Hepatitis B Treatment & Management

Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, high aminotransferase levels, positive hepatitis B virus [HBV] DNA findings, hepatitis B e antigen [HBeAg]). Various algorithms have been proposed, such as that by Keeffe and colleagues^[16] and the American Association for the Study of Liver Diseases (AASLD).^[17]

In general, for the HBeAg-positive patient population that is identified with evidence of chronic HBV disease, treatment is advised to be administered when the HBV DNA level is ≥20,000 IU/mL (10⁵ copies/mL) and when serum alanine aminotransferase (ALT) is elevated for 3-6 months.

For the HBeAg-negative chronic population with hepatitis B disease, treatment can be administered when the HBV DNA is ≥ 2000 IU/mL (10⁴ copies/mL) and serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.

Inpatient care

Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU), and these individuals should be considered as liver transplant candidates in the event they do not recover.

Patients with acute hepatitis should be monitored with blood tests in order to document biochemical improvement (see Workup).

Dietary limitations

For individuals with decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy), a 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) are indicated.

Patients with acute and chronic hepatitis without cirrhosis have no dietary restrictions.

Currently, interferon alfa (IFN-a), lamivudine, telbivudine, adefovir, entecavir, and tenofovir are the main treatment drugs approved globally for hepatitis B disease, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine, clevudine (l-FMAU), and therapeutic vaccines. It appears that lamivudine and telbivudine are not recommended as first-line agents in the treatment of hepatitis B disease.^[18]

Patients who have lost hepatitis B e antigen (HBeAg) and in whom hepatitis B virus (HBV) DNA is undetectable have an improved clinical outcome (ie, slower rate of disease progression, prolonged survival without complications, reduced rate of hepatocellular carcinoma [HCC], and clinical and biochemical improvement after decompensation).

Special attention must be given to patients on liver transplantation lists. Initiation of treatment with adefovir or entecavir or tenofovir 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^[19] treatment with 5 million U/d or 10 million U 3 times per week subcutaneously (SC) for 4 months, the HBV DNA levels and HBeAg become undetectable in 30-40% of patients. In addition, 10% of patients seroconvert from hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (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. However, Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment.

Loss of hepatitis B surface antigen (HBsAg) indicates resolution of the HBV infection, acute or chronic, but is rare in chronic infection. A study by Tseng et al followed Taiwanese patients with chronic hepatitis B infection who developed spontaneous HBeAg loss (seroconversion). Patients with low levels of HBsAg a year after their seroconversion had a higher probability of loss of HBsAg.^[20]

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 have a treatment response, these individuals can also deteriorate further.

The adverse effects of IFN-a treatment can sometimes 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 IFN-a 2a

A 48-week regimen of pegylated IFN-a 2a (PEG-IFN-a 2a) might induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA.^[21] Extension to treatment for 48 weeks resulted in an HBeAg seroconversion of 32%.

Placing patients that have HBeAg-negative chronic hepatitis B disease on 48 weeks of a PEG-IFN-a 2a regimen resulted in a significantly greater percentage of patients with a viral load that was nondetectable 24 weeks after the end of treatment (19%) compared with lamivudine monotherapy (7%).^[18]

It appears that patients infected by HBV genotype A or B have a better response to IFN treatment compared with patients infected by genotype C or D, and this kind of treatment appears to be more appealing, especially for patients with increased alanine aminotransferase (ALT) levels.

Lamivudine

A nucleoside analogue that inhibits the viral polymerase, lamivudine^{[18, 22, 23, 24]} has been associated with a 4-log reduction of the viral load. Lamivudine treatment (100 mg/d) has also been associated with a 16-18% seroconversion rate from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (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 lamivudine. The adverse effects are negligible.

Lamivudine appears to be effective for patients who do not have a treatment response to IFN-a (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 in hepatitis B disease.^{[25, 26]} 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

Adefovir is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil 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.^{[27, 28, 29, 30]}

The optimal dose seems to be 10 mg/d.^{[31, 32]} Higher doses are nephrotoxic.

