Hepatitis C Diagnosis and Treatment

HEPATITIS C
By- Dr.Armaan Singh

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?
2

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
DR. ARMAAN SINGH 3

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.
FEB, 17, 2015DR. ARMAAN SINGH 4

INTRODUCTION: FACT SHEET
 An estimated 130–170 million people are infected with
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

Figure 1. Seroprevalence of anti-HCV antibodies using chemiluminescent microparticle immunoassay.
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
The total seroprevalence among the 15323 tested individuals. B. HCV
seroprevalence in males in comparison to females

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:
 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:
 Genotype 4 is common
 Ia And Ib less common
 Genotype 2, 3, 5 and 6 are least common
Genotype helps determine therapy
duration and likelihood of responding to
therapy

EPIDEMIOLOGY
 Worldwide seroprevalence 3% based upon anti- HCV) up to 180 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.

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
 Sexual transmission

PATHOGENESIS: REPLICATION IN LIVER
CELLS

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

COURSE OF DISEASE
 Associated with Acute and Chronic Infections

COURSE OFTHE 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
 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%

COURSE OFTHE 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.

EXTRA-HEPATIC MANIFESTATIONS
 Rheumatoid arthritis
 Glomerulonephritis
 Cryo-globenemia

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

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
 Confirmation of Diagnosis
 Monitoring response to therapy
 Qualitative:
 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: for treatment duration and response

NOVACCINATION SO FAR
HEPATITIS C PREVENTION
AASLD, (American Association for the Study of Liver Diseases) guidelines-2009

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

PREVENTION
 NoVaccine 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

TREATMENT

GOALS OF THERAPY
 Eradicate HCV infection in acute
 Decrease HCV associated morbidity and mortality
 Attain SustainedVirologic Response (SVR)
 Undetectable HVC RNA, 24 weeks after therapy completion
 Normalize biochemical markers
 Improve clinical symptoms
 Prevent progression to cirrhosis an HCC
 Prevent development of end stage liver disease
 To prevents the development of chronic HCV infection
These goals
are partly achieved by
Pharmacotherapy

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

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

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

INFECTION Difficult patient population: individualized consideration
 Normal ALT (treatment dependent on genotype, degree of 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

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 Pegylated-IFN
Dose
weight Ribavirin Dose Duration
1 Peginterferon
α2a 180 mcg/wk
Less than 75 Kg 1000 mg 48 weeks
Peginterferon α2b
1.5 mcg/wk
More than 75 kg 1200 mg
2,3 Peginterferon á2a
180 mcg/wk
800 mg 24 weeks
Peginterferon α2b
1.5 mcg/wk
At week 1, 2, 4 and then interval of 4-8 weeks monitor:
•Symptom of Disease
•Side Effects of therapy
•Blood count
•Aminotransferases

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.

FOLLOW UP

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
(J Clin Gastroenterol 2005;39:S9-S13),

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.

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

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.

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:
 Eltrombopag, an orally active thrombopoietin receptor agonist that
received FDA approval for chronic ITP (hepatotoxic)

MANAGING THE ADVERSE EFFECTS OF
INTERFERON
 Neuropsychiatric:
 Prompt recognition and early treatment required
 Depression: 44% during first 3 months
 Tx:
 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

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

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: ???

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/ L has beenμ
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

TREATMENT NONRESPONSIVE OR
RELAPS No specific treatment regimen for chronic HCV infections not responding
to, or relapse after, pegIFN-based 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

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

DEALING WITH THE CHALLENGES: NEW
ANTIVIRALS
 Direct Acting Antiviral Drugs (DAA)
 The NS3 protease inhibitors
 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

TREATMENT UPDATES ADD ON THERAPY FOR
GENOTYPE-1:
 Boceprevir: Protease inhibitor : (DAA)
 Indicated for:
 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:
 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
Stop
Therapy

TREATMENT UPDATES ADD ON THERAPY FOR
GENOTYPE-1
 Telaprevir: protease inhibitor
 Indicated for:
 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:
 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

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

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
 MonitorTSH and fasting lipid panel every 12 weeks
 Monitor serum creatinine in patients receiving ribavirin
 To avoid ribavirin accumulation in renal insufficiency resulting in Hemolytic
anemia

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, 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

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

REFERENCES
 Houghton M Discovery of the hepatitis C virus.Liver Int. 2009
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-pharmtox-
011112-140254

FEB, 17, 2015DR. ARMAAN SINGH
50
Thank
You
Very
Much

Hepatitis C Diagnosis and Treatment

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