International standardization and coordination of the nomenclature of variants of hepatitis C virus (HCV) is increasingly needed as more is discovered about the scale of HCV-related liver disease and important biological and antigenic differences that exist between variants. A group of scientists expert in the field of HCV genetic variability, and those involved in development of HCV sequence databases, the Hepatitis Virus Database (Japan), euHCVdb (France), and Los Alamos (United States), met to re-examine the status of HCV genotype nomenclature, resolve conflicting genotype or subtype names among described variants of HCV, and draw up revised criteria for the assignment of new genotypes as they are discovered in the future. A comprehensive listing of all currently classified variants of HCV incorporates a number of agreed genotype and subtype name reassignments to create consistency in nomenclature. The paper also contains consensus proposals for the classification of new variants into genotypes and subtypes, which recognizes and incorporates new knowledge of HCV genetic diversity and epidemiology. A proposal was made that HCV variants be classified into 6 genotypes (representing the 6 genetic groups defined by phylogenetic analysis). Subtype name assignment will be either confirmed or provisional, depending on the availability of complete or partial nucleotide sequence data, or remain unassigned where fewer than 3 examples of a new subtype have been described. In conclusion, these proposals provide the framework by which the HCV databases store and provide access to data on HCV, which will internationally coordinate the assignment of new genotypes and subtypes in the future. (HEPATOLOGY 2005;42:962-973.)

Factors associated with hepatitis B virus (HBV) DNA breakthrough and the significance of YMDD variants without the presence of wild-type YMDD during prolonged lamivudine treatment are unknown. We studied the amino acid sequence of codon 552 (YMDD motif) and codon 528 by means of a line probe assay in 159 chronic HBV patients (median follow-up 29.6 months). Pretreatment HBV DNA levels and alanine transaminase (ALT) levels correlated inversely with the time to HBV DNA breakthrough with YMDD variants (r ‫؍‬ ؊0.46, P ‫؍‬ .001; r ‫؍‬ ؊0.45, P ‫؍‬ .001 respectively). Patients harboring YMDD variants 3 months before HBV DNA breakthroughs had higher HBV DNA breakthrough levels compared with those without YMDD variants 3 months before HBV DNA breakthroughs (18.9 ؋ 10 6 vs. 5.4 ؋ 10 6 copies/mL, P ‫؍‬ .007). Patients with HBV DNA breakthroughs had higher percentages of YMDD variants without the presence of wild-type YMDD compared with patients without HBV DNA breakthrough (25.6% vs. 9%, P ‫؍‬ .007 for single M552I variant; 20.9% vs. 8.1%, P ‫؍‬ .026 for single M552V variant; 30.2% vs. 9.9%, P ‫؍‬ .004 for M552I/M552V variants). Patients with HBV DNA levels of more than 10 3 copies/mL after 6 months of lamivudine therapy had a 63.2% chance of subsequently developing YMDD variants. HBeAg seroconversion occurred in 2 patients after the emergence of YMDD variants. Only one patient developed YMDD variant after HBeAg seroconversion. There was no increase in the rate of development of YMDD variants or L528M mutation in patients receiving lamivudine 25 mg daily or famciclovir 500 mg 3 times a day before being given lamivudine 100 mg daily. (HEPATOLOGY 2001;34:785-791.)Hepatitis B virus (HBV) infection is a major international health problem leading to around 1.2 million deaths per year world-wide. 1 Because of its profound suppression of HBV replication resulting in significant histologic improvement, lamivudine is commonly used as a treatment of chronic HBV infection. [2][3][4] However, in 14% to 32% of patients, a 1-year treatment regimen of lamivudine 100 mg daily is associated with mutation of the tyrosine, methionine, aspartate, aspartate (YMDD) motif in the C domain of the HBV DNA polymerase gene, corresponding to the amino acid codon 552 of the HBV. 2,3 The number of patients with YMDD mutation is higher with prolonged use of lamivudine. 5 For the YMDD variants, the methionine is substituted with either isoleucine (I), designated M552I or valine (V), giving rise to M552V. There may be another concomitant mutation occurring at the B domain of the HBV polymerase gene with the leucine (L) at amino acid codon 528 substituted by methionine (L528M). This mutation has been described for patients on famciclovir. 6,7 With lamivudine treatment, L528M is usually associated with M552V though M552I/L528M has also been reported. 8 Both in vitro and in vivo studies show that YMDD variants are less replication-competent compared with the wild-type, are associated with lower HBV DNA levels compared with pretreatment HBV DNA levels, and can...

