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HEPATITIS C VIRUS. Structure of presentation. HCV epidemiology,viral dynamics,immunopathogenesis,diagnosis HCV renal disease, management HCV in CKD,CKD5D,CKD5T KDIGO guidelines. by the late 1970s it was apparent that HBV was not the only cause of "serum" hepatitis,

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structure of presentation
Structure of presentation

HCV epidemiology,viral dynamics,immunopathogenesis,diagnosis

HCV renal disease, management

HCV in CKD,CKD5D,CKD5T

KDIGO guidelines

slide3
by the late 1970s it was apparent that HBV was not the only cause of "serum" hepatitis,
  • and that other "non-A-non-B" hepatitis viruses existed , which
  • could be transmitted by blood products to humans and chimpanzees
slide4
Houghton and colleagues cloned and expressed portions of a RNA virus from the plasma of an infected chimpanzee in 1989
  • This virus, designated hepatitis C virus (HCV), is now known to be a major
  • cause of both transfusion-associated and sporadic non-A-non-B hepatitis
slide5
The persistent and indolent nature of HCV infection often
  • results in prolonged viremia in spite of a strong humoral immune response
slide6
To date, around 170–200 million individuals worldwide are estimated by the WHO to be chronically infected with HCV.
the virus
THE VIRUS……
  • Flavi virus
  • 50 nm particles
  • Nucleocapsid
  • RNA
  • Envelope
  • Circulates…. a. lipo-viro-particles

b. Ig bound

c. free virions

the genome
The genome
  • RNA with 9600 nucleotides,encoding 3010 aminoacid polyprotein
  • Single polypeptide
  • Structural and non-structural

1. core – steatosis , IFN resistance

2. E1,E2 – cell entry

3. p7 – viral maturation & release

4. NS2 – autoprotease

5. NS3 – serine protease & helicase

6. NS4a – cofactor for 5

7. NS4b – membranous web for replication

8. NS5a – RNA binding , steatosis ,

9. NS5b – RNA dep. RNA polymerase

10. IRES – internal ribosome entry site

slide9
Significant nucleotide and amino acid heterogeneity is present throughout the HCV genome, with a well characterized
  • hypervariable region in the E2 envelope glycoprotein domain .
  • This has led to the recognition of at least six HCV subtypes based on differences in the nucleotide sequence for NS5 .
slide15
Infection is followed by an incubation period of 6 to 12 weeks prior to the development of clinical hepatitis.
  • In the majority of cases the hepatitis is mild and anicteric. Persistent viremia despite resolution of the acute hepatitis is seen in the majority of cases.
  • many of these patients have persistent viremia despite minimal liver pathology, suggesting the presence of a "healthy“ carrier state,
  • at least 50% of patients develop chronic hepatitis, of which 20% progress to cirrhosis or chronic active hepatitis
genotype
Genotype…
  • Genetically distinct groups of HCV isolates arisen during viral replication
  • 35% variation esp. E1 E2

Distribution

1 --- 40 – 80% worldwide

1a – USA ; 1b – Europe

2 --- 10-40% worldwide

3 ---- India , Australia

4 --- Middle East , Africa

5 --- South Africa

6 --- Hongkong

  • Do not influence severity
  • Treatment response
  • Genotype 3 – steatosis
  • Genotype 1b – progressive post transplant disease
quasispecies
Quasispecies…

Closely related heterogeneous sequences in HCV in single infected person

Mutation on replication

E1E2 HVR

Escape host immunity

Resistance to treatment

epidemiology
EPIDEMIOLOGY
  • Seroprevelance
          • Worldwide : 3% (Range 0.1 – 26%).Highest – Egypt
          • India : 5% (Intermediate)
          • Voluntary blood donor 0.6 – 0.8 %
          • Gen.Population 1.8%
          • Sex M: F 2.5 : 1.2
epidemiology1
Epidemiology
  • Epidemiology patterns
    • Peak prevalence (Age) 30-50 yrs

Recent source 1980-1990 IDU

    • Peak prevalence > 50 yrs

Remote acquisition 30 yrs ago

        • Unsafe injections
        • Folk medicine
transmission
Transmission
  • Percutaneous
      • Blood transfusion
      • Needle stick
  • Non percutaneous
      • Sexual
      • Perinatal
transfusion
Transfusion
  • Initial Post Transfusion hepatitis : 85% Hep C
  • Transfusion Hep C – 4% of Acute HCV
  • Decreased after anti-HCV introduced in May 1990
  • Present risk - 0.01 – 0.001 %
  • At risk
      • Patient Requiring multiple transfusions
        • Hemophilia
        • Thallasemia
  • Apollo chennai -

