Chronic Hepatitis B: Preventing, Detecting, and Managing Viral Resistance
2008; Elsevier BV; Volume: 6; Issue: 3 Linguagem: Inglês
10.1016/j.cgh.2007.12.043
ISSN1542-7714
AutoresEmmet B. Keeffe, Douglas T. Dieterich, Jean‐Michel Pawlotsky, Yves Benhamou,
Tópico(s)Hepatitis Viruses Studies and Epidemiology
ResumoLicensed oral agents for antiviral therapy in patients with chronic hepatitis B virus (HBV) infection include lamivudine, adefovir, entecavir, and telbivudine. Emtricitabine, tenofovir, and the combination of tenofovir plus emtricitabine in 1 tablet, which are licensed for the treatment of human immunodeficiency virus infection, are additional off-label options for treating HBV infection. Preventing HBV antiviral drug resistance to nucleoside/nucleotide analogues and appropriate management when resistance occurs has become a major focus in the management of chronic hepatitis B. HBV antiviral drug resistance may be best prevented by using an agent or combination of agents with a high genetic barrier to resistance, and 2 potent nucleoside and nucleotide drugs with different resistance profiles may prove to be the optimal first-line treatment for chronic hepatitis B. Frequent assessment of quantitative serum HBV DNA remains the best approach to early detection of resistance, and antiviral therapy should be modified as soon as resistance is detected. Results from several clinical trials have shown that the addition or substitution of newer antiviral agents can restore suppression of viral replication, normalize alanine aminotransferase levels, and reverse histologic progression in patients with resistance to lamivudine, but little information exists regarding the long-term benefits of second-line treatment regimens. Despite the substantial advances in treatment made to date, new agents with novel viral targets will be needed for patients who ultimately may fail second- or third-line therapy. Licensed oral agents for antiviral therapy in patients with chronic hepatitis B virus (HBV) infection include lamivudine, adefovir, entecavir, and telbivudine. Emtricitabine, tenofovir, and the combination of tenofovir plus emtricitabine in 1 tablet, which are licensed for the treatment of human immunodeficiency virus infection, are additional off-label options for treating HBV infection. Preventing HBV antiviral drug resistance to nucleoside/nucleotide analogues and appropriate management when resistance occurs has become a major focus in the management of chronic hepatitis B. HBV antiviral drug resistance may be best prevented by using an agent or combination of agents with a high genetic barrier to resistance, and 2 potent nucleoside and nucleotide drugs with different resistance profiles may prove to be the optimal first-line treatment for chronic hepatitis B. Frequent assessment of quantitative serum HBV DNA remains the best approach to early detection of resistance, and antiviral therapy should be modified as soon as resistance is detected. Results from several clinical trials have shown that the addition or substitution of newer antiviral agents can restore suppression of viral replication, normalize alanine aminotransferase levels, and reverse histologic progression in patients with resistance to lamivudine, but little information exists regarding the long-term benefits of second-line treatment regimens. Despite the substantial advances in treatment made to date, new agents with novel viral targets will be needed for patients who ultimately may fail second- or third-line therapy. See Deng G et al on page 716 for companion article in the March 2008 issue of Gastroenterology. See Deng G et al on page 716 for companion article in the March 2008 issue of Gastroenterology. It is estimated that 1.25 million people in the United States have chronic hepatitis B, and there were 60,000 new hepatitis B virus (HBV) infections in 2004.1Centers for Disease Control and Prevention (CDC)Viral hepatitis B. 2006.http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htmGoogle Scholar Acute HBV infection may be asymptomatic, result in self-limited or fulminant hepatitis, or progress to chronic hepatitis, which can lead to cirrhosis or hepatocellular carcinoma.2Glebe D. Recent advances in hepatitis B virus research: a German point of view.World J Gastroenterol. 