Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase

Previously, we have found that human liver annexin V (hA-V; in earlier reports referred as Endonexin II) is a specific hepatitis B surface antigen (HBsAg) binding protein. In this study, we demonstrate that transfection of rat hepatoma FTO 2B cells, a cell line that is not infectable by hepatitis B virus (HBV) and does not express hA-V, with a construct containing the hA-V gene, resulted in hA-V expressing cells susceptible to HBV infection. After in vitro infection, transfected FTO cells (assigned as FTO 9.1 cells) expressing hA-V in cultures were shown to contain HBV-precore/core, X mRNAs, and covalently closed circular (ccc) DNA as detected by polymerase chain reaction (PCR). The presence of HBV ccc and replicative intermediate DNA was also demonstrated by Southern blot hybridization assay. HBV DNA secreted in the culture medium was also evident as determined by quantitative branched DNA (bDNA) assay. HBsAg and hepatitis B core antigen (HBcAg) could also be detected by an immunocytochemical method in 10% to 15% of the cells at day 3 and day 5 after infection. Infectivity of in vitro-propagated HBV was demonstrated by infection of the naive FTO 9.1 cells with the culture supernatant from HBV-carrier cultures. In contrast to primary cultures of human hepatocytes and FTO 9.1 cells, primary rat and mouse hepatocytes, as well as rat hepatoma cell lines that do not express hA-V, are not susceptible to HBV infection. These findings suggest that hA-V plays a key role in the initial step of HBV infection and that the species-specific susceptibility to HBV infection and replication in hepatocytes is associated with the expression of hA-V.     

Estimation of the future numbers of patients with circulatory diseases in Japan based on the results of national patient surveys]

Virological response to treatment of chronic hepatitis B is defined as the loss of serum hepatitis B virus DNA (HBV DNA) and hepatitis B e antigen (HBeAg). The quantitative measurement of HBV DNA is useful for monitoring and predicting the response to therapy with interferon-alpha (IFN-alpha). In this study, we evaluated whether quantitative measurement of serum HBeAg and IgM antibody to hepatitis B core antigen (HBcAb) could also be used in this manner. Using a microparticle-capture enzyme immunoassay (IMx), a standard curve of fluorescence rate vs HBeAg concentration was constructed to provide quantitative results. The IgM HBcAb index was also measured using a microparticle enzyme immunoassay and serum HBV DNA was measured by a solution hybridization assay. We studied 48 patients who were initially positive for HBeAg and HBV DNA and who were treated with IFN-alpha2b. Their sera were serially evaluated for HBeAg concentration, and results were compared with HBV DNA levels. In the 14 patients who responded to IFN, similar disappearance curves were observed with good intraindividual correlation between the levels of the two markers. In the 34 non-responders, HBeAg levels decreased during treatment but never became negative; HBV DNA levels also decreased during treatment and became transiently undetectable in six patients, falsely suggesting treatment success. The IgM HBcAb index paralleled changes in alanine aminotransferase (ALT) concentration and did not provide additional information. Multiple logistic regression indicated that baseline ALT and HBeAg concentrations were independent predictors of the response to treatment and the addition of neither HBV DNA nor IgM HBcAb improved the model. We conclude that quantitative measurement of HBeAg provides information similar to that of HBV DNA in monitoring and predicting the response to treatment; this technique could be readily adaptable to clinical laboratories.     

Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications

OBJECTIVE: To compare two recently developed molecular techniques for quantitating the levels of hepatitis C virus (HCV) RNA in the serum of patients with a wide spectrum of chronic hepatitis C. DESIGN: Serum samples from 299 patients with HCV viremia, 101 control patients without HCV infection, and 19 consecutive patients receiving systemic interferon therapy were evaluated by a commercially available branched-chain DNA (bDNA) assay and a quantitative competitive polymerase chain reaction (PCR). SETTING: University-based hepatology clinics and reference virology laboratory. PATIENTS: Patients with HCV viremia as defined by results of qualitative RNA PCR, including 53 HCV-infected blood donors, 34 patients receiving renal dialysis, and 212 patients attending a hepatology clinic. RESULTS: Results of in vitro and in vivo experiments indicated that the sensitivity and dynamic range of the PCR assays were greater than those of the bDNA assay. Detection of HCV viremia by the bDNA assay was highly dependent on viral RNA titers, with a sensitivity of 5% at HCV RNA titers of 5.0 logs per mL or less and 94% at titers of 5.5 logs per mL or greater. The best correlation between assays was observed in specimens with HCV RNA titers between 6.0 and 7.5 logs per mL (r = 0.73). In patients with high-titer HCV viremia, including liver transplant recipients and patients with cirrhosis, quantitative PCR results were an average of 12-fold higher than bDNA assay results. Results of repetitive testing of discordant specimens showed that these discrepancies were caused by a high kit-to-kit coefficient of variation (112%) in the bDNA assay. Of 19 patients receiving interferon therapy, 9 (47%) became bDNA negative, but only 5 became quantitative PCR negative. The bDNA-negative, quantitative PCR-positive patients all had relapse when therapy was discontinued. CONCLUSIONS: The bDNA assay has a narrower linear range for quantitation of HCV viremia than quantitative PCR. Because persons with low HCV titers may respond well to therapy, seropositive persons with negative bDNA results should be retested with PCR-based assays. Similarly, the bDNA assay may underestimate the true degree of HCV viremia in persons with end-stage infection (> 10(7) RNA equivalents/mL of sera). Despite these limitations, the combination of bDNA- and PCR-based assays appears to be optimal for selecting and following patients during interferon therapy.     

Evaluation of enzyme immunoassay for hepatitis B virus DNA based on anti-double-stranded DNA

We have evaluated a new enzyme immunoassay technology to detect the products of PCR-based amplification that may be applicable to routine testing of hepatitis B virus (HBV) DNA. Two hundred eight serum samples were studied: 73 were basal samples and 135 were sequential serum samples from patients with chronic hepatitis, some of whom were being treated with alpha interferon. We compared the new detection method (PCR-DNA enzyme immunoassay [DEIA]) with dot blot hybridization performed without prior PCR amplification and with two other methods for detection of PCR products: agarose gel electrophoresis with ethidium bromide staining (PCR-EB) and dot blot (PCR-dot blot). For hepatitis B-antigen-positive basal samples, HBV DNA was detected in 70.4% by dot blot, 74.1% by PCR-EB, and 100% by PCR-DEIA and PCR-dot blot; for anti-hepatitis B e-antigen basal samples, HBV DNA was found in 10.5% by dot blot and PCR-EB and in 42.1% by PCR-DEIA and PCR-dot blot. Chi-square tests showed a strong association between dot blot and PCR-EB and between PCR-DEIA and PCR dot blot. Using PCR-dot blot as the reference, dot blot shows a 56.9% sensitivity and a 100% specificity, PCR-EB shows a 55.0% sensitivity and a 100% specificity, and PCR-DEIA shows a 95.4% sensitivity and a 97% specificity. We conclude that the technical advantages of the DEIA method and its high sensitivity and specificity may facilitate the use of PCR in routine testing for HBV DNA in clinical microbiology laboratories.     

A system for the quantitation of DNA using a microtiter plate-based hybridization and enzyme amplification technology

A quantitative hybridization technique for the detection of plasmid DNA by the action of a nuclease enzyme is described. The process utilizes the specific capture and detection of a sandwich hybridization, in a microtiter plate, that occurs in a single step. The detector probe is labeled with nuclease P1. The pH-dependent specificity of this enzyme for 3'-dinucleotides is used to generate a measurable signal by activating apo-glucose oxidase, which triggers an enzyme amplification cascade in the same microtiter plate. The sensitivity of the assay system is demonstrated in an assay of a mutated form of the human pancreatic ribonuclease gene inserted into the plasmid pUC 18. The system was able to detect 35 amol of target DNA in an assay composed of a 60-min hybridization and 20 min of signal generation. This use of nuclease P1 as the enzyme label and apo-glucose oxidase as the trigger for the amplification cascade results in an assay that is more sensitive than previously described enzyme amplification systems using colorimetric detection.     

