Kepaniteraan Klinik Stase Penyakit Dalam RSIJ Sukapura

Program Studi Pendidikan Dokter

Fakultas Kedokteran dan Kesehatan

Universitas Muhammadiyah Jakarta

TutorialHepatitis B

Disusun Oleh:Zaras Yudisthira Saga

2008730133Rikke Varianti 2008730108Pembimbing: Dr. Iwan B. ,

Sp.PD

Epidemiology

• Hepatitis B virus (HBV) infection is an important global health problem and is one of the most common chronic viral infections.

• Approximately 350–400 million persons have chronic infection, and more than 1 million deaths annually are due to end-stage liver disease or hepatocellular cancer (HCC)

• HBV infection is highly prevalent in Asia, Africa, and parts of southern and eastern Europe

• In the UK, more than 300,000 people may have chronic HBV infection

Virology

• Human HBV is a member of the Hepadnaviridae family, and humans and higher primates are the only hosts for HBV infection

• The viral genome is a 3.2-kb partially double-stranded DNA with four overlapping reading frames

• The viral genome encodes the viral polymerase (which includes the reverse transcriptase function), the core and surface proteins, and the non-structural proteins (HBV e antigen [HBeAg] and X protein)

• There are eight distinct HBV genotypes, which have well-defined geographical distribution They differ in some important respects, including their natural history and response to interferon (IFN)-based antiviral therapy

Pathogenesis and NaturalHistory

• The pathogenesis of liver disease in HBV infection is related to the persistence and magnitude of viral replication.

• The course of viral infection and the severity of liver damage are determined by the balance between viral replication and host immune defence mechanisms

• Following acute HBV infection of adults, 95% recover spontaneously with viral clearance not needing treatment

• Intrauterine infection and infection at a young age are strongly associated with failure to clear the virus and with the development of chronic infection.

• Chronic infection is defined as the persistence of HBsAg in serum for at least 6 months after infection with hepatic inflammation

• Liver inflammation requires both high levels of replication and targeted inflammatory responses

• Chronic infection may be associated with production and secretion by infected hepatocytes of the HBeAg. In that case, the level of viral replication is almost invariably very high

• When HBeAg negativity is associated with high levels of replication, the associated hepatitis may be referred to as e-negative hepatitis.

Pathogenesis and NaturalHistory

• Classically, four phases of chronic HBV infection have been described.– They are the immune tolerant phase,– The immune reactive phase, – The inactive/resolution phase and – The reactivation phase.

immune tolerant phase•High levels of replication (usually more than 10 million IU/mL)•absence of inflammatory response•HBeAg-positive infection•no cytotoxic•T-cell reaction to virus

immune reactive phase•virus is recognized as foreign antigen by the immune system•elevated or fluctuating ALT•HBeAg-positivity•moderate to severe inflammation on liver biopsy•serum HBV DNA falls and HBeAg secretion may stop

inactive/resolution phase •inactive hepatitis B carriers•HBeAg-negativity•low serum HBV (< 2,000 IU/mL)•normal ALT•This phase may persist for life with sustained and effective cytotoxic T-cell responses•1–3% per annum will achieve resolution phase with clearance of HBsAg from serum

reactivation phase

•Reappearance of higher levels of virus despite HBeAg-negativity•There is resumed liver inflammation and progressive fibrosis

Clinical Presentation and

Diagnosis

• Acute infection is characterized by arthralgia, fever, urticaria and flu-like symptoms, followed by jaundice.

• More than 90% recover with acquired immunity;• Fulminant hepatitis is rare, but a small proportion is persistently infected• The majority of infection is asymptomatic, and a high proportion becomes

chronic• Presentation in middle age with cirrhosis, which is either compensated

(features of chronic liver disease) or decompensated (ascites, hepatic encephalopathy, and variceal bleed), is not uncommon.

Investigations: Viral Serology

• Those patients who present with acute hepatitis typically have both HBsAg and immunoglobulin M (IgM) antibodies to HBV in serum (IgM reactivity to the core antigen is typically measured).

• Chronic HBV patients who present to clinics should be checked for HBsAg, HBeAg and HBV DNA level.

• HBV DNA quantification is a key determinant for selection of patients for therapy, and its measurement is necessary to monitor response to antiviral therapy

• HBV infection can be associated with hepatitis delta virus (HDV) infection, so HDV serology should be routinely performed.

Liver Biochemistry •Assessment of liver damage requires routine biochemical liver function tests, including serum albumin, and international normalized ratio

Assessment of Fibrosis •A liver biopsy can determine the degree of hepatic necroinflammation (grading) and fibrosis (staging)•serum markers and transient elastography

Monitoring Cirrhosis and Surveillance of HCC

•Liver ultrasound should be performed at first assessment for all patients and every 6 months for patients with high risk of liver cancer

Management

• The management of HBV has improved during recent years with the use of IFN and with the development of safe and potent oral antiviral nucleoside/nucleotide analogues

• The goal of therapy is to prevent the progression to cirrhosis and to reduce risk of HCC. Antiviral efficacy is measured by the degree of HBV

• DNA suppression and rates of HBeAg and HBsAg loss, and is reflected by improvement in liver histology.

• HBV treatment is recommended for those patients who have moderate hepatic necroinflammation or fibrosis and high serum HBV DNA

• First-line therapy for the treatment-naive non-cirrhotic patient is either IFN or an oral antiviral.

