hepatitis b
TRANSCRIPT
HEPATITIS B HEPATITIS B
Hepatitis B is a major health problem
2.5% of the population is chronically infected with HBsAg
Significant portion of them will Significant portion of them will ultimately develop severe liver ultimately develop severe liver disease, including cirrhosis, disease, including cirrhosis, hepatocellular carcinoma and hepatocellular carcinoma and other complications other complications
Hepatitis B Virus
HBV is a DNA virus of the HBV is a DNA virus of the Hepadnaviridae family. Hepadnaviridae family.
Its genome is double-stranded Its genome is double-stranded with four genes, each one with four genes, each one encoding a specific structural encoding a specific structural protein or proteinsprotein or proteins
Genotypes
In HBV infection, the virus itself does not injure liver cells. Rather, the damage of hepatitis is immune-mediated and begins to appear as the host’s immune system attempts to clear the virus.
LIFE CYCLE OF HBV IN LIFE CYCLE OF HBV IN HEPATOCYTESHEPATOCYTES The infectious HBV virion is taken up into the
liver cell. Double-stranded DNA is then moved to the
nucleus and covalently closed circular DNA, cccDNA, is formed.
Messenger RNA is formed from the covalently closed circular DNA and moved to the cytoplasm where it is packaged.
A minor strand and then a partially double-stranded DNA is formed using both the polymerase and reverse transcriptase to make a complete viral particle.
LIFE CYCLE OF HBV IN LIFE CYCLE OF HBV IN HEPATOCYTESHEPATOCYTES
Precore/core protein is used and e antigen is formed in parallel to the core/precore protein.
Surface antigen is also formed from the messenger RNA.
This concludes complete viral packaging and release of complete virions or subviral particles of e-antigen as well as some core antigen and surface antigen, which serve as decoys to the immune system and probably modulate the immune system directly.
Hepatitis B virus is not cytopathic, except in rare situations, such as liver transplantation, where the patient has high levels of immune suppression.
clinicaloptions.com/hep
HBV Core Curriculum 2008: Epidemiology and Natural History
Life Cycle of HBV in the Hepatocyte
Adapted from Lai CL, et al. J Med Virol. 2000;61:367-373.
InfectiousHBV virion
Viral polymeraseconverts pregenomic RNAto partially ds DNA
PartiallydsDNA
Subviralparticles
Hepatocyte
mRNA
Cytoplasm
NucleusPrecore/core
HBeAg
ER
HBcAg
HBsAg
cccDNA
Minus strand DNA
Encapsulated pregenomic mRNA
DIAGNOSIS OF HEPATITIS B Initial Evaluation of Patients with Chronic HBV Infection Symptoms Medical history and physical examination
– Family history of HBV infection and liver cancer– Screen for HCC in at-risk patients: AFP and ultrasound
Consider liver biopsy to grade and stage possible liver disease Laboratory tests to assess liver disease
– CBC with platelets, hepatic panel, prothrombin time Serology
– HBeAg/anti-HBe– HBsAg/anti-HBs– Anti HBc
Virology– HBV DNA (PCR based)
Test for viral coinfection (HIV, HCV, ± HDV)
HBsAgGeneral infection markerFirst serologic marker to appearInfection considered chronic if persistent for > 6 months
HBeAgIndicates active replication of virus Absent in some mutations
Anti-HBc total (HBcAb total)Past exposure to HBV
Anti-HBs (HBsAb)Recovery and/or immunity to HBVDetectable after immunity conferred by HBV vaccinationOccasionally seen in chronic carriers
Anti-HBe (HBeAb)Generally indicates virus is no longer replicatingPresent in HBeAg negative
PCR tests
PCR tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens. These tests are called viral loads and are used to assess a person's infection status and to monitor treatment
Indicates chronic hepatitis when still positive 6 months after diagnosis of acute HBV infection – Can differentiate chronic, inactive carrier (< 2000 IU/mL)
vs resolved HBV infection (undetectable) Change in HBV DNA level used to monitor response to
therapy Increasing HBV DNA level during antiviral therapy
indicates emergence of resistant variants HBV DNA level correlates with disease progression
Biopsy
– Establishes disease baseline before initiation of therapy
– Helps to exclude other causes of liver disease
– More sensitive and accurate than ALT– May be considered in patients who
meet criteria for chronic hepatitis
FOUR PHASES OF FOUR PHASES OF CHRONIC HBV INFECTIONCHRONIC HBV INFECTION
clinicaloptions.com/hep
HBV Core Curriculum 2008: Epidemiology and Natural History
< <> >HBeAg+ HBeAg-/anti-HBe+ (precore/core promoter variants)
ALT
HBV DNA
Normal/mild CH
Moderate/severe CH Moderate/severe CHNormal/mild CH
Cirrhosis
Immune Tolerance
Immune Clearance
Low Replicative Phase
Reactivation Phase
Cirrhosis
< 2000 IU/mL> 2000 IU/mL
Inactive cirrhosis
2 x 108 -2 x 1011 IU/mL
Phases of Chronic HBV Infection
Slide courtesy of A. S. F. Lok, MD.
