Gastroenterology Hepatology

Hepatitis B, delta

How can I be sure that the patient has hepatitis B virus infection?

HBV infection presents with nonspecific features. Infection with HBV has a wide spectrum of manifestations, including subclinical hepatitis, anicteric hepatitis, icteric hepatitis, and fulminant hepatitis during the acute phase and the asymptomatic carrier state. HBV infection includes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during the chronic phase.

Approximately 70% of patients with acute HBV infection have subclinical hepatitis or anicteric hepatitis, whereas 30% become icteric. Acute liver failure develops in approximately 0.1% to 0.5% of patients. The incubation period lasts 1 to 4 months. A serum sickness-like syndrome may develop during the prodromal period. This is followed by constitutional symptoms such as low-grade fever, malaise, anorexia, nausea and vomiting, and right upper quadrant (RUQ) or midepigastric pain. Jaundice usually appears as the constitutional symptoms begin to subside. Clinical symptoms and jaundice generally disappear after 1 to 3 months, but some patients may have prolonged fatigue, even after normalization of aminotransferase levels.

In chronic hepatitis B and hepatitis delta (HDV) coinfection, many patients are asymptomatic, whereas others may have nonspecific symptoms such as fatigue and mild RUQ discomfort. Some patients experience exacerbations that may be asymptomatic, mimic acute hepatitis, or manifest as liver failure. Physical examination may be normal or there may be stigmata of chronic liver disease. In patients with cirrhosis, additional findings such as jaundice, splenomegaly, ascites, peripheral edema, and encephalopathy may be present.

A tabular or chart listing of features and signs and symptoms

HBV or HDV infection does not have any pathognomonic or characteristic features.

Some less common clinical presentations

Extrahepatic manifestations occur in approximately 10% of patients with chronic HBV infection. Mediated by circulating immune complexes, acute hepatitis may be heralded by a serum sickness-like syndrome manifested as fever, skin rashes, arthralgia, and arthritis, which usually subside with the onset of jaundice.

Hepatitis B virus-related glomerulonephritis, most commonly membranous glomerulonephritis, is another manifestation.

Other extrahepatic manifestations include rarely essential mixed cryoglobulinemia and aplastic anemia.

Other diseases and conditions that might mimic the signs, symptoms, or clinical features of HBV infection

Other viral hepatitis (HCV), perform HCV antibodies, and HCV RNA.

How can I confirm the diagnosis?

What tests should be ordered first?

BsAg is the hallmark of HBV infection. It is usually detectable 1 to 10 weeks after an acute exposure to HBV, and approximately 2 to 6 weeks before the onset of clinical symptoms. Most patients who recover from acute hepatitis B clear HBsAg in 4 to 6 months. Persistence of HBsAg in serum for more than 6 months implies chronic infection. Anti-HBs can be detected in individuals who recovered from HBV infection and in those who successfully responded to hepatitis B vaccination.

The antigen HBeAg is a marker of HBV replication and infectivity. Its presence is usually associated with the detection of HBV DNA in serum and a high risk of transmission of infection. However, HBeAg-negative and anti-HBe-positive patients may continue to have active liver disease and moderate levels of HBV DNA in serum. These patients usually have HBV variants with diminished or abolished production of HBeAg.

In patients with acute hepatitis B, serum HBV DNA appears early and may precede the detection of HBsAg.

Chronic hepatitis B is categorized into four phases based on the virus activity (HBV DNA level as a surrogate marker) and the patient’s immune response to the virus activity (ALT and liver histology as surrogate markers). Patients may evolve through some or all phases with variable duration.

  • Inactive carrier: HBeAg (-), HBV DNA low, ALT normal

  • Immune tolerant: HBeAg (+), HBV DNA elevated, ALT normal

  • Immune active: HBeAg (+), HBV DNA elevated, ALT elevated

  • Immune reactivation: HBeAg (-), HBV DNA elevated, ALT elevated

In the immune tolerant phase, viral replication is high with little or no inflammatory response. HBeAg seroconversion (loss of HBeAg, development of anti-HBe) occurs infrequently at this stage. Patients transition to the immune active phase with increasing likelihood over time.

In the immune active phase, viral replication is high with inflammatory response and liver injury. HBeAg seroconversion (loss of HBeAg, development of anti-HBe) marks transition from this phase to the inactive phase in 8-15% of adults per year but rarely in children or immunocompromised patients.

In the inactive carrier phase, viral replication is low with little or no inflammatory response. Up to 20% of patients in this phase will reactivate due to loss of immunologic control by the host and/or use of immunosuppressive drug therapy.