The results of 2 multicenter trials that used adefovir for 48 weeks^{[31, 32]} noted that in HBeAg-positive patients who received 10 mg of adefovir daily, there was a median 3.52 log reduction of the viral load (HBV DNA) level. In 48% of the patients, normalized aminotransferase levels were reported, and histologic improvement was seen in 53% of the patients who received this regimen.^[31] The HBeAg seroconversion rate was 12%.

Furthermore, 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.^{[31, 32]} The outcomes were maintained if treatment was continued for 144 weeks, but the benefits were lost if treatment was discontinued at 44 weeks. The development of resistant mutations (rtN236T and rtA181V) has been estimated to be around 6%.^[32]

Entecavir

Entecavir is a potent guanosine analogue inhibitor of the viral polymerase with 1.2% resistance in patients who have no history of previous treatment with nucleostide/nucleoside analogues and almost 56 % in lamivudine-resistant patients during a 6-year treatment period.^[33]

HBeAg-positive patients

With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues relative to patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group compared with 62% of the lamivudine group.^[34] Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients compared with 36% of lamivudine-treated patients.

Normalized ALT levels were achieved in 68% of the entecavir group versus 60% of the lamivudine group.^[34] The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients relative to 5.4 log copies/mL in the lamivudine-treated patients. HBeAg seroconversion occurred in 21% of patients treated with entecavir and 18% of patients treated with lamivudine.^[34]

HBeAg-negative patients

With regard to the HBeAg-negative population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues compared with patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group versus 61% of the lamivudine group.^[33] Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients versus 72% of the lamivudine-treated patients.

Normalized ALT levels were achieved in 78% of the entecavir group compared with 71% of the lamivudine group.^[33] The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients versus 4.5 log copies/mL in the lamivudine-treated patients.^[33]

Telbivudine

Telbivudine, a cytosine nucleoside analogue, is a potent inhibitor of the HBV DNA polymerase.

HBeAg-positive patients

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 reported that in 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.^{[35, 36]}

Of the patients receiving telbivudine, 26% lost the e antigen versus 23% of the patients receiving lamivudine.^{[35, 36]} 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.

HBeAg-negative patients

In the HBeAg-negative patients, the response rates at 1 year were 75% for the telbivudine group and 77% in the lamivudine group, whereas 88% of the telbivudine-treated patients versus 71% of the lamivudine-treated patients were HBV DNA nondetectable. The HBV DNA log reduction was 5.2 (telbivudine group) versus 4.4 (lamivudine group).^{[35, 36]}

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.^{[35, 36]}

Tenofovir

Tenofovir is a nucleotide analogue (adenosine monophosphate) reverse transcriptase and HBV polymerase inhibitor.

HBeAg-positive naïve patients

In a study that randomized patients in 2 arms to receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily) for 48 weeks, with the adefovir-treated patients then switched to tenofovir, 79% of the patients who received tenofovir were found to have a viral load below 400 copies/mL, whereas in the adefovir group, 76% of patients receiving adefovir before switching to tenofovir were found to have a viral load below 400 copies/mL.^[37]

In addition, 72% of the patients in the adefovir arm that were found to have a viral load greater than 400 copies/mL achieved viral suppression after they were switched to tenovofir, whereas for those who had achieved viral suppression, the effect was maintained after they were switched to tenofovir.^[37] Biochemical response was reported in 77% of patients in the tenofovir arm at week 72 and in 61% of those switching from adefovir to tenofovir.

With regard to seroconversion, 26% of patients who received tenofovir seroconverted at week 64 relative to the adefovir arm, in which the observed seroconversion rate was reported as 21%.^[37] It is noteworthy to mention that 5% of patients in the tenofovir arm experienced loss of the "s" antigen.

