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Hepatitis B Virus Drug Resistance, Genotype, and BCP/Precore Mutations

Hepatitis B Virus Drug Resistance, Genotype, and BCP/Precore Mutations

Test Summary

Hepatitis B Virus Drug Resistance, Genotype, and BCP/Precore Mutations

  

Clinical Use

  • Confirm resistance-associated mutation(s) as a potential cause of virologic breakthrough

  • Assist with selection of patient-specific therapy after virologic breakthrough

  • Assess prognosis

Clinical Background

Treatment of chronic hepatitis B (CHB) is geared to achieving sustained suppression of hepatitis B virus (HBV) replication and remission of liver disease, with the aim of preventing liver failure, cirrhosis, and hepatocellular carcinoma.1 Several drugs have been approved for treatment, including interferon-alfa, peginterferon alfa-2, and the nucleotide/nucleoside analogs (NAs) lamivudine (3TC), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir (TDF).1,2 Mutations in the HBV genome, and the HBV genotype itself, may affect treatment response and disease course.

Treatment with NAs can lead to prolonged viral suppression (loss of HBV DNA, antigen seroconversion, and, rarely, HBsAg loss and HBsAb appearance) in patients with HBV infection. However, prolonged therapy may select for mutations in the HBV DNA polymerase gene (including M204V in the YMDD motif), leading to drug resistance (Table). The rate of acquired resistance varies with the NA used and baseline viral load, among other factors. During treatment with NAs, viral load should be assessed every 12 to 24 weeks with a quantitative HBV DNA assay.1 In patients with confirmed treatment adherence who exhibit virologic breakthrough or rebound, genotypic resistance testing can be used to confirm the presence of mutations1 and therefore guide selection of subsequent therapy.

In addition to detecting resistance-associated mutations, this assay also assesses HBV genotype (A–H) and mutations in the precore (pre-C) and basal core promoter (BCP) regions. HBV genotypes A–H are classified according to sequence variations in the HBV “S” gene and have distinct geographic distributions. Genotype analysis may have prognostic value. Genotype C has been associated with more severe liver disease than genotype B,3,4 although contradictory findings have been reported. Genotype has also been associated with response to interferon-based therapy.5-7

Mutation at nucleotide 1896 of the pre-C region (TAG mutation) abolishes production of the HBeAg, leading to HBeAg-negative CHB, while mutations at nucleotides 1762 and 1764 of the BCP region may play a role in HBeAg clearance. The pre-C and BCP mutations also appear to influence response to interferon treatment.8 Testing for these mutations may therefore have prognostic value.

Individuals Suitable for Testing

  • Patients with diagnosed CHB

Method

  • Amplification of relevant portions of the HBV genome by polymerase chain reaction with HBV-specific primers

  • Analysis of sequence data for mutations at codons 80, 169, 173, 180, 181, 184, 194, 202, 204, 207, 236, and 250 in the reverse transcriptase region of the polymerase gene; nucleotide 1896 of the
    pre-C region; and nucleotides 1762 and 1764 of the BCP region

  • HBV genotype determination via computer-aided alignment and phylogenetic analysis of the amplified portion of the S gene

  • Analytical sensitivity: 1,000 HBV copies/mL (500 IU/mL) plasma; 500 HBV copies/mL (300 IU/mL) serum

  • Analytical specificity: no known cross-reaction with other blood-borne pathogens

Interpretive Information

Mutations associated with resistance to available NAs are listed in the Table. The presence of such mutations in patients with virologic breakthrough or rebound suggests the need to add or replace a drug in the regimen. Practice guidelines from the American Association for the Study of Liver Diseases provide detailed information on treatment options for patients with confirmed resistance to an NA.1

Table. HBV DNA Polymerase Gene Mutations Associated with Resistance to
Nucleos(t)ide Analogs

  Lamivudine (3TC) Adefovir (ADV) Entecavir (ETV) Telbivudine (LdT)
Mutation(s)

L180M+M204V/I;

A181T

N236T; A181V

M250V; T184G;

S202Ia

M204I; L180M+M204V

a Associated with reduced susceptibility to ETV when combined with lamivudine-associated mutations.

At present, the effects of HBV genotype (A–H) on disease course and treatment response are not understood well enough to influence treatment decisions.

Detection of BCP mutations at nucleotides 1762 and 1764 is associated with low levels of HBeAg and may predict a more favorable response to interferon treatment. The G1896A pre-C variant, which abrogates HBeAg formation, is associated with lower rates of interferon response. Patients with mutations in either region can return to high levels of HBV viremia after loss of HBeAg.8

References

  1. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.

  2. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662.

  3. Kao JH, Chen PJ, Lai MY, et al. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol. 2002;40:1207-1209.

  4. Lindh M, Hannoun C, Dhillon AP, et al. Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis. 1999;179:775-782.

  5. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alfa-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56:699-705.

  6. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-129.

  7. Kao JH, Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J Hepatol. 2000;33:998-1002.

  8. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.

This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Content reviewed 12/2012
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