Effectiveness of Hepatitis B Treatment in Clinical Practice
2012; Elsevier BV; Volume: 142; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2012.01.044
ISSN1528-0012
AutoresSteven Scaglione, Anna S. Lok,
Tópico(s)Hepatitis C virus research
ResumoIt is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care. It is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care. View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Efficacy of CHB Treatment in Clinical Trials vs Effectiveness in Clinical PracticeEfficacyEffectivenessUtility of a medical treatment evaluated under optimal conditionsUtility of medical treatment in routine clinical settings (ie, real life)Highly selected, motivated patientsAll patientsExperienced physicians and support staffAll physicians with varying knowledge and experience, limited or no support staff Standardized algorithm for monitoring of response and management of suboptimal response/breakthroughFrequent visits and laboratory tests Monitoring of response and management of suboptimal response/breakthrough at discretion of physicianLess frequent office visits and laboratory tests Free medications, evaluations, and testsCosts borne by health insurance and/or patient Open table in a new tab A chasm between efficacy in clinical trials and effectiveness in the community was described in the 2010 Institute of Medicine (IOM) report Hepatitis and Liver Cancer,1Mitchell A.E. Colvin H.M. Palmer Beasley R. Institute of Medicine recommendations for the prevention and control of hepatitis B and C.Hepatology. 2010; 51: 729-733Crossref PubMed Scopus (154) Google Scholar and a Hepatitis Summit Report, The State of Hepatitis B and C in Europe.2Hatzakis A. Wait S. Bruix J. et al.The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference.J Viral Hepat. 2011; 18: 1-16Crossref PubMed Scopus (189) Google Scholar We review the efficacy of hepatitis B treatment, as evaluated in clinical trials, and discuss the effectiveness of these treatments in practice, the barriers between efficacy and effectiveness, and strategies to remove these barriers.Burden of Hepatitis BDespite advances in prevention and treatment, HBV infection remains a global public health concern. Worldwide, approximately 2 billion people have been exposed and 350 million people are chronically infected with HBV, which is estimated to be responsible for 620,000 deaths per year.3World Health OrganizationHepatitis B vaccines.Wkly Epidemiol Rec. 2004; 79: 253-264PubMed Google Scholar HBV infection is a major burden in resource-limited countries, accounting for 30% of cases of cirrhosis and 53% of cases of hepatocellular carcinoma (HCC).4Perz J.F. Armstrong G.L. Farrington L.A. et al.The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.J Hepatol. 2006; 45: 529-538Abstract Full Text Full Text PDF PubMed Scopus (1938) Google Scholar Even in developed countries with universal vaccination programs and availability of efficacious treatment, the burden of HBV-related disease remains high.The prevalence of chronic HBV infection in the US population is estimated to be 0.27%,5Ioannou G.N. Hepatitis B virus in the United States: infection, exposure, and immunity rates in a nationally representative survey.Ann Intern Med. 2011; 154: 319-328Crossref PubMed Scopus (125) Google Scholar but many screening programs conducted in Asian American communities have shown prevalence rates of 10%–15%.6CDCScreening for chronic hepatitis B among Asian/Pacific islander populations-New York City, 2005.Morb Mortal Wkly Rep. 2006; 55: 505-509PubMed Google Scholar Furthermore, the IOM committee estimated that of the 0.8–1.4 million persons in the United States with chronic HBV infection, 65% are not aware of their infection.1Mitchell A.E. Colvin H.M. Palmer Beasley R. Institute of Medicine recommendations for the prevention and control of hepatitis B and C.Hepatology. 