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![Page 1: THE CHANGING FACE OF VIRAL HEPATITIS D. Robert Dufour, MD, FACB, FCAP Consultant Pathologist Attending, Liver Clinic VAMC, Washington DC Emeritus Professor.](https://reader033.fdocuments.in/reader033/viewer/2022051214/56649e195503460f94b055a7/html5/thumbnails/1.jpg)
THE CHANGING FACE OF VIRAL
HEPATITISD. Robert Dufour, MD, FACB, FCAP
Consultant PathologistAttending, Liver ClinicVAMC, Washington DC
Emeritus Professorof Pathology
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• Acute viral hepatitis has become an increasingly rare disease
• Reported incidences are at their lowest recorded values for all major viruses
• Childhood immunization has led to near universal immunity to HBV in USA
• From this standpoint, we are winning the war against viral hepatitis
SIGNIFICANCE
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Source: CDC Viral Hepatitis Surveillance and Statistics
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Source: CDC Viral Hepatitis Surveillance and Statistics
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Source: CDC Viral Hepatitis Surveillance and Statistics
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• Chronic HBV and HCV remain common• In US, chronic HCV affects at least 2% (2.7
million individuals), while chronic HBV affects approximately 1 million (85% born outside US)
• Both may lead to cirrhosis (20-30% after 20 yr), hepatocellular carcinoma (HCC) (3-5%/yr once cirrhosis present)
SIGNIFICANCE
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SIGNIFICANCE• Symptoms of chronic infection minimal, most unaware
until complications develop• Cirrhosis expected to increase 4-fold over next 30 years• HCC incidence doubled over past 20 years, expected to
increase further 3x; at VAMC DC, have gone from 5-6/yr to 3-4/month
• Effective therapies available for HBV, HCV
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HEPATITIS A, E
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HEPATITIS A• Peak age incidence now 20-35
• Major risk factors injection drug use, males having sex with males
• IgM anti-HAV now largely (62%) false positive; CDC recommends use only in clinical setting of acute hepatitis (MMWR 2005;54:453)
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HEPATITIS E• Recognized as an enteric virus in locations with poor hygiene;
anti-HEV < 5% in children, but 30-60% in young adults, men > women
• High mortality in pregnant women (30-50%); low mortality rate otherwise (as with HAV)
• As with HAV, thought not to have a chronic phase
• In developed countries, felt to not occur without travel to endemic areas
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HEPATITIS E• HEV is endemic in pigs and rats worldwide• Link between pork ingestion, death from chronic liver
disease in 18 countries• Studies have shown high frequency (10-20%) anti-HEV in
blood donors in western countries• Has raised issue of zoonotic spread of HEV, but known cases
of HEV difficult to link to pork ingestion or pig exposure
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HEPATITIS E• In past few years, well documented case series of HEV in
Europe with the same genotype as found in animals (J Med Virol 2008;80:646); age range similar but mortality higher (10%), esp. in those with chronic liver disease (70%)
• Anti-HEV more common in IV drug users; post-transfusion cases in several countries
• Recently, reports of chronic HEV in liver transplant recipients (Liv Transpl 2008;14:547)
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HEV DIAGNOSIS• IgM anti-HEV best test for acute infection; as with HAV,
false positive possible, may be false negative in early stage
• IgG anti-HEV long-lasting (but probably not life-long); rise in titer can also be used for acute infection diagnosis
• HEV RNA viremia persists for an average of 4 weeks in acute infection; no commercial labs in US currently offer HEV RNA, however
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HEPATITIS B
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• Partially double-stranded DNA virus, belongs to family hepadnaviridae
• Peculiar pattern of coding, replication unique among viruses
• Virus is not hepatotoxic; damage occurs from T-cell response to the virus
• Virus may be carcinogenic (? Related to HBV X antigen)
HBV BIOLOGY
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HBV Replication
Circulating HBV
Infection Reservoir
Replication HBV mRNA
ReverseTranscriptase
RNA-DNA Hybrid
Partially ds-DNA Pre-S
Free HBsAg
Free HBeAg
HBVparticle
RnaseDNA Polymerase
Partially ds-DNA
Covalently ClosedCircular (ccc) DNA
HBV core AgHBVpolymeraseHBV
mRNAHBVmRNA
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HBV BIOLOGY• RNA replication leads to high rate of mutations (not as high as
