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Inicio Enfermedades Infecciosas y Microbiología Clínica Resistencias a los antivirales en los virus de las hepatitis B y C
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Vol. 24. Issue 9.
Pages 576-584 (November 2006)
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Vol. 24. Issue 9.
Pages 576-584 (November 2006)
Formación médica continuada
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Resistencias a los antivirales en los virus de las hepatitis B y C
Hepatitis B and C virus antiviral resistance
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11254
Ana Sáez-Lópeza,
Corresponding author
anasaezlopez@gamil.com

Correspondencia: Dra. A. Sáez-López. Servicio de Microbiología. Hospital Universitario Marqués de Valdecilla. Avda. de Valdecilla, s/n. 39008 Santander. España.
, Jesús Agüero-Balbína,b
a Servicio de Microbiología. Hospital Universitario Marqués de Valdecilla. España
b Departamento de Biología Molecular. Universidad de Cantabria. Santander. España
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Los virus de las hepatitis B (VHB) y C (VHC) son responsables de una elevada morbimortalidad de distribución mundial. Las consecuencias clínicas de las infecciones por estos virus (hepatitis crónica, cirrosis, hepatocarcinoma) van a depender de factores relacionados con el huésped y con el agente viral. Entre estos últimos, cada vez cobran más importancia aquellos que se relacionan con la respuesta al tratamiento antiviral, como son la aparición de mutantes de resistencia y la infección asociada a genotipos específicos del virus. En el caso del VHB, al igual que lo establecido para el virus de la inmunodeficiencia humana (VIH), es de vital importancia la presencia y acumulación de mutaciones responsables de la resistencia a los antivirales aprobados para el tratamiento de la infección, o de otros de reciente aplicación. Se han desarrollado técnicas para la detección de dichas mutaciones, así como algoritmos para predecir la respuesta al tratamiento. En los pacientes infectados por el VHC, sin embargo, la respuesta al tratamiento se encuentra más relacionada con la infección por genotípicos específicos, aunque en los últimos años se ha ampliado notablemente el conocimiento sobre los mecanismos moleculares de la respuesta al interferón en dichos pacientes.

Palabras clave:
VHB y VHC
Resistencias
Antivirales

Infection by the hepatitis B (HBV) and C (HCV) viruses is a major cause of morbidity and mortality world-wide. The clinical outcomes of infection by these viruses (e.g., chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma) depend on several factors related to the host and the viral agent. Among the latter, factors associated with the response to current antiviral therapies, such as he emergence of resistance mutants and the genotype responsible for the infection, are gaining increasing importance. As has been established for human immunodeficiency virus (HIV), the presence of resistance mutations in the viral polymerase constitutes the main problem for treating HBV infection with approved drugs and those recently applied. Methods have been developed to detect these mutations, as well as algorithms to predict the response to treatment. The outcome of treatment for HCV infection is highly influenced by the viral genotype, however, and our inderstanding of the molecular basis for the response to interferon in these patients has grown considerably in recent years.

Key words:
HBV and HCV
Resistance
Antiviral drugs
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Bibliografía
[1.]
M. Nowak, S. Bonhoeffer, A. Hill, R. Boehme, H. Thomas, H. McDade.
Viral dynamics in hepatitis B virus infection.
Proc Natl Acad Sci U S A, 29 (1996), pp. 31-33
[2.]
R. Girones, R.H. Miller.
Mutation rate of the hepadnavirus genome.
Virology, 170 (1989), pp. 595-597
[3.]
A. Barthololomeusz, S. Locarnini.
Antiviral drug resistance: clinical consequences and molecular aspects.
Semin Liver Dis, 26 (2006), pp. 162-170
[4.]
L.J. Stuyver, S.A. Locarnini, A. Lok, D.D. Richman, W.F. Carman, J.L. Dienstag, et al.
Nomenclature for antiviral-resistance human hepatitis B virus mutations in the polymerase region.
