Hepatitis C:Diagnosis and management.pdf

This slideshow is about current diagnosis ,prevention and management of hepatitis c Virus

1. HEPATITIS C VIRUS:
CURRENT DIAGNOSTIC EVALUATION,PREVENTION AND
ITS MANAGEMENT
PRESENTER- DR. PRAJNYAPARAMITA MOHANTY
JUNIOR RESIDENT
PRECEPTOR- DR. ATANU THAKUR
ASSISTANT PROFESSOR,
DEPT.OF GENERAL MEDICINE
VIMSAR,BURLA

2. Introduction
•Hepatitis C virus was discovered in 1989
•Previously known as nonA nonB hepatitis virus
•Genus-Hepacivirus
•Family- flaviviridae
•Spherical and heterogeneous in size ranging
from 40-80 nm in diameter
•7 HCV genotypes and more than 67 subtypes
currently recognised
2

3. Structure
•1. Envelope
•2. Capsid
•3. RNA
3 parts
3

4. HCV PROTEINS
A polyprotein of ~3000 AA is formed by translation of viral RNA
Composed of 1.STRUCTURAL PROTEINS
core protein, E1 & E2
2.NONSTRUCTURAL PROTEINS
P7,NS2,NS3,NS4A,NS4B,NS5A,NS5B
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5. Functions of HCV proteins
Core protein:- forms viral capsid and protects viral genome
E1 & E2:- heavily glycosylated envelope proteins ,form heterodimers,E2 protects E1
from immune response of host and initiates viral entry by binding to CD 81 and
scavenger receptor SR-B1
P7:-membrane ion channel protein, helps in viral assembly and release
NS2:-cysteine protease, cleaves NS3 from NS2
NS3-4A:-serine protease cleaves all other NS proteins from polyprotein.NS 3 also acts
as helicase, helps in unwinding of RNA
NS4B & NS5A:- forms viral replication membranous web
NS5B:-RNA dependent RNA polymerase
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6. Modes of transmission
.High risk sexual contacts
.From mother to infants during
Pregnancy or during labor
•Blood transfusion
•Injection drug use
•Needle stick injuries
•Chronic hemodialysis
•Receipt of clotting factor concentrates,immunoglobulins
•Organ and tissue transplantation
•Unsanitary tattooing and piercing
•Sharing of personal items(razors,,nail scissors
etc.)
•
PERCUTANEOUS
TRANSMISSION
NON
PERCUTANEOUS
TRANSMISSION
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7. NATURAL HISTORY OF HCV INFECTION
ACUTE INFECTION
20-30% with symptoms
HCV INFECTION
FULMINANT HEPATITIS
Rare
CLEARANCE OF HCV RNA
15-25%
CHRONIC INFECTION
55-85%
CHRONIC ACTIVE HEPATITIS
EXTRAHEPATIC
MANIFESTATIONS
CIRRHOSIS
10-20% over years
HCCDECOMPENSATED CIRRHOSIS
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8. PATHOGENESIS
•Chronic hepatitis develops in 55-85% of persons with acute infection,in
minority of patients in whom acute HCV resolves spontaneously, an early and
multispecific T cell response occur
•Determinants of persistence of HCV include
1) evasion of immune response through several viral mechanisms
2) inadequate induction of innate immune response
3) insufficient induction and maintenance of adaptive immune response
4) production of viral quasispecies
5) induction of immunologic tolerance or exhaustion
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9. ACUTE HEPATITIS C
•HCV accounts for an estimated 20% cases of acute hepatitis
•Nearly all cases are asymptomatic
•Jaundice- most specific liver related symptom, develop in 50-84% of cases in clinically
overt acute HCV infection
•Within 7-21days of viral infection,HCV RNA becomes detectable in serum
•Rise in ALT levels occurs after 4-12 weeks
•The rate of viral persistence ranges from 45 to more than 90%
9

10. SPONTANEOUS VIRAL CLEARANCE
•The reason HCV infection persists in some patients but resolves spontaneously in
some is not well understood .Different studies found the following characteristics
have been associated with lower rate of chronicity-
1.younger age
2.female gender
3.race
4.symptomatic acute infection
5.absence of HIV coinfection
6. IL 28B CC genotype
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11. CHRONIC HEPATITIS C
•Asymptomatic
•Fluctuating ALT levels
•Extrahepatic manifestations
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12. EXTRAHEPATIC MANIFESTATIONS
12