In the immune reactivation phase, viral replication is high with inflammatory response and liver injury.

Resolution of chronic hepatitis B (clearance of HBsAg, development of HBsAb) occurs in 0.5% of inactive carriers per year.

The prevalence of coinfection with hepatitis delta virus (HDV) has dramatically decreased in the last 10 years. Coinfection with HDV is considered as a pejorative cofactor for the progression of the liver disease, the risk of development of cirrhosis, and HCC. However, the patterns of chronic HBV-HDV infection vary from mild to rapidly evolving chronic hepatitis.

Liver biopsy is useful in assessing the severity of liver disease, in predicting prognosis, and in discussing the indication for therapy in patients with chronic hepatitis B.

What other diseases, conditions, or complications should I look for in patients with hepatitis B virus infection?

Acute HBV infection can lead to fulminant hepatitis. Acute liver failure develops in approximately 0.1% to 0.5% of patients.

Prothrombin time, which reflects hepatic synthetic function, is the best indicator of prognosis.

Progression to cirrhosis occurs in up to 20% of patients with untreated chronic hepatitis B. Annual incidence of hepatic decompensation is 5-8% and hepatocellular carcinoma is 2-4% in patients with cirrhosis. Rates of cirrhosis and HCC increase substantially with HBV DNA level, alt levels, HBeAg positivity, and genotype C. Additional risk factors include advanced age, male gender, immunocompromised state, concomitant viral infection (HCV, HDV, HIV), alcohol use, and metabolic syndrome. Furthermore, risk of HCC is higher in patients from Sub-Saharan Africa, positive family history, and smoking.

What is the right therapy for the patient with hepatitis B virus infection?

Treatment with antiviral therapy is recommended in patients with chronic hepatitis B in the immune active phase with elevated HBV DNA levels (>2,000 IU/mL if HBeAg negative, > 20,000 IU/mL if HBeAg positive) and ALT greater than 2x the ULN. Patients with cirrhosis and HBV DNA >2,000 IU/mL should be treated regardless of ALT levels. If patients do not meet these cutoff criteria, antiviral therapy should still be considered if older age, positive family history, presence of extrahepatic manifestations, or prior treatment).

Treatment with antiviral therapy is generally not recommended for patients with immune tolerant chronic hepatitis B. However, patients should have labs checked every 6 months to look for evidence of activation. Additionally, in spite of normal ALT levels, patients should be treated with antiviral therapy if there is evidence of necroinflammation or fibrosis.

What treatment options are effective?

Several agents are currently approved for the treatment of chronic hepatitis B: interferon alpha (IFN), pegylated interferon (PEG-IFN) alfa 2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. Each agent has inherent limitations.

PEG-IFN is effective in a minority of patients and has frequent side effects. The efficacy of lamivudine is limited by the emergence of resistance. Adefovir is well tolerated but its antiviral effect is not optimal. Telbivudine is efficient; however, its long-term efficacy might be hampered by its resistance profile. Entecavir and tenofovir have potent antiviral effects, low risk of resistance, and are well tolerated. Analogues have the advantages of oral administration and good safety profiles; however, they need to be indefinitely administered in the majority of patients.

With the drugs currently available, the physician may consider two different concepts for the treatment of chronic hepatitis B: the first concept is that of sustained response obtained after a limited duration of therapy with pegylated interferon; the second concept is that of maintained response obtained during prolonged administration of therapy with analogues.

With the highly potent, low resistance drugs such as entecavir and tenofovir, the question of preventing resistance assumes far less importance. We currently recommend de novo monotherapy with an agent that has a high genetic barrier to resistance, such as entecavir or tenofovir or even telbivudine in patients with HBV DNA levels that are lower than 9 log10 copies/mL. There is no evidence so far regarding the benefit of combination therapy with two analogues. Studies are ongoing on the potential superior efficacy of the combination of potent analogues with pegylated interferon. Pegylated interferon is the only approved treatment for chronic hepatitis delta.

What is the most effective initial therapy?

N/A

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Goals of antiviral therapy are HBeAg seroconversion (if HBeAg positive at initiation of treatment), HBsAg loss, and suppression of HBV DNA. All patients with cirrhosis should continue treatment indefinitely. Patients without cirrhosis can consider discontinuation after 12 months of achieving above mentioned goal. However, the risk for seroconversion or recurrent viremia persists and patients need to be monitored every 3 months for at least one year after discontinuation of antiviral therapy.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

There are currently six medications approved for use in the United States. Choice of antiviral agent is driven by side effect profile, co-morbidities, prior therapy exposure, HBV genotype, costs, and pregnancy state.