200,000 - 2 x 109 IU/mL
Inactive-carrier state HBeAg-chronic hepatitis
HBeAg+ chronic hepatitis
The immune tolerance phase The initial phase of chronic HBV infection, is
seen almost exclusively in those who acquired HBV infection vertically or during early childhood.
Although patients have high HBV DNA levels, they do not have significant liver disease.
This discrepancy is thought to be related to the immune tolerance to HBV.
Only 15% of those with immune tolerance have spontaneous HBV e antigen seroconversion (ie, loss of e antigen and appearance of anti-e antibody) within 20 years after infection.
The immune clearance phase (HBV e antigen-positive chronic hepatitis or wild type)
This phase marks the start of an immune mediated process aimed at clearing the viral infection, but it also leads to concomitant hepatocellular injury.
Appears about 20 to 30 years after the onset of the immune tolerance phase in patients who acquire HBV early in life. It is also often seen in patients with infections acquired late in childhood or in adulthood.
Spontaneous clearance of the e antigen increases in this phase to an annual rate of 10% to 20%
ALT levels are elevated and there is evidence on liver biopsy of chronic active hepatitis, this phase is usually asymptomatic.
Depending on the duration of the chronic hepatitis and the frequency and severity of flares, about 12% to 20% of patients in the immune-clearance phase develop serious liver disease within 5 years.
The inactive carrier phase (HBV e antigen seroconversion)
Characterized by undetectable or low HBV DNA levels (< 1,000 copies/mL),
Normal ALT levels, and minimal or No necroinflammation on liver
biopsy. 4% to 20% of them spontaneously
revert to being positive for e antigen at least once.
The reactivation phase(HBV e antigen negative chronic hepatitis or precore
mutant) It is seen in some HBV-infected patients,
in whom the virus has a spontaneous pre-core or core mutation that makes infected cells unable to secrete the e antigen.
These patients have: – no e antigen in their blood, – intermittent or persistent elevation of ALT, – elevated HBV DNA, and – Biopsy reveals histopathologic findings of
chronic hepatitis.
Cirrhosis, liver failure, cancer Cirrhosis, hepatic decompensation, and
hepatocellular carcinoma are the major long-term complications of HBV infection. In untreated patients, the annual rate of progression to cirrhosis has been estimated to be 2% to 6% in patients with HBV e antigen-positive chronic hepatitis and 8% to 9% in those with e antigen- negative chronic hepatitis.
MANAGEMENT OF CHRONIC HEPATITIS B PATIENTS
Goals of Therapy for Chronic Hepatitis B To improve quality of life To improve survival by preventing
progression of disease to cirrhosis, end stage liver disease, HCC and death– These goals can be achieved by sustained
suppression of HBV replication, – Reduction in histological activity of chronic
hepatitis – Lessening the risk of cirrhosis– Decreasing the risk of HCC in non
cirrhotic/cirrhotic patients Avoidance of resistance ~
Who should be treated?
HBV is probably never cured but rather controlled by limiting viral
replication
It is not a question of whom to treat but when. In other words, the main question should be whether to initiate treatment now or to monitor the patient and initiate treatment at a later time when the indication arises.
All hepatitis B carriers are potential treatment candidates, and a patient who is not a treatment candidate now may be a treatment candidate in the future if a change is seen in the hepatitis B replication status and/or the activity and stage of liver disease.
Treatment options
There are currently 7 US Food and Drug Application (FDA)–approved medications available for the treatment of chronic hepatitis B.
Markers of treatment response
Decreased serum HBV DNA to low or undetectable levels (10 -15IU/mL)
Decreased or normalized serum ALT levels
Induce HBeAg loss or seroconversion (in HBeAg-positive patients)
Induce HBsAg loss or seroconversion Improved liver histology
Definition of response on NUC therapy
Primary non-response is defined as less than 1 log10 IU/mL decrease in HBV DNA level from base line at 3 months therapy
Virologic response is defined as undetectable HBV DNA by real time PCR assay within 48 weeks of therapy
Partial virologic response is defined as a decrease in HBV DNA of more than 1 log10 IU/mL. but detectable HBV DNA by real time PCR assay.