13. SCREENING
2020 CDC RECOMMENDATION FOR HCV SCREENING
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14. DIAGNOSIS OF HCV
Serologic antibody assay
Molecular HCV RNA tests
Immune assays for HCV core antigen
Genotyping
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15. A.SEROLOGIC ANTIBODY ASSAYS: -
1.used for initial testing for diagnosis of HCV infection
2.detect human antibodies generated as a response to HCV infection
3.a positive HCV antibody test indicates one of following three scenarios
A. active infection
B. Past HCV infection that has resolved
C. false positive test
Demerits-
- these tests can’t differentiate whether the infection is active ,chronic or no
longer present
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16. TYPES OF SEROLOGIC ANTIBODY ASSAYS
1.Enzyme immune assays (EIA):-
•third generation HCV EIA detects antibodies that binds recombinant antigens derived from
four HCV regions:core,NS3,NS4,NS5
•- sensitivity approx.98%
•- false negative
1. acute HCV infection
2. persons with major immunosuppression
3. persons with chronic renal failure with long term hemodialysis
•- specificity greater than 99%
•- false positive
1. increased gamma globulin production,
2. autoimmune conditions
3. following immunisation
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17. 2.Chemiluminescence immune assays (CIA ):-an antibody test similar to EIA, used less frequently than
EIA, sensitivity and specificity similar to EIA
3.Point of care rapid immune assays :- the OraQuick HCV rapid antibody test approved by FDA in 2010
as a point of care test for use with whole blood samples obtained either by venipuncture or fingerstick
- can be used as alternative to EIA in initial HCV antibody testing
4.Recombinant immune blot assays (RIBA):- identifies specific antibodies generated in response to
specific antigens
- no longer used

