Hepatitis B

Background: In 1965, Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion. Since then, considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus.

Hepatitis B is a worldwide health care problem, especially in developing areas. An estimated one third of the global population has been infected with this virus. Approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of this disease.

HBV is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction resulting in either an acute symptomatic disease or an asymptomatic disease. Patients may become immune to HBV or may develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC). Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates, liver transplantation currently seems to be the only viable treatment for the latest stages of this disease.

Pathophysiology: HBV is a Hepadna virus. It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive when stored for 15 years at -20°C, for 24 months at -80°C, for 6 months at room temperatures, and for 7 days at 44°C. The viral genome consists of a partially double-stranded circular DNA of 3.2 kilobase pairs that encodes 4 overlapping open reading frames, as follows:

• S for the surface or envelope gene encoding the pre-S1, pre-S2, and the S protein
• C for the core gene, encoding for the core nucleocapsid protein and the e antigen
• X for the X gene encoding the X protein
• P for the polymerase gene encoding a large protein promoting priming, RNA-dependent and DNA-dependent DNA polymerase and RNase H activities

An upstream region for the S and C genes has been found, named pre-S and pre-C, respectively. The structure of this virion is a 42-nm spherical double-shelled particle consisting of small spheres and rods, with an average width of 22 nm.

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: a, common to all HBsAg, and d, y, w, and r, which are epidemiologically important. The core antigen, HBcAg, is the protein that encloses the viral DNA. It also can be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, comes from the core gene and is a marker of active viral replication. Usually, HBeAg can be detected in patients with circulating serum HBV DNA.

The best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum.

The role of the X gene is to encode proteins that act as transcriptional transactivators aiding viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to HBV. The immunoglobulin, immunoglobulin M (IgM) subtype, is indicative of acute infection or reactivation, while the immunoglobulin G (IgG) subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state, and the antigen has been cleared.

With the newest PCR techniques, scientists are able to identify variations in the HBV genome (variant strains). A mutation at the 1896 nucleotide (precore/core region) processing the production of the HBeAg was identified first. The prevalence of this mutant virus varies among different areas. Estimates indicate that 50-60% of the patients from southern Europe, the Middle East, Asia, and Africa and 10-30% of patients in the United States and Europe who have chronic HBV infection have been infected by this strain.

The pathogenesis and clinical manifestations are due to the interaction of the virus and the host immune system. The latter attacks the HBV and causes liver injury. Activated CD4⁺ and CD8⁺ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. Impaired immune reactions (eg, cytokine release, antibody production) or relatively tolerant immune status results in chronic hepatitis. In particular, a restricted T cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.

The final state of the disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop HCC. In the United States, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission). Four different stages have been identified in the viral life cycle.

The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period often is decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.

In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of HBV DNA is seen. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops.

In the third stage, the host can target the infected hepatocytes and the HBV. Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.

In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and co-infection with other viruses.

Eight different genotypes A through H representing a divergence of the viral DNA at around 8% have been identified. The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated, and the response to treatment with antivirals is less favorable for patients infected by genotype C compared with those infected by genotype B

History: The spectrum of the symptomatology varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC during the chronic phase.

• Acute phase

• The incubation period is 1-6 months.

• Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis.

• Icteric hepatitis is associated with the prodromal period, during which a serum sickness–like syndrome can occur. The symptomatology is more constitutional and includes the following:
• Anorexia
• Nausea
• Vomiting
• Low-grade fever
• Myalgia
• Fatigability
• Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
• Right upper quadrant and epigastric pain (intermittent, mild to moderate)

• Patients with hyperacute, acute, and subacute hepatitis may present with the following:
• Hepatic encephalopathy
• Somnolence
• Disturbances in sleep pattern
• Mental confusion
• Coma

• Chronic phase

• Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic.

• Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:
• Symptoms similar to those of acute hepatitis
• Fatigue
• Anorexia
• Nausea
• Mild upper quadrant pain or discomfort
• Hepatic decompensation

Physical: The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease.

• Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:

• Low-grade fever

• Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo)

• Hepatomegaly (mildly enlarged soft liver)

• Splenomegaly (5-15%)

• Palmar erythema (rarely)

• Spider nevi (rarely)

• The physical examination of patients with chronic hepatitis B can reveal stigmata of chronic liver disease such as the following:

• Hepatomegaly

• Palmar erythema

• Spider angioma

• Patients with cirrhosis may have the following symptoms:

• Ascites

• Jaundice

• History of variceal bleeding

• Peripheral edema

• Gynecomastia

• Testicular atrophy

• Abdominal collateral veins (caput medusa

Lab Studies:

• Acute hepatitis B

• High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), at a range of 1000-2000 IU/mL, is the hallmark of the disease, although values 100 times more than the upper limit of normal can be identified. Higher values are found in patients with icteric hepatitis. ALT levels usually are higher than AST levels.

• Alkaline phosphatase levels may be elevated, but usually they are not more than 3 times the upper limit of normal.

• Albumin levels can be slightly low, and serum iron levels may be elevated. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the sedimentation rate.

• Anemia due to a shortened red blood survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding.

• Patients with severe hepatitis experience a prolongation of the prothrombin time.

• Several viral markers can be identified in the serum and the liver. HBsAg (Australian antigen) and HBeAg (marker of infectivity) are the first markers that can be identified in the serum. HBcAb (IgM) follows.

• For patients who recover, seroconversion to HBsAb and HBeAb is observed, and the HBcAb is of the IgG class. Patients with persistent HBsAg for longer than 6 months develop chronic hepatitis.

• Chronic inactive hepatitis B

• Healthy carriers have normal AST and ALT levels, and the markers of infectivity (ie, HBeAg, HBV DNA) may be negative.

• HBsAg, HBcAb of IgG type, and HBeAb also are present in the serum.

• Chronic active hepatitis B

• Patients have mild-to-moderate elevation of the aminotransferases (< 5 times the upper limit of normal). The ALT levels usually are higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease and can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time). HBV DNA levels are high during this phase. HBsAg and HBcAb of IgG or IgM type (in case of reactivation) are identified in the serum.

• If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be excluded. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as antismooth muscle antibodies (20-25%) or antinuclear antibodies (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), also can be found. Mildly elevated levels of rheumatoid factor usually are present.

• Cirrhosis

• In early stages, findings of chronic viral hepatitis can be found.

• Later on as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged prothrombin time, low platelet count and white blood cell count, and AST levels higher than ALT levels can be identified.

• Alkaline phosphatase levels and gamma-glutamyl transpeptidase can be slightly elevated.

Imaging Studies:

• Acute hepatitis B

• Performing abdominal ultrasonography, CT scan, or MRI is important to help exclude biliary obstruction.

• Nonspecific findings include increased echogenicity of the liver parenchyma.

• Chronic hepatitis B: Nonspecific findings may include increased echogenicity of the liver parenchyma.

• Cirrhosis

• Findings include coarse echogenicity of the liver, with a nodular appearance, and findings compatible with portal hypertension (eg, varices, splenomegaly, ascites, pleural effusion [ie, hepatic hydrothorax]).

• Lesions can be detected and may be very difficult to evaluate because they can be mistaken for regenerating nodules. For these cases, highly sophisticated techniques, such as MRI with superparamagnetic iron oxide (ferumoxides), should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver, producing predominant T2 imaging on MRI. Therefore, a marked decrease of the signal in the normal liver parenchyma occurs, effectively permitting the identification of tumors.

Procedures:

• Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease for patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of HBV DNA).

Histologic Findings: Although liver biopsy is not indicated for patients with acute hepatitis B, the findings are predominantly lobular, with degenerative and regenerative hepatocellular changes and accompanying inflammation. Necrosis may be predominantly centrilobular.

Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for HBsAg (see Image 1). Immunohistochemical staining of the specimen can help identify the presence of HBsAg or HBcAg (ie, chronic infection).

