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• W2017100810 abstract "1. IntroductionVirological diagnosis and monitoring of hepatitis B virus (HBV) infection are based on serologic assays detecting specific anti-HBV antibodies, and assays that can detect, quantify or characterize the components of HBV viral particles, such as HBV DNA and various viral antigens. HBV DNA detection and quantification now play a key role in the diagnosis of infection, therapeutic decision-making, and assessment of the response to therapy. However, clinically relevant HBV DNA thresholds remain to be established in various settings. HBV DNA quantification can also be used to monitor viral replication kinetics to better understand the mechanisms of infection and the virologic response to antiviral therapy.2. HBV DNA, a marker of viral replicationThe presence of HBV DNA in peripheral blood is a reliable marker of active HBV replication. HBV DNA is detectable within a few days after infection. It generally increases to reach a peak at the time of acute hepatitis, before progressively decreasing and disappearing when the infection resolves spontaneously [[1]Whalley S.A. Murray J.M. Brown D. Webster G.J.M. Emery V.C. Dusheiko G.M. et al.Kinetics of acute hepatitis B virus infection in humans.J Exp Med. 2001; 193: 847-853Crossref PubMed Scopus (159) Google Scholar]. In the patients progressing towards chronic hepatitis B surface antigen (HBsAg) carriage, chronic infection evolves through successive phases. HBV DNA levels are not stable over time and depend on the infection phase: the immuno-tolerance after acute infection is characterized by high levels of viral replication; the immuno-elimination phase is characterized by generally lower, often fluctuating HBV DNA; the ‘clinical latency’ phase is characterized by very low or undetectable levels of viral replication, depending on the sensitivity of the assay used; during reactivation phases, that are facilitated by immunosuppressive treatments, viral replication generally reaches high levels. During all phases in chronic HBsAg carriers, HBV DNA and supercoiled DNA (cccDNA, the persistent form of HBV in hepatocytes) are detectable in the liver with sensitive techniques. The HBV DNA load does not appear to be affected by the severity of liver lesions, but a non-causal relationship may exist, because liver lesions develop principally during the immuno-elimination phase.3. Available HBV DNA testsThe principles of the molecular biology-based techniques that can be used to detect and quantify HBV DNA in peripheral blood have been reviewed recently [[2]Pawlotsky J.M. Molecular diagnosis of viral hepatitis.Gastroenterology. 2002; 122: 1554-1568Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]. These techniques are based on signal amplification following molecular hybridization (including the ‘hybrid capture’ and the ‘branched DNA’ methods) or target amplification (including polymerase chain reaction, PCR, and transcription-mediated amplification, TMA) [[2]Pawlotsky J.M. Molecular diagnosis of viral hepatitis.Gastroenterology. 2002; 122: 1554-1568Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]. Table 1 shows the commercial assays that can currently be used to detect and quantify HBV DNA. HBV DNA quantitative units used in the various assays do not represent the same actual amount of HBV DNA in a given clinical sample. The World Health Organization has established an international standard for universal standardization of HBV DNA quantification units, and an HBV DNA international unit (IU) has been defined [[3]Saldanha J. Gerlich W. Lelie N. Dawson P. Heermann K. Heath A. An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques.Vox Sang. 2001; 80: 63-71Crossref PubMed Scopus (212) Google Scholar]. International unit conversion factors for the non-standardized units used in commercial HBV DNA quantitative assays are currently being calculated. This IU must be preferred to any other quantitative unit and should now be implemented in all commercial HBV DNA quantitative assays for establishing clinically relevant thresholds and