Información del artículo
La infección por el virus de la hepatitis B (VHB) es un problema de salud pública mundial. Se estima que hay en el mundo 350 millones de personas infectadas crónicamente por el VHB que pueden evolucionar a cirrosis y hepatocarcinoma, con cerca de un millón de muertes anuales. En los últimos años, las opciones terapéuticas de la hepatitis B crónica (HBC) han aumentado y en la actualidad se dispone de 6 tratamientos autorizados: interferón alfa (IFNα) estándar, interferón pegilado alfa (PEG-IFNα), lamivudina, adefovir, entecavir y telbivudina. Desde hace 25 años se ha utilizado el IFNα convencional como tratamiento de la HBC y actualmente se indica el PEG-IFNα por ser más eficaz. Ambos constituyen opciones terapéuticas de primera línea para la HBC AgHBe positivo y AgHBe negativo. Las ventajas del IFNα y PEG-IFNα son su administración con duración definida en el tiempo, consiguen mayor tasa de respuesta sostenida y no inducen mutantes del VHB con resistencia antiviral. Consiguen mayor aclaramiento de AgHBe y AgHBs debido a su acción antiviral e inmunomoduladora. El PEG-IFNα induce una respuesta sostenida bioquímica y virológica en alrededor de un tercio de los pacientes con HBC AgHBe positivo. Responden mejor al IFNα y PEG-IFNα los pacientes que tienen transaminasas elevadas, carga viral moderada y los genotipos A y B del VHB. El IFNα y el PEG-IFNα tienen el inconveniente de ser fármacos con efectos secundarios y contraindicaciones. No se pueden administrar a pacientes con cirrosis descompensada. La combinación de análogos de nucleóstidos/nucleótidos con PEG-IFNα podría conseguir tasas de respuesta sostenida más elevadas, pero debe investigarse qué estrategia terapéutica es la más adecuada.
Palabras clave:
Virus de la hepatitis B
Hepatitis crónica por virus de la hepatitis B
Interferón alfa
Interferón pegilado alfa
Respuesta sostenida
Genotipos del virus de la hepatitis B
Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-α, pegylated interferon-α (PEG-IFNα), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNα has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNα is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNα and PEG-IFNα are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNα induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNα and PEG-IFNα is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNα and PEG-IFNα are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNα could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.
Key words:
Hepatitis B virus (HBV)
Chronic hepatitis HBV (CHB)
Interferon α (IFNα)
Pegylated interferon α (PEG-IFNα)
Sustained response
Hepatitis B virus genotypes
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Bibliografía
[1.]
D. Ganem, A.M. Prince.
Hepatitis B virus infection:natural history and clinical consequences.
N Engl J Med, 350 (2004), pp. 1118-1129
[2.]
C.L. Lai, V. Ratziu, M.F. Yuen, T. Poynard.
Viral hepatitis B.
Lancet, 362 (2003), pp. 2089-2094
[3.]
J.H. Hoofnagle, E. Doo, T.J. Liang, R. Fleischer, A.S. Lok.
Management of hepatitis B: summary of a clinical research workshop.
Hepatology, 45 (2007), pp. 1056-1075
[4.]
A.S. Lok, B.J. McMahon.
AASLD Practice Guidelines. Chronic hepatitis B.
Hepatology, 45 (2007), pp. 507-539
[5.]
The EASL Jury.
EASL International consensus conference on hepatitis B 13-14 September 2002. Geneva, Switzerland. Consensus statement.
J Hepatol, 38 (2003), pp. 533-540
[6.]
Y.F. Liaw, N. Leung, R. Guan, G.K. Lau, I. Merican, G. McCaughan, et al.
Asian-Pacific consensus update working party on chronic hepatitis B. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update.
Liver Int, 25 (2005), pp. 472-489
[7.]
E.B. Keeffe, D.T. Dieterich, S.H. Han, I.M. Jacobson, P. Martin, E.R. Schiff, et al.
A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update.
Clin Gastroenterol Hepatol, 4 (2006), pp. 936-962
[8.]
G.C. Farrell, N.C. Teoh.
Management of chronic hepatitis B virus infection: a new era of disease control.
Intern Med J, 36 (2006), pp. 100-113
[9.]
R.G. Gish.
Clinical trial results of new therapies for HBV: implications for treatment guidelines.
Semin Liver Dis, 25 (2005), pp. 29-39
[10.]
R.P. Perrillo.
Current treatment of chronic hepatitis B: benefits and limitations.
Semin Liver Dis, 25 (2005), pp. 20-28
[11.]