Staging:

• Liver damage grading according to the inflammatory component is described as follows:

• Grade 0 - Portal inflammation only, no activity
• Grade 1 - Minimal portal inflammation and patchy lymphocytic necrosis with minimal lobular inflammation and spotty necrosis
• Grade 2 - Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage
• Grade 3 - Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change
• Grade 4 - Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent diffuse hepatocellular damage

• Liver damage staging (ie, fibrosis) is described as follows:

• Stage 0 - No fibrosis

• Stage 1 - Portal fibrosis

• Stage 2 - Periportal fibrosis

• Stage 3 - Septal, bridging fibrosis (see Image 2)

• Stage 4 - Cirrhosis (see Image 3

Medical Care: Therapy is currently recommended for patients with evidence of chronic active disease (ie, high aminotransferase levels, positive HBV DNA findings, HBeAg). See the Medication section. Currently, interferon alfa (IFN-a), lamivudine, adefovir dipivoxil, and entecavir are the main drugs approved globally, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine, BL-thymidine (L-dT), DAPD, clevudine (l-FMAU), thymosin, and therapeutic vaccines. No clear-cut guidelines are available as to which medication should be chosen.

Patients who have lost HBeAg and in whom HBV DNA is undetectable have an improved clinical outcome (ie, slower rate of progression, prolonged survival without complications, reduced rate of HCC, and clinical and biochemical improvement after decompensation).

Special attention must be given to patients on transplantation lists. Initiation of treatment with adefovir or entecavir or in combination with lamivudine is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure.

• Interferon alfa
• Published reports indicate that after IFN-a treatment with 5 million U/d or 10 million U 3 times per week subcutaneously for 4 months, the HBV DNA levels and HBeAg become undetectable in 30-40% of patients. In addition, 10% of patients seroconvert from HBsAg to HBsAb. Unfortunately, 5-10% of patients relapse after completion of treatment. A transient "flare" (ie, increased aminotransferase levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.
• High levels of aminotransferases, a low viral load, and infection with the wild type are good prognostic factors for response to IFN-a treatment.
• Asian patients and patients with the precore mutant virus tend to not respond to IFN-a treatment.
• Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a because of the fact that, although they occasionally may respond, they also can deteriorate further.
• The adverse effects of IFN-a treatment sometimes can be severe, even devastating. Some patients cannot complete treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.
• Pegylated interferon has been used with or without the addition of nucleoside analogues with encouraging results.

• Lamivudine
• A nucleoside analogue inhibiting the viral polymerase, lamivudine has been associated with a 4-log reduction of the viral load. Lamivudine treatment (100 mg/d) has been associated with a 16-18% seroconversion rate from HBeAg to HBeAb, a 30-33% rate of HBeAg loss, a 40-50% normalization of the value of the aminotransferases, and a 1-2% HBsAg seroconversion rate.
• Histologic improvement (ie, reduction of histologic activity index of >2 points) has been noticed in approximately 50% of patients taking this medication. The adverse effects are negligible.
• Lamivudine appears to be effective for patients who do not respond to IFN-a treatment (eg, patients infected by the precore mutant virus). A transient elevation of aminotransferases can be noticed shortly after starting treatment.
• The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.
• Lamivudine treatment has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation.
• The emergence of viral variants is the major complication. Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment, and approximately 50% develop a mutation after 3 years of treatment. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.

• Adefovir dipivoxil
• This agent is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of this drug has been tested in HBeAg-positive, HBeAg-negative, and lamivudine-resistant patients with encouraging results.
• The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment.
• The optimal dose seems to be 10 mg/d. Higher doses are nephrotoxic.
• The results of 2 multicenter trials using adefovir for 48 weeks were published.
• In HBeAg-positive patients who received 10 mg of adefovir daily, a median 3.52 log reduction of the viral load (HBV DNA) level was noted. In 48% of the patients, normalized aminotransferase levels were reported. Histologic improvement was noticed in 53% of the patients who received this regimen. The HBeAg seroconversion rate was 12%.
• Of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. The serum HBV DNA level was decreased in 51% of subjects (Hadziyannis, 2003; Marcellin, 2003). The outcomes are maintained if treatment is continued for 144 weeks, but the benefits are lost if treatment is discontinued at 44 weeks. The development of resistant mutations (rtN236T and rtA181V) has been estimated around 6% (Hadziyannis, 2005).