recommendations for clinical decisions based on HBV DNA load.Table 1Available HBV DNA detection and quantification assaysaThe dynamic ranges of quantification are given in non-standardized units. Conversion factors to IUs are currently being calculated.ManufacturerAssayMethodDynamic range of quantificationDigene Corp., Gaithersburg, MD, USAHBV Digene Hybrid-Capture™ IHybrid capture signal amplification in tubes700,000–560,000,000 copies/mlHBV Digene Hybrid-Capture™ IIHybrid capture signal amplification in microplates142,000–1,700,000,000 copies/mlUltra-sensitive HBV Digene Hybrid-Capture™ IIHybrid capture signal amplification in microplates after centrifugation4700–57,000,000 copies/mlRoche Molecular Systems, Pleasanton, CA, USAAmplicor HBV Monitor™Manual quantitative RT-PCR1000–4,000,000 copies/mlCobas Amplicor HBV Monitor™Semi-automated quantitative RT-PCR200–200,000 copies/mlBayer Corporation, Tarrytown, NY, USAVersant™ HBV DNA 1.0 AssayManual branched DNA signal amplification700,000–5,000,000,000 genome equivalents/mlVersant™ HBV DNA 3.0 AssaySemi-automated branched DNA signal amplification2000–100,000,000 copies/ml or 350–17,850,000 ui/mla The dynamic ranges of quantification are given in non-standardized units. Conversion factors to IUs are currently being calculated. Open table in a new tab The dynamic ranges of quantification of the available assays are shown in Table 1 (in non-standardized units). Samples with a viral content above the upper limit of a given assay must be retested after 1/10 or 1/100 dilution for accurate quantification. These assays have been shown to be specific and accurate within their respective dynamic ranges of quantification [4Aspinall S. Steele A.D. Peenze I. Mphahlele M.J. Detection and quantitation of hepatitis B virus DNA: comparison of two commercial hybridization assays with polymerase chain reaction.J Viral Hepat. 1995; 2: 107-111Crossref PubMed Scopus (23) Google Scholar, 5Barlet V. Cohard M. Thelu M.A. Chaix M.J. Baccard C. Zarski J.P. et al.Quantitative detection of hepatitis B virus DNA in serum using chemiluminescence: comparison with radioactive solution hybridization assay.J Virol Methods. 1994; 49: 141-151Crossref PubMed Scopus (31) Google Scholar, 6Krajden M. Minor J. Cork L. Comanor L. Multi-measurement method comparison of three commercial hepatitis B virus DNA quantification assays.J Viral Hepat. 1998; 5: 415-422Crossref PubMed Scopus (40) Google Scholar, 7Chan H.L. Leung N.W. Lau T.C. Wong M.L. Sung J.J. Comparison of three different sensitive assays for hepatitis B virus DNA in monitoring of responses to antiviral therapy.J Clin Microbiol. 2000; 38: 3205-3208PubMed Google Scholar, 8Hendricks D.A. Stowe B.J. Hoo B.S. Kolberg J. Irvine B.D. Neuwald P.D. et al.Quantitation of HBV DNA in human serum using a branched DNA (bDNA) signal amplification assay.Am J Clin Pathol. 1995; 104: 537-546Crossref PubMed Scopus (121) Google Scholar, 9Ho S.K. Chan T.M. Cheng I.K. Lai K.N. Comparison of the second-generation Digene hybrid capture assay with the branched-DNA assay for measurement of hepatitis B virus DNA in serum.J Clin Microbiol. 1999; 37: 2461-2465PubMed Google Scholar, 10Niesters H.G. Krajden M. Cork L. de Medina M. Hill M. Fries E. et al.A multicenter study evaluation of the Digene hybrid capture II signal amplification technique for detection of hepatitis B virus DNA in serum samples and testing of EUROHEP standards.J Clin Microbiol. 2000; 38: 2150-2155PubMed Google Scholar, 11Pawlotsky J.M. Bastie A. Lonjon I. Remire J. Darthuy F. Soussy C.J. et al.What technique should be used for routine detection and quantification of HBV DNA in clinical samples?.J Virol Methods. 1997; 65: 245-253Crossref PubMed Scopus (54) Google Scholar, 12Pawlotsky J.M. Bastie A. Hezode C. Lonjon I. Darthuy F. Remire J. et al.Routine detection and quantification of hepatitis B virus DNA in clinical laboratories: performance of three commercial assays.J Virol Methods. 2000; 85: 11-21Crossref PubMed Scopus (83) Google Scholar, 13Poljak M. Marin I.J. Seme K. Brinovec V. Maticic M. Meglic-Volkar J. et al.Second-generation Hybrid capture test and Amplicor Monitor test generate highly correlated hepatitis B virus DNA levels.J Virol Methods. 