- Email: [email protected]
Can genetic variations predict HCV treatment outcomes?
Journal of Hepatology 49 (2008) 494–497 www.elsevier.com/locate/jhep
Editorial
Can genetic variations predict HCV treatment outcomes? q Nazia Selzner1, Ian McGilvray1,2,* 2
1 Multiorgan Transplant Program, University Health Network, University of Toronto, Canada Banting and Best Department of Medical Research, University of Toronto, 11C 1250 Toronto General Hospital, 585 University Avenue, Toronto, Ont., Canada M5G 2N2
See Article, pages 548–556
Chronic infection with hepatitis C virus (HCV) is a huge problem both globally and at the level of the individual patient. Part of the problem relates to the fact that the current standard of care treatment for HCV, combination pegylated interferon-alpha (PegIFNa) and ribavirin (Rib), is expensive, associated with significant side effects, and results in only a 50% rate of sustained virological response (SVR). Predicting the likelihood of response to treatment prior to initiating therapy (or soon after starting therapy) would be very useful [1]. The problem is particularly acute for patients who are infected with genotype 1 HCV. These patients have a particularly low SVR rate (in the range of 40–50%) when compared to more favourable genotypes [2–4], such as genotypes 2 and 3 (SVR rates of 80–90%). In the patient population infected with genotype 1 HCV, there are really no pre-treatment predictors of the response to therapy that are robust enough to warrant denying an individual patient combination therapy. There are also few accepted pre-treatment factors that strongly encourage treatment. In addition to viral and patients characteristics, the genetic diversity of the host contributes to the outcome of infection and treatment of chronic HCV. In the current issue of the Journal, Morgan et al. [5] present the
Associate Editor: M. Colombo q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +1 416 340 5230; fax: +1 416 340 5242. E-mail address: [email protected] (I. McGilvray).
association of various genetic variations, previously reported to be associated with either response to interferon-based therapy or with the risk of fibrosis development, in a sub-population of patients participating in the Hepatitis C anti-viral Long-term Treatment against Cirrhosis (HALT-C) trial. These patients, non-Hispanic Caucasians with genotype 1 HCV infection, achieved SVR following treatment with PegIFNa/Rib. Eight single nucleotide poymorphisms (SNPs) previously reported to be associated with treatment response were assessed by polymerase chain reaction-based assays. The presence of any single SNP was not associated with SVR; however, SVR was more common among the patients who were homozygous for the ACC variant IL-10 promoter diplotype (OR, 3.24; p = 0.001). How HCV, IFN and the host interact at a molecular level is being studied in many contexts, and there is an expanding body of literature that seeks to define this complex interplay in a clinically useful way. Several groups have used microarray-based approaches and have reported distinct subgroups of genes whose expression level varies between treatment responders and nonresponders. For example, we identified a discrete set of 18 genes whose pre-treatment hepatic expression levels differentiated between responders and non-responders [6]. Many of these genes were IFN sensitive genes (ISGs), and three of them (USP18/UBP43, CEB1, and ISG15) play roles in the same IFN regulatory pathway, suggesting a possible rationale for treatment resistance. These results have now been substantiated by other groups [7,8], and have been validated prospectively in a larger cohort of chronic HCV patients prior to initiating anti-viral treatment [9]. Subsequently a two-gene signature (IF127 and CXCL9) was identified by Asselah
0168-8278/$34.00 Ó 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2008.07.006
N. Selzner, I. McGilvray / Journal of Hepatology 49 (2008) 494–497
