How do you Manage the Adult with Perinatally Acquired Hepatitis B?

October 22, 2010

Nathaniel Rosso Smilowitz, MD

Faculty Peer Reviewed

Hepatitis B virus is a DNA hepadnavirus affecting 1.25 million people in the United States and nearly 400 million worldwide.  The virus is transmitted perinatally, sexually, and percutaneously, and is endemic in many countries in South East Asia, Central Asia, and Africa.  When exposure occurs early in life, the likelihood of chronic infection is high; up to 90% of cases of vertical transmission result in the persistence of the viral envelope protein, the hepatitis B surface antigen (HBsAg), in the serum, indicative of chronic infection.[1],[2] Over time, chronic hepatitis is associated with a risk of progression to cirrhosis, liver failure, and hepatocellular carcinoma that is proportional to levels of viral replication.[3] Screening for serum HBsAg should be performed in patients with abnormal liver transaminases and those with risk factors, including immigration from Asia or Africa, high-risk sexual intercourse, IV drug use, occupational exposure, and blood transfusions.

Once an asymptomatic patient has been identified as being chronically-infected with HBV, the physician should check liver transminase values every 3 to 6 months, which serve as a surrogate to the presence of ongoing liver damage.  Viral replication should be assessed every 6-12 months by performing a quantitative viral DNA PCR-based assay, and by screening for HBeAg, a soluble nucleocapsid protein, as well as for anti-HBe antibodies. The distinction between viral activity and liver damage is important for management.  When HBV is acquired perinatally, immunologic tolerance is manifest, characterized by an absent cellular immune response to viral proteins and by high viral replication without significant liver injury.  Later in life, an immune-reactive phase occurs whereby the host immune response recognizes the foreign viral proteins and attacks HBV-infected hepatocytes, resulting in elevated aminotransferases and histologic liver damage. Most patients are infected with wild-type HBV virus that expresses the HBeAg, and they typically experience high levels of viral replication. Some will undergo spontaneous or treatment-related seroconversion to HBeAg negative, at which point they are considered to have inactive disease.  This seroconversion is associated with a reduction in HBV replication and clinical improvement.[4] Thus, in asymptomatic patients newly diagnosed with HBV, treatment should be postponed for three to six months to determine whether spontaneous seroconversion will occur, except in rare instances of fulminant hepatic failure.  Other individuals are infected with HBV with a “pre-core” mutation that results in lack of, or severely reduced production of HBeAg.  These patients have a serologic pattern of HBeAg negativity and HBeAB positivity, but they are still in danger of progressive liver injury, despite lower levels of viral replication.  Furthermore, since patients with HBeAg-negative disease already have HBeAB positivity, they lack a clear treatment-induced endpoint of HBeAg seroconversion that can signify inactive disease.

The goal of treatment in chronic hepatitis B is to achieve a sustained reduction in levels of HBV replication that can limit liver disease and improve clinical outcomes.  However, indications for initiation of antiviral therapy are complex.  In the immune-tolerant stage of disease, treatment of patients with high HBV DNA levels (≥20,000 IU per mL) and normal serum ALTs, is unlikely to result in a meaningful biochemical or serologic response and is not recommended.  Instead, close monitoring of serial ALTs can identify progression to active liver disease at which time treatment may be considered.  For patients older than 40 years or with elevated ALTs less than twice the upper limit of normal, physicians may consider a liver biopsy to help dictate management, though this is controversial.  Prompt initiation of treatment is indicated for patients with more than 3-6 months of HBeAg-positive immune-reactive infection (HBV DNA levels ≥20,000 IU per mL and serum ALT more than twice the upper limit of normal).[5] These patients are most likely to achieve durable responses to therapy, and without antiviral treatment, progression to fibrosis occurs in 25% of patients within 1 year.[6] Similarly, patients with HBeAg-negative chronic hepatitis with ALT elevated above two times the upper limit of normal and HBV levels of ≥20,000 IU are eligible for initiation of treatment.  For HBeAg-negative chronic hepatitis B with lower ALTs (between one and two times the upper limit of normal) and HBV DNA ≥2,000 IU, antiviral treatment is not routinely recommended.  In this situation, liver biopsy can be considered to guide management.  Finally, patients with HBeAg-negative disease, DNA levels less than 2,000 IU, and ALTs less than twice the upper limit of normal do not require treatment.v