17

18. B.MOLECULAR HCV RNA TESTS
Specifically detects HCV RNA and the process is commonly referred to as Nucleic acid tests(NAT)
or Nucleic Acid Amplification Tests(NAAT)
becomes positive approximately 1 to 2 weeks after initial HCV infection
HCV RNA usually persists for decades in patient who develop chronic disease
The NAT test has become gold standard supplemental test for patients who have a positive HCV
EIA screening test.
Can determine whether a patient with positive antibody test has current(active) or resolved HCV
infection
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19. •QUALITATIVE HCV RNA TEST
- Provides a yes or no answer whether detectable HCV RNA present in Patient blood sample
- do not provide a quantitative level of HCV RNA and are not used for baseline HCV RNA levels or
for monitoring response to therapy
•QUANTITATIVE HCV RNA TESTS
-These assays generate an actual HCV RNA level that may provide useful information as baseline
level in anticipation of HCV therapy
- polymerase chain reaction(PCR) provides a sensitive and specific assay for HCV RNA in blood
and tissue sample
- currently, the limit of detection for plasma HCV RNA is 5-15IU/ml
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20. C.IMMUNE ASSAYS FOR HCV CORE ANTIGEN
•New tests for HCV core antigen and are in development
•Less sensitive than HCV RNA assays
•Lower limit for detection equal to 500-3000 HCV RNA IU/ml
•Useful for monitoring patient on treatment and establishing
reinfection ,but insufficiently sensitive for HCV screening without
concurrent antiHCV testing,or to confirm sustained virological response
(SVR) after treatment
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21. D. GENOTYPING
•Identification of genotypes and subtypes important because certain DAA regimen are
only recommended for certain genotypes and subtypes
•Can be done by
- RFLP( Restriction fragment length polymorphism)
-type-specific primers in PCR reactions
- reverse hybridisation with type-specific probes
•Definitive method for genotyping is viral sequencing
•A line probe assay ( INNO-LiPA) using genotype specific probes for reverse
transcription of 5’ portion HCV genome is most commercial assay for HCV genotyping
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22. HCV TESTING SEQUENCE
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23. CDC has generated counselling messages for persons with positive HCV EIA
and positive HCV RNA tests
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24. INITIAL EVALUATION OF PERSONS WITH CHRONIC HCV
•Alcohol history
•Injection drug use
•Prior treatment
•Presence of medical
comorbidities
•Presence of significant
coinfections
•Psychiatric illnesses
•BMI
•Jaundice
•Palmar Erythema
•Spider nevi
•Ascites
•Splenomegaly
•Terry’s nail
•General lab evaluation
( CBC,S.Creatinine,platelet
count,TFT)
•Liver function
tests( ALT,AST,S,Bilirubin,A
LP, S.Albumin,INR)
•Assays to detect
coinfection
•HCV RNA level
•HCV Genotype
•Assessment of liver
fibrosis
HISTORY
PHYSICAL
EXAMINATION
LABORATORY
EVALUATION
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25. ASSESSMENT OF FIBROSIS
•The risk of progressive hepatic injury from HCV infection varies considerably,with
some patients showing little or no progression after decades of infection and other
progressing rapidly to cirrhosis.
•The presence and absence of cirrhosis influences the choice and duration of
treatment,therefore,an assessment of degree of liver injury is recommended in all
patients undergoing initial evaluation for chronic hepatitis C.
• Two methods
A. Per cutaneous Liver Biopsy
B. Non invasive methods
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26. LIVER BIOPSY
•Now a days ,percutaneous liver biopsy is done only when
- noninvasive markers are indeterminate,noninvasive test results are incongruent with
other noninvasive liver fibrosis markers or with the clinical picture
-or other causes of liver disease need to be excluded
•Should be done with at least a 16 gauge needle,be 15-20mm or more in length and contain
at least 6 portal triads,although 11 or more considered optimal
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27. •The histologic scoring system used namely
1.knodell. 2.METAVIR. 3.Ishak
The METAVIR scoring system is most popular in practice ; inflammation is graded
0-4( none,mild,moderate,severe) and fibrosis is staged from 0 to 4
0 - no fibrosis
1 - portal fibrotic expansion
2 - portal fibrosis with septa formation
3 - bridging fibrosis
4 - cirrhosis
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28. NONINVASIVE METHODS
1.FIbroSure ( or FibroTest) :- it creates a composite score, adjusted for gender and
age, derived from
-alpha 2 macroglobulin
-haptoglobulin
-apolipoprotein A1
-GGTP
- total bilirubin
•Accurately categories stage 0 and 1 fibrosis and those with cirrhosis but it is less
useful in patients with intermediate scores
2.APRI:- AST to platelet ratio index used to diagnose or exclude cirrhosis (score<=0.5
rule out cirrhosis)
3.FIB-4:- a score is calculated using age,ALT,AST and platelet count ( <1.45 excludes
fibrosis and >3.25 confirms fibrosis )
4.FibroScan ( Transient Elastography):- most frequently used to assess liver
stiffness ,correlates with the amount of hepatic fibrosis
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29. TREATMENT
•GOAL:- 1. Eradicate HCV
2. Improve HCV-related health outcomes and
survival in all populations
3. Reduce transmission of HCV to others
• The gold standard for determining cure of HCV is the
demonstration of SVR.
•SUSTAINED VIROLOGICAL RESPONSE (SVR):-
An undetectable HCV RNA level in blood using a sensitive
assay at least 12 weeks after completion of therapy
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30. DRUGS USED
1.Interferons (IFN )
2.Ribavirin
3.Directly acting antivirals ( DAA )
- IFN alpha monotherapy was approved for treatment of chronic hepatitis C,then known as nonA nonB
hepatitis,before HCV was even identified
-substantial advances have been made since then with the introduction of prolonged treatment
periods,longer acting pegylated formulation IFNs, oral guanosine analog RBV and most recently IFN-free
DAA regimens
-the choice of agents is being highly individualized ,based on availability of DAAs,HCV genotype and
stage of liver disease ( cirrhotic vs non-cirrhotic,presence of decompensation), treatment naive vs
treatment experienced
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31. INTERFERONS
•IFNs are naturally occurring glycoproteins
•Exerts a wide array of antiviral,antiproliferative and immunomodulatory effects
•Pegylated IFNs consists of IFN bound to a molecule of polyethylene glycol (PEG) of
varying length ,the large size of molecules increases the half life,thereby allowing once
weekly dose
•Two pegylated IFNs are licensed for use.
- 1. 40-kd peginterferon alpha-2a - used in a fixed dose of 180microgram per week
-2. 12-kd peginterferon alpha-2b- prescribed as per patient’s body weight in a dose of
1.5microgram/ kg per week
•The use of IFNs has been succeeded by IFN-free DAA regimens
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32. RIBAVIRIN
•An oral guanosine analog with activity against DNA and RNA viruses
•When used in combination with IFN, treatment response improves and relapse
rate decreases
•The dose depends upon patient’s weight and patient’s Hb level must be
monitored during treatment
•Causes dose dependent hemolytic anemia
•Excreted by kidney- should be administered with extreme caution to patients
with creatinine clearance <50ml/min
•Teratogenic
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33. DIRECTLY ACTING ANTIVIRALS (DAA)
Currently 13 DAAs are approved by FDA
NS3/4A PROTEASE
INHIBITOR
( -PREVIRS)
NS5A INHIBITORS
(-ASVIRS)
NS5B POLYMERASE
INHIBITORS
(-BUVIRS)
DACLATASVIR DASABUVIR
GLECAPREVIR LEDIPASVIR SOFOSBUVIR
GRAZOPREVIR ELBASVIR
PARITAPREVIR OMBITASVIR
SIMEPREVIR PIBRENTASVIR
VOXILAPREVIR VELPATASVIR
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34. •DAAs inhibit HCV replication by interfering with different steps of HCV life
cycle
•An ideal DAA regimen should have
- activity against all genotypes
- high antiviral potency
- good oral bioavailability
- allowing once daily dosing
- few drug-drug interactions
- well tolerated with minimal toxicity
- high barrier to resistance
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35. Approved DAAs in common use
Sofosbuvir -
- a pangenotypic nucleotide NS5B polymerase inhibitor
- administered as a single 400mg tablet or as part of FDC with other DAAs
- excreted renally(80%) ,dose reduction recommended when eGFR <30ml/min
- no dose adjustment required in severe hepatic impairment,so can be administered in
decompensated cirrhosis
-Side effects - fatigue and headache
Sofosbuvir-Ledipasvir-
- administered as 2 drug FDC of sofosbuvir 400mg and ledipasvir 90 mg single,once daily
tablet,with or without food
- ledipasvir is metabolized predominantly by liver, excreted unchanged in bile
- however can be given safely in patients with severe hepatic impairment
-side effects - fatigue and headache
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36. Sofosbuvir-Velpatasvir
- sofosbuvir 400mg and velpatasvir 100mg are coformulated in a single FDC tablet,given once daily,with or
without food
- velpatasvir undergo hepatic metabolism,can be administered to patients with severe hepatic impairment
without alteration in plasma concentrations
- side effects- headache ,fatigue and nausea
Sofosbuvir-Daclatasvir
- Daclatasvir 60mg is used as single dose once daily in combination with sofosbuvir 400mg
-for daclatasvir major route of excretion is fecal,no dose adjustment is required for severe hepatic impairment
or renal failure
- side effects - fatigue,nausea,headache
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37. Checklist before starting Hepatitis C therapy
General checklist for all patient
Willing to adhere to DAA therapy
Psychiatrically stable
Drug and/or alcohol use evaluated and addressed so as not to interfere
with therapy
Potential drug interaction addressed and plan in place to monitor
If treatment with Ribavirin
Not pregnant or planning to become pregnant during therapy
If patient or partner of child bearing potential ,willing to use 2 or more
reliable birth control methods
No significant cardiac or respiratory issues
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38. WHAT REGIMEN TO USE
For Treatment-naive patients
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39. 39