2001; 97: 165-169Crossref PubMed Scopus (11) Google Scholar]. The possible influence of the HBV genotype on quantification has not been studied. Whatever the assay, differences or variations of less than 0.5 log (i.e. less than 3-fold) should not be taken into account, as they may be due to intrinsic or between-patient variability.4. Practical use of HBV DNA quantification4.1 Diagnosis of HBV infection4.1.1 Acute hepatitis BHBV DNA detection or quantification is not necessary for the diagnosis of acute hepatitis B, which is based on serologic testing.4.1.2 Chronic HBV infectionIn chronic HBV infection, HBV DNA detection-quantification is necessary to determine whether or not HBV is replicating [[14]Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B 2000: summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (728) Google Scholar]. The quantitative result does not really matter in the presence of hepatitis B ‘e’ antigen (HBeAg), because the diagnosis of replicating chronic hepatitis B can be made independent of the viral load. In contrast, the interpretation of HBV DNA quantification is difficult in HBeAg-negative/anti-HBe antibody-positive patients. Indeed, the ‘inactive carriers’ appear to have lower mean HBV DNA levels than the patients with clinically active chronic hepatitis B [15Martinot-Peignoux M. Boyer N. Colombat M. Akremi R. Pham B.N. Ollivier S. et al.Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.J Hepatol. 2002; 36: 543-546Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 16Manesis E.K. Papatheodoridis G.V. Hadziyannis S.J. Serum HBV-DNA levels in inactive hepatitis B virus carriers.Gastroenterology. 2002; 122: 2092-2093Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. However, the discriminating HBV DNA threshold remains to be established in appropriate clinical studies using highly sensitive and accurate HBV DNA assays, and standardized IUs [[17]Chu C.J. Lok A.S.F. Clinical utility in quantifying serum HBV DNA levels using PCR assays.J Hepatol. 2002; 36: 549-551Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar].4.2 Assessment of disease severity and prognosisHBV DNA detection provides valuable prognostic information. Indeed, the presence of HBV DNA is associated with a significant risk of progression of chronic hepatitis B to cirrhosis and hepatocellular carcinoma [[14]Lok A.S. Heathcote E.J. Hoofnagle J.H. Management of hepatitis B 2000: summary of a workshop.Gastroenterology. 2001; 120: 1828-1853Abstract Full Text Full Text PDF PubMed Scopus (728) Google Scholar]. This risk is low in the absence of detectable HBV DNA, except in patients with cirrhosis who may subsequently develop hepatocellular carcinoma despite the absence of HBV replication. The possible prognostic significance of HBV DNA load, i.e. what level of HBV DNA is associated with progressive liver disease, remains to be determined in appropriate clinical studies.4.3 Treatment of HBV infection4.3.1 Decision to treatThe decision to treat chronic hepatitis B must be made in patients with elevated serum alanine aminotransferase (ALT) activity, a liver biopsy showing chronic hepatitis with or without cirrhosis, and the presence of significant levels of HBV DNA. The decision to treat is practically easy if HBeAg is present. It is more difficult in HBeAg-negative patients with detectable HBV DNA and mild to moderate lesions on liver biopsy, because no precise clinically relevant HBV DNA thresholds are known. Prospective trials are needed to determine HBV DNA loads (in IU/ml) above which patients with chronic hepatitis B should be treated (and below which they should not).4.3.2 Selection of optimal therapyThe current treatment of chronic hepatitis B is based on standard interferon (IFN)-α or lamivudine [18Perrillo R.P. Schiff E.R. Davis G.L. Bodenheimer Jr, H.C. Lindsay K. Payne J. et al.A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B.N Engl J Med. 1990; 323: 295-301Crossref PubMed Scopus (777) Google Scholar, 19Dienstag J.L. Perrillo R.P. Schiff E.R. Bartholomew M. Vicary C. Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection.N Engl J Med. 1995; 333: 1657-1661Crossref PubMed Scopus (819) Google Scholar, 20Lok A.S. Lai C.L. Wu P.C. Leung E.K. Long-term follow-up in a randomised controlled trial of recombinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection.Lancet. 1988; 2: 298-302Abstract PubMed Scopus (163) Google Scholar, 21Lai C.L. Lok A.S. Lin H.J. Wu P.C. Yeoh E.K. Yeung C.Y. Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children.Lancet. 1987; 2: 877-880Abstract PubMed Scopus (172) Google Scholar, 22Dienstag J.L. Schiff E.R. Wright T.L. Perrillo R.P. Hann H.W. Goodman Z. et al.Lamivudine as initial treatment for chronic hepatitis B in the United States.N Engl J Med. 1999; 341: 1256-1263Crossref PubMed Scopus (1329) Google Scholar, 23Lai C.L. Chien R.N. Leung N.W. Chang T.T. Guan R. Tai D.I. et al.A 1-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339: 61-68Crossref PubMed Scopus (1784) Google Scholar]. The choice will change in the near future for the following reasons: promising preliminary results have been reported with pegylated IFN-α [24Cooksley W.G.E. Piratvisuth T. Wang Y.J. Mahachai V. Chao Y.C. Tanwandee T. et al.Evidence for the efficacy of peginterferon alfa-2a (40 kD) (Pegasys) in the treatment of HBeAg-positive chronic hepatitis B and impact of baseline factors.J Hepatol. 2002; 36: 8Abstract Full Text PDF PubMed Google Scholar, 25Sypsa V. Tassopoulos N.C. Chrysagis D. Mimidis K. Vassiliadis T. Raptopoulou M. et al.A viral kinetic study using pegylated interferon alpha-2b and lamivudine in naive patients with HBeAg(−)/HBV DNA(+) chronic hepatitis B: preliminary results.J Hepatol. 2002; 36: 94Abstract Full Text PDF Google Scholar]; new potent antiviral molecules, such as adefovir dipivoxil and others, are and will soon be available [26Benhamou Y. Bochet M. Thibault V. Calvez V. Fievet M.H. Vig P. et al.Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study.Lancet. 2001; 358: 718-723Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 27Perrillo R. Schiff E. Yoshida E. Statler A. Hirsch K. Wright T. et al.Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants.Hepatology. 2000; 32: 129-134Crossref PubMed Scopus (453) Google Scholar, 28Xiong X. Flores C. Yang H. Toole J.J. Gibbs C.S. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro.Hepatology. 1998; 28: 1669-1673Crossref PubMed Scopus (244) Google Scholar]; combination therapy has not been appropriately evaluated to date and might yield interesting results. HBV DNA quantification could help selecting optimal therapy. The patients with a low HBV DNA may have a higher rate of sustained response to IFN-α than those with a high HBV DNA level. Conversely, the patients with a high HBV DNA level might be the best candidates for antiviral therapy with nucleoside/nucleotide analogs. Again, the precise HBV DNA cutoff that discriminates between ‘low’ and ‘high’ pretreatment replication needs to be determined in prospective clinical trials, using standardized quantification units.4.3.3 Treatment monitoringHBV DNA quantification, together with repeated ALT determinations and HBeAg/anti-HBe antibody assessments in HBeAg-positive patients, is critical in treatment monitoring [18Perrillo R.P. Schiff E.R. Davis G.L. Bodenheimer Jr, H.C. Lindsay K. Payne J. et al.A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B.N Engl J Med. 1990; 323: 295-301Crossref PubMed Scopus (777) Google Scholar, 19Dienstag J.L. Perrillo R.P. Schiff E.R. Bartholomew M. Vicary C. Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection.N Engl J Med. 1995; 333: 1657-1661Crossref PubMed Scopus (819) Google Scholar, 20Lok A.S. Lai C.L. Wu P.C. Leung E.K. Long-term follow-up in a randomised controlled trial of recombinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection.Lancet. 1988; 2: 298-302Abstract PubMed Scopus (163) Google Scholar, 21Lai C.L. Lok A.S. Lin H.J. Wu P.C. Yeoh E.K. Yeung C.Y. Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children.Lancet. 