Hepatology, 33 (2001), pp. 751-757
[5.]
A. Barthololomeusz, B.G. Tehan, D.K. Chalmers.
Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations.
Antivir Ther, 9 (2004), pp. 149-160
[6.]
S. Locarnini, A. Hatzakis, J. Heathcote, E.B. Keeffe, T.J. Liang, D. Multimer, et al.
Management of antiviral resistance in patients with chronic hepatitis B.
Antivir Ther, 9 (2004), pp. 679-693
[7.]
A. Severini, X-Y. Liu, J. Wilson, D. Tyrell.
Mechanism of inhibition of duck hepatitis B virus polymerase by (-)-b-L-2’,3’-dideoxy-3’-thyacytidine.
Antimicrob Agents Chemother, 39 (1995), pp. 1430-1435
[8.]
Y.F. Liaw, N.W. Leung, T.T. Chang, R. Guan, D.I. Tai, K.Y. Ng, et al.
Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B.
Gastroenterology, 119 (2000), pp. 172-180
[9.]
N.W. Leung, C.L. Lai, T.T. Chang, R. Guan, C.M. Lee, K.Y. Ng, et al.
Extended lamivudine treatment in patients with chronic hepatitis b enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy.
Hepatology, 33 (2001), pp. 1527-1532
[10.]
T.T. Chang, C.L. Lai, R.N. Chien, R. Guan, S.G. Lim, C.M. Lee, et al.
Four years of lamivudine treatment in Chinese patients with chronic hepatitis B.
J Gastroenterol Hepatol, 19 (2004), pp. 1276-1282
[11.]
W.E. Delaney, H. Yang, C.E. Westland, K. Das, E. Arnold, C.S. Gibbs, et al.
The hepatitis B virus polymerase mutation rtV173L is selected during lamivudina therapy and enhances viral replication in vitro.
J Virol, 77 (2003), pp. 11833-11841
[12.]
M. Melegari, P.P. Scaglioni, J.R. Wands.
Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective.
Hepatology, 27 (1998), pp. 628-633
[13.]
S. Locarnini.
Hepatitis B viral resistance: mechanisms and diagnosis.
J Hepatol, 39 (2003), pp. S124-S132
[14.]
N. Ogata, K. Fujii, S. Takigawa, M. Nomoto, T. Ichida, H. Asakura.
Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudina therapy in Japanese patients with chronic hepatitis B.
J Med Virol, 59 (1999), pp. 270-276
[15.]
K. Das, X. Xiong, H. Yang, C.E. Westland, C.S. Gibbs, S.G. Sarafianos, et al.
Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B polymerase resistance to lamivudine (3TC) and emtricitabine (FTC).
[16.]
C.L. Lai, J. Dienstag, E. Schiff, N.W. Leung, M. Atkins, C. Hunt, et al.
Prevalence and clinical correlates of YMDD variants during lamivudina therapy for patients with chronic hepatitis B.
Clin Infect Dis, 36 (2003), pp. 687-696
[17.]
M.F. Yuen, E. Sablon, C.K. Hui, H.J. Yuan, H. Decraemer, C.L. Lai.
Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolongad lamivudine therapy.
Hepatology, 34 (2001), pp. 785-791
[18.]
P. Angus, R. Vaughan, S. Xiong, H. Yang, W. Delaney, C. Gibbs, et al.
Resistance to adefovir dipivoxil therapy associated with development of a novel mutation in the HBV polymerase.
Gastroenterology, 125 (2003), pp. 292-297
[19.]
J.P. Villeneuve, D. Durantel, S. Durantel, C. Westland, S. Xiong, C.L. Brosgart, et al.
Selection of hepatitis B virus strain resistant to adefovir in a liver transplantation patient.
J Hepatol, 39 (2003), pp. 1085-1089
[20.]
O. Schildgen, H. Sirma, A. Funk, C. Olotu, U.C. Wend, H. Hartmann, et al.
Variant of hepatitis B virus with primary resistance to adefovir.