A new class of defective hepatitis B virus genomes with an internal poly(dA) sequence

Sequence heterogeneity of hepatitis B virus (HBV) is increasingly recognized to play a role in virus-host interaction. We have used a recently established method for HBV full-length genome amplification to search for novel types of HBV variants and to investigate further the sequence heterogeneity of HBV genome populations. Using this method, a substantial fraction of HBV genomes much shorter than wildtype size was found in some sera and liver biopsies from infected patients. Cloning and sequencing of a number of these HBV genomes as well as hybridization studies revealed a new minor class of HBV genomes with an internal poly(dA) sequence approximately 60 to more than 100 nucleotides long in 4 of 10 patients. The 5'-ends of the internal poly(dA) sequences are located at positions corresponding to the authentic processing/polyadenylation sites of the RNA pregenome, whereas the positions of the 3'-ends are variable due to different sizes of adjacent deletions. These data suggest that the poly(A) tail of the pregenomic RNA is occasionally reverse transcribed by the HBV P-protein and during this process a deletion seems to be introduced into the DNA minus strand. We propose a mechanism by which this could be accomplished during DNA minus strand synthesis.     

Fluoroquinolone prophylaxis for the prevention of bacterial infections in patients with cancer--is it justified?

A method for signal enhancement in a colorimetric, nonradioactive and quantitative microplate hybridization assay is described. The signal enhancement provides for the direct detection of viral DNA in serum samples without the use of DNA amplification.     

The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis

Orthotopic liver transplantation (OLT) in patients infected with hepatitis B virus (HBV) is known to be associated with a high recurrence rate and poor prognosis. Interferon treatment in these patients offers little benefit and may lead to further complications. Lamivudine, the (-)enantiomer of 3'-thiacytidine, a 2'3'-dideoxynucleoside, is known to be a potent inhibitor of HBV replication in patients with chronic HBV infection. Three HBV-positive OLT patients were administrated lamivudine, 100 mg x 1 orally, for a period of at least 20 weeks, in an open, compassionate-use basis. All three patients were HBV DNA-negative before OLT. HBV reinfection occurred at a median time of 7 months (range, 6-9 months) after OLT, in spite of adequate immunoprophylaxis. All three patients had high serum transaminase levels (alanine aminotransferase [ALT], 103-324 U/L) and histologic evidence of recurrent HBV infection of the grafted liver, and HBV DNA was evident in the sera of all of them. Six weeks after lamivudine treatment, HBV DNA disappeared from the serum of all patients (detected by hybridization); by the 10th week, HBV DNA was also negative by polymerase chain reaction in two out of three patients. Interestingly, the one patient who was HBV DNA positive by polymerase chain reaction still has mildly elevated ALT levels, whereas the other two patients have normal ALT levels. We also noted that on the 5th week there was a transient elevation of serum ALT levels in two patients. No adverse effects or rejection episodes were noted. In conclusion, lamivudine is a beneficial and well-tolerated therapy in OLT patients with recurrent HBV infection. We are studying the effect of lamivudine in other patients and for a longer period of time.     

Evaluation and comparison of different hepatitis C virus genotyping and serotyping assays