HCV in blood donors : 3-5/ year (14,000 donations)

  • HCV RNA screening
idu others
IDU & others…

Prevalence : 48 – 90%

More than HIV & HBV

Positive in 6 months

Tattooing – 2- 24%

Acupuncture

hemodialysis
Hemodialysis
  • Anti HCV prevalence: 10- 20%
  • Underestimate (4-15%)
  • Duration on HD
  • Annual Risk : 0.15% (HD) & 0.03% (CAPD)
  • Chr.HCV : 70-90%

At Apollo

      • HCV+ve on HD – 11/140
hcv in ckd on hd
HCV in CKD on HD
  • Prevalence –

1. Developed nations – 7 – 40%

2. Developing nations– 16 – 80%

3. India – 12 – 40% ( Saha etal 2001)

4. Apollo – 12%

  • Risk factors –

1. Duration on HD

2. Local prevalence

3. Blood transfusions

4. Nosocomial transmission

November 17, 2014

HCV and Renal Disease

nosocomial transmission
Nosocomial Transmission…
  • Breach of standard infection control precautions

1. Hand wash , glove change

Okuda et al ; Arenas et al

2. Multi-dose vials

3. Spillage

  • Dialysis internal circuits minor contributor
  • DOPPS – Isolation does not protect
  • CDC – 1. No isolation

2. No dedicated machines

  • Belgian study – 0% transmission by standard precautions only
  • Slow seroconversion ( 5 months)
  • Regular EIA / NAT , ALT / AST

November 17, 2014

HCV and Renal Disease

nosocomial
Nosocomial
  • Health workers
  • Needle stick : 0-4% by anti-HCV 10% by PCR
  • Overall seroprevelance is as gen.population
  • Risks of transmission < HBV,HIV
  • HCW  patient

0.014%

  • Patient  HCW

2- 10%

non percutaneous
Non-percutaneous

Sexual – controversial

More common in male homosexuals

Associated risk factors

RNA levels in semen low

HCV in spouse 3%

perinatal transmission
Perinatal Transmission
  • Risk upto 10%
  • No difference in CS vs. vaginal
  • Increased risk 
          • RNA +ve
          • Increased RNA levels
          • HIV-HCV

decreased with HAART

  • Not transmitted by breast feed
  • Passive transfusion of Anti HCV
  • Anti HCV upto 18 months
sporadic hcv
Sporadic HCV

Upto 30- 40% of cases

Occult / unidentified percutaneous

Sharing of hygiene items

Forgotten risks, Transfusion

Multi-dose vials

Cocaine snorting

pathogenesis
Pathogenesis
  • Viral
  • Human
  • Environmental

Main sites : Hepatocyte

Other : Mononuclear

: Dendritic cells

immune mediated mechanism
Immune Mediated Mechanism
  • Humoral Response
  • CMI
      • CD4
      • CD8 - liver infiltrating
      • NK
cmi response
CMI Response
  • CD4,CD8, NK
  • Protective and Destructive
  • More in Acute cases
  • Activated by antigen presentation
  • CD4+ (polyclonal) TH1

TH2

  • TH1 IFN + IL2 NK cells & CTLs
  • TH2 IL4 + IL10 decrease TH1
  • TH1 viral clearance
viral persistence
Viral persistence
  • Quasi-species nature
  • Immune evasion
  • Inadequate innate immunity
  • Insufficient adaptive response
  • Re-infection with different strain
pathogenesis1
Pathogenesis..
  • Pathogenesis - Viral

- Host

- Environmental

viral
Viral
  • Direct cytopathic effect
        • Viral Protein
        • Viral particles
  • Steatosis  30 – 70%
          • C, NS5a viral proteins
          • Genotype 3
          • Activation of lipid peroxidation
          • Increased RNA  Increased Steatosis
          • Contribution of fibrosis