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Tumor necrosis factor (TNF), but not lymphotoxin (LT), is directly trypanolytic for salivarian trypanosomes. This activity was not blocked by soluble 55-kilodalton and 75-kilodalton TNF receptors, but was potently inhibited by N,N'-diacetylchitobiose, an oligosaccharide that binds TNF. Comparative sequence analysis of TNF and LT localized the trypanocidal region, and synthetic peptides were trypanolytic. TNF molecules in which the trypanocidal region was mutated or deleted retained tumoricidal activity. Thus, trypanosome-TNF interactions occur via a TNF domain, probably with lectin-like affinity, which is functionally and spatially distinct from the mammalian TNF receptor binding sites.

Few studies have examined Chinese patients with chronic hepatitis B who exhibit hepatitis B surface antigen (HBsAg) seroclearance. We comprehensively studied the biochemical, virological, histological, and clinical aspects of 92 patients with HBsAg seroclearance (median follow-up, 126 months). Ninety-two HBsAg-positive controls matched for age, sex, and duration of follow-up were also recruited. Liver biochemistry, serum hepatitis B virus (HBV) DNA levels, and development of clinical complications were monitored. Intrahepatic total and covalently closed circular (ccc) HBV DNA were measured quantitatively in 16 patients. HBV genotype was determined in 30 patients. The mean age at HBsAg seroclearance was 48.8 (؉ 13.81) years. There was a significant improvement in serum alanine aminotransferase levels after HBsAg seroclearance (p<0.0001). Patients with genotype B had a higher chance of HBsAg seroclearance than those with genotype C (P ‫؍‬ .014). Ninety-eight percent of patients had undetectable serum HBV DNA. Thirty-seven percent of patients had low titer of intrahepatic HBV DNA, mainly in the form of cccDNA (71%-100%). All 14 patients with liver biopsies had near normal histology. There was no difference in the risk of development of hepatocellular carcinoma (HCC) between patients with and without HBsAg seroclearance. However, the mean age of HBsAg seroclearance was significantly older in patients with HCC than in patients without HCC (P ‫؍‬ .016). In conclusion, patients with HBsAg seroclearance had favorable biochemical, virological, and histological parameters. Intrahepatic HBV DNA level was low and predominantly in the form of cccDNA. However, HCC could still develop, particularly in patients with cirrhosis who had HBsAg seroclearance at an older age. (HEPATOLOGY 2004;39:1694 -1701.) H epatitis B surface antigen (HBsAg) seroclearance is a rare event in Chinese patients with chronic hepatitis B virus (HBV) infection who acquire the disease early in life. The estimated annual incidence of HBsAg seroclearance is 0.1% to 0.8%. 1,2 Undetectable HBsAg in the serum is usually due to a decrease in viremia rather than the emergence of HBsAg mutants. 3 Some studies demonstrate a favorable outcome in terms of histological features and development of hepatocellular carcinoma (HCC). 2,4 However, these findings are not confirmed by other studies. 5,6 The presence of HBV DNA within the liver in patients with HBsAg seroclearance has been demonstrated in some studies, 7-9 but it is not known whether the intrahepatic HBV DNA is replicative or nonreplicative-that is, in the form of covalently closed circular (ccc) DNA. Also, it is uncertain how much residual virus is in extrahepatic reservoirs like peripheral blood mononuclear cells (PBMC).Therefore, we sought to determine the factors associated with and the significance of HBsAg seroclearance in Chinese HBV patients by examining the following parameters: (1) liver biochemistry, (2) HBV DNA in the serum and PBMC, (3) HBV genotypes, (4) intrahepatic total and cccDNA, (5) liver h...