N Engl J Med, 354 (2006), pp. 1807-1812
[21.]
S. Locarnini, X. Qi, S. Arterburn, A. Snow, C.L. Brosgart, G. Currie, et al.
Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB) (abstract).
J Hepatol, 42 (2005), pp. A36
[22.]
S. Hadziyannis, N.C. Tassopoulos, E.J. Heathcote, T.T. Chang, G. Kitis, M. Rizzetto, et al.
Long-term therapy with adefovir dipivoxil for HbeAg-negative chronic hepatitis B.
N Engl J Med, 352 (2005), pp. 2673-2681
[23.]
S.K. Fung, H.B. Chae, R.J. Fontana, H. Conjeevaram, J. Marrero, K. Oberhelman, et al.
Virologic response and resistance to adefovir in patients with chronic hepatitis B.
J Hepatol, 44 (2006), pp. 283-290
[24.]
H. Yang, C.E. Westland, W.E. Delaney, E.J. Heathcote, V. Ho, J. Fry, et al.
Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks.
Hepatology, 36 (2002), pp. 464-473
[25.]
D.J. Tenney, S.M. Levine, R.E. Rose, A.W. Walsh, S.P. Weinheimer, L. Discotto, et al.
Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine.
Antimicrob Agents Chemother, 48 (2004), pp. 3498-3507
[26.]
R.J. Colonno, R. Rose, S. Levine, J. Baldick, K. Pokornowski, M. Plym, et al.
Entecavir two year resistance update: no resistance observed in nucleoside naïve patients and low frequency resistance emergence in lamivudine refractory patients.
Hepatology, 42 (2005), pp. A962
[27.]
S.K. Ono, N. Kato, Y. Shiratori, J. Kato, T. Goto, R.F. Schinazi, et al.
The polymerase L528M cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance.
J Clin Invest, 107 (2001), pp. 449-455
[28.]
B. Seigneres, C. Pichoud, P. Martin, P. Furman, C. Trepo, F. Zoulim.
Inhibitory activity of dioxolane purine analogs on wild-type and lamivudine-resistant utants of hepadnaviruses.
Hepatology, 36 (2002), pp. 710-722
[29.]
F. Van Boemmel, H.H. Feucht, U. Spengler, B. Möller, C. Sarrazin, B. Zöllner, et al.
Tenofovir rescue for patients with lamivudine resistant HBV infection with suboptimal virologic response to adefovir.
Hepatology, 42 (2005), pp. 589A
[30.]
J. Sheldon, N. Camino, B. Rodes, A. Bartholomeusz, M. Kuiper, F. Tacke, et al.
Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.
Antivir Ther, 10 (2005), pp. 727-734
[31.]
W. Delaney, H. Yang, M. Miller, C. Gibbs, S. Xiong.
Lamivudine-resistant HBV is cross-resistant to L-dT and L-dC in vitro.
J Hepatol, 36 (2002), pp. 89.
[32.]
H. Yang, X. Qi, A. Sabogal, M. Millar, S. Xiong, W.E. Delaney.
Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine- resistant HBV.
Antivir Ther, 10 (2005), pp. 625-633
[33.]
M.N. Brunelle, A.C. Jacquard, C. Pichoud, D. Durantel, S. Carrouée-Durantel, J.P. Villeneuve, et al.
Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir.
Hepatology, 41 (2005), pp. 1391-1398
[34.]
H. Norder, A.M. Courouce, L.O. Magnius.
Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.
Virology, 198 (1994), pp. 489-503
[35.]
L. Stuyver, S. De Gendt, C. Van Geyt, F. Zoulim, M. Fried, R.F. Schinazi, et al.
A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness.
J Gen Virol, 81 (2000), pp. 67-74
[36.]
P. Arauz-Ruiz, H. Norder, B.H. Robertson, L.O. Magnius.
Genotype H: A new Amerindian genotype of hepatitis B virus revealed in Central America.