HIV, though)• Certain sites of mutation more common - #1 is stop codon in
pre-core coding region, also commonly affect core promoter region; both decrease production of HBeAg (latter may also increase risk of HCC)
• Mutations commonly induced by some reverse transcriptase inhibitors used to treat virus
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OUTCOME• Outcome mainly dependent on age at exposure, less affected
by immune status
• In infants, 95% chronically infected; in young children, 30-50% chronically infected
• In adults and adolescents, HBV is usually “cleared” after exposure, < 5% chronically infected (may be < 1%)
• In immunosuppressed adults and adolescents, 10-20% chronically infected
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HBVExposure
HBV Outcomes in Infants and Children < 5
Immune Control
Loss of HBsAgImmune Tolerance
Immune Active
5%
1-2%/yr
95%
50-70% 30-50%
7-8%/yr
0.5-1%/yr
7-8%/yr1-2%/yr
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HBVExposure
Outcomes of HBV exposure in Adults
Immune Control
Loss of HBsAgAcute
Hepatitis
Immune Active
10-20% (low immune status)
30-50%50-70%
7-8%/yr
1-2% (normal immune status)
? 0.5%
1%/yr
0.5%/yr
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HBV SEROLOGIC TESTS• Complicated set of markers lead to confusing patterns
• Even more complicated by increased knowledge of biology of HBV
• Still most widely used tests for HBV diagnosis, becoming less widely used for monitoring of treatment
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HBsAg• Responsible for genotypes of HBV; common “a” determinant in all
genotypes
• Vaccine response mainly to “a” determinant
• Mutants in “a” determinant may not be recognized by vaccine, HBsAg serologic tests
• Multiple mutants occur; none recognized by all current HBsAg test kits
• Little data, but mutants usually occur with wild-type virus, in low amounts, and rare as sole infection
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ISOLATED ANTI-HBc• Early in viral clearance (“Core window” in acute hepatitis,
during recovery)
• Many years following infection; especially common in HCV infected
• Failure to develop anti-HBs (?especially in immune deficient)
• False positive result (post-influenza vaccine, other states)
• HBsAg mutants (recent study – 3%)
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HBeAg• Produced along with viral particles, but not part of virus; not
needed for replication, function uncertain (? immune response)
• Correlates with replicating virus in untreated; loss usually = low level (or no) viremia
• Not produced by pre-core or core promoter mutants• During treatment, loss indicates likelihood of continued
response after discontinuation
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HBV DNA in HBeAg Pos vs Neg
0%
20%
40%
60%
80%
100%
< 2 2 3 4 5 6 > 7
Log HBV DNA (IU/mL)
HBeAg Pos HBeAg neg
Source: VA Medical Center Washington DC
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ANTI-HBe• Appears with loss of HBeAg, indicating loss of
circulating virus• Formerly used to indicate transition to carrier state• Also present if HBeAg lost due to development of pre-
core mutant strains• Usually persists for life, but some lose anti-HBe and re-
develop HBeAg (and re-activate HBV DNA production)
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HBV DNA• Assays have marked difference in detection limit;
reported in pg/mL, copies/mL (1 pg = 285,000 copies)
• WHO standard now used for most assays (IU/mL), but correlation not linear (unresolved issue)
• Most with chronic hepatitis have > 105 copies/mL (often > 109); levels < 102 thought to have low transmission risk
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Lower Detection Limits for HBV DNA
Method Detection Limit IU/mL pg/mL
Hybrid Capture 1.0 * 106 10.5
Branched DNA 2.0 1 * 105 2.5 Liquid Hybridization 4.0 * 103 0.02 Branched DNA 3.0 2.0 * 103 0.01 PCR 1-2 * 102 0.001 Real Time PCR 2-5 * 101 0.0001
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HBV OUTCOMES & SEROLOGYState HBsAg Anti-
HBsAnti-HBc
HBeAg Anti-HBe
HBV* DNA
ALT
Acute hepatitis Pos Neg Pos‡ Pos Neg > 106
Immune tolerance
Pos Neg Pos Pos Neg > 106 Nl
Immune active Pos Neg Pos Pos Neg > 106
HBeAg + hepatitis
Pos Neg Pos Neg Pos < 106
Immune control Pos Neg Pos Neg Pos < 102† Nl
Occult Neg Pos Pos Neg Pos < 102† Nl
*In IU/mL; ‡ Typically IgM anti-HBc positive; †May be positive with very sensitive techniques in serum or liver biopsy
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HBV REACTIVATION• Return of HBV replication where previously inactive• More common form: HBsAg positive but in immune
control phase, virus again replicative (often with return of HBeAg)
• Less common form: HBsAg negative, anti-HBc positive when viral replication returns (sometimes termed seroreversion)
