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 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):GeographicpatternofHepatitisBprevalence(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).

Egypt was reported by Andre (2000) to be an areaofhighprevalenceforHBV;however, Poynard(2002) reportedittobean 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 years of age (Abdelaziz et al., 2000).

24 % All -ve 13 % 21 % 25%25% 16 % HBV HAVHAV HEV 1 % Mixed HCV Median Age 26 Median Age 12 Median Age 44 Median Age 46 Median Age 34 Analysis of 1860 Acute hepatitis cases

Age distribution of patients with acute hepatitis B < 14 ys14-30 ys ys> 50 ys Sedes 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 ofunknown 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.

Occult HBV infection is characterized by the presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg).

Laboratory Markers ofHBV infection: HBsAg: Present in acute or chronic infection. HBsAb: Marker ofimmunity acquired through natural HBV infection, vaccination or passive antibody (immune globulin). HBcAb : IgM  indicateinfectionintheprevioussix 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 ofviral replication. HBeAb:correlateswithlowratesofviral replication. HBV DNA: correlates with active replication; useful in monitoring response to treatment of HBeAg – ve HBVinfection,especiallyin mutants.

Diagnostic Criteria for HBV infection : Chronic disease: -HBsAg +ve for longer than 6 months. -Serum HBV DNA > 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 < 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 <10 5 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 DrugApproval Dose in HBV-Infected Patients Interferon-alpha-2b1991 *5 million units daily for 16 weeks Peginterferon-alpha 2a ug once weekly for 48 weeks subcutaneous Lamivudine mg PO daily at least 1 or 2 years. Adefovir mg PO daily for 1 year mg PO once dailyEntecavir2005 * Dose for HBeAg +ve (duration 16 weeks) Dose for HBeAg -ve (duration 12 months)

Table (2): Non Yet FDA-Approved Therapies for HBV DrugStatusDose Tenofovir300 mg PO daily Emtricitabine200 mg PO daily Peginterferon alpha 2b 1.0 µ g/kg/week subcutaneously for 1 year.

IndicationsInterferonLamivudineAdefovir HBeAg+ve, normal ALT Not indicated Not indicated Not indicated HBeAg+ve chronic Hepatitis Indicated HBeAg-ve chronic Hepatitis Indicated HBeAg+ve chronic hepatitis Duration: 4-6 months≥1 year HBeAg-ve chronic hepatitis Duration : 1 year>1 year RouteSubcutaneousOral Side Effects Many e.g.: depression, hair loss, diarrhea and fatigue Negligible Potential nephrotoxicity Drug Resistance-0%, year 1None, year 1 70%, year 53%, year 2 CostHighLowIntermediate Table (3): Comparison of Three Approved Treatments of Chronic Hepatitis B (Shen et al., 2004).

Incidence of Lamivudine Resistance During Monotherapy 49% 67% 38% 20% 0% 40% 60% 80% 14 Chang, 2000 Percent Lamivudine Resistant Resistance = HBeAg loss 23 Years of Lamivudine

 Currently available monotherapies have limited long-term efficacy  Treatments need to affect a broader range ofpatients (e.g., normal/near normal ALT)  Treatments that are both safe (e.g., no withdrawal flares) and more easily afford- able 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).

beachieved Thiscan combination ofLamivudine bythe therapy withpre-andpost-transplantation HBIG post transplantation.

Recommendations

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 ofchronically 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 days later.

 Newborns ofHBV infected mother should receive HBIG plus the hepatitis B vaccine within l2 hours ofbirth and two additional doses ofvaccine at one and six to twelve months ofage.  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.

 Strict observation ofblood donors, the presence of normal ALT, AST are not sufficient. Evaluation for occult HBV infection by determination ofHBV DNA in serum or tissues should be considered in the context ofthe prevalence ofHBV infection in this geographical area and the type ofpopulation.  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 ofcare for most liver transplant programs.

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