1987; 2: 877-880Abstract PubMed Scopus (172) Google Scholar, 22Dienstag J.L. Schiff E.R. Wright T.L. Perrillo R.P. Hann H.W. Goodman Z. et al.Lamivudine as initial treatment for chronic hepatitis B in the United States.N Engl J Med. 1999; 341: 1256-1263Crossref PubMed Scopus (1329) Google Scholar, 23Lai C.L. Chien R.N. Leung N.W. Chang T.T. Guan R. Tai D.I. et al.A 1-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339: 61-68Crossref PubMed Scopus (1784) Google Scholar]. Non-responders to IFN-α-based treatment have little or no change in HBV DNA load during therapy, whereas responders show a significant decrease. Successful IFN-α treatment is characterized by HBe seroconversion in HBeAg-positive patients, and a reduction in HBV DNA load below the detection cutoff of signal amplification assays. Small amounts of HBV DNA often remain detectable in HBe seroconverters with more sensitive target amplification assays. In patients receiving nucleoside/nucleotide analogs, the viral load significantly and rapidly decreases, but low-level replication remains detectable with sensitive assays in most cases. To what level HBV DNA should be reduced to ensure sustained virologic and clinical remission remains to be prospectively determined.HBV resistance, which has been shown to be frequent with lamivudine monotherapy, is characterized by a relapse of HBV replication during treatment [29Zollner B. Petersen J. Schroter M. Laufs R. Schoder V. Feucht H.H. Twenty-fold increase in risk of lamivudine resistance in hepatitis B virus subtype adw.Lancet. 2001; 357: 934-935Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 30Schalm S.W. Clinical implications of lamivudine resistance by HBV.Lancet. 1997; 349: 3-4Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 31Yao F.Y. Terrault N.A. Freise C. Maslow L. Bass N.M. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort.Hepatology. 2001; 34: 411-416Crossref PubMed Scopus (248) Google Scholar, 32Lau D.T. Khokhar M.F. Doo E. Ghany M.G. Herion D. Park Y. et al.Long-term therapy of chronic hepatitis B with lamivudine.Hepatology. 2000; 32: 828-834Crossref PubMed Scopus (358) Google Scholar, 33Villeneuve J.P. Condreay L.D. Willems B. Pomier-Layrargues G. Fenyves D. Bilodeau M. et al.Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.Hepatology. 2000; 31: 207-210Crossref PubMed Scopus (416) Google Scholar, 34Benhamou Y. Bochet M. Thibault V. Di Martino V. Caumes E. Bricaire F. et al.Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients.Hepatology. 1999; 30: 1302-1306Crossref PubMed Scopus (384) Google Scholar, 35Dienstag J.L. Schiff E.R. Mitchell M. Casey Jr, D.E. Gitlin N. Lissoos T. et al.Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy.Hepatology. 1999; 30: 1082-1087Crossref PubMed Scopus (193) Google Scholar, 36Tillmann H.L. Trautwein C. Bock T. Boker K.H. Jackel E. Glowienka M. et al.Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation.Hepatology. 1999; 30: 244-256Crossref PubMed Scopus (122) Google Scholar, 37Perrillo R. Rakela J. Dienstag J. Levy G. Martin P. Wright T. et al.Multicenter study of lamivudine therapy for hepatitis B after liver transplantation.Hepatology. 1999; 29: 1581-1586Crossref PubMed Scopus (273) Google Scholar, 38Ono-Nita S.K. Kato N. Shiratori Y. Masaki T. Lan K.H. Carrilho F.J. et al.YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection.Hepatology. 1999; 29: 939-945Crossref PubMed Scopus (156) Google Scholar, 39Tipples G.A. Ma M.M. Fischer K.P. Bain V.G. Kneteman N.M. Tyrrell D.L. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo.Hepatology. 1996; 24: 714-717PubMed Google Scholar]. Patients with lamivudine resistance are generally kept on lamivudine or may be switched to adefovir dipivoxil in case of rapidly progressing liver disease.5. HBV viral kineticsThe advent of sensitive, reproducible and accurate tools to measure HBV DNA levels has recently opened the way to the monitoring of HBV replication kinetics in various clinical settings.5.1 HBV kinetics during acute infectionThe kinetics of acute HBV infection have been recently characterized in patients infected from a single source [[1]Whalley S.A. Murray J.M. Brown D. Webster G.J.M. Emery V.C. Dusheiko