HBeAg-negative patients

In another report, of patients who were randomized receive either tenofovir (300 mg once daily) or adefovir (10 mg once daily), and then after 48 weeks when all eligible adefovir-treated patients were switched to tenofovir, 91% of patients receiving tenofovir at 72 weeks of treatment were found to have a viral load below 400 copies/mL.^[38] In contrast, in the adefovir arm, of patients who switched to tenofovir after 48 weeks, 88% had a viral load below 400 copies/mL by week 72 of the study. All the adefovir-treated patients who had a viral load below 400 copies/mL at week 48 maintained a viral load below this level after switching to tenofovir.^[38] For the patient population in the adefovir arm who did not achieve optimal viral response (viral load above 400 copies/mL) at the time of switch to tenofovir, 94% had a viral load below this level by week 72.

Normal ALT levels at week 72 were observed in 79% of patients who initiated therapy with tenofovir and in 77% of patients who switched to tenofovir drug from adefovir.^[38]

HBeAg-negative or HBeAg-positive chronic HBV patients

In 2 double-blind, phase 3 studies, in which patients with HBeAg-negative or HBeAg-positive chronic hepatitis B were randomized to receive tenofovir disoproxil fumarate (DF) (300 mg) or adefovir dipivoxil (10 mg) (ratio, 2:1) once daily for 48 weeks,^[39] Marcellin et al concluded that among patients with chronic hepatitis B, tenofovir at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir at a daily dose of 10 mg through week 48.^[39]

At week 48 in both studies, a significantly higher proportion of patients receiving tenofovir than of those receiving adefovir had reached the primary end point (plasma HBV DNA level < 400 copies/mL [69 IU/mL]), and viral suppression occurred in more HBeAg-negative patients in the tenofovir group (93%) than patients in the adefovir group (63%), as well as in more HBeAg-positive patients receiving tenofovir (76%) than those receiving adefovir (13%).^[39]

In addition, significantly more HBeAg-positive patients in the tenofovir group (68%) not only had normalized ALT levels relative to those in the adefovir group (54%) but also had loss of HBsAg (3% tenofovir group vs 0% adefovir group).^[39] At the end of 48 weeks, none the patients had developed the amino acid substitutions within HBV DNA polymerase that are associated with phenotypic resistance to tenofovir or other drugs used to treat hepatitis B; tenofovir produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not; and the 2 treatments in both studies had similar safety profiles.^[39]

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 after the OLT period, and of lamivudine or adefovir in the pre- and post-OLT periods, dramatically improves the recurrence rate of hepatitis B.

Complications from hepatitis B include progression to hepatocellular carcinoma (HCC), glomerulonephritis, and polyarteritis nodosa, as well as various dermatologic, cardiopulmonary, joint, neurologic, hematologic, and gastrointestinal (GI) tract manifestations.

Hepatocellular carcinoma

Even the presence of hepatitis B surface antibody (HBsAb) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with hepatitis B and cirrhosis reported in Taiwan is 2.8%. The estimated US annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska.

HBV and HDV coinfection

The prevalence of hepatitis D virus (HDV) coinfection among patients infected with hepatitis B virus (HBV) worldwide is 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different. Therefore, delta superinfection does not appear to increase the rate of HCC.

HBV and HCV coinfection

The prevalence of HCC among patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is higher than in those with a single infection alone. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and hepatitis B infection, 3.7% in patients with HCV infection, and 6.4% in patients with dual HBV and HCV infection. This points to a probable synergistic effect on the risk of HCC.

Possible pathogenic mechanisms

The mechanism by which chronic hepatitis B infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors for nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk for HCC.

The fact that facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm.

Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of alpha-fetoprotein (AFP). Although the cellular targets of carcinogenesis have not been identified, some evidence resulting from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC. Although cirrhosis is found in the majority of these patients, it is not obligatory, because chronic carriers may develop HCC even without the evidence of cirrhosis.

