I nfection with hepatitis B virus (HBV) causes acute and chronic hepatitis and is strongly associated with the development of cirrhosis and hepatocellular carcinoma. Immediately after infection of hepatocytes, the viral DNA is transferred to the nucleus, where the viral polymerase is removed, and the double-stranded, open circular DNA is converted to a covalently closed circular DNA molecule (cccDNA). During chronic HBV infection (CH-B), cccDNA accumulates in hepatocyte nuclei, apparently at a level of about 5-50 copies per cell, where it persists as a minichromosome and functions as the template for the transcription of viral genes. 1 The RNA pregenome, in addition to producing capsid and polymerase proteins, becomes encapsidated and is reverse-transcribed. A particularity of the hepadnavirus life cycle is that DNA-containing nucleocapsids can either recycle back to the nucleus to amplify and maintain the pool of cccDNA or become enveloped and secreted into the blood, where new viral particles can spread to other hepatocytes. 2,3 Because cccDNA is the transcriptional template of the virus, it is required for maintenance of HBV infection.Evidence from the woodchuck hepatitis virus system indicated that the pool of cccDNA persisted even when viral production was strongly reduced by the presence of nucleoside analogues. 4,5 Woodchuck studies 6,7 and recent

Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine-resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxil fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg؉), viral breakthrough during lamivudine therapy, and persistent viral replication (>10 4 copies/mL) after 15 months of ADV monotherapy (range 4-28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow-up (median 12 months, range 3-24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti-HBs after 16 months of TDF therapy. Lamivudine-associated mutations (rtV173L, rtL180M, rtM204V/I) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV-resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV-infected patients with altered responsiveness to treatment with lamivudine and ADV. (HEPATOLOGY 2006;44:318-325.) See Editorial on Page 309 C omplete and sustained suppression of viral replication remains the most important goal in the treatment of patients with chronic hepatitis B virus (HBV) infection. 1,2 In this respect, the introduction of the nucleoside analogue lamivudine and the nucleotide analogue adefovir dipivoxil (ADV) largely improved the outcome in these patients, also by preventing hepatitic decompensation or the development of hepatocellular carcinoma. [3][4][5] These compounds also have a place when interferon-alpha based therapy is contraindicated, as in patients with acute liver failure, decompensated cirrhosis, or extrahepatic manifestations.However, a major disadvantage of nucleoside/nucleotide analogues is that resistant hepatitis B virus mutants develop during long-term treatment, limiting the efficacy of these analogues in suppressing viral replication. As demonstrated in recent studies, approximately 70% of patients receiving lamivudine therapy for more than 4 years suffer the emergence of lamivudine-resistant HBV Abbreviations: ADV, adefovir dipivoxil; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate; HBeAg, hepatitis B virus e antigen. From the

Viral differences among lamivudine resistant hepatitis B (HBV) genotypes have not been yet investigated. Therefore, we analyzed the characteristics of these viral strains in vivo. Fortyone patients carrying lamivudine resistant HBV were enrolled. Twenty-six patients (63%) carried resistant HBV genotype A (group A) and 15 patients (37%) carried resistant HBV genotype D (group D). The rate of reverse transcriptase 204I mutants was significantly higher in group D (67%) compared with group A (19%), whereas rt204V mutants (81% in group A vs 33% in group D; P ‫؍‬ .006) and rt180M mutants (81% in group A vs 40% in group D, P ‫؍‬ .015) prevailed in group A. The median time of shift from rt204I to rt204V mutants was significantly shorter in group A (4 months in group A, >12 months in group D, P < .001). Additional resistance associated mutations were detected exclusively in group D (P ‫؍‬ .004). In a multivariate analysis, HBV genotype (P ‫؍‬ .039) and pretreatment serum HBV DNA (P ‫؍‬ .001) were independently associated with emerging rt204I or rt204V mutants, respectively. Serum HBV copy numbers after emergence of resistance were higher in group A (mean log 10 6.99 copies/ml; range 3-9) compared with group D (mean log 10 6.1 copies/ml; range 3.3-8; P ‫؍‬ .04). There was no difference between both groups regarding core promoter/precore mutations, viral turnover, and number of flares or disease progression during follow-up. T he emergence of drug resistant hepatitis B virus (HBV) during lamivudine treatment for chronic hepatitis B is a major problem with an incidence of 14 -36% after 1 year of treatment. [1][2][3][4] This frequency increases to 38%, 49%, and 66% after 2, 3, and 4 years of treatment, respectively. 5-7 Lamivudine resistant HBV is characterized by amino acid variations in the reverse transcriptase domain of the HBV polymerase. In particular, an exchange of the methionine within the YMDD motif by an isoleucine or a valin (rtM204I/V mutants) is associated with lamivudine resistance. Breakthrough of these drug-resistant HBV mutants leads to a viral rebound to baseline levels, 8,9 to a decrease in the rate of loss of hepatitis B e antigen (HBeAg), 10 a high rate of relapses of serum alanine transaminase (ALT) levels, 11,12 and worsening liver histology. 13 Therefore, the emergence of viral resistance is one of the critical issues in the longterm outcome of patients treated for chronic hepatitis B. On the other hand, lamivudine resistant HBV is considered to have reduced viral fitness due to less replication efficiency in vitro 14 and lower ALT levels in vivo as compared with baseline levels. 4,15,16 This led to the recommendation to continue lamivudine treatment despite the emergence of resistant variants as long as benefit to the patient is maintained. 17 Taken together, it would be useful to identify factors which are associated with a better Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; ALT, serum alanine transaminase; PCR, polymerase chain reaction; CP, core promoter. From the

The prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters can be frequently detected and may impact the success of antiretroviral therapy.

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Hepatitis A, B, and C viruses are the most causative agents structural (core) and nonstructural proteins (NS3 and NS4) of infectious viral hepatitis worldwide. Hepatitis A virus of HGV produced in Escherichia coli. Seropositivity for HGV (HAV) is responsible for 32% of these infections, hepatitis B was evaluated and concordanced with HGV polymerase chain virus (HBV) for 44%, and hepatitis C virus (HCV) for 20%. 1 reaction (PCR) results in 709 subjects. These individuals were In 4%, the causative agent of infectious hepatitis is unknown. classified into a nonrisk or a risk group, on the basis of infec-A new agent was detected recently by molecular biological tion with human immunodeficiency virus (HIV) or hepatitis methods and was named hepatitis G virus (HGV).1 HGV is C virus (HCV) or frequent parenteral exposure, including about 9,400 bases long, a single-stranded, enveloped RNA hemophilia, intravenous drug addiction, receipt of blood virus, and like HCV it is a member of the Flaviviridae. HGV transfusion, or hemodialysis. The nonrisk group consisted of shares a nearly identical nucleotide sequence (ú98%) with 257 healthy blood donors with normal alanine transaminase another recently described virus: GB virus type C (GBV-C). 2,3(ALT) levels (ALT õ 30 U/L) and 154 patients with suspected Therefore, HGV and GBV-C seem to be isolates of the same non-A-E hepatitis (ALT ú 45 U/L). In the group of healthy virus. The HGV genome codes for structural proteins of the blood donors, 1.9% (5 of 257) had detectable HGV viremia viral core and envelope (core, E1, and E2) and for a number and 15.9% (41 of 257) showed antibody response to HGV. of nonstructural proteins (NS2-NS5) that are important durIn the collective of patients with suspected non-A-E hepatitis, ing viral replication. results from 1.9% of patients (3 of 154) were positive by HGV Until now, prevalence, clinical impact, and character of PCR, and 15.6% of patients (24 of 154) showed seropositivity antibody response regarding HGV infection were unclear. against the recombinant HGV proteins. In six groups of pa-Therefore, an immunoblot assay was established using retients (n Å 298) with different risk factors, the prevalence of combinant proteins from structural (core) and nonstructural both HGV viremia (V) and serological reactivity (SR) was regions (NS3 and NS4) of HGV produced in Escherichia coli. higher compared with that of the nonrisk group: V, 6.8%-To evaluate the prevalence of HGV infection, 709 individuals 35.2%; serological reactivity (SR), 25.4%-52.9%. The follow-were tested for both antibody response to HGV recombinant ing conclusions can be derived from our data. HGV infection proteins by the immunoblot assay and presence of HGV vireis widespread in the general population. The prevalence of mia by reverse transcriptase-polymerase chain reaction (RTantibodies against HGV or detectable HGV viremia is higher PCR). These 709 subjects differed in biochemical signs of in patients with risk factors for parenteral viral transmission hepatitis (alanine transamin...

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