Información del artículo
Resumen
Únicamente el 50% de los pacientes con infección crónica por el genotipo 1 del virus de la hepatitis C responde con éxito a la terapia estándar con interferón alfa pegilado y ribavirina, y los recientemente aprobados inhibidores de la proteasa deberán administrarse conjuntamente con estos dos fármacos. En consecuencia, predecir la respuesta a la terapia estándar, idealmente antes de iniciarla, sigue siendo un reto importante. Aunque se han descrito varios factores basales predictivos del fallo terapéutico, tanto del hospedador como del virus, ninguno de ellos es capaz de proporcionar predicciones fiables a nivel individual. Por otro lado, el desarrollo de modelos multivariantes que agrupan varios factores predictivos, hasta el momento no ha permitido obtener predicciones con el grado de fiabilidad necesario para poder ser implementados en la práctica clínica. Por lo tanto es necesario seguir investigando para mejorar estos modelos predictivos y describir nuevos factores que nos ayuden a predecir la respuesta de manera más fiable y reproducible. El desarrollo de algoritmos de selección de candidatos a recibir las nuevas terapias en función de sus probabilidades de responder o no a la terapia estándar permitirá reducir los costes asociados al tratamiento y mejorar la calidad de vida de los pacientes. Con esta revisión hemos querido dar una visión de las posibilidades actuales para predecir la respuesta a la terapia estándar en los pacientes con hepatitis C crónica por el genotipo 1 del virus de la hepatitis C.
Palabras clave:
Virus de la hepatitis C
Genotipo 1
Interferón alfa pegilado
Predicción de la respuesta a la terapia
Modelos multivariantes
Abstract
Only about 50% of patients chronically infected with hepatitis C virus genotype 1 achieve a successful response to standard treatment with pegylated interferon-alfa and ribavirin. Moreover, the recently approved protease inhibitors will have to be administered together with these drugs. Consequently, predicting response to standard treatment, ideally before starting it, remains an important challenge. Although several baseline predictors of treatment failure have been described, including clinical and virological factors, none of them is able to provide reliable predictions at the individual level. In addition, the development of multivariate models combining several predictive factors has not yet yielded predictions with the requisite reliability for use in clinical practice. Therefore, further research is needed to improve predictive models and to describe new factors that would enable us to predict treatment outcome with greater reliability and reproducibility. The development of candidate selection algorithms that help clinicians to identify which patients could benefit from the new therapies on the basis of their chances of responding to standard therapy is of major interest for both patient well-being and healthcare expense. This review attempts to provide a view of the current options for predicting the response to pegylated interferon-alfa plus ribavirin therapy in patients chronically infected with hepatitis C virus genotype 1.
Keywords:
Hepatitis C virus
Genotype 1
Pegylated interferon alfa
Treatment response prediction
Multivariate models
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Bibliografía
[1.]
L.B. Seeff.
Natural history of chronic hepatitis C.
Hepatology, 36 (2002), pp. S35-S46
[2.]
Brody H. Hepatitis C. Nature Outlook. 2011; 474:S1-21 [consultado 1-8-2011]. Disponible en: http://www.nature.com/nature/journal/v474/n7350_ supp/full/474S1a.html
[3.]
K.E. Reed, C.M. Rice.
Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties.
Curr Top Microbiol Immunol, 242 (2010), pp. 55-84
[4.]
P. Simmonds, J. Bukh, C. Combet, G. Deleage, N. Enomoto, S. Feinstone, et al.
Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes.
Hepatology, 42 (2005), pp. 962-973
[5.]
P. Farci, R.H. Purcell.
Clinical significance of hepatitis C virus genotypes and quasispecies.
Semin Liver Dis, 20 (2000), pp. 103-126
[6.]
J.I. Esteban, S. Sauleda, J. Quer.
The changing epidemiology of hepatitis C virus infection in Europe.
J Hepatol, 48 (2008), pp. 148-162
[7.]
European Association for the Study of the Liver.
EASL Clinical Practice Guidelines: Management of hepatitis C virus infection.
J Hepatol, 55 (2011), pp. 245-264
[8.]