G.M. et al.Kinetics of acute hepatitis B virus infection in humans.J Exp Med. 2001; 193: 847-853Crossref PubMed Scopus (159) Google Scholar]. HBV DNA was shown to replicate rapidly. The HBV DNA peak occurred on average 127±47 days after infection and reached very high levels, in the order of 1010 copies/ml. In these patients (who spontaneously recovered), HBV DNA clearance started at the time of symptomatic acute hepatitis. It followed a two or three phase decay pattern with an initial rapid decline with unclear mechanisms, and a final phase that might be related to infected hepatocyte loss. The peak HBV production rate was estimated to be on average in the order of 1013 virions per day, with a maximum production rate of each infected hepatocyte of 200–1000 virions per day only [[1]Whalley S.A. Murray J.M. Brown D. Webster G.J.M. Emery V.C. Dusheiko G.M. et al.Kinetics of acute hepatitis B virus infection in humans.J Exp Med. 2001; 193: 847-853Crossref PubMed Scopus (159) Google Scholar]. The authors estimated that at this peak rate of virion production, every possible single and most double mutations would be created each day [[1]Whalley S.A. Murray J.M. Brown D. Webster G.J.M. Emery V.C. Dusheiko G.M. et al.Kinetics of acute hepatitis B virus infection in humans.J Exp Med. 2001; 193: 847-853Crossref PubMed Scopus (159) Google Scholar]. The latter finding suggests that viral escape is not the primary mechanism of HBV persistence, which occurs in approximately 5% of adult patients with acute hepatitis B.5.2 HBV kinetics during chronic infectionAt the chronic stage of infection, HBV DNA kinetics are at a steady state, which explains that HBV DNA levels remain relatively stable over time within each phase of infection. The daily production rate of HBV virions has been estimated to be on average 1011 viral particles per day, with a mean half-life of free HCV virions in the order of 1 day [40Nowak M.A. Bonhoeffer S. Hill A.M. Boehme R. Thomas H.C. McDade H. Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA. 1996; : 93Google Scholar, 41Zeuzem S. De Man R.A. Honkoop P. Roth W.K. Schalm S.W. Schmidt J.M. Dynamics of hepatitis B virus infection in vivo.J Hepatol. 1997; 27: 431-436Abstract Full Text PDF PubMed Scopus (103) Google Scholar]. The minimum half-life of infected cells remains debated [40Nowak M.A. Bonhoeffer S. Hill A.M. Boehme R. Thomas H.C. McDade H. Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA. 1996; : 93Google Scholar, 41Zeuzem S. De Man R.A. Honkoop P. Roth W.K. Schalm S.W. Schmidt J.M. Dynamics of hepatitis B virus infection in vivo.J Hepatol. 1997; 27: 431-436Abstract Full Text PDF PubMed Scopus (103) Google Scholar].5.3 HBV kinetics during antiviral therapyHBV kinetics during antiviral therapy with various molecules have been recently described. Given the small number of reports and the small numbers of patients in each study, these results should be considered preliminary, pending further studies on larger groups of patients. In a Greek study, pegylated IFN-α 2b, 100 μg qw and 200 μg qw, induced a 29.4 and 67.4% mean inhibition of HBV replication (IFN-α blocking effectiveness), respectively. The addition of lamivudine to 100 μg qw of pegylated IFN-α 2b increased the mean blocking effectiveness to 90.7% [[25]Sypsa V. Tassopoulos N.C. Chrysagis D. Mimidis K. Vassiliadis T. Raptopoulou M. et al.A viral kinetic study using pegylated interferon alpha-2b and lamivudine in naive patients with HBeAg(−)/HBV DNA(+) chronic hepatitis B: preliminary results.J Hepatol. 2002; 36: 94Abstract Full Text PDF Google Scholar]. The mean death rate of infected cells was increased with the higher dose of pegylated IFN-α and when lamivudine was added [[25]Sypsa V. Tassopoulos N.C. Chrysagis D. Mimidis K. Vassiliadis T. Raptopoulou M. et al.A viral kinetic study using pegylated interferon alpha-2b and lamivudine in naive patients with HBeAg(−)/HBV DNA(+) chronic hepatitis B: preliminary results.J Hepatol. 