It has been reported that hepatitis B virus (HBV) mutants carrying mutations in the pre-S region can be found in infected patients. In this study, we investigated the prevalence of the HBV variant with the pre-S mutant in different geographic regions, including countries with low and high levels of endemic HBV infection, and analyzed the correlation with clinical findings. We examined 387 HBV DNA-positive serum samples from individuals among 12 countries, consisting of Vietnam, Myanmar, Thailand, China, Korea, Nepal, Japan, Russia, Spain, United States, Bolivia, and Ghana. HBV pre-S mutants were detected in 71 (18.3%) of 387 serum samples tested. This mutant was the most prevalent in Vietnam (36%), followed by Nepal (27.3%), Myanmar (23.3%), China (22.4%), Korea (14.3%), Thailand (10.5%), Japan (7.7%), and Ghana (4.3%). In contrast, no case with this mutation was found in Russia, Spain, United States, and Bolivia. Among the HBV deletion mutations, 15.5% (11 of 71) occurred in the pre-S1 and 46.5% (33 of 71) in the pre-S2 regions. Eight (11.3%) cases had a mutation in both the pre-S1 and pre-S2 regions. In addition, a point mutation at the pre-S2 starting codon was observed in 19 (26.7%) cases. The detection rate of the HBV mutant in patients with hepatocellular carcinoma was significantly higher than in other patients (P < 0.05). Furthermore, these mutants were found more frequently in genotype B (25%) and genotype C (24.5%) than in the other genotypes (P < 0.05). Our results indicated that there was a high prevalence of HBV pre-S mutation in regions of endemic HBV infection in Asia. Furthermore, the pre-S mutation appeared to be correlated with hepatocellular carcinoma and HBV genotypes.Hepatitis B virus (HBV) is a small, enveloped 3.2-kb DNA virus with four open reading frames (ORFs). HBV envelope proteins are encoded by three overlapping envelope genes contained within a single ORF: pre-S1, pre-S2, and S. Depending on the translated initiation site among S, pre-S2, or pre-S1, three different-size proteins are produced: a small hepatitis B surface protein (small HBs), containing 226 amino acid residues; a middle hepatitis B surface protein (middle HBs), containing 55 additional amino acid residues; and a large hepatitis B surface protein (large HBs), containing 108 or 119 additional amino acid residues, depending on the serotype. The pre-S region has been proved to mediate hepatocyte attachment of the virus (amino acids 21 to 47 in pre-S1) (1,20,21,26), to contain B-cell and T-cell epitopes (5, 16, 17) and a binding site for neutralizing anti pre-S2 antibody (amino acids 120 to 145) (1,20,26); and an S promoter for controlling the production of middle HBs and small HBs. Naturally occurring HBV with the pre-S mutation has been reported in patients with chronic infections, fulminant hepatitis (32), post-lamivudine treatment (14), and post-liver transplantation (29). It is known that the rate of occurrence has varied in the literature (4, 7-9, 27, 31). However, the clinical significance of this mutation is still ...

We performed a retrospective study to determine the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis G virus (HGV) genomes in formalinfixed, paraffin-embedded liver tissues from hepatocellular carcinoma (HCC) patients in various geographic areas. Hepatocellular carcinoma (HCC) is increasing in incidence worldwide and is one of the most common malignant tumors in the world. It has been well documented that chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections play a major role in the development of this cancer. In Japan, the incidence of HCC has been increasing over the last 30 years. However, as the prevalence of the HBV infection has been decreasing, this trend for HCC increase might be attributable to chronic hepatitis and cirrhosis caused by HCV. In fact, HCC often occurs in patients with chronic HCV infection, and anti-HCV has been found frequently in affected patients. [1][2][3][4] Since the discovery of the HCV genome in 1989, 5 although knowledge about HCV has been growing rapidly, it still remains uncertain whether HCV plays a direct or indirect role in hepatocarcinogenesis. We have previously reported a highly sensitive method of detecting and identifying sequences of the RNA genome in formalin-fixed, paraffinembedded (FFPE) tissues by polymerase chain reaction (PCR) assay. 6 In the present study, using this method to assess the pathological role of persistent infection of hepatitis viruses, including HBV, HCV, and newly isolated hepatitis G virus (HGV), 7 in the origin of HCC, we performed a retrospective study to determine the prevalence of these hepatitis virus genomes in FFPE specimens from patients with HCC in various geographic areas. PATIENTS AND METHODSPatients. We selected sequential liver samples of all HCC tissues seen at the participating institutions. We analyzed routinely processed FFPE liver specimens of surgical origin from patients consisting of 122 Japanese (89 males and 33 females, ranging in age from 38 to 82 years, collected from 1984 to 1996), 55 Koreans (42 males and 13 females, ranging in age from 33 to 72 years, collected from 1989 to 1995), 65 Americans (40 males and 25 females, ranging in age from 39 to 80 years, collected from 1990 to 1995), 8 Japanese Americans in Hawaii (8 males, ranging in age from 57 to 77 years, collected in 1994), and 15 Spanish (9 males and 6 females, ranging in age from 61 to 72 years, collected in 1994) with HCC. All of them underwent liver surgery and were diagnosed with HCC by histopathological examination. We used paraffin blocks that have nontumor areas other than tumor in a part of cases, although it mainly consists of tumor areas. We also compared a frequency of HCC in patients with primary biliary cirrhosis who were excluded from analysis as hepatitis virus infections in the present study.Nucleic Acids Extraction and PCR. Extraction of the nucleic acids (RNA and DNA) from FFPE liver specimens and PCR was performed as described in detail previously. 6 Briefly, sections were cut and placed into l.5-m...

Summary Antiviral treatment can be complex in decompensated hepatitis B virus (HBV) cirrhosis because of potential emergence of lamivudine‐resistant mutants and worsening liver function, and to multifactorial nephrotoxicity. Negative HBV‐DNA status by hybridization before liver transplantation is a favorable prognostic factor. We present the case of a 54‐year‐old HBV+ liver transplantation candidate who, after testing negative for HBV‐DNA, developed YMDD lamivudine‐resistant mutants resulting in a deteriorated clinical condition. After 8 months of adefovir plus lamivudine double therapy, only partial response was achieved. Tenofovir was added to this regimen, and an early decline of HBV‐DNA was seen at 4 weeks without adverse events. The patient underwent transplantation. At 21‐month postoperative follow‐up, the patient's outcome was excellent. Post‐transplantation HBV prophylaxis, taking into account the prior development of mutants, consists of hepatitis B immunoglobulin plus lamivudine and adefovir. Tenofovir was well tolerated and produced a fast antiviral response, suggesting its potential value in combined antiviral treatment for liver transplantation candidates.

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