Agencia Española de Medicamentos y Productos Sanitarios. Informe mensual sobre Medicamentos de Uso Humano y Productos Sanitarios. 2011 [consultado, 3-8-2011]. Disponible en: http://www.aemps.gob.es/informa/informeMensual/2011/mayo/docs/informe-mensual_mayo-2011.pdf
[9.]
I.M. Jacobson, J.G. McHutchison, G. Dusheiko, A.M. Di Bisceglie, K.R. Reddy, N.H. Bzowej, et al.
Telaprevir for previously untreated chronic hepatitis C virus infection.
N Engl J Med, 364 (2011), pp. 2405-2416
[10.]
F. Poordad, J. McCone Jr., B.R. Bacon, S. Bruno, M.P. Manns, M.S. Sulkowski, et al.
Boceprevir for untreated chronic HCV genotype 1 infection.
N Engl J Med, 364 (2011), pp. 1195-1206
[11.]
J.G. McHutchison, M. Manns, K. Patel, T. Poynard, K.L. Lindsay, C. Trepo, et al.
Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.
Gastroenterology, 123 (2002), pp. 1061-1069
[12.]
M.W. Fried, M.L. Shiffman, K.R. Reddy, C. Smith, G. Marinos, F.L. Goncales Jr., et al.
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
N Engl J Med, 347 (2002), pp. 975-982
[13.]
M.P. Manns, J.G. McHutchison, S.C. Gordon, V.K. Rustgi, M. Shiffman, R. Reindollar, et al.
Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
Lancet, 358 (2001), pp. 958-965
[14.]
P. Ferenci, M.W. Fried, M.L. Shiffman, C.I. Smith, G. Marinos, F.L. Goncales Jr., et al.
Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.
J Hepatol, 43 (2005), pp. 425-433
[15.]
A. Kau, J. Vermehren, C. Sarrazin.
Treatment predictors of a sustained virologic response in hepatitis B and C.
J Hepatol, 49 (2008), pp. 634-651
[16.]
D. Ge, J. Fellay, A.J. Thompson, J.S. Simon, K.V. Shianna, T.J. Urban, et al.
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
Nature, 461 (2009), pp. 399-401
[17.]
V. Suppiah, M. Moldovan, G. Ahlenstiel, T. Berg, M. Weltman, M.L. Abate, et al.
IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.
Nat Genet, 41 (2009), pp. 1100-1104
[18.]
Y. Tanaka, N. Nishida, M. Sugiyama, M. Kurosaki, K. Matsuura, N. Sakamoto, et al.
Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.
Nat Genet, 41 (2009), pp. 1105-1109
[19.]
M. Lagging, A.I. Romero, J. Westin, G. Norkrans, A.P. Dhillon, J.M. Pawlotsky, et al.
IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection.
Hepatology, 44 (2006), pp. 1617-1625
[20.]
C.M. Lange, J. Bojunga, E. Ramos-López, M. Von Wagner, A. Hassler, J. Vermehren, D. Vitamin, et al.
deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy.
J Hepatol, 54 (2011), pp. 887-893
[21.]
J. Fellay, A.J. Thompson, D. Ge, C.E. Gumbs, T.J. Urban, K.V. Shianna, et al.
ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C.
Nature, 464 (2010), pp. 405-408
[22.]
L. Chen, I. Borozan, J. Feld, J. Sun, L.L. Tannis, C. Coltescu, et al.
Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection.
Gastroenterology, 128 (2005), pp. 1437-1444
[23.]
Y. Murakami, M. Tanaka, H. Toyoda, K. Hayashi, M. Kuroda, A. Tajima, et al.
Hepatic microRNA expression is associated with the response to interferon treatment of chronic hepatitis C.
BMC Med Genomics, 3 (2010), pp. 48
[24.]
S.J. Hadziyannis, H. Sette Jr., T.R. Morgan, V. Balan, M. Diago, P. Marcellin, et al.
Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
Ann Intern Med, 140 (2004), pp. 346-355
[25.]
J.G. McHutchison, E.J. Lawitz, M.L. Shiffman, A.J. Muir, G.W. Galler, J. McCone, et al.
Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.
N Engl J Med, 361 (2009), pp. 580-593
[26.]
A. Wohnsland, W.P. Hofmann, C. Sarrazin.
Viral determinants of resistance to treatment in patients with hepatitis C.
Clin Microbiol Rev, 20 (2007), pp. 23-38
[27.]
N. Akuta, F. Suzuki, H. Sezaki, Y. Suzuki, T. Hosaka, T. Someya, et al.
Association of amino acid substitution pattern in Core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy.
Intervirology, 48 (2005), pp. 372-380
[28.]
N. Akuta, F. Suzuki, H. Sezaki, Y. Suzuki, T. Hosaka, T. Someya, et al.
Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load.
J Med Virol, 78 (2006), pp. 83-90
[29.]
N. Akuta, F. Suzuki, Y. Kawamura, H. Yatsuji, H. Sezaki, Y. Suzuki, et al.
Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the Core region and low-density lipoprotein cholesterol levels.
J Hepatol, 46 (2007), pp. 403-410
[30.]
N. Akuta, F. Suzuki, M. Hirakawa, Y. Kawamura, H. Yatsuji, H. Sezaki, et al.
A matched case-controlled study of 48 and 72 weeks of peginterferon plus ribavirin combination therapy in patients infected with HCV genotype 1b in Japan: amino acid substitutions in HCV Core region as predictor of sustained virological response.
J Med Virol, 81 (2009), pp. 452-458
[31.]
F. Kurbanov, Y. Tanaka, K. Matsuura, F. Sugauchi, A. Elkady, A. Khan, et al.
Positive selection of Core 70Q variant genotype 1b hepatitis C virus strains induced by pegylated interferon and ribavirin.
J Infect Dis, 201 (2010), pp. 1663-1671
[32.]
A. Blindenbacher, F.H. Duong, L. Hunziker, S.T. Stutvoet, X. Wang, L. Terracciano, et al.
Expression of hepatitis C virus proteins inhibits interferon alpha signaling in the liver of transgenic mice.
Gastroenterology, 124 (2003), pp. 1465-1475
[33.]
J.G. Bode, S. Ludwig, C. Ehrhardt, U. Albrecht, A. Erhardt, F. Schaper, et al.
IFN-alpha antagonistic activity of HCV Core protein involves induction of suppressor of cytokine signaling-3.
FASEB J, 17 (2003), pp. 488-490
[34.]
Y. Funaoka, N. Sakamoto, G. Suda, Y. Itsui, M. Nakagawa, S. Kakinuma, et al.
Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of Core amino acids 70 and 91.
J Virol, 85 (2011), pp. 5986-5994
[35.]
P. Farci, A. Shimoda, D. Wong, T. Cabezon, D. De Gioannis, A. Strazzera, et al.
Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein.
Proc Natl Acad Sci USA, 93 (1996), pp. 15394-15399
[36.]
F. Penin, C. Combet, G. Germanidis, P.O. Frainais, G. Deleage, J.M. Pawlotsky.
Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment.
J Virol, 75 (2001), pp. 5703-5710
[37.]
J.M. Pawlotsky, L. Cocquerel, D. Durantel, D. Lavillette, H. Lerat, E.I. Pecheur, et al.
HCV research 20 years after discovery: a summary of the 16th international symposium on hepatitis C virus and related viruses.
Gastroenterology, 138 (2010), pp. 6-12
[38.]
M. Troesch, I. Meunier, P. Lapierre, N. Lapointe, F. Álvarez, M. Boucher, et al.
Study of a novel hypervariable region in hepatitis C virus (HCV) E2 envelope glycoprotein.
Virology, 352 (2006), pp. 357-367
[39.]
B.I. Yeh, K.H. Han, H.W. Lee, J.H. Sohn, W.S. Ryu, D.J. Yoon, et al.
Factors predictive of response to interferon-alpha therapy in hepatitis C virus type 1b infection.
J Med Virol, 66 (2002), pp. 481-487
[40.]