W.G. Cooksley.
Treatment with interferons (including pegylated interferons) in patients with hepatitis B.
Semin Liver Dis, 24 (2004), pp. 45-53
[12.]
G.W. Robins, L.J. Scott, G.M. Keating.
Peginterferon-alpha-2a (40kD): a review of its use in the management of patients with chronic hepatitis B.
Drugs, 65 (2005), pp. 809-825
[13.]
A. Isaacs, J. Lindenmann.
Virus interference. I. The interferon.
J Interferon Res, 7 (1987), pp. 429-438
[14.]
H.B. Greenberg, R.B. Pollard, L.I. Lutwick, P.B. Gregory, W.S. Robinson, T.C. Merigan.
Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis.
N Engl J Med, 295 (1976), pp. 517-522
[15.]
Ch.E. Samuel.
Antiviral actions of interferons.
Clin Microbiol Rev, 14 (2001), pp. 778-809
[16.]
J.U. Gutterman.
Cytokine therapeutics: lessons from interferon alpha.
Proc Natl Acad Sci USA, 91 (1994), pp. 1198-1205
[17.]
S. Goodbourn, L. Didcock, R.E. Randall.
Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures.
J Gen Virol, 81 (2000), pp. 2341-2364
[18.]
G.R. Stark, I.M. Kerr, B.R. Williams, R.H. Silverman, R.D. Schreiber.
How cells respond to interferons.
Annu Rev Biochem, 67 (1998), pp. 227-264
[19.]
D.L. Brassard, M.J. Grace, R.W. Bordens.
Interferon-alpha as an immunotherapeutic protein.
J Leukoc Biol, 71 (2002), pp. 565-581
[20.]
A. Craxi, W.G. Cooksley.
Pegylated interferons for chronic hepatitis B.
Antiviral Res, 60 (2003), pp. 87-89
[21.]
W.G.E. Cooksley, T. Piratvisuth, S.D. Lee, V. Mahachai, Y.C. Chao, T. Tanwandee, et al.
Pegynterferon a-2a (40 KDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.
J Viral Hepat, 10 (2003), pp. 298-305
[22.]
R. Perrillo, C. Tamburro, F. Regenstein, L. Balart, H. Bodenheimer, M. Silva, et al.
Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.
Gastroenterol, 109 (1995), pp. 908-916
[23.]
J.H. Hoofnagle, A.M. Di Bisceglie, J.G. Waggoner, Y. Park.
Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B.
Gastroenterol, 104 (1993), pp. 1116-1121
[24.]
E.H. Buster, B.E. Hansen, M. Buti, J. Delwaide, C. Niederau, P.P. Michielsen, HBV 99-01 Study Group, et al.
Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis.
Hepatology, 46 (2007), pp. 388-394
[25.]
M. Van Zonneveld, P. Honkoop, B.E. Hansen, H.G. Niesters, S.D. Murad, R.A. De Man, et al.
Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.
Hepatology, 39 (2004), pp. 804-810
[26.]
H.L. Janssen, G. Gerken, V. Carreno, P. Marcellin, N.V. Naoumov, A. Craxi, et al.
Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).
Hepatology, 30 (1999), pp. 238-243
[27.]
P. Lampertico, E. Del Ninno, M. Viganò, R. Romeo, M.F. Donato, E. Sablon, et al.
Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy.
Hepatology, 37 (2003), pp. 756-763
[28.]
H.L. Chan, N.W. Leung, A.Y. Hui, V.W. Wong, C.T. Liew, A.M. Chim, et al.
A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha 2b and lamivudine with lamivudine alone.
Ann Intern Med, 142 (2005), pp. 240-250
[29.]
J.B. Wong, R.S. Koff, F. Tine, S.G. Pauker.
Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive chronic hepatitis B.
Ann Intern Med, 122 (1995), pp. 664-675
[30.]
Almasio P, Camma C, Giunta M, Craxi A. treatment of chronic hepatitis B: an evidence-based review. En: McDonald JWD, Borroughs A, Feagan BG, editors. Evidence-based gastroenterology and hepatology. London: BMJ Publications. 1999. p: 305-21.
[31.]
F. Tine, A. Liberati, A. Craxi, P. Almasio, L. Pagliaro.
Interferon treatment in patients with chronic hepatitis B: a meta-analysis of the published literature.
J Hepatol, 18 (1993), pp. 154-162
[32.]
D.K. Wong, A.M. Cheung, K. O’Rourke, C.D. Naylor, A.S. Detsky, J. Heathcote.
Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.
Ann Intern Med, 119 (1993), pp. 312-323
[33.]