There are now seven antiviral drugs licensed for use in the United States, including interferon alfa, pegylated interferon alfa-2a, and the oral nucleoside and nucleotide analogs lamivudine, adefovir, entecavir, telbivudine, and tenofovir.vi Interferon therapy and the newer oral nucleotide analogs have comparable rates of HBsAg seroconversion at 1 year, although interferon therapy is associated with a substantial side effect profile.[7] Viral resistance to oral drug therapy also poses a continuing challenge to Hepatitis B treatment; currently entecavir and tenofovir are the preferred first line oral therapies, with less utility for lamivudine and telbivudine. Ultimately, the decision to start oral antivirals or a fixed 48-week schedule of injectable interferon therapy is dictated by patient and physician preference. Regardless of treatment modality, clinical endpoints of treatment are typically seroconversion to HBeAg-negative infection (or more rarely, HBsAg-negative disease), reductions in HBV DNA levels, normalization of serum ALT, and improvement in grade and stage of fibrosis on liver biopsy.v

In conclusion, the criteria for initiation of antiviral therapy in adults presenting with perinatally acquired Hepatitis B are complex, and begin with evaluation of viral replication and liver damage.  Patients ineligible for antiviral therapy need periodic evaluation (with liver function and viral replication studies) to identify the earliest possible opportunity for therapeutic intervention.

Dr. Smilowitz is a recent medical student graduate of NYU School of Medicine

Peer reviewed by Michael Poles, MD, GI Section Editor, Clinical Correlations

Image of Philippe Maupas (hepatitis B vaccine discoverer) courtesy of Wikimedia Commons.

References:

1. Cooke GS, Main J, Thursz MR. Treatment for hepatitis B.  BMJ. 2010 Jan 5;340:b5429.  http://www.bmj.com/content/340/bmj.b5429.extract

2. Gay NJ, Hesketh LM, Osborne KP, Farrington CP, Morgan-Capner P, Miller E. The prevalence of hepatitis B infection in adults in England and Wales.  Epidemiol Infect. 1999 Feb;122(1):133-8.  http://www.ncbi.nlm.nih.gov/pubmed/10098796

3. Iloeje UH, Yang HI, Jen CL, Su J, Wang LY, You SL, Chen CJ; Risk and predictors of mortality associated with chronic hepatitis B infection.  Clin Gastroenterol Hepatol. 2007 Aug;5(8):921-31.  http://www.ncbi.nlm.nih.gov/pubmed/17678844

4. Lok AS, Lai CL, Wu PC, Leung EK, Lam TS.  Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B virus infection.  Gastroenterology. 1987 Jun;92(6):1839-43.  http://www.ncbi.nlm.nih.gov/pubmed/3569757

5. Lok AS, McMahon BJ.  Chronic hepatitis B.  Hepatology. 2007 Feb;45(2):507-39

6. Dienstag JL.  Hepatitis B virus infection.  N Engl J Med. 2008 Oct 2;359(14):1486-500.  http://www.ncbi.nlm.nih.gov/pubmed/18832247

7. Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, Han KH, Chao YC, Lee SD, Harris M, Yang J, Colonno R, Brett-Smith H.  Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.  Gastroenterology. 2007 Nov;133(5):1437-44.  http://www.ncbi.nlm.nih.gov/pubmed/17983800

One Response to How do you Manage the Adult with Perinatally Acquired Hepatitis B?

  1. Charlesw Maltz, M. D. on October 24, 2010 at 6:09 pm

    Good summary of present treatment recommendations. I would also add the group with positive HBSAg who need immunosuppresive therapy such as for a bone marrow transplant, regardless of their viral load.

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