Virologic break through is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/mL compared to nadir (lowest value) HBV DNA level on therapy
Treatment of HBeAg-Positive Patients Treatment Recommendations for
HBeAg-Positive Patients– HBV DNA > 20,000 IU/mL and ALT > 2 x
ULN– Treated after 3-6 months of observation if
no spontaneous HBeAg seroconversion– Biopsy if age > 40 yrs, ALT 1-2 x ULN, or
family history of HCC Treatment given in moderate or severe
inflammation, significant fibrosis
HBeAg positiveHBeAg positive
HBV DNAHBV DNA< 20,000 IU/mL< 20,000 IU/mL
HBV DNAHBV DNA≥ ≥ 20,000 IU/mL20,000 IU/mL
ALT normalALT normal ALT elevatedALT elevated No treatmentNo treatment Monitor every 6-12Monitor every 6-12 monthsmonths
Monitor ALT every 3-12Monitor ALT every 3-12 months (immune tolerant)months (immune tolerant) Consider biopsy, if age is Consider biopsy, if age is > 35-40 years and treat if> 35-40 years and treat if significant diseasesignificant disease
Treat to HBeAgTreat to HBeAg seroconversionseroconversion ETV, TDF,ETV, TDF, and pegIFN areand pegIFN are first-line optionsfirst-line options
Treatment of HBeAg-Negative Patients Treatment Recommendations
for HBeAg-Negative Patients with Compensated Disease– HBV DNA > 20,000 IU/mL and ALT >
2 x ULN– HBV DNA ≥ 2000 IU/mL and ALT 1-2
x ULN: – Biopsy and – treated as needed
HBeAg negativeHBeAg negative
HBV DNAHBV DNA< 2000 IU/mL< 2000 IU/mL
HBV DNAHBV DNA≥ ≥ 2000 IU/mL2000 IU/mL
ALT normalALT normal ALT elevatedALT elevated No treatmentNo treatment Monitor everyMonitor every 6-12 months6-12 months
Monitor ALT andMonitor ALT and HBV DNA, orHBV DNA, or Consider biopsy,Consider biopsy, since ALT oftensince ALT often fluctuates and treat iffluctuates and treat if significant diseasesignificant disease
Treat long termTreat long term ETV, TDF,ETV, TDF, or PegIFN areor PegIFN are first-line optionsfirst-line options
Keeffe EB, et al. DDW 2008. Abstract 198.
Treatment Recommendations: Cirrhosis
Compensated Cirrhosis
– HBeAg positive or negative– HBV DNA > 2000 IU/mL; no ALT specified– HBV DNA < 2000 IU/mL; consider treating
if ALT elevated– HBV DNA negative; observe– INF for well compensated cirrhosis
–Entecavir and tenofovir is particularly relevant in this group
Decompensated Cirrhosis
– HBeAg positive or negative– Any HBV DNA level– Potent NUCs with good resistance
profile (entecavir and tenofovir) should be used (limited data is available on the safety)
– Liver transplantation,
HIV coinfected patients Therapy with entecavir is not
recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
Management Roadmap According toWeek 12 Virologic Response
Management Roadmap According toManagement Roadmap According toWeek 12 Virologic ResponseWeek 12 Virologic Response
Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Week 12Week 12 Assess for primary nonresponseAssess for primary nonresponse
Primary responsePrimary responseHBV DNA HBV DNA 1 log 1 log1010 IU/mL drop IU/mL drop
Primary treatment failurePrimary treatment failureHBV DNA < 1 logHBV DNA < 1 log1010 IU/mL drop IU/mL drop
ContinueContinue
Start treatmentStart treatment
If nonadherent,If nonadherent, counselcounsel
If adherent,If adherent,add a more potent add a more potent
drugdrug
Management Roadmap According toWeek 24 Virologic Response
Keeffe E, et al. Clin Gastroenterol Hepatol. 2007;5:890-897.
Patients with primary response
Week 24 Assess early predictors of efficacy
Complete responseHBV DNA negative by PCR
Partial responseHBV DNA
60 to < 2000 IU/mL
Continue therapy;monitor every 6 months
Inadequate responseHBV DNA ≥ 2000 IU/mL
Add a more potent drug;monitor every 3 months
Does the Roadmap Concept Apply to ETV During First Year? The roadmap concept, as shown previously, may
not apply to all the oral agents that are available for treatment of patients with chronic hepatitis B.
The next logical question is whether the road map concept applies to entecavir during first year. Entecavir is very potent antiviral agents, as shown in clinical trials, and recent data has shown that the 5-year resistance rate of entecavir in nucleotide‑naive patients is only 1.2%.
Therefore, it may still be appropriate to continue monotherapy in patients with positive HBV DNA level at 48 weeks of entecavir therapy, especially if HBV DNA is still in decline (more data needed).