• Entecavir and tenofovir both have potent antiviral activity (90% of treated patients have undetectable serum HBV DNA at 12 months of therapy), good safety profiles, and very low rates of emergence of resistance.

• Lamivudine and telbivudine should not be used as first-line therapy because the risk of drug resistance is high.

• Adefovir has a good resistance profile, but lacks potency (50% undetectable HBV DNA at year 1).

• In normal practice, the emergence of drug resistance is recognized by a rise in viral load of at least 1 log10 IU/mL from nadir titre in a compliant patient. HBV resistance can be confirmed by genetic sequencing of the virus

Follow-up and HCC Surveillance

• African or Asian ethnicity, male gender, age over 40 years, family history of HCC, high HBV DNA titre and co-infection with other viruses are the risk factors which are associated with increased risk of HCC development.

• Most cancer is seen after development of cirrhosis, so prevention of cirrhosis dramatically reduces the risk of cancer

HBV Infection in SpecialCircumstancesPregnancy

• Antiviral therapy for the pregnant mother with very high titres may further reduce the risk of transmission to the baby.

• Current recommendations suggest that either lamivudine (Category C) or tenofovir (Category B) can be taken by the pregnant mother during the third trimester to further reduce the risk of transmission to the developing fetus and neonate.

• Breastfeeding by an HBV-positive mother is safe, and there is a low risk of infection (so long as the baby has been vaccinated).

Infants and ChildrenHBV infection is seldom associated with

significant liver damage during childhood years. Antivirals can be used

under specialist care

HBV Infection in SpecialCircumstances

Health-care WorkerHealth-care workers who undertake

exposure-prone procedures (eg, surgeons, obstetricians) can be

given antivirals to reduce the risk of transmission from doctor to patient.

Co-infectionHBV and HDV co-infection is not uncommon. Around 5% of HBV

carriers are co-infected with HDV. IFN is the treatment of choice for

HBV/HDV infection. In patients with HBV and HCV co-

infection, treatment is recommended to target the

dominant virus and IFN has the advantage of being active against

both viruses.

Prevention: HBV Vaccination

Most countries undertake maternal screening for HBsAg, and vaccinate the neonate born to the HBV carrier

mother

If a person is detected with HBV infection, family members should be screened and vaccination should be offered to household members and

close contacts who are HBsAg-negative

Liver Transplantation

• Liver transplantation is the preferred treatment for HBV-infected individuals who present with fulminant liver failure, decompensated liver disease and HBV-related HCC.

• Oral antiviral therapy alone or in combination with hyperimmune immunoglobulin can prevent graft reinfection

Conclusion

• Currently, HBV causes nearly 1 million deaths per annum globally. HBV vaccination will have a major impact on prevalence of infection.

• For those with established chronic infection and evidence of liver damage, antiviral treatment should be started early to prevent the development of HBVrelated cirrhosis, liver failure and liver cancer

Nukleosida / Nukleotida analog adalah agen antivirus oral yang menghambat sintesis DNA HBV dengan bertindak sebagai terminator rantai DNA dan ditoleransi dengan baik.Dibagi menjadi 3 kelompok yaitu:

Have potent antiviral activity (90% of treated patients have undetectable serum HBV DNA at 12 months of therapy), good safety profiles, and very low rates of emergence of resistance.Bukanlah terapi lini pertama karena risiko resistensi obat tinggiAdefovir has a good resistance profile, but lacks potency (50% undetectable HBV DNA at year 1)

Follow-up and HCC Surveillance 50 % kanker hati disebabkan oleh HBV Etnis Afrika atau Asia, laki-laki, usia > 40 tahun, genetik HCC, meningginya titer HBV

DNA dan co-infection dengan virus lainnya.

Pregnancy Vaksinasi dapat mencegah infeksi neonatal dalam sebagian besar kasus. Kegagalan vaksinasi dikarenakan titer virus ibu yang sangat tinggi. Terapi antiviral dapat mengurangi risiko penularan ke bayi. Rekomendasi obat adalah lamivudine (Kategori C) atau tenofovir (Kategori B) digunakan pada trimester ketiga untuk mengurangi risiko penularan ke janin. Menyusui oleh Ibu degan HBV-positif aman, risiko rendah erjadinya infeksi (syarat bayi harus divaksinasi).

Health-care Worker misalnya, ahli bedah, obstetricians dapat diberikan antivirus untuk mengurangi risiko penularan.

Co-infection

Immunosuppressed Patients Kemunculan HBV DNA pada pasien dengan Infeksi HBV sebelumnya diselesaikan atau tidak aktif kadang-kadang diamati di immunosuppressed Serikat. cccDNA, yang berada di dalam hepatosit terinfeksi, memainkan peran penting dalam Reaktivasi HBV selama kemoterapi kanker, selama penggunaan beberapa Agensia hayati (terutama rituximab anti-CD20) dan berikut transplantasi organ. Dalam keadaan ini, diindikasikan sering pro phylaxis dengan oral obat-obat antivirus.

Prevention1. Vaksinasi HBV

Vaccination is the most effective way to achieve global HBV control and to prevent cirrhosis, liver failure and liver cancer. Most countries include HBV vaccination as part of the routine universal childhood vaccination schedule. Universal vaccination has been shown to reduce the incidence of HBV infection, to reduce the frequency of childhood chronic infection, and to reduce the risk of childhood liver cancer.

2. Transplantasi hatiLiver transplantation is the preferred treatment for HBV-infected individuals who present with fulminant liver failure, decompensated liver disease and HBV-related HCC.