BACKGROUND/AIMS: Evidence that the geno/subtype of hepatitis C virus (HCV) is predictive of the response to interferon-alpha therapy suggests that typing methods are clinically useful. In the present study, HCV isolates obtained from 74 patients with chronic hepatitis C were used to evaluate three genotyping and two serotyping assays. METHODS: The reverse hybridization assay and the DNA immunoassay are based on immobilized type-specific probes for the 5'-noncoding and the core region, respectively. A third genotyping assay utilized type-specific primers for amplification of the core region. Serotyping assays detect type-specific antibodies of the nonstructural-4 region (enzyme immunoassay) or of the core and nonstructural-4 region (recombinant immunoblot assay). Gold standard geno/subtyping of HCV isolates was performed by sequence and phylogenetic analysis of the nonstructural-5B region. RESULTS: All genotyping systems amplified the respective target region of the HCV genome with high sensitivity. The reverse hybridization assay and the DNA immunoassay correctly identified HCV-1, -2, and -3. The DNA immunoassay misinterpreted all HCV-4 isolates as HCV-4 and -5 coinfection. In the type-specific amplification assay, coinfections of subtypes HCV-1a and HCV-3a with HCV-1b could not be excluded. The reverse hybridization assay misinterpreted 1/14 HCV-1a isolates as HCV-1h, and vice versa 3/36 HCV-1b isolates as HCV-1a. Furthermore, differentiation between HCV-2a and -2c was not possible using this assay. The DNA immunoassay correctly identified all HCV subtypes. The serotyping assays, recombinant immunoblot assay and enzyme immunoassay identified HCV-1, -2, and -3 in 93% and 89% of cases, respectively. HCV-4, however, could only be recognized by the enzyme immunoassay. CONCLUSIONS: The reverse hybridization assay and the DNA immunoassay specifically identified HCV genotypes 1, 2, and 3, while crossreactivity occurred in the primer-specific amplification assay. The DNA immunoassay achieved the best performance in HCV subtyping. Both serotyping systems correctly identified HCV-1, -2, and -3 in about 90% of cases, but lack the possibility of subtyping.     

Photochemical inactivation of duck hepatitis B virus in human platelet concentrates: a model of surrogate human hepatitis B virus infectivity

BACKGROUND: Photochemical decontamination of platelet concentrates (PCs) has been demonstrated by the use of 8-methoxypsoralen and ultraviolet A light. Systems for studying the inactivation of blood-borne viruses facilitate the evaluation of photochemical decontamination protocols. STUDY DESIGN AND METHODS: Duck hepatitis B virus (HBV), a model for human HBV, was adapted for the study of hepadnavirus inactivation. A highly specific in vitro infectivity assay used primary duck hepatocyte cultures and was followed by the detection of replicated duck HBV sequences. RESULTS: Duck HBV-infected primary duck hepatocyte cultures produced authentic infectious virus. High-titer (> 10(9) virus genome equivalents/mL) duck HBV-infected sera were completely inactivated in serum or PCs by the use of 100 micrograms per mL of 8-methoxypsoralen and 70 J per cm2 of ultraviolet A light. Intracellular duck HBV (> 4.2 log10) in PCs was also inactivated. Culture results were confirmed by a sensitive duckling infectivity assay that indicated that 6.3 log10 of infectious duck HBV had been inactivated by photochemical decontamination. CONCLUSION: The sensitivity of the culture assay was comparable to that of the duckling assay using polymerase chain reaction gene amplification to detect duck HBV. Duck HBV inactivation in PCs was dependent on the dose of ultraviolet A light and independent of 8-methoxypsoralen concentrations of 100 to 300 micrograms per mL: 100 micrograms per mL 8-methoxypsoralen inactivated 4 to 5 log10 of virus in conjunction with 20 to 40 J per cm2 of ultraviolet A light. The polymerase chain reaction-enhanced duck HBV culture system has utility in optimizing photochemical decontamination protocols.     

Development of a biosensor for E. coli based on a flexural plate wave (FPW) transducer

To fulfill the need for rapid, cost-effective and sensitive methods for the detection of bacteria in medical diagnostics, food technology, biotechnology and environmental monitoring, a development of a bacterial sensor was initiated. Our approach of a biosensor for E. coli is based on an acousto-gravimetric flexural plate wave (FPW) transducer (gravimetric detection limit of less than 6 ng in a 32 microns thick sensitive layer in aqueous media), and an immunoaffinity layer on the transducer membrane for the molecular recognition of the target bacteria. An intermediate layer of covalently coupled poly (acrylic acid) yielded a major reduction of the non-specific binding to the metal surface. Such a biosensor, using antibodies against E. coli K12 and E. coli 15 outer surface antigens, yielded a detection range of 3.0 x 10(5) to 6.2 x 10(7) cells/ml for samples with the corresponding bacteria. To increase the sensitivity further, an amplification method using microspheres coupled with antibodies against E. coli was tested as a sandwich assay, and up to now a five-fold amplification of the signal has been achieved.     

