10.6mg/kg/day) for 36weeks may also result in a sufficient
EVR.
 genotype 6:
 with Peg IFN-α plus ribavirin for 48 weeks was more
effective than treatment for 24 weeks.
Nov
Dr. Afzal Haq Asif

29. Follow up
 Genotype-1
 AT week 12

Retest HCV RNA level
 If Negative or decreased by 2log 10 units
 Continue for full 48 weeks
 Monitor for :
Symptoms
 Blood count
 ALT at 4-8 week interval
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If RNA hasn’t fallen by 2log 10 Units: STOP therapy
 Genotype 2, 3
 Retest HCV RNA level at 24 weeks:
 After therapy:
 Assess ALT 2, & 6 months
 Repeat HCV RNA, 6 months after stopping tx
Nov
Dr. Afzal Haq Asif

30. Ribavirin adverse effect monitoring
 Oral nucleoside analog
 Available as 200-mg tablets (Copegus) or capsules (Rebetol)
 Adverse Effect
 Hemolytic anemia:
Upto 10% of patients (usually within 1–2 weeks of initiating therapy):
 decrease dose to 600 mg/day when hemoglobin drops to 10 g/dL or less,
and discontinue when hemoglobin drops to 8.5 g/dL or less
May worsen underlying cardiac disease;
Monitor complete blood cell count (CBC) at baseline, 2 weeks, 4 weeks,
Decrease dose to 600 mg/day if hemoglobin drops more than 2 g/dL in
any 4-week period during treatment.
May use epoetin or darbepoetin to stimulate red blood cell production,
improve anemia
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Nov
(J Dr. AfzalGastroenterol 2005;39:S9-S13),
Clin Haq Asif

31. Ribavirin adverse effect monitoring
 Teratogenicity: Category X drug;
 Requires a negative pregnancy test at baseline and every
month up to 6 months after treatment,
 Use of two forms of barrier contraception during
treatment and for 6 months after treatment.
 Contraindicated in patients with a creatinine clearance
(CrCl) less than 50 mL/minute
 pancreatitis, pulmonary dysfunction (dyspnea,
pulmonary infiltrate, and pneumonitis), insomnia,
irritability or depression (often referred to as “riba
rage”), and pruritus.
Nov
Dr. Afzal Haq Asif

32. Interferon
 INF α 2 b:
 Used for HBV and HBC
infections
 Half life : 2-3 hours
 Dose: 3 MIU subcutaneous 3
times /week
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Geno-1: 4/48 weeks
Geno2: 3/24 weeks
 Peg IFN α2 a: with branched peg
 Used for HBV and HVC
infections
 Half life: 160 hours
 Dose: 180 mcg s/c once weekly
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Nov
chain
 Half life: 40 hours
 Dose 1.5 mcg/kg s/c once
weekly
 IFN alfaxon-1:
 Used for HCV treatment
 Dose:
chain
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 PegIFN -α2b : linear peg
Geno-1 4/48
Geno-2 3/24
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Dr. Afzal Haq Asif
naïve: 9 mcg
Non responder: 15 mcg s/c 3
times a week
Naïve for 24 weeks
INF non responder: 48
weeks

33. Interferon: adverse effects
 Most Common:
 influenza-like symptoms (e.g., fever, headache, myalgia, fatigue),
 Hematologic abnormalities: neutropenia, thrombocytopenia,
 Neuropsychiatric disorders (e.g., depression 40 % and anxiety),
 injection site reactions,
 diarrhea, nausea, insomnia, alopecia, pruritis, and anorexia.
 Less common but serious adverse
 severe psychiatric (i.e., suicidal ideation),
 cardiovascular (i.e., myocardial infarction),
 Endocrine (e.g., thyroid dysfunction, diabetes mellitus),
 immune (e.g., psoriasis, lupus),
 pulmonary, and ophthalmologic disorders,
 pancreatitis, colitis, and other serious infections.
Nov
Dr. Afzal Haq Asif