E. Ueda, N. Enomoto, N. Sakamoto, K. Hamano, C. Sato, N. Izumi, et al.
Changes of HCV quasispecies during combination therapy with interferon and ribavirin.
Hepatol Res, 29 (2004), pp. 89-96
[41.]
C. Morishima, S.J. Polyak, R. Ray, M.C. Doherty, A.M. Di Bisceglie, P.F. Malet, C. Hepatitis, et al.
virus-specific immune responses and quasi-species variability at baseline are associated with nonresponse to antiviral therapy during advanced hepatitis C.
J Infect Dis, 193 (2006), pp. 931-940
[42.]
F.X. López-Labrador, S. Ampurdanés, M. Giménez-Barcons, M. Guilera, J. Costa, M.T. Jiménez de Anta, et al.
Relationship of the genomic complexity of hepatitis C virus with liver disease severity and response to interferon in patients with chronic HCV genotype 1b infection [correction of interferon].
Hepatology, 29 (1999), pp. 897-903
[43.]
P. Farci, R. Strazzera, H.J. Alter, S. Farci, D. Degioannis, A. Coiana, et al.
Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome.
Proc Natl Acad Sci USA, 99 (2002), pp. 3081-3086
[44.]
W.P. Hofmann, C. Sarrazin, B. Kronenberger, B. Schonberger, K. Bruch, S. Zeuzem.
Mutations within the CD81-binding sites and hypervariable region 2 of the envelope 2 protein: correlation with treatment response in hepatitis C virusinfected patients.
J Infect Dis, 187 (2003), pp. 982-987
[45.]
I. Abbate, I.O. Lo, R. Di Stefano, G. Cappiello, E. Girardi, R. Longo, et al.
HVR-1 quasispecies modifications occur early and are correlated to initial but not sustained response in HCV-infected patients treated with pegylated or standardinterferon and ribavirin.
J Hepatol, 40 (2004), pp. 831-836
[46.]
T.J. Chambers, X. Fan, D.A. Droll, E. Hembrador, T. Slater, M.W. Nickells, et al.
Quasispecies heterogeneity within the E1/E2 region as a pretreatment variable during pegylated interferon therapy of chronic hepatitis C virus infection.
J Virol, 79 (2005), pp. 3071-3083
[47.]
J.M. Cuevas, M. Torres-Puente, N. Jiménez-Hernández, M.A. Bracho, I. García-Robles, F. Carnicer, et al.
Refined analysis of genetic variability parameters in hepatitis C virus and the ability to predict antiviral treatment response.
J Viral Hepat, 15 (2008), pp. 578-590
[48.]
M. Torres-Puente, J.M. Cuevas, N. Jiménez-Hernández, M.A. Bracho, I. García-Robles, B. Wrobel, et al.
Genetic variability in hepatitis C virus and its role in antiviral treatment response.
J Viral Hepat, 15 (2008), pp. 188-199
[49.]
N. Enomoto, I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, et al.
Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.
J Clin Invest, 96 (1995), pp. 224-230
[50.]
J.M. Pawlotsky, G. Germanidis, A.U. Neumann, M. Pellerin, P.O. Frainais, D. Dhumeaux.
Interferon resistance of hepatitis C virus genotype 1b: relationship to nonstructural 5A gene quasispecies mutations.
J Virol, 72 (1998), pp. 2795-2805
[51.]
M. Pascu, P. Martus, M. Hohne, B. Wiedenmann, U. Hopf, E. Schreier, et al.
Sustained virological response in hepatitis C virus type 1b infected patients is predicted by the number of mutations within the NS5A-ISDR: a meta-analysis focused on geographical differences.
Gut, 53 (2004), pp. 1345-1351
[52.]
H. Shirakawa, A. Matsumoto, S. Joshita, M. Komatsu, N. Tanaka, T. Umemura, et al.
Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors.
Hepatology, 48 (2008), pp. 1753-1760
[53.]
K. Hayashi, Y. Katano, M. Ishigami, A. Itoh, Y. Hirooka, I. Nakano, et al.
Mutations in the Core and NS5A region of hepatitis C virus genotype 1b and correlation with response to pegylated-interferon-alpha 2b and ribavirin combination therapy.