2007; 13: 8-13Crossref PubMed Scopus (35) Google Scholar Cirrhosis and hepatocellular carcinoma result in about 1 million deaths worldwide each year.3World Health OrganizationFact sheet no. 204. Hepatitis B. 2000.http://www.who.int/mediacentre/factsheets/fs204/en/Google Scholar In the United States, there has been a substantial decline in the incidence of acute hepatitis B over the past 15 to 20 years that has coincided with the national strategy to eliminate HBV transmission by vaccination and public health measures.4Wasley A. Miller J.T. Finelli L. Centers for Disease Control and Prevention (CDC)Surveillance for acute viral hepatitis—United States, 2005.MMWR Surveill Summ. 2007; 56: 1-24PubMed Google Scholar Nevertheless, because of a high HBV prevalence rate in many developing countries and population migrations to developed countries, chronic HBV infection is an important health problem in the United States and Europe. Antiviral therapy in patients with chronic hepatitis B is associated with improved outcomes.5Liaw Y.F. Sung J.J. Chow W.C. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (2013) Google Scholar, 6Arora G. Keeffe E.B. Chronic hepatitis B with advanced hepatic fibrosis or cirrhosis: impact of antiviral therapy.Rev Gastroenterol Disord. 2007; 7: 63-73PubMed Google Scholar Over the past 10 years, oral antiviral agents available for patients with chronic HBV infection have included lamivudine, adefovir, entecavir, and telbivudine, which are licensed to treat chronic hepatitis B, and emtricitabine, tenofovir, and the combination of tenofovir plus emtricitabine, which has been licensed for treatment of patients with human immunodeficiency virus (HIV) infection, but also is active against HBV infection.7Zoulim F. In vitro models for studying hepatitis B virus drug resistance.Semin Liver Dis. 2006; 26: 171-180Crossref PubMed Scopus (48) Google Scholar However, 20 years of experience with the treatment of HIV, as well as current HBV resistance data, point to the emergence of HBV antiviral drug resistance,8Bartholomeusz A. Locarnini S.A. Antiviral drug resistance: clinical consequences and molecular aspects.Semin Liver Dis. 2006; 26: 162-170Crossref PubMed Scopus (117) Google Scholar as illustrated by the case of lamivudine, the nucleoside that has the longest history of use in patients with chronic HBV infection and the highest rate of resistance. The development of resistance is associated with a poorer long-term prognosis.9Lok A.S. Lai C.L. Leung N. et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology. 2003; 125: 1714-1722Abstract Full Text Full Text PDF PubMed Scopus (697) Google Scholar, 10Andreone P. Gramenzi A. Cursaro C. et al.High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing lamivudine resistance.J Viral Hepat. 2004; 11: 439-442Crossref PubMed Scopus (58) Google Scholar Clinicians need to be aware of current approaches to resistance testing and of effective treatment strategies to minimize the emergence of resistant HBV strains, and they should be cognizant of regimens that may be effective after resistance has emerged. The genome of HBV consists of partially double-stranded, 3.2-kb, covalently closed, circular DNA (ccc DNA) comprising 4 overlapping open reading frames.11Locarnini S. Molecular virology of hepatitis B virus.Semin Liver Dis. 2004; 24: 3-10Crossref PubMed Scopus (186) Google Scholar The viral genome is transcribed into 4 major subgenomic viral messenger RNAs, under the control of specific enhancers,12Norder H. Courouce A.M. Magnius L.O. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.Virology. 1994; 198: 489-503Crossref PubMed Scopus (715) Google Scholar and is the template for the pregenomic RNA. The virus is encapsidated after binding of the polymerase and core to the pregenomic RNA in the cytoplasm. Nucleocapsids are enveloped by budding into the endoplasmic reticulum, after which they are secreted from the cell or return to the nucleus to amplify the cccDNA reservoir.13Beck J. Nassal M. Hepatitis B virus replication.World J Gastroenterol. 2007; 13: 48-64Crossref PubMed Scopus (370) Google Scholar Viral mutations occur spontaneously during HBV replication. Viral reverse transcriptases intrinsically are error prone and lack a proofreading function, allowing for replication errors to occur. These replication errors result in the emergence of multiple HBV variant quasispecies that coexist and reach population densities in direct proportion to their relative replication fitness.11Locarnini S. Molecular virology of hepatitis B virus.Semin Liver Dis. 2004; 24: 3-10Crossref PubMed Scopus (186) Google Scholar This phenomenon is responsible for the generation of significant diversity; it has been shown that HBV genomes in one given patient displayed a rate of 1.4 to 3.2 × 10−5 nucleoside substitutions per year, a value approximately 104 times greater than DNA genomes and about 10−2 less than that for HIV.14Okamoto H. Imai M. Kametani M. et al.Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission.Jpn J Exp Med. 1987; 57: 231-236PubMed Google Scholar A chronic HBV carrier can produce up to 1013 virions per day, and, as a result, every nucleotide of the 3.2-kb HBV genome theoretically can be substituted within one patient every day.2Glebe D. Recent advances in hepatitis B virus research: a German point of view.World J Gastroenterol. 2007; 13: 8-13Crossref PubMed Scopus (35) Google Scholar The dominant quasispecies is by definition the best adapted to its host environment, and, as expected, random mutations generally will impair its fitness to a degree. Thus, the emergence of successful HBV variants resistant to an antiviral drug is affected by the mutation rate and viral load and is determined eventually by the replication fitness of the mutant virus in relation to the antiviral potency of the drug and the number of mutations required to confer resistance (ie, the genetic barrier to resistance).15Bartholomeusz A. Locarnini S. Hepatitis B virus mutations associated with antiviral therapy.J Med Virol. 2006; 78: S52-S55Crossref PubMed Scopus (85) Google Scholar Treatment failure can be defined as primary or secondary. Primary treatment failure is the failure of a drug to reduce HBV DNA levels by 1 × log10 IU/mL or greater within 3 months of initiation of therapy, and secondary failure is defined as a rebound of HBV replication by 1 × log10 IU/mL or greater from nadir in patients in whom treatment initially produced a decrease in serum HBV DNA of 1 × log10 IU/mL or greater.16Locarnini S. Hatzakis A. Heathcote J. et al.Management of antiviral resistance in patients with chronic hepatitis B.Antivir Ther. 2004; 9: 679-693PubMed Google Scholar Secondary treatment failure due to resistance to antiviral therapy can result in a decreased rate of hepatitis B e antigen (HBeAg) seroconversion17Da Silva L.C. Pinho J.R. Sitnik R. et al.Efficacy and tolerability of long-term therapy using high lamivudine doses for the treatment of chronic hepatitis B.J Gastroenterol. 2001; 36: 476-485Crossref PubMed Scopus (24) Google Scholar; reversion of virologic, biochemical, and histologic improvement18Wright T.L. Clinical trial results and treatment resistance with lamivudine in hepatitis B.Semin Liver Dis. 2004; 24: 31-36Crossref PubMed Scopus (38) Google Scholar, 19Dienstag J.L. Goldin R.D. 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Pichoud C. et al.Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B.Hepatology. 2000; 32: 1078-1088Crossref PubMed Scopus (216) Google Scholar; and risk for graft loss and death after liver transplantation.22Mutimer D. Pillay D. Shields P. et al.Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient.Gut. 2000; 46: 107-113Crossref PubMed Scopus (125) Google Scholar Mutations resulting in resistance to nucleoside/nucleotide analogues mainly involve the viral polymerase gene (Figure 1).11Locarnini S. Molecular virology of hepatitis B virus.Semin Liver Dis. 2004; 24: 3-10Crossref PubMed Scopus (186) Google Scholar, 23Zoulim F. Mechanism and viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection.Antiviral Res. 2004; 64: 1-15Crossref PubMed Scopus (159) Google Scholar, 24Hussain M. Lok A.S. Mutations in the hepatitis B virus polymerase gene associated with antiviral treatment for hepatitis B.J Viral Hepat. 1999; 6: 183-194Crossref PubMed Scopus (43) Google Scholar, 25Poch O. Sauvaget I. Delarue M. et al.Identification of four conserved motifs among the RNA-dependent polymerase encoding elements.EMBO J. 1989; 8: 3867-3874Crossref PubMed Scopus (981) Google Scholar This gene contains 7 functional domains (A–G), and mutations that give rise to nucleoside/nucleotide resistance are located essentially in domains A through E.23Zoulim F. Mechanism and viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection.Antiviral Res. 2004; 64: 1-15Crossref PubMed Scopus (159) Google Scholar Lamivudine inhibits viral reverse-transcriptase activity as a competitive inhibitor of deoxycytidine triphosphate.23Zoulim F. Mechanism and viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection.Antiviral Res. 2004; 64: 1-15Crossref PubMed Scopus (159) Google Scholar High-level lamivudine resistance results from M204V and M204I mutations in the C domain.26Allen M.I. Deslauriers M. Andrews C.W. et al.Identification and characterization of mutations in hepatitis B virus resistant to lamivudine.Hepatology. 1998; 27: 1670-1677Crossref PubMed Scopus (785) Google Scholar HBV variants with these mutations display reduced reverse-transcriptase activity and replication capacity, but compensatory mutations in the B domain (V173L and L180M) restore the replication capacity of virus with the M204V or M204I mutation.27Delaney 4th, W.E. Yang H. Westland C.E. et al.The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.J Virol. 