J Gen Virol, 83 (2002), pp. 2059-2073
[37.]
J.M. Echevarría, P. León.
Hepatitis B virus genotypes identified by a Line Probe Assay (LiPA) among chronic carriers from Spain.
Enferm Infecc Microbiol Clin, 22 (2004), pp. 452-454
[38.]
Y. Miyakawa, M. Mizokami.
Classifying hepatitis B virus genotypes.
Intervirology, 46 (2003), pp. 329-338
[39.]
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
[40.]
H.G.M. Niesters, S. Pas, R.A. De Man.
Detection of hepatitis B virus genotypes and mutants: current status.
J Clin Virol, 34 (2005), pp. 4-8
[41.]
B. Zollner, J. Petersen, E. Puchhammer-Stockl, J. Kletzmayr, M. Sterneck, L. Fischer, et al.
Viral features of lamivudine resistant hepatitis B genotypes A and D.
Hepatology, 39 (2004), pp. 42-50
[42.]
M. Buti, M. Cotrina, A. Valdés, R. Jardi, F. Rodríguez-Frías, R. Esteban.
Is hepatitis B virus subtype testing useful in predicting virological response and resistance to lamivudine?.
J Hepatol, 6 (2002), pp. 445-446
[43.]
C.E. Westland, W.E. Delaney, H. Yang, S.S. Chen, P. Marcellin, S. Hadziyannis, et al.
Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil.
Gastroenterology, 125 (2003), pp. 107-116
[44.]
F. Zoulim.
Assesing hepatitis B virus resistance in vitro and molecular mechanisms of nucleoside resistance.
Semin Liver Dis, 22 (2002), pp. 23-31
[45.]
F. Zoulim.
In vitro models for studying hepatitis B virus drug resistant.
Semin Liver Dis, 26 (2006), pp. 171-180
[46.]
B. Clarke, S. Bloor.
Molecular genotyping of hepatitis B virus.
J Clin Virol, 25 (2002), pp. S41-S45
[47.]
S.W. Aberle, J. Kletzmayr, B. Watschinger, B. Schmeid, N. Vetter, E. Puchhammer-Stockl.
Comparison of sequence analysis and the INNO-LiPA HBV DR line probe assay for detection of lamivudine-resistant hepatitis B virus strains in patients under various clinical conditions.
J Clin Microbiol, 39 (2001), pp. 1972-1974
[48.]
A.SF. Lok, F. Zoulim, S. Locarnini, A. Mangia, G. Niro, H. Decraemer, et al.
Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudina therapy: evaluation of performance of INNO-LiPA HBV DR assay.
J Clin Microbiol, 40 (2002), pp. 3729-3734
[49.]
M. Hussain, S. Fung, E. Libbrecht, E. Sablon, C. Cursaro, P. Andreone, et al.
Sensitive line probe assay that simultaneously detects mutations conveying resistance to lamivudine and adefovir.
J Clin Microbiol, 44 (2006), pp. 1094-1097
[50.]
O. Gallego, L. Martín-Carbonero, J. Agüero, C. De Mendoza, A. Corral, V. Soriano.
Correlation between rules-based interpretation and virtual phenotype interpretation of HIV-1 genotypes for predicting drug resistance un HIV-infected individuals.
J Virol Methods, 121 (2004), pp. 115-118
[51.]
T. Shaw, A. Bartholomeusz, S. Locarnini.
HBV drug resistance: mechanisms, detection and interpretation.
J Hepatol, 44 (2006), pp. 593-606
[52.]
P. Simmonds, E.C. Holmes, T.A. Cha, S.W. Chan, F. McOmish, B. Irvine, et al.
Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region.
J Gen Virol, 74 (1993), pp. 2391-2399
[53.]
P. Farci, R.H. Purcell.
Clinical significance of hepatitis C virus genotypes and quasispecies.
Semin Liver Dis, 20 (2000), pp. 103-126
[54.]
G.L. Davis, J.Y. Lay.
