Update on prevalence, diagnosis, and treatment of hbv (thesis)

‫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).

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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.



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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