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HBV REACTIVATION• Usually occurs in setting of immune suppression (HIV,
transplant, steroids, cancer chemotherapy); frequency higher with more intense immune suppression
• While viral replication itself, immune response to virus often causes severe liver injury with recovery of immune function
• High morbidity and moratlity
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ImmuneSuppression
HBV Reactivation
Immune Control
Anti-HBc posHBsAg neg
Acute Hepatitis
Acute liver failure
30-50%
1-2% 20%
10-20%Restore
Immunity
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HBV REACTIVATION• Treatment of HBsAg positive pre-immune
suppression highly effective• Associated with reduced overall and liver-related
mortality• Recent guidelines suggest routine testing for HBsAg
and anti-HBc before immune suppression, treatment if HBsAg positive; less clear for anti-HBc positive
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HEPATITIS C
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HCV BIOLOGY• Single strand RNA virus, part of flaviridae family
(WNV, yellow fever, dengue)
• Relatively new virus (? Late 1880’s)
• High rate of spontaneous mutation leads to unique pattern of quasispecies in each individual after initial infection
• Virus not cytopathic, destroyed by T-cell response
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• Major screening test for HCV, detects antibody to 1 of 4 HCV antigens
• Two basic versions (2nd, 3rd generation) in use; 2nd sl less sensitive, not positive till avg 12 wk after exposure, 3rd sl less specific, pos. avg 9 wk.
• EIA tests less specific than CA, MEIA versions for same generation, but false positive results relatively common with all
ANTI-HCV
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ANTI-HCV• Most false positive are weakly positive
• Weak positive defined as 3.8 by EIA, 8 by Ortho, 10 by Abbott, < 11 by Siemens
• Majority of weakly positive are negative on other anti-HCV assays or on confirmatory tests
• CDC recommends performance of RIBA on all weakly positive before reporting
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Positives defined by S/C ratio
OR
OR
RIBA for anti-HCV
Screening test for Anti-HCV ReportNegative
Report ReportReport
Positive IndeterminateNegative
HCV RNA
All positives
RIBA for anti-HCV
Report
ReportReport Report
Negative
Positive
IndeterminateNegativePositive
Positive
Report
Positives with high S/C ratio Positives with low S/C ratio
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HCV RIBA Equivalent to western blot; uses purified HCV antigens from yeast recombinants
Positive: Ab to at least 2 Ag Indeterminate: Ab to one Ag, or to yeast marker (SOD) plus HCV Ags
Most patients with high titer anti-HCV have positive, usually used only when low titer anti-HCV (or in blood donors)
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TREATMENT OF CHRONIC
HBV AND HCV
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ACUTE HEPATITIS• No treatment is recommended for acute HBV (except in
rare cases with acute liver failure)• Acute HCV usually not recognized; when diagnosed
(e.g., post-needlestick) several studies suggest that treatment with interferon for 6 months can clear virus in 90-100% of cases, compared to 50% with no treatment
• Treatment effective in first 6 months
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• Seven agents approved: interferon (std., pegylated), lamivudine, adefovir, telbivudine, entecavir, tenofovir; last two most used
• Combination treatment not currently used• Response rate to IFN low in those with normal ALT, or viral load <
105 or > 1010 copies/mL• “Ideal” response: nl ALT, loss of HBeAg and HBV DNA, and
development of anti-HBe• Rarely, HBsAg is also cleared
CHRONIC HEPATITIS B
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• Histologic improvement usually seen with clearance• Relapses after treatment can occur• Success rate with 1 yr Rx about 30-40%• With oral agents, increasing treatment to 3-4 yrs increases
response to 70%, but resistant mutants also increase (28% with 5 yr treatment for adefovir, 70% for lamivudine, < 5% for entecavir, tenofovir [2 yr data only])
CHRONIC HEPATITIS B
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• In HBeAg +, ALT (> 1.5 x nl), or advanced biopsy findings (mod or higher inflammation, stage II or higher fibrosis), esp if > 40 yrs old
• In HBeAg -, similar, but also based on VL (treatment not recommended if < 2000 IU/mL, or if < 20,000 IU/mL and biopsy shows minimal damage), esp. if > 40 yrs old
• Patients not treated should be monitored, as changes in status are common
TREATMENT INDICATIONS
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Copyright restrictions may apply.Chen, C.-J. et al. JAMA 2006;295:65-73.
