The geographic distribution of hepatitis B virus (HBV) genotypes in Japan and its clinical relevance are poorly understood. We studied 731 Japanese patients with chronic HBV infection. HBV genotype was determined by the restriction fragment length polymorphism (RFLP) method after polymerase chain reaction (PCR). Of the 720 patients with positive PCR, 12 (1.7%) were HBV genotype A, 88 (12.2%) were genotype B, 610 (84.7%) were genotype C, 3 (0.4%) were genotype D, and 7 (1.0%) were of mixed genotype. Over 94% of patients on the Japanese mainland had genotype C, while 60% of the patients on Okinawa, the most southern islands, and 22.9% in the Tohoku area, the northern part of the mainland, harbored genotype B. Compared with genotype C patients, genotype B patients were older (53.6 to 42.2 years; P < .01), had a lower rate of positive hepatitis B e antigen (HBeAg) (18.4% to 50.6%; P < .01), and a lower level of serum HBV DNA (5.02 to 5.87 log genome equivalents (LGE)/mL; P < .01). The mean age of the genotype B patients with hepatocellular carcinoma was 70.1 ؎ 9.2 years, compared with 55.2 ؎ 9.7 of genotype C patients (P < .01). These results indicate that genotypes C and B are predominant in Japan, and there are significant differences in geographic distribution and clinical characteristics among the patients with the different genotypes. (HEPATOLOGY 2001;34:590-594.)Hepatitis B virus (HBV), a member of hepadnaviridae, is a circular double-stranded DNA virus, and is one of the major causative agents of chronic liver diseases, especially in Asian and African countries. HBV had formerly been classified into 4 major subtypes, which were defined serologically. 1 However, the classification of HBV by serologic subtype is not rational because of a change of subtype resulting from one point mutation at the S gene. 2 Thus, according to the molecular evolutionary analysis of the genomic DNA sequence, HBV strains isolated in various countries are classified into 7 genotypes: genotypes A to G. 3

Clinical and molecular virological differences were evaluated in 50 Japanese patients chronically infected with HBV of genotype B and C who were matched for age and sex as well as the severity of liver disease in a case-control study. Hepatitis B e antigen (HBeAg) was significantly less frequent (16% vs. 42%, P < .01), whereas antibody to HBeAg (anti-HBe) was significantly more common (84% vs. 56%, P < .01) in genotype B than C patients. The predominance of mutants with G-to-A mutation at nucleotide (nt) 1896 in the precore region (A1896) over the wild-type was comparable between genotype B and C patients (60% and 62%, respectively), and it correlated with anti-HBe. The double mutation in the basic core promoter (A-to-T at nt 1762 and G-to-A at nt 1764), however, was significantly more frequent in genotype C than B patients (58% vs. 16%, P < .01), and it did not correlate with anti-HBe or HBeAg. By the multiple logistic regression analysis, the double mutation in the basic core promoter (T1762/A1764) was significantly associated with genotype C [odds ratio (OR), 9.3; 95% confidence interval (

A retrospective survey of Japanese patients histologically diagnosed with chronic hepatitis B was conducted to determine the effectiveness of lamivudine in preventing hepatocellular carcinoma (HCC). Of the 2,795 patients who satisfied criteria for analysis after treatment from any of 30 medical institutions, 657 had received lamivudine and the remaining 2,138 had not. A Cox regression model with liver biopsy as the starting point revealed seven factors related to HCC: lamivudine therapy, gender, family clustering of hepatitis B, age at liver biopsy, hepatic fibrosis stage, serum albumin level, and platelet count. In a matched case-controlled study, 377 patients in a lamivudine-treated group and 377 matched patients in a non-treated group were selected based on their propensity scores. The mean follow-up period was 2.7 years in the lamivudine group and 5.3 years in the control group. In the lamivudine group, HCC occurred in 4 patients (1.1%) with an annual incidence rate of 0.4%/patient/year, whereas in the control group HCC occurred in 50 patients (13.3%) for a rate of 2.5%/patient/year. A comparison of the cumulative HCC incidence between the two groups by the Kaplan-Meier method showed a significantly lower incidence of HCC in the lamivudine group (p<0.001). These findings suggest that lamivudine effectively reduces the incidence of HCC in patients with chronic hepatitis B.

To define the duration of viremia in the course of acute hepatitis B, we semiquantitatively determined the levels of hepatitis B virus (HBV) DNA in the sera, using polymerase chain reaction (PCR) coupled with Southern blotting, of non-immunocompromised patients with self-limited acute hepatitis B. In the sera of 10 of 11 patients, HBV DNA, which was presumably coated with viral proteins, was detected for a long period after recovery, even at the final observation times, which ranged from 6 to 19 months after disease onset. To characterize the mode of HBV that was present in serum, we immunoprecipitated immune complexes in sera by the addition of anti-human immunoglobulin G (IgG) and determined the levels of HBV DNA separately in the supernatants and pellets. In the acute phase of hepatitis B, high levels of HBV DNA were detected both in the supernatants and pellets at comparative levels. After the convalescent phase, the amount of HBV DNA in the supernatant decreased with respect to that in the pellets. It is notable that, in most cases, serum HBV persisted as a form of immune complex even after the seroconversion to antibody to hepatitis B surface antigen (anti-HBs). These data suggest that the replication of HBV may persist in some organs, most likely in the liver or peripheral blood cells, for a long period after recovery from acute hepatitis B, and the data indicate the possible transmission of HBV from organ transplantation donors who exhibit serological markers of past infection only. (HEPATOLOGY 1998;27:1377-1382.)The duration of viremia in acute hepatitis B has been considered to cease with the clearance of the hepatitis B surface antigen (HBsAg) from serum. 1,2 However, in view of the fact that viremia in chronic hepatitis B persists after the disappearance from serum of HBsAg and the appearance of an antibody to HBsAg (anti-HBs), both of which occur in the natural course of the disease and during interferon therapy, [3][4][5][6][7][8][9] the duration of viremia in acute hepatitis B must be determined using sensitive methods to prevent the transmission of hepatitis B upon transfusion of HBsAg-negative blood [10][11][12] from patients who are recovering from acute hepatitis. Indeed, a recent study using polymerase chain reaction (PCR) has shown that hepatitis B virus (HBV) persists even in serological recovery from acute hepatitis B. 13 It is also important to determine whether HBV exists in a free or immunoglobulin (Ig)-bound form if HBV persists in serum. The extent of viremia and the modality of the virus during and after the course of acute hepatitis B, however, have not been well described. In the present study, we semiquantitatively measured the level of HBV DNA in the sera of patients in Japan, where acute hepatitis B rarely evolves into chronic infection. 14,15 PATIENTS AND METHODSPatients. We studied 11 consecutive Japanese patients (male: female ϭ 10:1) with self-limited acute hepatitis B who were admitted to our hospitals from 1991 to 1995 (Table 1). All 11 patients exhibited single-peaked ele...

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