- Oxidative stress

- Hyperinsulinemia

cmi in pathogenesis
CMI in pathogenesis……

CD8+

Polyclonal activation

Increased in infected liver

IFN gamma

Hepatocyte cytolysis

Inhibit multiplication

humoral immunity
Humoral immunity……
  • Ig to viral proteins
  • Non neutralising
  • 4 – 8 weeks of infection
  • Marker of infection
  • Lymphoid aggregates
  • Extra hepatic manifestations

B cell ++ polyclonal Ig auto Ig

  • CD5 ++ rheumatoid factor

cryoglobulinemia ( Ig + RF )

summary of pathogenesis
Summary of Pathogenesis
  • Viral replication & persistence
  • Inhibition of innate immunity
  • Balance between CD4 & CD8

hepatocyte damage

  • Poor response in chronic disease
  • Viral cytopathic effect
  • Antibodies --- 1. diagnostic

2. extra hepatic manifestations

extrahepatic manifestations
Extrahepatic manifestations
  • Mixed Cryoglobulinemia
  • MPGN
  • Porphyria cutanea tarda
  • NHL
  • Leucocytoclastic vasculitis
  • Focal lymphocytic sialadenitis
  • Lichen planus
  • DM
  • Rheumatoid arthritis
  • Thyroid disease
  • Non specific antibodies

ANA – 20% , ASMA -20% , anti LKM – 5% , cryoglobulins-40%

mixed cryoglobulinemia
Mixed cryoglobulinemia
  • Circulating Igs precipitating at < 37c
  • Vasculitis by deposition of cryoprecipitate in small vessels
  • IgG, IgM RF, anti HCV, HCV RNA , LDL
  • IgM RF from liver
  • B cell activation by E1 E2 – CD81 interaction
  • 50 -90% EMC – HCV +
  • 60% HCV pts. - MC (30%asymptomatic)
  • Purpurae, arthralgias , weakness
  • Peripheral neuropathy
  • Raynaud’s phenomenon
  • MPGN – nephrotic syndrome

liver disease occult

  • Antiviral therapy
extrahepatic manifestations1
Extrahepatic manifestations….

B cell NHL –

HCV 15%

lymphotropism & clonal expansion

Sialadenitis – 10% patients

Diabetes Mellitus –

steatosis , insulin resistance,

in a nutshell
In a nutshell….
  • A RNA virus with hepatotropism
  • Widely distributed with distinct genotypes
  • Evades immune system
  • Pathogenesis by steatosis fibrogenesis & host immunity
  • Transmission by parenteral route
  • Acute hepatitis rarely recognised
  • High rate of chronicity
  • Multiple influences
  • Extrahepatic manifestations
  • HCC
slide44
Mesangio proliferative gn
  • igA
  • Fibrillary and immunotactoid gn
  • Diffuse endocapillary proliferative gn
  • MGN
  • MPGN
  • Renal vasculitis cryoglobulinemic
hcv induced renal disease
HCV induced renal disease
  • EMC type II ( 50% of HCV ; 1% symptomatic)
  • MPGN type I ( with or without MC)
  • Membranous glomerulonephritis
  • Pathology - Deposition of HCV RNA – Ig complexes
  • OLT – intraop renal biopsy – 25 – 30% GN
  • Proteinuria , Microscopic hematuria
  • Liver disese may be occult
  • Melzer Franklin triad (EMC)

Weakness , Arthralgia , Purpurae

Elevated Cryocrit ,Rheumatoid factor ; Decreased C4

  • Test annually 1. hematuria

2. proteinuria

3. GFR

  • Renal biopsy

November 17, 2014

HCV and Renal Disease

diagnostic tools
Diagnostic tools…
  • Serological

1. Enzyme Immunoassay (EIA)

2. Recombinant Antigen Immunoblot Assay (RIBA)

  • HCV RNA detection

a. Qualitative

b. Quantitative

Methods

1. PCR

2. TMA (Transcription mediated amplification)

  • HCV Genotyping
  • Liver biopsy
serological
Serological……
  • Detect Igs against viral proteins
  • EIA 3rd generation
  • NS3 , NS4 , NS5
  • Positive at 7 – 8 weeks
  • Sensitivity – 97%
  • RIBA for clarifying false positives
  • Negative anti- HCV in HCV infection