• Entecavir
• Entecavir is a potent guanosine analogue inhibitor of the viral polymerase with no resistance developed so far after 2 years of use in patients who have no history of previous treatment with nucleoside analogues.
• In regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who are naОve-to-nucleoside analogues versus patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 72% versus 62% of patients (p=0.009), respectively. Undetectable serum HBV DNA levels were reported in 67% versus 36% of patients (p<0.001), respectively. Normalized ALT levels were achieved in 68% versus 60% of patients (p=0.02), respectively. The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log versus 5.4 log (on a base-10 scale) copies per milliliter (p<0.001), respectively. HBeAg seroconversion occurred in 21% of patients treated with entecavir and 18% of patients treated with lamivudine (p=0.33).
• In regard to the HBeAg-negative population, administration of 0.5 mg of entecavir in patients who are naОve-to-nucleoside analogues versus patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 71% versus 61% of patients (p=0.01), respectively. Undetectable serum HBV DNA levels were found in 90% versus 72% of patients (p<0.001), respectively. Normalized ALT levels were achieved in 78% versus 71% of patients (p=0.045), respectively. The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log versus 4.5 log (on a base-10 scale) copies per milliliter (p<0.001), respectively.

• Telbivudine
• Telbivudine, a newly FDA approved cytosine nucleoside analogue, is a potent inhibitor of the HBV DNA polymerase.
• The results of the GLOBE Trial, a Phase III study, that tested the administration of 600 mg of telbivudine versus 100 mg of lamivudine over a 2-year period were announced. In regard to the HBeAg-positive population, therapeutic response (defined as HBV DNA <10,000 copies/mL, with either ALT normalization or HBeAg loss) was 75% for the patients treated with telbivudine compared with 67% for the patients treated with lamivudine. Of the patients receiving telbivudine, 26% lost the e antigen versus 23% of the patients receiving lamivudine. In addition, a 6.5 log reduction of the HBV DNA was noted for the patients receiving telbivudine versus a 5.5 log reduction for the patients receiving lamivudine.

• In the HBeAg-negative patients, the respective response rates at 1 year were 75% and 77%, while 88% versus 71% were HBV DNA nondetectable. The HBV DNA log reduction was 5.2 versus 4.4, respectively.
• Because resistance is a major issue, the reported rates at 1 year were 2.6% of patients on telbivudine and 8.2% of patients on lamivudine.

Surgical Care: Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease. The implementation of hepatitis B immunoglobulin (HBIG) during and post-OLT period, and of lamivudine or adefovir in the pre-OLT period and post-OLT period, dramatically improves the recurrence rate of HBV infection.

Diet:

• Acute and chronic hepatitis (patients without cirrhosis) - No restrictions

• Decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy) - Low-sodium diet (1.5 g/d), high-protein diet, ie, white-meat protein (eg, pork, turkey, fish), and, in cases of hyponatremia, fluid restriction (1.5 L/d)

Drug Category: Antivirals -- Interfere with replication; weaken or abolish viral activity ….Interferon alfa-2b (Intron A) or alfa-2a (Roferon-A) -- Protein product manufactured by recombinant DNA technology. Mechanism of antiviral activity is not clearly understood. However, modulation of host immune responses enhances cytolytic T-cell activity; stimulates natural killer cell activity and amplifies HLA class I protein on infected cells. Direct antiviral activity activates viral ribonucleases, inhibits viral entry to cells, and inhibits viral replication. Direct antifibrotic effect has been postulated. Prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 4 mo, discontinue treatment. If a response occurs, continue treatment until no further improvement is observed. Whether continued treatment is beneficial after that time remains unknown….

Entecavir (Baraclude) -- Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic HBV infection. Available as tab and as oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

Telbivudine (Tyzeka) -- Nucleoside analogue approved by FDA for chronic hepatitis B treatment. Inhibits hepatitis B viral DNA polymerase. Indicated for patients with evidence of ongoing hepatitis B viral replication and either persistent elevated aminotransferase activity or histologic evidence of active liver disease. Consider for patients who did not or are unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is major drawback of nucleoside analogue monotherapy..

Дата добавления: 2015-10-29