Cumulative Incidence of Hepatocellular Carcinoma by Serum HBV DNA Level at Study Entry
104-105
< 104
105-106
> 106HBsAg pos > 106
105-106
104-105
< 104
HBeAg neg
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• In those with cirrhosis, reduces likelihood of complications (including HCC), can delay or eliminate need for transplant
• Histologic improvement (including decreased fibrosis) common with viral response
• Felt to have similar benefits in those with less advanced disease, but long term data lacking (although histologic improvement documented)
TREATMENT BENEFITS
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• Loss of HBV DNA (< 100 IU/mL) is achieved in 70-80%; measurable HBV DNA indicates high rate of relapse
• Timing of measurements unclear; one study suggests response highest if < 100 at 12 wk
• If < 2 log decrease by 3 mo, we generally switch to another agent
• If viral load detectable but > 100, we usually continue treatment, re-evaluate at 6 mo
MONITORING Rx
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• In HBeAg + with loss HBV DNA, serial monitoring of HBeAg status prognostic; if HBeAg lost (and anti-HBe develops), treatment can be D/C after 6-12 mo with 80% success
• In HBeAg – (or HBeAg + who do not convert), D/C treatment leads to rapid reactivation of HBV replication; treatment usually long-term in these patients
MONITORING Rx
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CHRONIC HEPATITIS C• Current treatment of choice is pegylated interferon plus ribavirin
• Treatment usually for 24 wks with genotype 2 or 3, 48 wks for other genotypes
• Goal of treatment is clearance of virus that persists after therapy stopped
• Response rate is about 40% with genotype 1, 70-80% with genotypes 2, 3, 60-70% with genotype 4
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CHRONIC HEPATITIS C• Effectiveness monitored at 12 wk; failure to clear virus or
fall by > 2 logs (early virologic response, EVR) indicates < 5% likelihood of success
• Success evaluated 6 mo post-Rx as absent HCV RNA by sensitive method (sustained virologic response, SVR)
• In those with SVR, likelihood of recurrent viremia < 1%; however, virus persists in mononuclear cells in most
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CHRONIC HEPATITIS C• Intermediate time points provide additional data and can be used
to customize treatment duration• Rapid virologic response (RVR): absent HCV RNA after 4
weeks of treatment (~90% SVR)• In those still positive at 4 weeks but negative at 8 weeks, 70%
SVR rate• In those with EVR but viral load measurable at 8 wk, longer
treatment (72 wk G1, 48 wk G2/3) improves response rate
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RECENT ARTICLES• HBV Guidelines:
– AASLD - Hepatology 2007;45:507– CDC Recommentations: MMWR 2008;57(RR-08)
• HCV Guidelines:– AASLD - Hepatology 2004;39:1147– CDC (on lab testing) MMWR 2003;52 RR-3
• Reactivation Review– Ann Intern Med 2008;148:519
• HEV Review– Lancet Infect Dis 2008;8:698