بسم هللا الرحمن الرحيم
ا وما أوتيتم من العلم إال قليل صدق هللا العظيم
Update on Prevalence, Diagnosis and Treatment of Hepatitis B virus Dr.Hesham Noaman Abdel Raheem Mustafa M.B.B.CH
• HBV was discovered in 1966 (Wang et al., 2002a). • HBV the causative agent of B-type hepatitis in humans is a Hepatotropic DNA-containing virus that replicates via reverse transcription (Shen et al., 2004). • It is the only known DNA virus that has hepatocytes specificity (Lu et al., 2004a).
• 2 billion people infected worldwide, and 350 million suffering from chronic HBV infection (Alter, 2003). • Being the 10th leading cause of death worldwide, HBV infection results in 0.5 to 1.2 million deaths per year caused by chronic hepatitis, cirrhosis, and hepatocellular carcinoma; the last accounts for 320 000 deaths per year (Lavanchy, 2004).
Fig. (1): Electron microscopic presentation of HBV particles. The round 42 nm particles represent infectious virions (Dane particle). The small empty spheres and the filaments are non-infectious. The preparation was enriched in virus particles (Guptan et al., 2002).
Fig. (2): Geographic pattern of Hepatitis B prevalence (CDC, 2003).
Fig.(3):Geographic pattern of Hepatitis B prevalence (WHO, 2004).
Fig. (4): Global status of countries using HepB vaccine in their national infant immunization system (WHO, 2003).
Fig. (5): Geographic distribution of HBV Genotype (Hayashi and Furusyo, 2004).
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Egypt was reported by Andre (2000) to be an area of high prevalence for HBV; however, Poynard (2002) reported it to be an intermediate area. It was reported that the carrier rate of HBV is 8% among primary school children (Esmat, 2005). The seroprevalence of HBV was ranging from 24% in the general population to 66% in persons 40-67 years of age (Abdelaziz et al., 2000).
HCV 21 % Median Age 26
Median Age 46
All -ve
16 % HBV
Median Age 12
Median Age 34
25% HAV
Median Age 44
13 % 1% Mixed
HEV 24 %
Analysis of 1860 Acute hepatitis cases
Age distribution of patients with acute hepatitis B 70 60 50 40 Sedes 1
30 20 10 0 < 14 ys
14-30 ys
31-50 ys
> 50 ys
Graph (1): Age distribution of patients with acute hepatitis B (Esmat, 2005).
Blood and blood products.
Sexual contact.
Parentral drug abuse.
Peri-natal transmission.
Transmission in high endemic areas.
Exposure of unknown origin.
HBV can present as
Acute infection.
Fulminant hepatic failure (FHF).
Chronic hepatitis.
Extra-hepatic manifestations.
Post hepatitis B cirrhosis.
Combined HBV with HDV or HCV.
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Occult HBV infection is characterized by the presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg).
Laboratory Markers of HBV infection: HBsAg: Present in acute or chronic infection. HBsAb: Marker of immunity acquired through natural HBV infection, vaccination or passive antibody (immune globulin). HBcAb : IgM indicate infection in the previous six months. IgG indicate more distant HBV infection that may have been cleared by the immune system or that may persist.
HBeAg correlates with a high level of viral replication. HBeAb: correlates with low rates of viral replication. HBV DNA: correlates with active replication; useful in monitoring response to treatment of HBV infection, especially in HBeAg –ve mutants.
Diagnostic Criteria for HBV infection :
Chronic disease: - HBsAg +ve for longer than 6 months. - Serum HBV DNA > 100.000 copies per ml. - Persistent or intermittent elevation of transaminases level. - Liver biopsy showing chronic hepatitis. Inactive HBsAg carrier: - HBsAg +ve for longer than 6 months. - HBeAg –ve, HBeAb +ve. - Serum HBV DNA < 100.000 copies per ml. - Persisently normal transaminases level. - Liver biopsy to confirm absence of significant hepatitis. Resolved disease: - History of acute or chronic hepatitis B. - Presence of HBcAb HBsAb. - HBsAg –ve. - Normal transaminases level.
Goals of Antiviral Treatment of Chronic Hepatitis B 1. Sustained suppression of HBV replication:
- Decrease in serum HBV DNA to <105 copies/ml. - HBeAg to HBeAb seroconversion. - HBsAg to HBsAb seroconversion.