Peg-IFN-2a: dose of 180 mcg weekly. Side effects include flu-like symptoms, mood disturbances, cytopenias, autoimmune disorders. Monitoring should include a CBC and TSH every 3 months, monitoring for infection, autoimmune disorders, neuropsychiatric complications, and infections. Pregnancy category C.

Entecavir: dose of 0.5 or 1.0 mg daily. Side effects include lactic acidosis. Pregnancy category C.

Tenofovir: dose of 300mg daily. Side effects include nephropathy, Fanconi-like syndrome, osteomalacia, lactic acidosis. Monitoring should include yearly creatinine clearance, serum phosphate, urine glucose and protein annually, as well as bone density scan if at risk. Pregnancy category B.

Lamivudine: dose of 100mg daily. Side effects include pancreatitis, lactic acidosis. Monitoring should include creatinine kinase and lactic acid if clinical concerns. Pregnancy category C.

Telbivudine: dose of 600mg daily. Side effects include creatine kinase elevations, myopathy, peripheral neuropathy, and lactic acidosis. Monitor creatinine kinase if symptoms. Pregnancy category B.

Adefovir: dose of 10mg daily. Side effects include acute renal failure, Fanconi syndrome, nephrogenic diabetes insipidus, lactic acidosis. Monitoring should include creatinine clearance, serum phosphate, urine glucose, urine protein annually, as well as bone density if at risk. Pregnancy category C.

Listing of these, including any guidelines for monitoring side effects.

N/A

How should I monitor the patient with hepatitis B virus infection?

Prevention through universal vaccination has effectively decreased the incidence of liver cancer, and new therapeutic agents may delay or avoid the establishment of cirrhosis. All patients with cirrhosis should be screened for HCC with ultrasound every 6-12 months. Additionally, some high risk populations with chronic hepatitis B should be screened even in the absence of cirrhosis. These populations include Asian men over 40 years old, Asian women over 50 years old, African men and women over 20 years old, persistent ALT elevation, HBV DNA level >2,000 IU/mL, and patients with a family history of HCC.

The only chance for long-term survival after HCC diagnosis is to achieve early detection through regular surveillance by ultrasound and AFP (alpha-fetoprotein) determination. This will allow the indication of effective therapy such as surgical resection, liver transplantation or percutaneous ablation.

What's the evidence?

Guidelines and reviews for the management of chronic hepatitis B

Terrault, NA, Bzowej, NH, Chang, KM. "AASLD guidelines for treatment of chronic hepatitis B". Hepatology. 2016.

Lok, ASF, McMahon, BJ, Brown, RS. " Antiviral therapy for Chronic hepatitis B viral infection in adults: a systematic review and metaanalysis". Hepatology. 2016.

Hoofnagle, JH, Doo, E, Liang, TJ, Fleischer, R, Lok, AS. "Management of hepatitis B: summary of a clinical research workshop". Hepatology. vol. 45. 2007. pp. 1056-75.

Marcellin, P, Asselah, T, Boyer, N. "Treatment of chronic hepatitis B". J Viral Hepat. vol. 12. 2005. pp. 333-45.

Clinical trials: treatment of chronic hepatitis B

Marcellin, P, Lau, GK, Bonino, F. "Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B". N Engl J Med. vol. 351. 2004. pp. 1206-17.

Lau, GK, Piratvisuth, T, Luo, KX. "Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B". N Engl J Med. vol. 352. 2005. pp. 2682-95.

Hadziyannis, SJ, Tassopoulos, NC, Heathcote, EJ. "Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B". N Engl J Med. vol. 348. 2003. pp. 800-7.

Marcellin, P, Chang, T, Lim, SG. "Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B". N Engl J Med. vol. 348. 2003. pp. 808-16.

Chang, TT, Gish, RG, de Man, R. "A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B". N Engl J Med. vol. 354. 2006. pp. 1001-10.

Lai, CL, Gane, E, Liaw, YF. "Telbivudine versus lamivudine in patients with chronic hepatitis B". N Engl J Med. vol. 357. 2007. pp. 2576-88.

Marcellin, P, Heathcote, EJ, Buti, M. "Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B". N Engl J Med. vol. 359. 2008. pp. 2442-55.

Chronic hepatitis delta infection

Rizzetto, M. "Hepatitis D: thirty years after". J Hepatol. vol. 50. 2009. pp. 1043-50.

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