2003; 77: 11833-11841Crossref PubMed Scopus (236) Google Scholar, 28Fu L. Cheng Y.C. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(−)SddC (3TC) resistance.Biochem Pharmacol. 1998; 55: 1567-1572Crossref PubMed Scopus (122) Google Scholar Results from 998 patients with HBeAg-positive compensated chronic hepatitis B who took lamivudine for up to 6 years indicated that the proportion of patients with documented lamivudine-resistant mutations increased from 23% in year 1 to 43%, 55%, 71%, and 65% in years 2 through 5, respectively. Patients with lamivudine-resistant mutations who were followed up for more than 4 years had significantly higher risk for hepatic decompensation and liver disease–related severe adverse events.9Lok A.S. Lai C.L. Leung N. et al.Long-term safety of lamivudine treatment in patients with chronic hepatitis B.Gastroenterology. 2003; 125: 1714-1722Abstract Full Text Full Text PDF PubMed Scopus (697) Google Scholar Adefovir inhibits priming of reverse transcription by preventing the incorporation of deoxyadenosine triphosphate into the viral primer and inhibits viral-minus strand DNA elongation.29Seigneres B. Martin P. Werle B. et al.Effects of pyrimidine and purine analog combinations in the duck hepatitis B virus infection model.Antimicrob Agents Chemother. 2003; 47: 1842-1852Crossref PubMed Scopus (47) Google Scholar Two mutations have been described that confer approximately 5- to 10-fold reduced susceptibility to adefovir in vitro: N236T in the D domain of viral polymerase and A181V in the B domain.23Zoulim F. Mechanism and viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection.Antiviral Res. 2004; 64: 1-15Crossref PubMed Scopus (159) Google Scholar Most recently, another rare mutation, I233V, has been suggested to result in primary resistance to adefovir, but that mutation has not been confirmed to be associated with a reduced susceptibility to adefovir in vitro.30Curtis M. Zhu Y. Borroto-Esoda K. HBV rtI233V polymerase variant remains sensitive to adefovir (abstr).J Hepatol. 2007; 46: S26-S27Abstract Full Text PDF PubMed Google Scholar A study of adefovir in 125 patients who were followed up for up to 240 weeks indicated that the cumulative probabilities of mutations associated with a virologic breakthrough at 48, 96, 144, 192, and 240 weeks were 0%, 3%, 11%, 18%, and 29%, respectively. The respective values for mutations associated with virologic and biochemical breakthrough (alanine aminotransferase [ALT] increases) were 0%, 2%, 6%, 10%, and 11%.31Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.Gastroenterology. 2006; 131: 1743-1751Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 32Borroto-Esoda K. Arterburn S. Snow A. et al.Final analysis of virological outcomes and resistance during 5 years of adefovir dipivoxil monotherapy in HBeAg-negative patients (abstr).J Hepatol. 2006; 44: S179-S180Abstract Full Text PDF Google Scholar Entecavir is a deoxyguanosine analogue that is greater than 100-fold more potent against HBV in culture than either lamivudine or adefovir, and halts HBV DNA elongation after incorporation of a few bases more than lamivudine or adefovir.33Langley D.R. Walsh A.W. Baldick C.J. et al.Inhibition of hepatitis B virus polymerase by entecavir.J Virol. 2007; 81: 3992-4001Crossref PubMed Scopus (155) Google Scholar Analysis of results from 673 patients treated with entecavir indicated that 3% showed virologic rebound by 96 weeks of treatment. Three entecavir rebounds were attributable to lamivudine-resistant virus present at baseline, and none of the others was associated with either entecavir genotypic resistance or loss of entecavir susceptibility.34Colonno R.J. Rose R. Baldick C.J. et al.Entecavir resistance is rare in nucleoside naïve patients with hepatitis B.Hepatology. 2006; 44: 1656-1665Crossref PubMed Scopus (321) Google Scholar After administration of entecavir to patients who were refractory to lamivudine, entecavir resistance was detected in 1% of patients after 48 weeks and an additional 9% after 96 weeks. Entecavir resistance was associated with lamivudine-resistance–conferring mutations plus additional changes at T184, S202, and/or M250.35Tenney D.J. Rose R.E. Baldick C.J. et al.Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.Antimicrob Agents Chemother. 