The effect of i.v. enalaprilat in chronically treated hypertensive patients during cardiac surgery

In areas where hepatitis B virus (HBV) is prevalent, HBV carriers negative for hepatitis B surface antigen (HbsAg) by enzyme-linked immunosorbent assay (ELISA) have been reported. Moreover, even after screening donor blood for HbsAg and hepatitis B core antibody (HBcAb), post-transfusion hepatitis B continues to occur, though with a decreasing frequency. Therefore, screening tests far more sensitive for detecting HBsAg than those currently available are needed. We developed a highly sensitive method for HBsAg detection. It is based on the recognition of peroxidase activity through measuring the formation of stable nitroxide radical with electron spin resonance (ESR) spectroscopy in the presence of hydrogen peroxide, p-acetamidophenol (p-AP), and 4-hydrazonomethyl-1-hydroxy-2,2,5,5,-tetramethyl-3-imidazoline-3-o xide (HHTIO). A cut-off value was established by testing of 186 healthy adults and 50 HBsAg-positive individuals. The signal to noise (S/N) ratio of less than 1.488 obtained by ESR spectroscopy was considered to be negative and more than 2.181, positive. The p-AP/HHTIO method was found to be 10 times more sensitive than the standard ELISA and reproducibility was excellent. Additional investigations were made on the HBsAg levels in the serum from 26 healthy subjects, in whom cut-off index levels on ELISA were negative but relatively high (range: 0.6 to 1.0); and on 15 patients with non B non C hepatitis. Three of 26 cases and 3 of 15 with non B non C hepatitis were judged to be HBsAg positive. Of these, 5 were found to be positive for HBV DNA by polymerase chain reaction (PCR). It was shown in this study that the p-AP/HHTIO method is practical and useful in screening HBV carriers because of the sensitivity in HBsAg detection, which is comparable to PCR analysis.     

Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study

OBJECTIVE: To define chronic hepatitis C virus (HCV) infection among patients with persistently normal aminotransferase levels (PNAL). DESIGN: Retrospective chart review of all patients encountered during 1-yr with positive hepatitis C antibody (anti-C100-3 ELISA), no alternative cause for their liver disease and PNAL for 6 or more consecutive months prebiopsy. Blinded review of liver histology. SETTING: Outpatient hepatology clinics of two academic centers. PATIENTS: Fifty patients with PNAL among 303 with hepatitis C. MEASUREMENTS: Epidemiologic profiles, reasons for seroscreening and confirmatory analyses were tabulated. Histology was reviewed and grading of inflammatory activity and stage of fibrosis was determined by protocol. RESULTS: Among 50 patients with PNAL, 35 (70%) were female, 34 (68%) had parenterally acquired HCV, 44 (88%) abstained (> 2 yr) from ethanol, all were HIV-negative and none pharmacologically immunosuppressed. HCV infection was uniformly confirmed by RIBA II or HCV-RNA assay. The mean level of HCV-RNA by quantitative PCR was 3.79 x 10(5) copies/ml (range, 500 to 1.8 x 10(6) copies/ ml) and by B-DNA, 53 x 10(5) copies/ml (range, 3.5-230 x 10(5) copies/ml). Traditional histoevaluation yielded chronic hepatitis ("active", n = 15; "persistent", n = 25), cirrhosis (n = 7), and normal histology (n = 3). Blinded protocol review of histology (inflammatory grade/fibrotic stage) revealed 0/0 (n = 4), 1/0 (n = 6), 2/0 (n = 17), 2/1 (n = 3), 2/4 (n = 1), 3/0 (n = 2), 3/1 (n = 6), 3/2 (n = 2), and 3/3 (n = 9). CONCLUSIONS: In chronic HCV infection, active inflammation, fibrosis, and variable circulating HCV-RNA levels may coexist with PNAL, particularly among female nondrinkers. Asymptomatic carriers with normal histology comprise 6 to 8% of chronic hepatitis C with PNAL. Management guidelines for this group of patients need to be developed.     