et al. in the liver biopsy of treatment-naı¨ve chronic HCV patients that can accurately predict treatment response in 79% of patients being treated for HCV [8]. Both genes are ISGs and are upregulated in the liver biopsies of treatment non-responders. In another microarray-based study, Feld et al. confirmed that pretreatment ISG expression is higher in the pre-treatment liver tissue of slow responders than in the liver tissue of rapid responders [7]. After 72 h of treatment with PegIFNa/RBV there was little further upregulation of ISG expression in the liver tissue of non-responders, while ISG expression was strongly induced in the liver tissue of rapid responders. For reasons that are unclear, pre-treatment ISG upregulation fails to clear the virus in non-responders, but the upregulation of the same ISGs in rapid responders when treated with PegIFNa/Rib is associated with viral clearance. The response to treatment in circulating blood cells is also different in responders and non-responders: ISG upregulation in the peripheral mononuclear blood cells of treatment non-responders is relatively blunted when compared to treatment responders [10,11]. Host predispositions likely play a fundamental role in this altered regulation of IFN-sensitive pathways. The Morgan et al. [5] study looks at genetic polymorphisms, specifically single nucleotide polymorphisms (SNPs) that might play a role in this intriguing dys-regulation of components of the anti-viral response that influences HCV treatment response. Prior to this study SNPs have been analyzed both for prediction of HCV disease progression [12] and therapeutic response [13,14]. Genes that have been assessed by SNP analysis including those for ISGs with anti-viral activity such as 2-5oligoadenylate synthetase (2-5 OAS), dsRNA activated protein kinase (PKR) and MxA protein. Several studies have reported an association between treatment response and SNPs in the promoter regions of MxA, OAS-1 and PKR [13,15,16]. While it is difficult to draw firm conclusions from these relatively small studies, it is interesting that both OAS and MxA were found to be associated with treatment response in our group’s impartial gene expression profiling study [6]. SNPs specific to cytokines, chemokines and their receptors have also been examined for associations with the results of anti-HCV treatment [14,17,18]. One of the cytokines examined is IFN-c, which is produced by effector T and natural killer cells and has a critical role in the host defense against a variety of intracellular pathogens, including HCV. IFN-c efficiently inhibits HCV replication in the replicon system in vitro [19], and intrahepatic levels of IFN-c appear to be associated with viral clearance in the chimpanzee model [20]. In a recent study of two patient cohorts, Huang et al. demonstrated an important role between a specific polymorphism of IFN-c and treatment response [21]. The first cohort included 280 chronic HCV patients who had
495
received INFa-based therapy. The second cohort contained 250 IV drug abusers who either spontaneously cleared the virus or became chronically infected. The authors demonstrated that among the eight analyzed SNPs spanning the entire IFN-c gene in the two cohorts, only one SNP variant (-764G, located in the proximal I IFN-c promoter region) was significantly associated with sustained virological response in the first cohort and with spontaneous recovery in the second cohort. A number of studies have examined other cytokines, such as IL-10, in a manner analogous to Morgan et al. [5] IL-10 is a potent anti-inflammatory Th2 cytokine that down-regulates the expression of major histocompatibility complex (MHC) class 1 and class II molecules as well as the production of Th1 cytokines [22,23]. IL-10 levels differ widely between individuals, possibly due to polymorphisms in the promoter region of the IL-10 genes [24]. High serum levels of IL-10 have been correlated with poor response to interferon therapy, whereas IL-10 production has been found to be lower in responders than in non-responders [25]. Specifically, 3 SNPs in the promoter (at positions-1082, -819, and 592 relative to the transcription start site) form 3 combinations (ATA, ACC, GCC) which are associated with differential IL-10 expression [25,26]. Yee et al. examined whether polymorphisms in the IL-10 promotor region might play a role in the outcome of anti-viral therapy [27]. Their relationship to the outcome of anti-viral therapy for chronic HCV infection was studied in 49 Caucasian patients with SVR and in 55 non-responders. The presence of the -592A or -819T alleles; the -592A/A or -819T/T genotypes; the combination of (-592A)–(819T)/ (-592A)–(-819T) as a genotype; or the extended (108) TCATA haplotype was significantly associated with an SVR. However, after stratification for viral genotype, baseline viral RNA concentration, and