2010; 51: 729-733Crossref PubMed Scopus (154) Google Scholar The prevalence of HBV infection in Europe varies from 0.2% in Ireland to 7% in Turkey. It has been estimated that 14 million Europeans are chronically infected with HBV, resulting in 36,000 deaths each year, but accurate data are lacking in most European countries; as many as 90% of HBV-infected Europeans are not aware of their infection.2Hatzakis A. Wait S. Bruix J. et al.The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference.J Viral Hepat. 2011; 18: 1-16Crossref PubMed Scopus (189) Google ScholarEfficacy of Treatments for CHBGoals and End PointsThe ultimate goal of CHB treatment is to prevent the development of cirrhosis, liver failure, and HCC. Clinical trials have relied on surrogate end points that correlate with clinical end points. Surrogate end points are biochemical (a normalized level of alanine aminotransferase [ALT]), virologic (suppression of HBV DNA to undetectable levels by polymerase chain reaction [PCR] assays), serologic (loss of hepatitis B e antigen [HBeAg], with or without seroconversion to hepatitis B e antibody, in HBeAg-positive patients and loss of hepatitis B surface antigen [HBsAg], with or without seroconversion to hepatitis B surface antibody), as well as histologic (decrease in necrosis and inflammation score by ≥2 points with no worsening of fibrosis). PCR assays with lower limits of detection of 300–1000 copies/mL, or roughly 60–200 IU/mL, were used in phase 3 trials, but real-time PCR assays with improved sensitivity (a lower limit of detection of 10–20 IU/mL) are available and should be used to monitor virologic response.Eligibility CriteriaPhase 3 trials of therapies for CHB have focused on enrolling patients with high levels of HBV DNA, abnormal levels of ALT, and compensated liver disease. Phase 3 trials of pegylated-interferon (PEG-IFN), with or without lamivudine, compared with lamivudine monotherapy, enrolled adult HBeAg-positive patients with serum levels of HBV DNA greater than 500,000 copies/mL (∼100,000 IU/mL) and HBeAg-negative patients with levels of HBV DNA greater than 100,000 copies/mL (∼20,000 IU/mL), along with abnormal levels of ALT (1–10 times the upper limit of normal [×ULN]) and evidence of chronic hepatitis from liver biopsy specimens.7Lau G.K. Piratvisuth T. Luo K.X. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Crossref PubMed Scopus (1357) Google Scholar, 8Marcellin P. Lau G.K. Bonino F. et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217Crossref PubMed Scopus (1048) Google Scholar, 9Janssen H.L. van Zonneveld M. Senturk H. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar, 10Chan H.L. Leung N.W. Hui A.Y. et al.A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone.Ann Intern Med. 2005; 142: 240-250Crossref PubMed Scopus (262) Google Scholar Phase 3 trials of nucleos(t)ide analogues generally have enrolled HBeAg-positive patients with levels of HBV DNA greater than 1,000,000 copies/mL (∼200,000 IU/mL) and HBeAg-negative patients with levels of HBV DNA greater than 100,000 copies/mL (∼20,000 IU/mL), along with levels of ALT 1.3–10 ×ULN and evidence of chronic hepatitis from liver biopsy specimens.11Dienstag J.L. Schiff E.R. Wright T.L. 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, 12Marcellin P. Chang T.T. Lim S.G. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816Crossref PubMed Scopus (1278) Google Scholar, 13Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.N Engl J Med. 2005; 352: 2673-2681Crossref PubMed Scopus (497) Google Scholar, 14Lai C.L. Gane E. Liaw Y.F. et al.Telbivudine versus lamivudine in patients with chronic hepatitis B.N Engl J Med. 2007; 357: 2576-2588Crossref PubMed Scopus (697) Google Scholar, 15Lai C.L. Shouval D. Lok A.S. et al.Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2006; 354: 1011-1020Crossref PubMed Scopus (1050) Google Scholar, 16Chang T.T. Gish R.G. de Man R. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1241) Google Scholar, 17Marcellin P. Heathcote E.J. Buti M. et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl J Med. 2008; 359: 2442-2455Crossref PubMed Scopus (979) Google Scholar These trials excluded patients with decompensated liver disease; other causes of liver disease; co-infection with human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis D virus; severe or unstable medical comorbidities; or medical conditions that require chronic immunosuppressive therapies, along with women who were pregnant or of child-bearing potential but were unwilling to practice contraception.ResponsesPublished reports from phase 3 trials have focused on responses at the end of 1 year of treatment. Although responses up to year 5 had been reported from some trials, these follow-up studies did not include all patients in the original trial, and some studies had modifications to the original treatment after the first year. Table 2, Table 3 summarize responses to the approved drugs in HBeAg-positive and in HBeAg-negative patients with CHB.Table 2Response Rates to Approved Therapies for HBeAg-Positive CHBTreatment response parametersLamivudineAdefovir dipivoxilEntecavirTelbivudineTenofovir disoproxil fumaratePEG-IFNaLiver biopsy performed at weeks 72 or 78, 24 weeks after stopping treatment.PEG-IFN plus lamivudineaLiver biopsy performed at weeks 72 or 78, 24 weeks after stopping treatment.Responses at weeks 48–52 Log reduction in HBV DNA, copies/mL5.53.56.96.56.22–4.55–7.2 Undetectable HBV DNA, %36–4413–216760762569 ALT normalization, %41–7548–6168777734–3946–51 Loss of HBeAg, %17–3224222621∼3027–44 HBeAg seroconversion, %16–2112–182122212724 Loss of HBsAg, %<102<1333–7 Histologic improvement, %bHistologic improvement defined as a ≥2-point decrease in necroinflammatory score and no worsening of fibrosis score.49–56537265743841 Genotypic resistance27004.4004–11Responses during extended treatmentcThe time point at which response was assessed in years from start of treatment is shown in parentheses. Undetectable HBV DNA, %39 (2)39 (5)94 (5)79 (4)65 (5)19 (3.5)dAssessment performed off treatment.26 (3)dAssessment performed off treatment. HBeAg seroconversion, %47 (3)48 (5)41 (5)42 (4)31 (4)37 (3.5)dAssessment performed off treatment.25 (3)dAssessment performed off treatment. Loss of HBsAg, %0–3 (2–3)2 (5)5 (5)1.3 (2)10 (5)11 (3.5)dAssessment performed off treatment.15 (3)dAssessment performed off treatment. Genotypic resistance65 (5)42 (5)1.2 (6)21 (2)0 (5)0N/ANOTE. The percentage of patients in the original cohort included in extended response reports was as follows: lamivudine, 17%–72%; adefovir, 38%; entecavir, 49% (entecavir 1.0 mg was used beginning in year 3 instead of approved 0.5 mg); tenofovir, 76% (34 of 39 patients with detectable HBV-DNA levels at week 72 opted to add emtricitabine); PEG-IFN, 65%. Data are from references 10Chan H.L. Leung N.W. Hui A.Y. et al.A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone.Ann Intern Med. 2005; 142: 240-250Crossref PubMed Scopus (262) Google Scholar, 11Dienstag J.L. Schiff E.R. Wright T.L. 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, 12Marcellin P. Chang T.T. Lim S.G. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816Crossref PubMed Scopus (1278) Google Scholar, 13Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. et al.Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.N Engl J Med. 2005; 352: 2673-2681Crossref PubMed Scopus (497) Google Scholar, 14Lai C.L. Gane E. Liaw Y.F. et al.Telbivudine versus lamivudine in patients with chronic hepatitis B.N Engl J Med. 2007; 357: 2576-2588Crossref PubMed Scopus (697) Google Scholar, 15Lai C.L. Shouval D. Lok A.S. et al.Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2006; 354: 1011-1020Crossref PubMed Scopus (1050) Google Scholar, 16Chang T.T. Gish R.G. de Man R. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1241) Google Scholar, 17Marcellin P. Heathcote E.J. Buti M. et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl J Med. 2008; 359: 2442-2455Crossref PubMed Scopus (979) Google Scholar, 18Buster E.H. Flink H.J. Cakaloglu Y. et al.Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.Gastroenterology. 2008; 135: 459-467Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 19Wong V.W. Wong G.L. Yan K.K. et al.Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.Hepatology. 2010; 51: 1945-1953Crossref PubMed Scopus (93) Google Scholar, 20Marcellin P. Bonino F. Lau G.K. et al.Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a.Gastroenterology. 2009; 136 (e1–4): 2169-2179Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 21Zeng M. Mao Y. Yao G. et al.A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B.Hepatology. 2006; 44: 108-116Crossref PubMed Scopus (69) Google Scholar, 24Marcellin P. Chang T.T. Lim S.G. et al.Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.Hepatology. 2008; 48: 750-758Crossref PubMed Scopus (265) Google Scholar, 25Heathcote J. Long term (4 year) efficacy and safety of tenofovir disoproxil fumarate (TDF) treatment in HBeAg-positive patients (HBeAg+) with chronic hepatitis B (study 103).Hepatology. 2010; 52: 556A-557AGoogle Scholar, 26Reijnders J.G. Perquin M.J. Zhang N. et al.Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.Gastroenterology. 2010; 139: 491-498Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 27Lee H.W. Lee H.J. Hwang J.S. et al.Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.Hepatology. 2010; 51: 415-421Crossref PubMed Scopus (97) Google Scholar, 28Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.N Engl J Med. 2003; 348: 800-807Crossref PubMed Scopus (945) Google Scholar, 29Hadziyannis 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 (780) Google Scholar.N/A, not available.a Liver biopsy performed at weeks 72 or 78, 24 weeks after stopping treatment.b Histologic improvement defined as a ≥2-point decrease in necroinflammatory score and no worsening of fibrosis score.c The time point at which response was assessed in years from start of treatment is shown in parentheses.d Assessment performed off treatment. Open table in a new tab Table 3Response Rates to Approved Therapies for HBeAg-Negative CHBTreatment response parametersLamivudineAdefovir dipivoxilEntecavirTelbivudineTenofovir disoproxil fumaratePEG-IFNaLiver biopsy performed at week 72, 24 weeks after stopping treatment.PEG-IFN plus lamivudineaLiver biopsy performed at week 72, 24 weeks after stopping treatment.Responses: weeks 48–52 Histologic improvement, %bHistologic improvement defined as a ≥2-point decrease in necroinflammatory score and no worsening of fibrosis score.60–6664–697067724838 Undetectable HBV DNA, %60–73519088936387 HBsAg loss, %<10<1<1043 Genotypic resistance, %2300.22.7001Responses: extended treatmentcThe time point at which response was assessed in years from the start of treatment is shown in parentheses. Undetectable HBV DNA, %6 (4)67 (5)NA84 (4)83 (5)18 (3)dAssessment performed off treatment.13 (3)dAssessment performed off treatment. HBsAg loss, %<1 (4)5 (5)NA<1 (2)0.3 (5)8 (3)dAssessment performed off treatment.8 (3)dAssessment performed off treatment. Genotypic resistance, %70–80 (5)29 (5)NA8.6 (2)0 (5)0N/ANOTE. The percentage of patients in the original cohort included in the extended response reports was as follows: lamivudine, 17%–72%; adefovir, 47%; entecavir, 50%; telbivudine, 100%; tenofovir, 76% (34 of 39 patients with detectable HBV-DNA levels at week 72 opted to receive additional emtricitabine); PEG-IFN, 58%. Data are from references 11Dienstag J.L. Schiff E.R. Wright T.L. 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, 17Marcellin P. Heathcote E.J. Buti M. et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl J Med. 2008; 359: 2442-2455Crossref PubMed Scopus (979) Google Scholar, 18Buster E.H. Flink H.J. Cakaloglu Y. et al.Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.Gastroenterology. 2008; 135: 459-467Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 20Marcellin P. Bonino F. Lau G.K. et al.Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a.Gastroenterology. 