A PET study on cortical and subcortical control of pelvic floor musculature in women

The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an "inapparent" coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an "inapparent" coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6-12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5'NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all "responders" (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.     

Post-hemorrhagic shock mesenteric lymph is cytotoxic to endothelial cells and activates neutrophils

The aim of this study was to evaluate the Chiron branched DNA (bDNA) assay for detection of serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis B lacking hepatitis B e antigen (HBeAg) and undergoing interferon (IFN) therapy. Results obtained with the bDNA assay were compared with those obtained using the Abbott liquid hybridization (LH) assay and the polymerase chain reaction (PCR). Serial samples (274) from 34 patients were analysed. Analysis of variance results indicated that bDNA values were more significantly correlated than LH values with both PCR positive/negative results (probability of artifact (Prob > F) = 0.7 and 0.09 for LH and bDNA assays, respectively) and presence/absence of precore mutations (Prob > F = 0.21 and 0.001 for LH and bDNA assays, respectively). Both bDNA and LH results correlated highly with alanine aminotransferase (ALT) values (both had Prob > F values of 0.0) while PCR was not correlated with ALT (Prob > F = 0.05). In 26 evaluable patients, a model based on a generalized Knodell score was used to predict response to IFN therapy, as defined by normalization of ALT values during therapy. This model discriminated well between non-responders and responders. The bDNA results correlated well with the generalized Knodell score, while the LH results did not (Prob > F = 0.04 and 0.19 for the bDNA and LH assays, respectively). In conclusion, the bDNA assay appears to be useful for quantification of HBV DNA levels in HBeAg-negative chronic hepatitis as it correlates with biochemical and histological indications of disease severity as well as with response to IFN therapy.     

Enterohemorrhagic Escherichia coli O157 infection in an elderly patient with secondary hemolytic uremic syndrome who developed recurrent acute exacerbation of chronic cholecystitis]

The risk of hepatocellular carcinoma (HCC) varies significantly among hepatitis B virus (HBV) carriers from different geographic regions. We compared serological markers of HBV infection in adult male carriers from Haimen City, China and Senegal, West Africa, where the prevalence of chronic infection is similar. HCC mortality among HBV carriers is much higher in Haimen City than it is in Senegal (age-standardized rate, 878 versus 68 per l0(5) person-years). A dramatic difference was observed when HBV DNA levels in serum were assessed among carriers by Southern blot. In the Senegalese group (n = 289), 14.5% were HBV DNA positive by Southern blot in their 20s, and this percentage declined in each subsequent decade of age to 3.3, 2.9, and 0% thereafter. In the Chinese group (n = 285), a higher prevalence of HBV DNA positivity and a less consistent reduction were seen; 29.4% were positive in their 20s, and 30.2, 23.6, and 20.6%, respectively, were positive in each subsequent decade of age. Among 102 male Asian-American HBV carriers, the prevalence of HBV DNA positivity was intermediate between the Chinese and Senegalese populations (36.8, 10.7, 3.0, and 4.6% in each subsequent decade of age). Viral titers were similar among those who were HBV DNA positive in all three populations [median value, 10(7) virions/ml (range, 10(6)-10(9) virions/ml)]. The presence of HBV DNA in serum was positively associated with serum glutathione S-transferase, a marker of liver damage. These findings suggest that the more prolonged maintenance of productive virus infection in the Chinese carriers compared with the Senegalese carriers may explain their higher risk of HCC. This profound difference in the natural history of chronic infection may be due to earlier age of infection in China or to as yet unknown environmental or genetic factors.