1. immunosuppressed

2. CKD , on HD

3. Acute HCV

slide49
The original first generation enzyme immunoassay (EIA-l), which measured antibodies to the nonstructural Cl00-3 antigen (coded by the NS4 domain), lacked sensitivity and specificity, and was undetectable in 10 to 25% of patients with chronic HCV viremia and falsely present in both healthy individuals and patients with chronic autoimmune hepatitis
slide50
The second generation enzyme immunoassay (EIA-2) measures antibodies to recombinant core and NS3 antigens in addition to that coded by NS4, and has greatly improved sensitivity (—95%) and specificity.
  • A supplemental serologic assay, the recombinant immunoblot assay (RIBA II test), measures antibody to four HCV antigens (the nonstructural antigens 5-1-1, C100-3, and C33, and the core antigen C22), and has comparable sensitivity and slightly more specificity than the EIA-2 test
slide51
The most definitive test for diagnosing active HCV infection is the reverse transcription polymerase chain reaction (RT-PCR), which measures the presence of viral RNA in patient serum and hence determines potential infectivity
slide52
The detection of anti-HCV antibodies is based on the use of third-generation EIA that detects antibodies directed against various HCV epitope
  • RIBA has become obsolete because of this
  • In the near future, fourth-generation tests will be available, allowing the simultaneous detection of HCV antibodies and HCV core protein.
slide53
In the relevant published studies, the sensitivity of EIA varied from 53 to 100% and the specificity from 85 to 100%,
  • with pooled sensitivity and specificity of 75 and 95%, respectively
rna testing
RNA testing
  • Qualitative

1. high sensitivity 96- 100%

2. PCR / TMA

3. lower limit – 50iu / 5iu

4. confirm clearance

5. special situations

  • Quantitative

1. RT - PCR / branched DNA

2. closed tube systems

3. Amplicor – PCR - 3 copies – 1 unit

4. Versant – TMA – 5 copies = 1 unit

  • Indications

1. anti HCV positive

2. antiviral treatment monitoring

3. immunocompromised

rna analysis
RNA analysis…
  • Genotyping….

1. reverse hybridisation by line probe assay

2. failure – 0.3%

3. duration of treatment

4. response to treatment

histopathology
Histopathology
  • Degree of inflammation – grade
  • Extent of fibrosis – stage
  • Characteristic features

1. steatosis ( micro or macrovesicular)

2. lymphoid aggregates

3. bile ductular damage

  • Metavir and Knodell Ishak staging systems
  • Fibrosis – prognosis & treatment response
  • Metavir – fibrosis 0 – 4

grade – 0 -4

  • Knodell Ishak – fibrosis 0 – 6
  • Significant fibrosis - Metavir ≥2

Knodell Ishak ≥3

liver biopsy problems
Liver biopsy - problems…..
  • Inter observer variation – 60 – 90%
  • Variability within liver
  • Specimen size
  • Complications –

1. pain – 20%

2. hemorrhage – 0.5%

3. mortality – 0.1%

  • Sampling error – 10 – 40%

1. small size

2. less than 11 portal tracts analysed

slide61
Typically, a platelet count o50 000 and an INR >1.5 are regarded as contraindications to blind percutaneous liver biopsy
  • However, there is a controversy in recent medical literature about whether any platelet count level or INR derangement truly separates out those patients with liver disease most likely to bleed after liver biopsy.
slide62
A study performed in the early 1980s in 200 patients undergoing laparoscopic liver biopsy with direct visualization
  • of the site failed to establish any relationship between duration and extent of bleeding
  • and prothrombin times,platelet count, or whole clot time.
  • a systematic review of bleeding, including that associated with liverbiopsy, also failed to establish a relationship between risk and conventional tests of coagulation
noninvasive staging
Noninvasive staging
  • FIBROSCAN

transient elastography

assess liver stiffness

evaluates larger liver volume

better correlate with higher stage

problems –

1. obese

2. cannot differentiate steatosis

other markers
Other markers
  • FIBROTEST-

α2-macroglobulin , α2-globulin , gamma globulin , GGTP , bilirubin

sens. 75% & spec. 85% for Metavir >2

improved with Fibroscan

  • ACTITEST - Fibrotest + ALT
  • APRI – AST – Platelet count ratio
  • Ser. Hyaluronate levels
  • Collagen based panels
alt levels
ALT levels
  • Mildly elevated only
  • 10 fold increase – sig. necrosis
  • 30% normal ALT
  • 17% - levels fluctuate to normal
  • 30 – 40% - occ. elevations only
ad