2007; 51: 902-911Crossref PubMed Scopus (208) Google Scholar Recent results have indicated that the cumulative probability of virologic breakthrough associated with entecavir resistance in nucleoside-naive patients was 0.8% over 4 years, and that for patients who received prior lamivudine therapy it was 39.5%, with 1% having resistant virus after 1 year, 10% after 2 years, 16% after 3 years, and 15% after 4 years of treatment.36Colonno R.J. Rose R.E. Pokornowski K. et al.Four year assessment of ETV resistance in nucleoside-naïve and lamivudine refractory patients (abstr).J Hepatol. 2007; 46: S294Abstract Full Text PDF Google Scholar Telbivudine targets the synthesis of positive-strand HBV DNA, which is thought to result in slower emergence of resistance than lamivudine, which targets negative-strand synthesis.37Seifer M. Patty A. Dukhan D. et al.Telbivudine (LdT) preferentially inhibits second (+) strand HBV DNA synthesis (abstr).Gastroenterology. 2005; 128: A742-A743PubMed Google Scholar Results from the GLOBE trial indicated that the 2-year cumulative rate of virologic breakthrough for HBeAg-positive patients was 21.6%, and for HBeAg-negative patients was 8.6%.38Lai C.L. Gane E. Hsu C.W. et al.Two-year results from the GLOBE trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LdT) vs lamivudine (abstr).Hepatology. 2006; 44: 222AGoogle Scholar Emtricitabine inhibits HBV polymerase in essentially the same manner as lamivudine, and the M204V mutation that confers resistance to lamivudine also results in resistance to emtricitabine.39Lim S.G. Ng T.M. Kung N. et al.A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.Arch Intern Med. 2006; 166: 49-56Crossref PubMed Scopus (152) Google Scholar, 40Yang H. Qi X. Sabogal A. et al.Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.Antivir Ther. 2005; 10: 625-633PubMed Google Scholar Emtricitabine is effective as monotherapy in patients with chronic HBV infection, reducing HBV DNA levels to less than 400 copies/mL in 54% of patients over 48 weeks.39Lim S.G. Ng T.M. Kung N. et al.A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B.Arch Intern Med. 2006; 166: 49-56Crossref PubMed Scopus (152) Google Scholar However, at 48 weeks, 9% to 16% of patients treated with 25 to 200 mg/day of emtricitabine developed resistance-conferring mutations (M204I or M204V with or without L180M or V173L).41Gish R.G. Trinh H. Leung N. et al.Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study.J Hepatol. 2005; 43: 60-66Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Tenofovir is an acyclic nucleotide analogue that retains significant activity against HBV variants with mutations (M204V plus L180M), conferring resistance to lamivudine and N236T that results in resistance to adefovir.42Delaney 4th, W.E. Ray A.S. Yang H. et al.Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus.Antimicrob Agents Chemother. 2006; 50: 2471-2477Crossref PubMed Scopus (204) Google Scholar, 43Lada O. Benhamou Y. Cahour A. et al.In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir.Antivir Ther. 2004; 9: 353-363PubMed Google Scholar Tenofovir retains good activity in patients with lamivudine-resistant HBV variants, either as monotherapy or when added to continuing lamivudine treatment.44van Bömmel F. Zollner B. Sarrazin C. et al.Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy.Hepatology. 2006; 44: 318-325Crossref PubMed Scopus (253) Google Scholar, 45van der Eijk A.A. Hansen B.E. Niesters H.G. et al.Viral dynamics during tenofovir therapy in patients infected with lamivudine-resistant hepatitis B virus mutants.J Viral Hepat. 2005; 12: 364-372Crossref PubMed Scopus (31) Google Scholar HBV mutations that confer resistance to tenofovir have not yet been identified. Clinical evidence, as summarized earlier, indicates that resistance to antiviral monotherapy: (1) is common, particularly in patients treated with lamivudine; (2) increases with duration of treatment; and (3) is associated with poorer clinical outcomes. Many new antiviral agents, however, are available for initial therapy and as second-line treatment for those failing lamivudine. It is important that patients with lamivudine resistance be treated with agents that are not cross-resistant, such as the nucleotide analogues adefovir or tenofovir. The availability of genetic testing for identification of viral genotypes likely to show phenotypic resistance and the fact that different antiviral agents do not have completely overlapping resistance profiles raises 3 questions: When should genotypic resistance testing be performed in patients with HBV infection? What approach(es) to initial treatment are least likely to result in the rapid emergence of resistance? What treatment alternatives are most useful in patients who have developed resistance-conferring