2002; 36: 94Abstract Full Text PDF Google Scholar].The administration of nucleoside/nucleotide analogs, such as lamivudine, adefovir dipivoxil or entecavir, was shown to be associated with a dose-dependent inhibition of HBV replication, over 95% on average with the usual dosages. Various patterns of response, including both bi- and triphasic patterns, have been reported, the significance of which remains unclear [42Wolters L.L.M. Hansen B.E. Niesters H.G.M. Levi-Drummer R.S. Neumann A.U. Schalm S.W. et al.The influence of baseline characteristics on viral dynamics parameters in chronic hepatitis B patients treated with lamivudine.J Hepatol. 2002; 37: 253-258Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 43Lau G.K.K. Tsiang M. Hou J. Yuen S.T. Carman W.F. Zhang L. et al.Combination therapy with lamivudine and famciclovir for chronic hepatitis B-infected Chinese patients: a viral dynamics study.Hepatology. 2000; 32: 394-399Crossref PubMed Scopus (147) Google Scholar, 44Tsiang M. Rooney J.F. Toole J.J. Gibbs C.S. Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy.Hepatology. 1999; 29: 1863-1869Crossref PubMed Scopus (211) Google Scholar, 45Wolters L.L.M. Hansen B.E. Niesters H.G. De Hertogh D. De Man R.A. Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B.J Hepatol. 2002; 37: 137-144Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 46Neumann A.U. Havlin Y. Tal R. Tsiang M. Wulfsohn M. Brosgart C. Long-term H.B.V. et al.kinetics classification during treatment with adefovir dipivoxil.J Hepatol. 2002; 36: 121Google Scholar]. The second slope of viral decrease during lamivudine therapy was shown to be associated with baseline ALT levels in one study, emphasizing the relationship between disease activity and the immune response resulting in the death of infected cells [[42]Wolters L.L.M. Hansen B.E. Niesters H.G.M. Levi-Drummer R.S. Neumann A.U. Schalm S.W. et al.The influence of baseline characteristics on viral dynamics parameters in chronic hepatitis B patients treated with lamivudine.J Hepatol. 2002; 37: 253-258Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. The recent report of a sensitive and accurate method to quantify cccDNA in the liver [[47]Werle B. Wursthorn K. Petersen J. Bowden S. Locarnini S. James C. et al.Development of a quantitative assay for hepatic HBV cccDNA levels in patients with chronic hepatitis B.J Hepatol. 2002; 36: 4Abstract Full Text PDF PubMed Google Scholar] might improve interpretation of viral kinetics analyses in patients with chronic hepatitis B receiving antiviral therapy.6. ConclusionHBV DNA detection and quantification plays a key role in the management of patients with HBV infection. However, few practical guidelines can be derived at present because of the lack of published data and standardization of HBV DNA quantification units. Various clinical studies need to be performed in order to establish clinically relevant thresholds. A better understanding of the effects of antiviral drugs and the HBV DNA levels that should be targeted is also needed. The study of HBV kinetics might help to better understand the mechanisms of action of antiviral drugs and improve the global management of these patients. 1. IntroductionVirological diagnosis and monitoring of hepatitis B virus (HBV) infection are based on serologic assays detecting specific anti-HBV antibodies, and assays that can detect, quantify or characterize the components of HBV viral particles, such as HBV DNA and various viral antigens. HBV DNA detection and quantification now play a key role in the diagnosis of infection, therapeutic decision-making, and assessment of the response to therapy. However, clinically relevant HBV DNA thresholds remain to be established in various settings. HBV DNA quantification can also be used to monitor viral replication kinetics to better understand the mechanisms of infection and the virologic response to antiviral therapy." @default.
• W2017100810 created "2016-06-24" @default.
• W2017100810 creator A5051956323 @default.
• W2017100810 date "2003-01-01" @default.
• W2017100810 modified "2023-10-18" @default.
• W2017100810 title "Hepatitis B virus (HBV) DNA assays (methods and practical use) and viral kinetics" @default.
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