34. Managing the adverse effects of interferon
 Hematological:
 Anemia: common reason for discontinuation and dose
reduction (upto 23% of patients)
 Tx: Erythropoitic growth factor:
 Epoitin Alfa: 40-6000 units weekly
 Darbepoitin alfa 3 mcg every 2 weeks
 IFN induced neutropenia:
 Recombinant granulocyte colony stimulating factor
(filgrastim) is safe and effective
 Thrombocytopenia:
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Nov
Eltrombopag, an orally active thrombopoietin receptor agonist
that received FDA approval for chronic ITP (hepatotoxic)
Dr. Afzal Haq Asif

35. Managing the adverse effects of interferon
 Neuropsychiatric:
 Prompt recognition and early treatment required
 Depression: 44% during first 3 months
 Tx:
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Nov
Close monitoring and follow up by a team of health care
providers including psychiatrist
Prophylactic anti-depressants are debated
Uncontrolled psychiatric symptoms: contraindication for Tx
Dr. Afzal Haq Asif

36. Treatment Challenges
 High viral load
 HCV RNA greater than 800,000 IU/mL
 Advanced fibrosis and cirrhosis,
 Continued drug and/or alcohol use,
 Psychiatric conditions,
 Coinfection with HBV or HIV, advanced age,
 Immunosuppression (e.g., liver transplantation
recipients),
 African American race,
 Obesity and insulin resistance,
 Previous treatment with suboptimal therapy
Nov
Dr. Afzal Haq Asif

37. African Americans: variable response
 Result of 2 prospective , multicenter clinical trials,
 In African American patients, SVR occurred in only 19%
to 28% of HCV genotype 1 infected African American
patients treated with pegIFN and ribavirin therapy, in
contrast to the 40% to 50% seen in other studies
 Difference cannot be explained
 New strategies: ???
Nov
Dr. Afzal Haq Asif

38. HIV and HCV co-infection
 30% HIV patient also have HCV infection
 Rapid progression of liver damage
 SVR is lower as compared to HVC alone
 A threshold CD4 count of at least 350 cells/μL has been
suggested for initiation of antiviral therapy;
 Treatment is not recommended if CD4 counts lower than
200 cells/mL.
 Adverse effects are more common:
 Anemia with Ziduvodine and Ribavirin combination
 Mitochondrial toxicity, pancreatitis, liver failure, and death ; more
common with Didanosine and Ribavirin combination
 ???? Liver transplant
Nov
Dr. Afzal Haq Asif

39. Treatment Nonresponsive or relaps
 No specific treatment regimen for chronic HCV
infections not responding to, or relapse after, pegIFNbased therapy.
 High-dose IFN alfacon-1 in combination with ribavirin
is currently being evaluated in clinical trials for partial
or no response to pegIFN-based therapy
 Extension to 72 weeks: needs evidence
Nov
Dr. Afzal Haq Asif

40. Liver Transplant. Is this a solution?
 Most common indication in US:
 Hepatitis C virus–related end-stage liver disease
 Outcome:
 Recurrence is essential outcome
 Progression of liver disease is accelerated, Within 5 years after
transplantation, 20% to 40% of liver allografts progress to cirrhosis;
 60% to 70% of cirrhotics experience hepatic decompensation
within 3 years
 Response rates to pegIFN and ribavirin treatment after liver
transplant are lower than for patients in the pretransplant setting,
 Drug toxicity remains a limiting factor. 1/3 require discontinuation
Nov
Dr. Afzal Haq Asif

41. Dealing with the challenges: New antivirals
 Direct Acting Antiviral Drugs (DAA)
 The NS3 protease inhibitors
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Nov
Telaprevir and Boceprevir
An update on treatment of genotype 1 chronic hepatitis
C virus infection: 2011 practiceguideline by the American
Association for the Study of Liver Diseases
Dr. Afzal Haq Asif

42. Treatment updates Add on therapy for Genotype-1:
 Boceprevir: Protease inhibitor : (DAA)
 Indicated for:
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Adult naïve patients
Who failed previous treatment with Peginferon + ribavirin
SVR rate with triple therapy is 63-66% in comparison to double
therapy (50%)
Higher incidence of anemia and neutropenia
Monitor after every 4 weeks
 Dose:
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800 mg t.i.d. with food (200mg cap available) with double therapy
Added to double therapy at week 5
 If RNA viral load is > 100 IU/ml at week 12
 Decreased at week 12 but Detectable at week 24
Nov
Dr. Afzal Haq Asif
Stop
Therapy