histology status, homozygosity for the (108) TCATA haplotype was found to be the principal determinant for SVR (OR crude = 13.7; p = 0.025) of SVR to INF/Rib [27]. The overall results from previous studies of how IL10 haplotype and/or individual Il-10 promoter polymorphisms are associated with the HCV response to IFN-based treatment are inconsistent. The Morgan et al. [5] study sheds more light on the intriguing and complex association between host genetics variations and response to treatment by analyzing a larger cohort of patients. The large size of the study population, uniform treatment regimen and close follow-up are key considerations when interpreting the presented data. However, some of the inclusion criteria related to the initial design of the HALT C trial could influence Morgan et al.’s findings. One obvious concern is the enrollment of only non-responder patients to anti-viral therapy – this likely eliminates the more favorable
496
N. Selzner, I. McGilvray / Journal of Hepatology 49 (2008) 494–497
responders (approximately 50% of genotype 1 patients). Although the authors argue that despite exclusion from the therapy of naı¨ve patients, they were able to replicate the reported risk factor for treatment failure in previous studies with untreated patients, it is possible that one reason that the current study did not confirm any of the previous SNP associations was the exclusion of treatment-naı¨ve genotype 1 patients. The exclusion of treatment responders does complicate the generalization of Morgan et al.’s findings, but does not detract from the overall worth of the data. Clearly, the challenge faced by all studies on the associations of gene polymorphism and drug efficacy/ response is the complexity of the interacting factors contributing to variable drug responses. These include numerous genes (often dozens) signaling molecules and multiple environmental factors [28,29]. One of the greatest challenges for the future is understanding how these factors contribute to drug response in the individual patient with HCV. Only large cohort studies, such as the work by Morgan et al., have the power to face this challenge, but even larger studies are needed. In our opinion, the path forward is to pool data from individual investigators and groups, and the marked improvements in the consistency of genomics-type data should permit this.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
References [1] Selzner N, Chen L, Borozan I, Edwards A, Heathcote EJ, McGilvray I. Hepatic gene expression and prediction of therapy response in chronic hepatitis C patients. J Hepatol 2008;48:708–713. [2] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales Jr FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982. [3] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 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 2001;358:958–965. [4] Hadziyannis SJ, Sette Jr H, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–355. [5] Morgan TR, Lambrecht RW, Bonkovsky HL, Chung RT, Naishadham D, Sterling RK, et al. DNA polymorphisms and response to treatment in patients with chronic hepatitis C: Results from the HALT-C trial. J Hepatol 2008;49:548–556. [6] Chen L, Borozan I, Feld J, Sun J, Tannis LL, Coltescu C, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 2005;128:1437–1444. [7] Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 2007;46:1548–1563. [8] Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault MP, et al. Liver gene expression signature to predict
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008;57:516–524. Chen L, Borozan I, Sun J, Anand N, Heathcote EJ, Edwards A, et al. Validation of a gene signature predicting response to treatment in chronic hepatitis C virus infection. Hepatology 2007;A46:256. Lempicki RA, Polis MA, Yang J, McLaughlin M, Koratich C, Huang DW, et al. Gene expression profiles in hepatitis C virus (HCV) and HIV coinfection: class prediction analyses before treatment predict the outcome of anti-HCV therapy among HIVcoinfected persons. J Infect Dis 2006;193:1172–1177. Taylor MW, Tsukahara T, Brodsky L, Schaley J, Sanda C, Stephens MJ, et al. Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy. J Virol 2007;81:3391–3401. Houldsworth A, Metzner M, Rossol S, Shaw S, Kaminski E, Demaine AG, et al. Polymorphisms in the IL-12B gene and outcome of HCV infection. J Interferon Cytokine Res 2005;25:271–276. Suzuki F, Arase Y, Suzuki Y, Tsubota A, Akuta N, Hosaka T, et al. Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection. J Viral Hepat 2004;11:271–276. Abbas Z, Moatter T, Hussainy A, Jafri W. Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3. World J Gastroenterol 2005;11:6656–6661. Hijikata M, Ohta Y, Mishiro S. Identification of a single nucleotide polymorphism in the MxA gene promoter (G/T at nt -88) correlated with the response of hepatitis C patients to interferon. Intervirology 2000;43:124–127. Knapp S, Yee LJ, Frodsham AJ, Hennig BJ, Hellier S, Zhang L, et al. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes Immun 2003;4:411–419. Naito M, Matsui A, Inao M, Nagoshi S, Nagano M, Ito N, et al. SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C. J Gastroenterol 2005;40:381–388. Gao B, Hong F, Radaeva S. Host factors and failure of interferon-alpha treatment in hepatitis C virus. Hepatology 2004;39:880–890. Frese M, Schwarzle V, Barth K, Krieger N, Lohmann V, Mihm S, et al. Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology 2002;35:694–703. Woollard DJ, Grakoui A, Shoukry NH, Murthy KK, Campbell KJ, Walker CM. Characterization of HCV-specific Patr class II restricted CD4+ T cell responses in an acutely infected chimpanzee. Hepatology 2003;38:1297–1306. Huang Y, Yang H, Borg BB, Su X, Rhodes SL, Yang K, et al. A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection. Proc Natl Acad Sci USA 2007;104:985–990. Tsuruma T, Yagihashi A, Torigoe T, Sato N, Kikuchi K, Watanabe N, et al. Interleukin-10 reduces natural killer sensitivity and downregulates MHC class I expression on H-ras-transformed cells. Cell Immunol 1998;184:121–128. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174:1209–1220. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998;95:9465–9470. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 1999;30:526–530.
N. Selzner, I. McGilvray / Journal of Hepatology 49 (2008) 494–497 [26] Eskdale J, Keijsers V, Huizinga T, Gallagher G. Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1999;1: 151–155. [27] Yee LJ, Tang J, Gibson AW, Kimberly R, Van Leeuwen DJ, Kaslow RA. Interleukin 10 polymorphisms as predictors of
497
sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology 2001;33:708–712. [28] Shastry BS. SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet 2007;52:871–880. [29] Roden DM, Altman RB, Benowitz NL, Flockhart DA, Giacomini KM, Johnson JA, et al. Pharmacogenomics: challenges and opportunities. Ann Intern Med 2006;145:749–757.
Editorial
Can genetic variations predict HCV treatment outcomes? q Nazia Selzner1, Ian McGilvray1,2,* 2
1 Multiorgan Transplant Program, University Health Network, University of Toronto, Canada Banting and Best Department of Medical Research, University of Toronto, 11C 1250 Toronto General Hospital, 585 University Avenue, Toronto, Ont., Canada M5G 2N2
See Article, pages 548–556
Chronic infection with hepatitis C virus (HCV) is a huge problem both globally and at the level of the individual patient. Part of the problem relates to the fact that the current standard of care treatment for HCV, combination pegylated interferon-alpha (PegIFNa) and ribavirin (Rib), is expensive, associated with significant side effects, and results in only a 50% rate of sustained virological response (SVR). Predicting the likelihood of response to treatment prior to initiating therapy (or soon after starting therapy) would be very useful [1]. The problem is particularly acute for patients who are infected with genotype 1 HCV. These patients have a particularly low SVR rate (in the range of 40–50%) when compared to more favourable genotypes [2–4], such as genotypes 2 and 3 (SVR rates of 80–90%). In the patient population infected with genotype 1 HCV, there are really no pre-treatment predictors of the response to therapy that are robust enough to warrant denying an individual patient combination therapy. There are also few accepted pre-treatment factors that strongly encourage treatment. In addition to viral and patients characteristics, the genetic diversity of the host contributes to the outcome of infection and treatment of chronic HCV. In the current issue of the Journal, Morgan et al. [5] present the
Associate Editor: M. Colombo q The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. * Corresponding author. Tel.: +1 416 340 5230; fax: +1 416 340 5242. E-mail address: [email protected] (I. McGilvray).