HBV has been speculated to have intrinsic hepatocarcinogenic activity, interacting with host DNA in different ways. After entering the hepatocyte, viral DNA is integrated within the genome. The site of integration is not constant but usually involves the terminal repeat sequences. Chromosomal deletions, translocations, rearrangements, inversions, or even duplications of normal DNA sequencing accompany integration.

Transactivation of the function of genes controlling transcriptional factors (ie, insulinlike growth factor II [IGF-2], transforming growth factor-alpha [TGF-a], TGF-beta, cyclin-a [a protein that controls cell division], epidermal growth factor-r [EGFR], retinoic acid receptor [RAR]) and oncogenes such as c-myc, fos, ras (activating the internal signal transduction cascade upregulating ras/mitogen–activated kinase, c-Jun N terminal kinase, nuclear factor–kB, Jak-1-STAT, src- dependent pathways) influence the normal hepatocyte differentiation or cell cycle progression.

Furthermore, the integrated part of the hepatitis B virus (HBV) controlling the production of the HBxAg (antigen for the X gene of HBV) is overexpressed. These observations suggest the site of viral genomic integration into the host's DNA alone is not the factor.

Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB (cyclic adenosine monophosphate [cAMP]–response element-binding protein) and ATF-2 (activating transcription factor 2), which alters their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.

Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53 and (1) sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept); (2) reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD; (3) reduce p21WAF1 expression, which is a cell cycle regulator; and (4) bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B, thus altering its function.

Tumor necrosis factor-alpha (TNF-a) (a proinflammatory cytokine) levels are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-a are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc, and this upregulates the expression of TGF-a by transactivation.

Glomerulonephritis

The most common type of glomerulonephritis described in association with hepatitis B is membranous glomerulonephritis (MGN), mainly in children. However, membranoproliferative glomerulonephritis (MPGN) and, even more rarely, immunoglobulin (Ig) A nephropathy, have been identified.

The prevalence rate of glomerulonephritis among patients with chronic hepatitis B is not well known, although observations have been made in children that suggest a range of 11% to 56.2%. However, such a high prevalence is not recognized in the United States, and this may be because of the differences in epidemiology of HBV, which might be predominantly perinatal in other geographic areas of the world (see Epidemiology).

A previous history of chronic liver disease is not present in the majority of these patients at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. Serologic markers of an HBV replicative state are often evident, and complement activation is suggested by low levels of C3 and C4.

Generally, the most prominent finding among affected children is MGN, primarily with capillary wall deposits of HBeAg. In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy has also been described.

Possible pathogenic mechanisms

The mechanism by which patients with chronic hepatitis B develop glomerulonephritis is not completely understood. One possible explanation is that HBV antigens (ie, HBsAg, HBeAg) act as triggering factors, eliciting immunoglobulins and thus forming immune complexes, which are dense irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and in the epithelial cells of renal tubules.

IFN-a therapy

IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously (SC) daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation.

Prognosis

The prognosis of renal disease in hepatitis B is related to several factors, such as age and response to therapy. Children with MGN have a more favorable response than adults. White persons have a better response than Asians and black patients. Approximately 30-60% of cases with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which the virus is endemic is not benign. Regardless of treatment, hepatitis B disease has a slow but relentlessly progressive clinical course in approximately one third of patients who have progressive renal failure, necessitating maintenance dialysis therapy.

Polyarteritis nodosa

An association between hepatitis B and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN). This very serious complication presents early during the course of hepatitis B, and the incidence is high among certain populations, such as Alaskan Eskimos.

The pathogenesis of PAN is not clear. Circulating immune complexes containing HBsAg, immunoglobulins (IgG and IgM), and complement have been demonstrated by immunofluorescence in the walls of the affected vessels, which might trigger the onset of PAN. However, whether these represent the primary etiology of the disease remains unclear.

The clinical manifestations of PAN include cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure), renal (eg, hematuria, proteinuria, renal insufficiency), GI (eg, abdominal pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis), neurologic (eg, mononeuritis), and dermatologic (eg, rashes) involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum creatinine >1.58 mg/dL), GI and central nervous system involvement, and cardiomyopathy, are associated with increased mortality.