A. Craxi, D. Di Bona, C. Camma.
Interferon-alpha for HBeAg-positive chronic hepatitis B.
J Hepatol, 39 (2003), pp. S99-S105
[34.]
D.T. Lau, J. Everhart, D.E. Kleiner, Y. Park, J. Vergalla, P. Schmid, et al.
Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa.
Gastroenterology, 113 (1997), pp. 1660-1667
[35.]
S.M. Lin, I.S. Sheen, R.N. Chien, C.M. Chu, Y.F. Liaw.
Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.
Hepatology, 29 (1999), pp. 971-975
[36.]
J. Korenman, B. Baker, J. Waggoner, J.E. Everhart, A.M. Di Bisceglie, J.H. Hoofnagle.
Long-term remission of chronic hepatitis B after alpha-interferon therapy.
Ann Intern Med, 114 (1991), pp. 629-634
[37.]
Y.S. Hsu, R.N. Chien, C.T. Yeh, I.S. Sheen, H.Y. Chiou, C.M. Chu, et al.
Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
Hepatology, 35 (2002), pp. 1522-1527
[38.]
E.M. Sokal, H.S. Conjeevaram, E.A. Roberts, F. Alvarez, E.M. Bern, P. Goyens, et al.
Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
Gastroenterol, 114 (1998), pp. 988-995
[39.]
P. Jara, F. Bortolotti.
Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children.
J Pediatr Gastroenterol Nutr, 29 (1999), pp. 163-170
[40.]
D. Torre, R. Tambini.
Interferon-alpha therapy for chronic hepatitis B in children: a meta-analysis.
Clin Infect Dis, 23 (1996), pp. 131-137
[41.]
L. D’Antiga, M. Aw, M. Atkins, A. Moorat, D. Vergani, G. Mieli-Vergani.
Combined lamivudine/interferon-alpha treatment in «immunotolerant» children perinatally infected with hepatitis B: a pilot study.
J Pediatr, 148 (2006), pp. 228-233
[42.]
G. Fattovich, G. Giustina, J. Sanchez-Tapias, C. Quero, A. Mas, P.G. Olivotto, et al.
Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP).
Am J Gastroenterol, 93 (1998), pp. 896-900
[43.]
C. Niederau, T. Heintges, S. Lange, G. Goldmann, C.M. Niederau, L. Mohr, et al.
Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.
N Engl J Med, 334 (1996), pp. 1422-1427
[44.]
M.R. Brunetto, F. Oliveri, B. Coco, G. Leandro, P. Colombatto, J.M. Gorin, et al.
Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.
J Hepatol, 36 (2002), pp. 263-270
[45.]
G.V. Papatheodoridis, E. Manesis, S.J. Hadziyannis.
The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.
J Hepatol, 34 (2001), pp. 306-313
[46.]
F. Oliveri, T. Santantonio, G. Bellati, P. Colombatto, G.C. Mels, L. Carriero, et al.
Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type and schedule of interferon.
Am J Gastroenterol, 94 (1999), pp. 1366-1372
[47.]
F. González-Mateos, C. García-Monzón, L. García-Buey, A. García-Sánchez, J.M. Pajares, R. Moreno-Otero.
Long-term effect of interferon alpha alone or after prednisone withdrawal in chronic hepatitis B. Interim report and review of the literature.
Hepatogastroenterol, 42 (1995), pp. 893-899
[48.]
M. Cohard, T. Poynard, P. Mathurin, J.P. Zarski.
Prednisone-interferon combination in the treatment of chronic hepatitis B: direct and indirect metanalysis.
Hepatology, 20 (1994), pp. 1390-1398
[49.]
S.W. Schalm, J. Heathcote, J. Cianciara, G. Farrell, M. Sherman, B. Willems, et al.
Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.
Gut, 46 (2000), pp. 562-568
[50.]
G. Barbaro, F. Zechini, A.M. Pellicelli, R. Francavilla, G. Scotto, D. Bacca, Lamivudine Italian Study Group Investigators, et al.
Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial.
J Hepatol, 35 (2001), pp. 406-411
[51.]
T. Sanantonio, G.A. Niro, E. Sinisi, et al.
Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B: a controlled pilot study.
J Hepatol, 36 (2002), pp. 799-804
[52.]
H.L. Janssen, S.W. Schalm, L. Berk, R.A. De Man, R.A. Heijtink.
Repeated courses of alpha-interferon for treatment of chronic hepatitis type B.
J Hepatol, 17 (1993), pp. S47-S51
[53.]
G.K. Lau, T. Piratvisuth, K.X. Luo, P. Marcellin, S. Thongsawat, G. Cooksley, Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group, et al.
Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
N Engl J Med, 352 (2005), pp. 2682-2695
[54.]
P. Marcellin, G.K. Lau, F. Bonino, P. Farci, S. Hadziyannis, R. Jin, Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group, 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, 351 (2004), pp. 1206-1217
[55.]
A.Y. Hui, H.L. Chan, A.Y. Cheung, G. Cooksley, J.J. Sung.
Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon.
Aliment Pharmacol Ther, 22 (2005), pp. 519-528
[56.]
H.L. Chan, A.Y. Hui, V.W. Wong, A.M. Chim, M.L. Wong, J.J. Sung.
Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B.
Hepatology, 41 (2005), pp. 1357-1364
[57.]
H.L. Janssen, M. Van Zonneveld, H. Senturk, S. Zeuzem, U.S. Akarca, Y. Cakaloglu, HBV 99-01 Study Group; Rotterdam Foundation for Liver Research, et al.
Pegylated interferon alfa-2b alone or in combination with lamivudine for HBe-Ag-positive chronic hepatitis B: a randomised trial.
Lancet, 365 (2005), pp. 123-129
[58.]
M. Van Zonneveld, P.E. Zondervan, Y. Cakaloglu, C. Simon, U.S. Akarca, T.M. So, HBV 99-01 Study Group, et al.
Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine.
Liver Int, 26 (2006), pp. 399-405
[59.]
H.J. Flink, B.E. Hansen, E.J. Heathcote, S.V. Feinman, H. Simsek, S. Karayalcin, HBV 99-01 Study Group, et al.
Successful treatment with peginterferon alfa-2b of HBeAg-positive HBV non-responders to standard interferon or lamivudine.
Am J Gastroenterol, 101 (2006), pp. 2523-2529
[60.]
W.F. Leemans, H.J. Flink, H.L. Janssen, H.G. Niesters, S.W. Schalm, R.A. De Man.
The effect of pegylated interferon-alpha on the treatment of lamivudine resistant chronic HBeAg positive hepatitis B virus infection.
J Hepatol, 44 (2006), pp. 507-511
[61.]
S. Kaymakoglu, D. Oguz, G. Gur, S. Gurel, E. Tankurt, G. Ersöz, et al.
Pegylated interferon Alfa-2b monotherapy and pegylated interferon Alfa-2b plus lamivudine combination therapy for patients with hepatitis B virus E antigen-negative chronic hepatitis B.
Antimicrob Agents Chemother, 51 (2007), pp. 3020-3022
[62.]
S.K. Sarin, A. Sood, M. Kumar, A. Arora, D. Amrapurkar, B.C. Sharma, National Collaborative Group on Hepatitis B, India, et al.
Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic hepatitis B.
Am J Gastroenterol, 102 (2007), pp. 96-104
[63.]
K. Wursthorn, M. Lutgehetmann, M. Dandri, T. Volz, P. Buggisch, B. Zollner, et al.
Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.
Hepatology, 44 (2006), pp. 675-684
[64.]
J.M. Sánchez-Tapias, J. Costa, A. Mas, M. Bruguera, J. Rodés.
Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.
Gastroenterology, 123 (2002), pp. 1848-1856
[65.]
J.H. Kao, P.J. Chen, M.Y. Lai, D.S. Chen.
Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.
Gastroenterology, 118 (2000), pp. 554-559
[66.]
C.T. Wai, C.J. Chu, M. Hussain, A.S. Lok.
HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.
Hepatology, 36 (2002), pp. 1425-1430
[67.]
S.K. Fung, A.S. Lok.
Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection?.
Hepatology, 40 (2004), pp. 790-792
[68.]
M. Enomoto, A. Tamori, S. Nishiguchi.
Hepatitis B virus genotypes and response to antiviral therapy.
Clin Lab, 52 (2006), pp. 43-47
[69.]
A. Erhardt, D. Blondin, K. Hauck, A. Sagir, T. Kohnle, T. Heintges, et al.
Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.
Gut, 54 (2005), pp. 1009-1013
[70.]
H.J. Flink, M. Van Zonneveld, B.E. Hansen, R.A. De Man, S.W. Schalm, H.L. Janssen, HBV 99-01 Study Group.
Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype.
Am J Gastroenterol, 101 (2006), pp. 297-303
[71.]
M.J. Ter Borg, M. Van Zonneveld, S. Zeuzem, H. Senturk, U.S. Akarca, C. Simon, HBV 99-01 Study Group, et al.
Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response.
Hepatology, 44 (2006), pp. 721-727
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