association of various genetic variations, previously reported to be associated with either response to interferon-based therapy or with the risk of fibrosis development, in a sub-population of patients participating in the Hepatitis C anti-viral Long-term Treatment against Cirrhosis (HALT-C) trial. These patients, non-Hispanic Caucasians with genotype 1 HCV infection, achieved SVR following treatment with PegIFNa/Rib. Eight single nucleotide poymorphisms (SNPs) previously reported to be associated with treatment response were assessed by polymerase chain reaction-based assays. The presence of any single SNP was not associated with SVR; however, SVR was more common among the patients who were homozygous for the ACC variant IL-10 promoter diplotype (OR, 3.24; p = 0.001). How HCV, IFN and the host interact at a molecular level is being studied in many contexts, and there is an expanding body of literature that seeks to define this complex interplay in a clinically useful way. Several groups have used microarray-based approaches and have reported distinct subgroups of genes whose expression level varies between treatment responders and nonresponders. For example, we identified a discrete set of 18 genes whose pre-treatment hepatic expression levels differentiated between responders and non-responders [6]. Many of these genes were IFN sensitive genes (ISGs), and three of them (USP18/UBP43, CEB1, and ISG15) play roles in the same IFN regulatory pathway, suggesting a possible rationale for treatment resistance. These results have now been substantiated by other groups [7,8], and have been validated prospectively in a larger cohort of chronic HCV patients prior to initiating anti-viral treatment [9]. Subsequently a two-gene signature (IF127 and CXCL9) was identified by Asselah
0168-8278/$34.00 Ó 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2008.07.006
N. Selzner, I. McGilvray / Journal of Hepatology 49 (2008) 494–497
et al. in the liver biopsy of treatment-naı¨ve chronic HCV patients that can accurately predict treatment response in 79% of patients being treated for HCV [8]. Both genes are ISGs and are upregulated in the liver biopsies of treatment non-responders. In another microarray-based study, Feld et al. confirmed that pretreatment ISG expression is higher in the pre-treatment liver tissue of slow responders than in the liver tissue of rapid responders [7]. After 72 h of treatment with PegIFNa/RBV there was little further upregulation of ISG expression in the liver tissue of non-responders, while ISG expression was strongly induced in the liver tissue of rapid responders. For reasons that are unclear, pre-treatment ISG upregulation fails to clear the virus in non-responders, but the upregulation of the same ISGs in rapid responders when treated with PegIFNa/Rib is associated with viral clearance. The response to treatment in circulating blood cells is also different in responders and non-responders: ISG upregulation in the peripheral mononuclear blood cells of treatment non-responders is relatively blunted when compared to treatment responders [10,11]. Host predispositions likely play a fundamental role in this altered regulation of IFN-sensitive pathways. The Morgan et al. [5] study looks at genetic polymorphisms, specifically single nucleotide polymorphisms (SNPs) that might play a role in this intriguing dys-regulation of components of the anti-viral response that influences HCV treatment response. Prior to this study SNPs have been analyzed both for prediction of HCV disease progression [12] and therapeutic response [13,14]. Genes that have been assessed by SNP analysis including those for ISGs with anti-viral activity such as 2-5oligoadenylate synthetase (2-5 OAS), dsRNA activated protein kinase (PKR) and MxA protein. Several studies have reported an association between treatment response and SNPs in the promoter regions of MxA, OAS-1 and PKR [13,15,16]. While it is difficult to draw firm conclusions from these relatively small studies, it is interesting that both OAS and MxA were found to be associated with treatment response in our group’s impartial gene expression profiling study [6]. SNPs specific to cytokines, chemokines and their receptors have also been examined for associations with the results of anti-HCV treatment [14,17,18]. One of the cytokines examined is IFN-c, which is produced by effector T and natural killer cells and has a critical role in the host defense against a variety of intracellular pathogens, including HCV. IFN-c efficiently inhibits HCV replication in the replicon system in vitro [19], and intrahepatic levels of IFN-c appear to be associated with viral clearance in the chimpanzee model [20]. In a recent study of two patient cohorts, Huang et al. demonstrated an important role between a specific polymorphism of IFN-c and treatment response [21]. The first cohort included 280 chronic HCV patients who had