The course of PAN is independent of the severity and the progression of the liver disease. Of these patients, 20-45% die as a consequence of vasculitis in 5 years, despite treatment, and the mortality rate is similar for patients with PAN who are HBsAg seropositive and for those with PAN who are seronegative.

Small and medium-sized arteries and arterioles are affected in PAN. Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they potentially may have a deleterious effect on the course of hepatitis B liver disease because of viral reactivation, particularly after the withdrawal of treatment. Adenine arabinoside, an antiviral drug, and IFN-a, an immunomodulator and antiviral protein, have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results. The combination of short-term corticosteroids accompanied by plasmapheresis and lamivudine resulted in 100% clinical recovery and 66 % seroconversion, although the number of patients studied was relatively small.^[40] .

Skin manifestations

A variety of cutaneous manifestations have already been recognized during the early course of viral hepatitis, among which are hives and a fleeting maculopapular rash. Women are more prone to developing cutaneous manifestations.

The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities.

Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, more commonly with acute infection in children.^[41]

Cardiopulmonary, joint, neurologic, hematologic, and GI tract manifestations

The following multisystem manifestations may occur in HBV:

• Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis
• Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis
• Arthralgias and arthritis (serum sickness) subcutaneous nodules may also occur, but these are rare.
• Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B
• Patients may develop pancreatitis
• Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon
• Diffuse intravascular coagulation may occur in patients with fulminant hepatitis

Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. The hepatitis B vaccine consists of recombinant hepatitis B surface antigen (HBsAg) produced in yeast. A series of 3 injections may achieve HBsAb levels greater than 10 million IU/mL in approximately 95% of people vaccinated. Vaccination with a single dose must be repeated every 5-10 years.

All newborns must be vaccinated against hepatitis B. For infants born to mothers with active hepatitis B, a passive-active (immunoglobulin [HBIG] and vaccination) approach is recommended.

Healthcare workers or people who have had a needle-stick accident from a patient with active hepatitis B infection must receive the active-passive immunization approach (HBIG and the first dose of the vaccine at the same time), and these individuals must be monitored with blood tests.

Current guidelines recommend all previously unvaccinated adults aged 19 through 59 years with diabetes mellitus (type 1 and type 2) be vaccinated against hepatitis B as soon as possible after a diagnosis of diabetes is made. Clinicians may use their discretion in determining whether to vaccinate elderly diabetic patients (≥60 years).^[42]

Low response rates have been associated with obesity, smoking, immunosuppression, and advanced age.

Approximately 25-50% of persons who initially do not have a vaccine response will show a response to 1 additional vaccine dose, and 50-75% of persons will have a response to a second 3-dose series.

A combined hepatitis A virus (HAV) and hepatitis B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time.

The HBV vaccine seems to be safe, although some questions exist regarding neurologic complications.

Inactive carriers of the hepatitis B virus (HBV) should have routine blood tests annually to check their aminotransferase levels.

Patients with chronic active hepatitis should undergo blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, and viral load), liver biopsy, and treatment.

Current guidelines recommend monitoring of HBV DNA and alanine aminotransferase (ALT) levels at least annually; however, a study conducted by Juday et al suggests that adherence falls below recommendations.^[43] Following the recommended guideline reduces the risk of disease progression.

Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein (AFP) measurements and abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance.

Precautions

Physicians should keep the following in mind when managing a patient with hepatitis B

• Identify cases of hyperacute fulminant hepatic failure, and list the patient as a candidate for liver transplantation
• Monitor healthy carriers for probable disease reactivation
• Inform the patients' spouses and sexual partners about the infectivity of hepatitis B and their possible need for vaccination
• Monitor patients with cirrhosis and perform HCC surveillance studies (ie, AFP levels and liver ultrasonography) every 3-6 months
• Put patients with cirrhosis on liver transplantation lists when needed
• Identify hepatitis D virus (HDV) superinfection