Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine†

Abstract

Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n ‫؍‬ 7) and LAM (n ‫؍‬ 36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n ‫؍‬ 6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n ‫؍‬ 12, 0.456 log copies/ml, P ‫؍‬ 0.0125) or in whom the YMDD mutant never emerged (n ‫؍‬ 18, 0.688 log copies/ml, P ‫؍‬ 0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy. (HEPATOLOGY 2007;45:1179-1186 T he hepatitis B virus (HBV) is a member of the hepadnaviridae family. Worldwide, approximately 350 million people are estimated to be chronically infected with HBV. 1 Patients with chronic HBV infection develop chronic hepatitis, cirrhosis, and hepatocellular carcinoma, accounting for approximately 1 million deaths per year. 2 Recently, inhibitors of reverse transcriptase have been developed and widely used for patients with chronic HBV infection. Lamivudine (LAM), a cytosine nucleoside analogue, was first developed as an antiviral agent against HIV and later was used effectively against HBV because HBV also uses reverse transcriptase for replication. 3,4 Because LAM suppresses HBV replication, patients who are treated with LAM show a decreased level or disappearance of HBV DNA in serum and hepatitis B e antigen, normalization of serum alanine aminotransferase (ALT) level, and histological improvement. [5][6][7][8][9][10][11][12] However, discontinuation of therapy often leads to reactivation of HBV. 6,8,13,14 Therefore, long-term therapy is necessary for many patients with chronic HBV infection. During long-term LAM therapy, drug-resistant mutants with amino acid substitutions in the tyrosine-methionine-aspartate-aspartate (YMDD) motif emerge, resulting in expression of HBV DNA increasing again and in worsening of hepatitis. 6,10,[15][16][17][18] Moreover, some patients develop a severe flare-up of hepatitis that could lead to fatal hepatic failure. Therefore, prediction of the emergence of YMDD mutants is an important issue.In our hunt for useful serum markers to detect the early emergence of YMDD mutants, we noticed some patients who showed a discrepancy in the expression of HBV DNA measured by the transcription-mediated amplifica-

Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment?

“…The results enabled us to evaluate the clinical significance of HBV RNA levels with confidence. Previous studies reported that serum HBV RNA is transcribed from intrahepatic HBV cccDNA and thus that it may be a potential alternative marker for intrahepatic cccDNA levels (8,11,15). Here, we confirmed that serum HBV RNA is a valid marker but that it is nevertheless inferior to serum HBV DNA with respect to reflecting the level of intrahepatic cccDNA before treatment.…”

The Significance of Enzyme Immunoassay for the Assessment of Hepatitis B Virus Core-Related Antigen following Liver Transplantation

“…(Fig. 3A, case 2) (23), HBV-RNA (22,24) and serum HBsAg quantitative (25) are HBV replication markers. In addition to the HBcrAg assay, we should evaluate these markers to fully understand HBV dynamics after LT. (26,27 …”

Characterization of Serum HBV RNA in Patients with Untreated HBeAg-Positive and -Negative Chronic Hepatitis B Infection

“…The serum HBV RNA are reported detectable in patients with chronic HBV infection (3,6,7) and its clinical significance are also suggested (8)(9)(10). It showed that serum HBV RNA dynamics had a strong correlation with HBeAg loss in patients treated with nucleoside-analogue or pegin-terferon (PegIFN)-α (9).…”

“…It showed that serum HBV RNA dynamics had a strong correlation with HBeAg loss in patients treated with nucleoside-analogue or pegin-terferon (PegIFN)-α (9). It also showed that serum HBV RNA level is a valuable early predictor for the occurrence of antiviral resistant mutations (10) and reactivation of chronic hepatitis B (CHB) after antiviral therapy cessation (8). Serum HBV RNA is a novel biomarker of HBV infection and is useful to optimize antiviral strategies (9,11).…”