mutations? Genotypic resistance precedes phenotypic resistance with virologic breakthrough, which in turn precedes biochemical and/or clinical breakthrough. Phenotypic resistance is defined as virologic breakthrough (ie, an increase in serum HBV DNA by >1 log10 above nadir after achieving virologic response during continued treatment), or virologic rebound (ie, increase in serum HBV DNA to >20,000 IU/mL or to above pretreatment level after achieving virologic response during continued treatment). Biochemical relapse is characterized as an increase of ALT to above the upper limit of normal after achieving normalization with treatment and may be associated with a hepatitis flare (Figure 2).46Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2166) Google Scholar, 47Keeffe E.B. Dieterich D.T. Han S.H. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update.Clin Gastroenterol Hepatol. 2006; 4: 936-962Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Development of resistance can be detected readily by monitoring serum HBV DNA levels and is indicated by a greater than 1 log10 increase from the patient's lowest level confirmed by measurement on 2 assays. Patients taking lamivudine should have HBV DNA levels evaluated with a sensitive assay every 3 to 6 months and those being treated with adefovir or entecavir should be monitored every 6 months after the first year of treatment. Patients with advanced liver disease should be monitored every 3 months.47Keeffe E.B. Dieterich D.T. Han S.H. et al.A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update.Clin Gastroenterol Hepatol. 2006; 4: 936-962Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Guidelines published by the American Association for the Study of Liver Diseases (AASLD) recommend serum HBV DNA monitoring every 3 to 6 months for patients receiving therapy for chronic hepatitis B.46Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2166) Google Scholar It also has been noted that monitoring the emergence of resistance-conferring mutations may be the most sensitive way to assess patients who remain viremic on current treatments.48Tillmann H.L. Antiviral therapy and resistance with hepatitis B virus infection.World J Gastroenterol. 2007; 13: 125-140Crossref PubMed Scopus (82) Google Scholar The reference method for detection of resistance-conferring mutations is population-based sequencing (ie, a direct sequence analysis of the HBV polymerase gene). Line-probe assays using probes for individual mutations are specific and reproducible and can detect a mutant representing as little as 5% of the viral population. However, this approach is limited in that it can detect only known mutations. It requires periodic updating with new probes specific to novel mutations because HBV strains resistant to newly developed antiviral drugs are isolated and characterized.49Lok A.S. Zoulim F. Locarnini S. et al.Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO-LiPA HBV DR assay.J Clin Microbiol. 2002; 40: 3729-3734Crossref PubMed Scopus (140) Google Scholar, 50Zoulim F. New nucleic acid diagnostic tests in viral hepatitis.Semin Liver Dis. 2006; 26: 309-317Crossref PubMed Scopus (19) Google Scholar Other powerful technologies are in development, including high-throughput systems capable of detecting polymorphisms in the entire HBV genome using gene chip technology.51Tran N. Berne R. Chann R. et al.European multicenter evaluation of high-density DNA probe arrays for detection of hepatitis B virus resistance mutations and identification of genotypes.J Clin Microbiol. 2006; 44: 2792-2800Crossref PubMed Scopus (37) Google Scholar This method is limited by the fact that it, too, can detect only known polymorphisms and needs to be updated as resistance-conferring mutations are identified.50Zoulim F. New nucleic acid diagnostic tests in viral hepatitis.Semin Liver Dis. 2006; 26: 309-317Crossref PubMed Scopus (19) Google Scholar Clinicians might consider testing at the following times: (1) before selection of initial therapy, (2) routinely during the course of therapy, and (3) at the time of virologic breakthrough, before changing the therapeutic regimen. Evaluation of viral genetic mutations has been used extensively in patients with HIV infection, and it is useful to review current recommendations for HIV genotypic resistance testing. Current guidelines recommend HIV drug resistance testing before initiation of therapy.52Department of Health and Human Services (DHHS)Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. October 10, 2006.http://AIDSinfo.nih.gov/contentfiles/Adult
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