2009; 136 (e1–4): 2169-2179Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 23Lok 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 (695) Google Scholar, 26Reijnders J.G. Perquin M.J. Zhang N. et al.Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.Gastroenterology. 2010; 139: 491-498Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 32Lin S.M. Yu M.L. Lee C.M. et al.Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma.J Hepatol. 2007; 46: 45-52Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 33Niederau C. Heintges T. Lange S. et al.Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.N Engl J Med. 1996; 334: 1422-1427Crossref PubMed Scopus (800) Google Scholar.N/A, not available.a Liver biopsy performed at week 72, 24 weeks after stopping treatment.b Histologic improvement defined as a ≥2-point decrease in necroinflammatory score and no worsening of fibrosis score.c The time point at which response was assessed in years from the start of treatment is shown in parentheses.d Assessment performed off treatment. Open table in a new tab PEG-IFNA large, phase 3 trial of PEG-IFN with or without lamivudine, compared with lamivudine monotherapy, in HBeAg-positive patients showed that PEG-IFN, with or without lamivudine, was superior to lamivudine monotherapy—the addition of lamivudine to PEG-IFN did not provide any benefit.7Lau G.K. Piratvisuth T. Luo K.X. et al.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695Crossref PubMed Scopus (1357) Google Scholar Similar responses were observed in other trials of PEG-IFN (Table 2).9Janssen H.L. van Zonneveld M. Senturk H. et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129Abstract Full Text Full Text PDF PubMed Scopus (1020) Google Scholar, 10Chan H.L. Leung N.W. Hui A.Y. et al.A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone.Ann Intern Med. 2005; 142: 240-250Crossref PubMed Scopus (262) Google Scholar Follow-up evaluation of patients from one trial in Europe and Asia (of mixed HBV genotypes) showed that 19% had undetectable levels of HBV DNA, 37% had lost HBeAg, and 11% had lost HBsAg after a mean of 3.5 years from completion of PEG-IFN treatment. Patients with genotype A infection had a significantly higher rate of HBsAg loss than those with non-A genotype infection (28% vs 3%). Among the initial responders, 81% had durable loss of HBeAg and 30% lost HBsAg.18Buster E.H. Flink H.J. Cakaloglu Y. et al.Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.Gastroenterology. 2008; 135: 459-467Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar By contrast, follow-up evaluation of patients in a trial in Hong Kong (only genotypes B and C) found that only 2.4% of patients lost HBsAg at 5 years, despite similarly high rates (82%) of durable seroconversion of HBeAg.19Wong V.W. Wong G.L. Yan K.K. et al.Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.Hepatology. 2010; 51: 1945-1953Crossref PubMed Scopus (93) Google ScholarA large, phase 3 trial of a 48-week course of PEG-IFN, with or without lamivudine, compared with lamivudine monotherapy, in patients with HBeAg-negative CHB showed that patients who received PEG-IFN had a significantly higher rate of sustained, off-treatment response (Table 3).8Marcellin P. Lau G.K. Bonino F. et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217Crossref PubMed Scopus (1048) Google Scholar This difference was maintained when patients were re-evaluated 3 years after treatment was discontinued.20Marcellin P. Bonino F. Lau G.K. et al.Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a.Gastroenterology. 2009; 136 (e1–4): 2169-2179Abstract Full Text Full Text PDF PubMed Scopus (278) Google ScholarNucleos(t)ide analoguesPhase 3 clinical trials of nucleos(t)ide analogues in patients with HBeAg-positive CHB showed that after 1 year of treatment, 21%–76% had an undetectable level of HBV DNA and 41%–77% had a normalized level of ALT, but only 12%–22% achieved HBeAg seroconversion and 0%–3% lost HBsAg (Table 2).11Dienstag J.L. Schiff E.R. Wright T.L. 