Factors predictive of a beneficial response to therapy of hepatitis C.
Hepatology, 26 (1997), pp. 122-127
[55.]
M.J. Gale, M.J. Korth, N.M. Tang, S.L. Tan, D.A. Hopkins, T.E. Dever, et al.
Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein.
Virology, 230 (1997), pp. 217-227
[56.]
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.
J Clin Invest, 96 (1995), pp. 224-230
[57.]
M.J. Gale, C. Blakely, B. Kwieciszewski, S.L. Tan, M. Dossett, N.M. Tang, et al.
Control of PKR protein kinase by hepatitis C virus non-structural 5a protein: molecular mechanisms of kinase regulation.
Mol Cell Biol, 18 (1998), pp. 5208-5218
[58.]
T. Taguchi, M. Nagano-Fujii, M. Akutsu, H. Kadoya, S. Ohgimoto, S. Ishido, et al.
Hepatitis C virus NS5A protein interacts with 2’,5’-oligoadenylate synthetase and inhibits antiviral activity of IFN in an IFN sensitivity-determining region-independent manner.
J Gen Virol, 85 (2004), pp. 959-969
[59.]
S.J. Polyak, K.S. Khabar, D.M. Paschal, H.J. Ezelle, G. Duverlie, G.N. Barber, et al.
Hepatitis C nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response.
[60.]
S.J. Polyak, K.S. Khabar, M. Rezeiq, D.R. Gretch.
Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy.
[61.]
N. Horiike, K. Michitaka, T. Masumoto, I. Okura, S. Akbar, M. Onji.
Relationship between the effect of interferon therapy and the change of hepatitis C virus non-structural 5B gene.
J Gastroenterol Hepatol, 14 (1999), pp. 345-351
[62.]
I. Okura, H. Horiike, K. Michitaka, M. Onji.
Effect of mutation in the hepatitis C virus nonstructural 5B region on HCV replication.
J Gastroenterol, 39 (2004), pp. 449-454
[63.]
K. Hamano, N. Sakamoto, N. Enomoto, N. Izumi, Y. Asahina, M. Kurosaki, et al.
Mutations in the NS5B region of the hepatitis C virus genome correlate with clinical outcomes of interferon-alpha plus ribavirin combination therapy.
J Gastroenterol Hepatol, 20 (2005), pp. 1401-1409
[64.]
N. Kumagai, N. Takahashi, M. Kinoshita, S. Tsunematsu, K. Tsuchimoto, H. Saito, et al.
Polymorphisms of NS5B protein relates to early clearance of hepatitis C virus by interferon plus rivabirin: a pilot study.
J Viral Hepat, 11 (2004), pp. 225-235
[65.]
K.C. Young, K.L. Lindsay, K.J. Lee, W.C. Liu, J.W. He, S.L. Milstein, et al.
Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus durin rivabirin monotherapy.
Hepatology, 38 (2003), pp. 869-878
[66.]
H. Mo, L. Lu, T. Pilot-Matias, R. Pithawalla, R. Mondal, S. Masse, et al.
Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro.
Antimicrob Agents Chemother, 49 (2005), pp. 4305-4314
[67.]
T. Saito, T. Ito, H. Ishiko, M. Yonaha, K. Morikawa, A. Miyokawa, et al.
Sequence analysis of PePHD within HCV E2 region and correlation with resistance of interferon therapy in japanese patients infected with HCV genotypes 2a and 2b.
Am J Gastroenterol, 98 (2003), pp. 1377-1383
[68.]
R. Gupta, M. Subramani, M.N. Khaja, C. Madhavi, S. Roy, C.M. Habibullah, et al.
Analysis of mutations within the 5’ untranslated region, interferon sensitivity region, and PePHD region as a function of response to interferon therapy in hepatitis C virus-infected patients in India.
J Clin Microbiol, 44 (2006), pp. 709-715
[69.]
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
Copyright © 2006. Elsevier España S.L.. Todos los derechos reservados
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