40. For Treatment experienced
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41. Follow up investigations
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42. MANAGEMENT OF HEALTHCARE PERSONNEL EXPOSED TO HCV
the type and nature of exposure
-It is important to understand the details and type of exposure ( percutaneous,mucous
membrane,contact with non intact skin) and the body fluid involved
- this helps to stratify the risk of acquiring HCV from exposure as well as identify exposure that are
unlikely to pose any real threat of HCV transmission
Initial wound care
For any wound or area of skin,thoroughly wash with soap and water
For mucus membranes, thoroughly flush with water
For eyes,irrigate eyes with clean water or sterile irrigation solution
For percutaneous injuries,don’t squeeze,scrape or scrub the wound
Don’t apply any caustic agents or bleach the body part involved
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43. POST EXPOSURE PROPHYLAXIS
•PEP is not recommended
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45. REFERENCES
•Feldman M,Friedman LS,Brandt LJ,editors.Sleisenger and Fordtran’s gastrointestinal and liver disease:
pathophysiology,diagnosis and management .Elsevier health sciences;2021
•Kasper D,Fauci A,Hauser S,LongoD,Jameson J,Loscalzo J.Harrison’s principle of internal medicine,21e,Newyork,NY,USA::
Macgraw-hill;2022
•Dooley JS, Lok AS, Garcia-Tsao G, Pinzani M, editors. Sherlock's diseases of the liver and biliary system. John Wiley & Sons; 2018
Aug 6.
•Schillie S, Wester C, Osborne M, Wesolowski L, Ryerson AB. CDC Recommendations for Hepatitis C Screening Among Adults -
United States, 2020. MMWR Recomm Rep. 2020;69:1-17.
•Centers for Disease Control and Prevention (CDC). Testing for HCV infection: an update of guidance for clinicians and
laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62:362-5.
•Ministry of Health and Family Welfare,Government of India.National guidelines for diagnosis and management of viral
hepatitis,2018
•Paul J. Thuluvath, Anoop Saraya, Mohamed Rela, An Introduction to Liver Disease in India, Clinical Liver Disease, 10.1002/
cld.1149, 18, 3, (105-107), (2021).
•Moorman AC, de Perio MA, Goldschmidt R, Chu C, Kuhar D, Henderson DK, Naggie S, Kamili S, Spradling PR, Gordon SC, Russi
MB. Testing and clinical management of health care personnel potentially exposed to hepatitis C virus—CDC guidance, United
States, 2020. MMWR Recommendations and Reports. 2020 Jul 7;69(6):1.
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46. Thank you !