43. Treatment updates Add on therapy for Genotype-1
 Telaprevir: protease inhibitor
 Indicated for:
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Adult naïve patients
Who failed previous treatment with Peginferon + ribavirin
SVR rate with triple therapy 72-79% in comparison to double therapy
(50%)
Anemia, skin rash, pruritus, nausea, diarrhea, ano-rectal discomfort
 Dose:
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Nov
750 mg t.i.d after 30 minutes of food (with 20 g of fat) for absorption
If Start with double therapy from day 1 continue upto 12 weeks
Dr. Afzal Haq Asif

44. Nov
Dr. Afzal Haq Asif

45. Outcome evaluation parameters
Parameter
Rapid virologic response
(RVR)
Early virologic response
(EVR)
Definition
Undetectable HCV RNA at week 4 of treatment
End-of-treatment response
(ETR)
Sustained virologic response
(SVR)
Breakthrough
Undetectable HCV RNA at the end of a 24- or
48-week course depending on genotype
Undetectable HCV RNA 24 weeks after finishing
treatment
Reappearance of HCV RNA while on treatment
Relapse
Reappearance of HCV RNA after finishing a
course of treatment
Failure to clear HCV RNA from serum after 24
weeks of therapy
Failure to decrease HCV RNA by < 2 logs after 24
weeks of therapy
Decrease in HCV RNA
Nonresponder
Null responder
Partial responder
Nov
> 2-log reduction in HCV RNA compared with
baseline or undetectable HCV RNA at 12 weeks
Dr. Afzal Haq Asif

46. Outcome evaluation
 Disease:
 As discussed above + Check ALT after every 4 weeks
 Therapy
 Patient on Peginterferone: and Ribavirin or
Peginterferone alone:

Check WBC, ANC (absolute neutrophil count ), platelets and
Hemoglobin
 weekly or biweekly during first month
 Monthly after first month
 Monitor TSH and fasting lipid panel every 12 weeks
 Monitor serum creatinine in patients receiving ribavirin
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Nov
To avoid ribavirin accumulation in renal insufficiency resulting in
Hemolytic anemia
Dr. Afzal Haq Asif

47. Patient care and education-1
 Educate patient for risk factors for acquiring hepatitis
 Educate patient about hepatotoxic drugs
 Educate regarding vaccination against A & B
 Obtain thorough PMH regarding psychiatric, cardiac,
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Nov
endocrine and renal disorders
Assess fro adverse effects periodically
Encourage for medication compliance to increase SVR
Encourage fluid intake to avoid dehydration
Educate all women of child bearing age, and men who are
able to father a child to use 2 forms of contraception during
and 6 months after therapy
Dr. Afzal Haq Asif

48. Patient care and education contd-2
 Provide patient education:
 How to prevent viral hepatitis
 Importance of taking all medication daily at
scheduled time
 Adverse effects of medications
 How to self administer pegylated interferon
injection correctly
 Importance of appropriate disposal of used
injection
Nov
Dr. Afzal Haq Asif

49. References
 Houghton M Discovery of the hepatitis C virus.Liver Int. 2009
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Nov
Jan;29 Suppl 1:82-8. doi: 10.1111/j.1478-231.2008.01925.x.
World Health Organization HepatitisC Fact Sheet 2012. http://
www.who.int/ mediacentre/factsheets/ fs164/en/). [Accessed 26
January 2013].
Wise M, Balek S, Fineli L, et al. Changing trends in hepatitis C-related
mortality in the United States, 1995–2004. Hepatology 2008; 47:1128–
1135.
ACCP updates on therapeutics-2011
http://www.annualreviews.org/doi/pdf/10.1146/annurev-pharmtox011112-140254
Dr. Afzal Haq Asif

50. Thank
You
Very
Much
Nov
Dr. Afzal Haq Asif