J Viral Hepat, 18 (2011), pp. 280-286
[54.]
S. Yoneda, T. Umemura, Y. Katsuyama, A. Kamijo, S. Joshita, M. Komatsu, et al.
Association of serum cytokine levels with treatment response to pegylated interferon and ribavirin therapy in genotype 1 chronic hepatitis C patients.
J Infect Dis, 203 (2011), pp. 1087-1095
[55.]
M. Kurosaki, Y. Tanaka, N. Nishida, N. Sakamoto, N. Enomoto, M. Honda, et al.
Pretreatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors.
J Hepatol, 54 (2011), pp. 439-448
[56.]
J.I. Esteban, S. Sauleda, J. Quer.
The changing epidemiology of hepatitis C virus infection in Europe.
J Hepatol, 48 (2008), pp. 148-162
[57.]
M. Bruguera, X. Forns.
Hepatitis C in Spain.
Med Clin (Barc), 127 (2006), pp. 113-117
[58.]
S. Raimondi, S. Bruno, M.U. Mondelli, P. Maisonneuve, C. Hepatitis.
virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis.
J Hepatol, 50 (2009), pp. 1142-1154
[59.]
J.M. Costa, D. Telehin, M. Munteanu, T. Kobryn, Y. Ngo, V. Thibault, et al.
HCVGenoFibrotest: a combination of viral, liver and genomic (IL28b ITPA, UGT1A1) biomarkers for predicting treatment response in patients with chronic hepatitis C.
Clin Res Hepatol Gastroenterol, 35 (2011), pp. 204-213
[60.]
M. Lagging, G. Askarieh, F. Negro, S. Bibert, J. Soderholm, J. Westin, et al.
Response prediction in chronic hepatitis C by assessment of IP-10 and IL28B-related single nucleotide polymorphisms.
PLoS One, 6 (2011), pp. e17232
[61.]
G. Fattovich, L. Covolo, S. Bibert, G. Askarieh, M. Lagging, S. Clement, et al.
IL28B polymorphisms IP-10 and viral load predict virological response to therapy in chronic hepatitis C.
Aliment Pharmacol Ther, 33 (2011), pp. 1162-1172
[62.]
M. Kurosaki, N. Sakamoto, M. Iwasaki, M. Sakamoto, Y. Suzuki, N. Hiramatsu, et al.
Sequences in the interferon sensitivity-determining region and Core region of hepatitis C virus impact pretreatment prediction of response to PEG-interferon plus ribavirin: data mining analysis.
J Med Virol, 83 (2011), pp. 445-452
[63.]
D. Bitetto, G. Fattovich, C. Fabris, E. Ceriani, E. Falleti, E. Fornasiere, et al.
Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C.
Hepatology, 53 (2011), pp. 1118-1126
[64.]
R. Aurora, M.J. Donlin, N.A. Cannon, J.E. Tavis.
Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans.
J Clin Invest, 119 (2009), pp. 225-236
[65.]
V. Saludes, M.A. Bracho, O. Valero, M. Ardèvol, R. Planas, F. González-Candelas, et al.
Baseline prediction of combination therapy outcome in hepatitis C virus 1b infected patients by discriminant analysis using viral and host factors.
PLoS One, 5 (2010), pp. e14132
[66.]
M.T. Dill, F.H. Duong, J.E. Vogt, S. Bibert, P.Y. Bochud, L. Terracciano, et al.
Interferoninduced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C.
Gastroenterology, 140 (2011), pp. 1021-1031
[67.]
E. Martínez-Bauer, J. Crespo, M. Romero-Gómez, R. Moreno-Otero, R. Solà, N. Tesei, et al.
Development and validation of two models for early prediction of response to therapy in genotype 1 chronic hepatitis C.
Hepatology, 43 (2006), pp. 72-80
[68.]
Y. Hashimoto, H. Ochi, H. Abe, Y. Hayashida, M. Tsuge, F. Mitsui, et al.
Prediction of response to peginterferon-alfa-2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b.
J Med Virol, 83 (2011), pp. 981-988
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