2. Remission of liver disease: - Normalization of serum ALT levels. - Decreased necroinflammation in liver. 3. Improvement in clinical outcome: - Decreased risks of developing cirrhosis, liver failure and HCC. - Increased survival.
Table (1) : FDA-Approved Therapies for HBV Infection Approval
Dose in HBV-Infected Patients
Interferon-alpha-2b
1991
*5 million units daily for 16 weeks
Peginterferon-alpha 2a
2005
180 ug once weekly for 48 weeks subcutaneous
Lamivudine
1998
150 mg PO daily at least 1 or 2 years.
Adefovir
2002
10 mg PO daily for 1 year.
Entecavir
2005
0.5-1.0 mg PO once daily
Drug
*Dose for HBeAg +ve (duration 16 weeks) Dose for HBeAg -ve (duration 12 months)
Table (2): Non Yet FDA-Approved Therapies for HBV
Drug
Status
Dose
Tenofovir
300 mg PO daily
Emtricitabine
200 mg PO daily
Peginterferon alpha 2b
1.0 Âľg/kg/week subcutaneously for 1 year.
Table (3): Comparison of Three Approved Treatments of Chronic Hepatitis B (Shen et al., 2004). Indications
Interferon
Lamivudine
Adefovir
HBeAg+ve, normal ALT
Not indicated
Not indicated
Not indicated
HBeAg+ve chronic Hepatitis
Indicated
Indicated
Indicated
HBeAg-ve chronic Hepatitis
Indicated
Indicated
Indicated
HBeAg+ve chronic hepatitis
Duration: 4-6 months
â&#x2030;Ľ1 year
â&#x2030;Ľ1 year
HBeAg-ve chronic hepatitis
Duration : 1 year
>1 year
>1 year
Subcutaneous
Oral
Oral
Many e.g.: depression, hair loss, diarrhea and fatigue
Negligible
Potential nephrotoxicity
-
0%, year 1
None, year 1
70%, year 5
3%, year 2
Low
Intermediate
Route Side Effects Drug Resistance
Cost
High
Incidence of Lamivudine Resistance During Monotherapy 80%
Resistance = HBeAg loss
Percent 60% Lamivudine Resistant 40%
49%
67%
38% 20%
20% 0% 1
2
3
Years of Lamivudine Chang, 2000
4
Currently available monotherapies have
limited long-term efficacy
Treatments need to affect a broader range of patients (e.g., normal/near normal ALT) Treatments that are both safe (e.g., no withdrawal flares) and more easily affordable are still lacking
The hepatitis B virus is a DNA virus and has the propensity to integrate (i.e., insert) parts of itself to the human host’s DNA.
The virus can hide inside the nucleus of the host’s liver cells in the form of ccc DNA (covalently closed circular DNA).
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This
can
be
combination of
achieved
by
the
Lamivudine therapy
pre- and post- transplantation with
HBIG post transplantation.
Recommendations
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Hepatitis B vaccination is the best protection as it provides protection against hepatitis B for 15 years and possibly much longer. It is recommended that all infants, health care workers and persons at risk of exposure e.g. sexual partners of chronically infected persons; should be vaccinated. Hepatitis B Immune globulin is recommended for accidentally exposed persons, ideally within 24 hours of exposure and no later than 7 days. A repeated dose is necessary 28 - 30 days later.
ď&#x201A;§ Newborns of HBV infected mother should receive HBIG plus the hepatitis B vaccine within l2 hours of birth and two additional doses of vaccine at one and six to twelve months of age. ď&#x201A;§ Strict governmental instructions for hygiene and sterilization should be followed particularly in risky procedures e.g. surgical intervention, dental procedures, endoscopies and blood or body fluids sampling.
ď&#x201A;§ Strict observation of blood donors, the presence of normal ALT, AST are not sufficient. Evaluation for occult HBV infection by determination of HBV DNA in serum or tissues should be considered in the context of the prevalence of HBV infection in this geographical area and the type of population. ď&#x201A;§ In order to prevent HBV reinfection after liver transplantation, it is recommended to combine Lamivudine therapy pre- and post-transplantation with HBIG post-transplantation. This regimen has become the standard of care for most liver transplant programs.
Thank you