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, 12Marcellin P. Chang T.T. Lim S.G. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816Crossref PubMed Scopus (1278) Google Scholar, 14Lai C.L. Gane E. Liaw Y.F. et al.Telbivudine versus lamivudine in patients with chronic hepatitis B.N Engl J Med. 2007; 357: 2576-2588Crossref PubMed Scopus (697) Google Scholar, 16Chang T.T. Gish R.G. de Man R. et al.A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010Crossref PubMed Scopus (1241) Google Scholar, 17Marcellin P. Heathcote E.J. Buti M. et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl J Med. 2008; 359: 2442-2455Crossref PubMed Scopus (979) Google Scholar, 21Zeng M. Mao Y. Yao G. et al.A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B.Hepatology. 2006; 44: 108-116Crossref PubMed Scopus (69) Google Scholar Extension of the duration of nucleos(t)ide analogue treatment to 4–5 years was associated with a progressive increase in the rate of HBeAg seroconversion, to 31%–48%, but the rate of HBsAg loss remained low (0%–10%) (Table 2). In some studies, treatment in later years differed from that of standard clinical practice; the dose was increased (1 mg/d instead of the approved dose, 0.5 mg/d) from year 3 onward in the entecavir study, and 34 of 39 patients who had detectable levels of HBV DNA at week 72 opted to receive additional emtricitabine treatment in the tenofovir study.22Hou J.L. Xu D.Z. Guangeng S. et al.Long-term telbivudine therapy with effective viral control results in resolution of liver fibrosis and inflammation achieving treatment goals in patients with chronic hepatitis B (abstr).Hepatology. 2011; : 1048APubMed Google Scholar, 23Lok 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 (695) Google Scholar, 24Marcellin P. Chang T.T. Lim S.G. et al.Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.Hepatology. 2008; 48: 750-758Crossref PubMed Scopus (265) Google Scholar, 25Heathcote J. Long term (4 year) efficacy and safety of tenofovir disoproxil fumarate (TDF) treatment in HBeAg-positive patients (HBeAg+) with chronic hepatitis B (study 103).Hepatology. 2010; 52: 556A-557AGoogle ScholarThe durability of HBeAg seroconversion after treatment with nucleos(t)ide analogues has been reported to be less than 50% in some studies and more than 80% in others. Nucleos(t)ide analogues were found to induce only temporary HBeAg seroconversion in one study of 9 patients.26Reijnders J.G. Perquin M.J. Zhang N. et al.Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.Gastroenterology. 2010; 139: 491-498Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar However, a study of 178 patients reported the durability of HBeAg seroconversion to be 78% in the overall cohort and 91% among 117 patients who completed at least 12 months of consolidation therapy (the duration of continued treatment after HBeAg seroconversion).27Lee H.W. Lee H.J. Hwang J.S. et al.Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.Hepatology. 2010; 51: 415-421Crossref PubMed Scopus (97) Google ScholarA 1-year course of treatment with nucleos(t)ide analogues produced high rates of undetectable levels of HBV DNA (51%–93%) and normalization of ALT levels (62%–78%), but low rates of HBsAg loss (<1%) in nucleoside-naive patients with HBeAg-negative CHB (Table 3).14Lai C.L. Gane E. Liaw Y.F. et al.Telbivudine versus lamivudine in patients with chronic hepatitis B.N Engl J Med. 2007; 357: 2576-2588Crossref PubMed Scopus (697) Google Scholar, 15Lai C.L. Shouval D. Lok A.S. et al.Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2006; 354: 1011-1020Crossref PubMed Scopus (1050) Google Scholar, 17Marcellin P. Heathcote E.J. Buti M. et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl J Med. 2008; 359: 2442-2455Crossref PubMed Scopus (979) Google Scholar, 28Hadziyannis S.J. Tassopoulos N.C. Heathcote E.J. et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.N Engl J Med. 2003; 348: 800-807Crossref PubMed Scopus (945)
Referência(s)