495
received INFa-based therapy. The second cohort contained 250 IV drug abusers who either spontaneously cleared the virus or became chronically infected. The authors demonstrated that among the eight analyzed SNPs spanning the entire IFN-c gene in the two cohorts, only one SNP variant (-764G, located in the proximal I IFN-c promoter region) was significantly associated with sustained virological response in the first cohort and with spontaneous recovery in the second cohort. A number of studies have examined other cytokines, such as IL-10, in a manner analogous to Morgan et al. [5] IL-10 is a potent anti-inflammatory Th2 cytokine that down-regulates the expression of major histocompatibility complex (MHC) class 1 and class II molecules as well as the production of Th1 cytokines [22,23]. IL-10 levels differ widely between individuals, possibly due to polymorphisms in the promoter region of the IL-10 genes [24]. High serum levels of IL-10 have been correlated with poor response to interferon therapy, whereas IL-10 production has been found to be lower in responders than in non-responders [25]. Specifically, 3 SNPs in the promoter (at positions-1082, -819, and 592 relative to the transcription start site) form 3 combinations (ATA, ACC, GCC) which are associated with differential IL-10 expression [25,26]. Yee et al. examined whether polymorphisms in the IL-10 promotor region might play a role in the outcome of anti-viral therapy [27]. Their relationship to the outcome of anti-viral therapy for chronic HCV infection was studied in 49 Caucasian patients with SVR and in 55 non-responders. The presence of the -592A or -819T alleles; the -592A/A or -819T/T genotypes; the combination of (-592A)–(819T)/ (-592A)–(-819T) as a genotype; or the extended (108) TCATA haplotype was significantly associated with an SVR. However, after stratification for viral genotype, baseline viral RNA concentration, and histology status, homozygosity for the (108) TCATA haplotype was found to be the principal determinant for SVR (OR crude = 13.7; p = 0.025) of SVR to INF/Rib [27]. The overall results from previous studies of how IL10 haplotype and/or individual Il-10 promoter polymorphisms are associated with the HCV response to IFN-based treatment are inconsistent. The Morgan et al. [5] study sheds more light on the intriguing and complex association between host genetics variations and response to treatment by analyzing a larger cohort of patients. The large size of the study population, uniform treatment regimen and close follow-up are key considerations when interpreting the presented data. However, some of the inclusion criteria related to the initial design of the HALT C trial could influence Morgan et al.’s findings. One obvious concern is the enrollment of only non-responder patients to anti-viral therapy – this likely eliminates the more favorable
496
N. Selzner, I. McGilvray / Journal of Hepatology 49 (2008) 494–497
responders (approximately 50% of genotype 1 patients). Although the authors argue that despite exclusion from the therapy of naı¨ve patients, they were able to replicate the reported risk factor for treatment failure in previous studies with untreated patients, it is possible that one reason that the current study did not confirm any of the previous SNP associations was the exclusion of treatment-naı¨ve genotype 1 patients. The exclusion of treatment responders does complicate the generalization of Morgan et al.’s findings, but does not detract from the overall worth of the data. Clearly, the challenge faced by all studies on the associations of gene polymorphism and drug efficacy/ response is the complexity of the interacting factors contributing to variable drug responses. These include numerous genes (often dozens) signaling molecules and multiple environmental factors [28,29]. One of the greatest challenges for the future is understanding how these factors contribute to drug response in the individual patient with HCV. Only large cohort studies, such as the work by Morgan et al., have the power to face this challenge, but even larger studies are needed. In our opinion, the path forward is to pool data from individual investigators and groups, and the marked improvements in the consistency of genomics-type data should permit this.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
References [1] Selzner N, Chen L, Borozan I, Edwards A, Heathcote EJ, McGilvray I. Hepatic gene expression and prediction of therapy response in chronic hepatitis C patients. J Hepatol 2008;48:708–713. [2] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales Jr FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982. [3] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, 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 2001;358:958–965. [4] Hadziyannis SJ, Sette Jr H, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–355. [5] Morgan TR, Lambrecht RW, Bonkovsky HL, Chung RT, Naishadham D, Sterling RK, et al. DNA polymorphisms and response to treatment in patients with chronic hepatitis C: Results from the HALT-C trial. J Hepatol 2008;49:548–556. [6] Chen L, Borozan I, Feld J, Sun J, Tannis LL, Coltescu C, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 2005;128:1437–1444. [7] Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 2007;46:1548–1563. [8] Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault MP, et al. Liver gene expression signature to predict
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008;57:516–524. Chen L, Borozan I, Sun J, Anand N, Heathcote EJ, Edwards A, et al. Validation of a gene signature predicting response to treatment in chronic hepatitis C virus infection. Hepatology 2007;A46:256. Lempicki RA, Polis MA, Yang J, McLaughlin M, Koratich C, Huang DW, et al. Gene expression profiles in hepatitis C virus (HCV) and HIV coinfection: class prediction analyses before treatment predict the outcome of anti-HCV therapy among HIVcoinfected persons. J Infect Dis 2006;193:1172–1177. Taylor MW, Tsukahara T, Brodsky L, Schaley J, Sanda C, Stephens MJ, et al. Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy. J Virol 2007;81:3391–3401. Houldsworth A, Metzner M, Rossol S, Shaw S, Kaminski E, Demaine AG, et al. Polymorphisms in the IL-12B gene and outcome of HCV infection. J Interferon Cytokine Res 2005;25:271–276. Suzuki F, Arase Y, Suzuki Y, Tsubota A, Akuta N, Hosaka T, et al. Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection. J Viral Hepat 2004;11:271–276. Abbas Z, Moatter T, Hussainy A, Jafri W. Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3. World J Gastroenterol 2005;11:6656–6661. Hijikata M, Ohta Y, Mishiro S. Identification of a single nucleotide polymorphism in the MxA gene promoter (G/T at nt -88) correlated with the response of hepatitis C patients to interferon. Intervirology 2000;43:124–127. Knapp S, Yee LJ, Frodsham AJ, Hennig BJ, Hellier S, Zhang L, et al. Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR. Genes Immun 2003;4:411–419. Naito M, Matsui A, Inao M, Nagoshi S, Nagano M, Ito N, et al. SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C. J Gastroenterol 2005;40:381–388. Gao B, Hong F, Radaeva S. Host factors and failure of interferon-alpha treatment in hepatitis C virus. Hepatology 2004;39:880–890. Frese M, Schwarzle V, Barth K, Krieger N, Lohmann V, Mihm S, et al. Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology 2002;35:694–703. Woollard DJ, Grakoui A, Shoukry NH, Murthy KK, Campbell KJ, Walker CM. Characterization of HCV-specific Patr class II restricted CD4+ T cell responses in an acutely infected chimpanzee. Hepatology 2003;38:1297–1306. Huang Y, Yang H, Borg BB, Su X, Rhodes SL, Yang K, et al. A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection. Proc Natl Acad Sci USA 2007;104:985–990. Tsuruma T, Yagihashi A, Torigoe T, Sato N, Kikuchi K, Watanabe N, et al. Interleukin-10 reduces natural killer sensitivity and downregulates MHC class I expression on H-ras-transformed cells. Cell Immunol 1998;184:121–128. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174:1209–1220. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 1998;95:9465–9470. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 1999;30:526–530.
N. Selzner, I. McGilvray / Journal of Hepatology 49 (2008) 494–497 [26] Eskdale J, Keijsers V, Huizinga T, Gallagher G. Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun 1999;1: 151–155. [27] Yee LJ, Tang J, Gibson AW, Kimberly R, Van Leeuwen DJ, Kaslow RA. Interleukin 10 polymorphisms as predictors of
497
sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology 2001;33:708–712. [28] Shastry BS. SNPs in disease gene mapping, medicinal drug development and evolution. J Hum Genet 2007;52:871–880. [29] Roden DM, Altman RB, Benowitz NL, Flockhart DA, Giacomini KM, Johnson JA, et al. Pharmacogenomics: challenges and opportunities. Ann Intern Med 2006;145:749–757.