Alimentary Pharmacology and Therapeutics
Letters to the Editors Letter: response-guided treatment of hepatitis C virus genotype 5 may be feasible V. Papastergiou & S. Karatapanis First Department of Internal Medicine, General Hospital of Rhodes, Rhodes, Greece. E-mail: [email protected] doi:10.1111/apt.12702
SIRS, We read with great interest the review article by Wantuck et al. discussing the epidemiology and treatment outcomes of hepatitis C virus (HCV) genotypes 4 through 6.1 HCV genotype 5 (HCV-5) is an uncommon genotype with few reports outside South Africa, including a cluster of the infection described in Greece.2 Although a fixed 48-week course of pegylated interferon (PegIFN) and ribavirin is currently recommended, this suggestion is not based on solid evidence.1 Indeed, most therapeutic data come from retrospective studies with small sample sizes and extreme heterogeneity regarding treatment modalities (e.g. use of standard interferon) and patient sampling (e.g. inclusion of relapsers). As stated by Wantuck et al., HCV-5 has been claimed to be an easier to treat genotype (as compared with HCV genotype 1), showing response rates similar to genotypes 2 and 3. However, this has been questioned by other reports showing an overall response more similar to genotype 1.3 Clearly, comparison with other HCV genotypes is not a solid basis for standardising treatment of HCV-5. Prospective trials, to date hampered by obvious difficulties in patient sampling, are urgently needed to establish the optimal therapeutic strategy for HCV-5. This includes assessment of the potential cost utility of a response-guided approach, as originally adopted for HCV genotype 1 and recently proposed for genotype 6.1 Including 27 treatment-na€ıve patients with HCV-5 infection, we have prospectively assessed the efficacy of combined anti-viral treatment showing a sustained viral
response (SVR) of 63%.3 Congruently with previous reports, our patients were more frequently females of advanced age, characterised by high baseline viraemia and advanced hepatic fibrosis. Albeit adequately powered studies are warranted for definitive conclusions, it seems that neither these factors nor IL-28B polymorphisms, known to adversely affect treatment of other HCV genotypes,4 impact therapy of HCV-5.5 In our study, 16/27 patients (59.3%) had undetectable HCV-RNA by week 24, all but one of whom (85.2%) went on to achieve a 48-week response.3 Nevertheless, a substantial relapse rate, in our setting as high as 26.1%, may decisively discourage a fixed shortening of treatment duration to 24 weeks. However, our finding of an excellent predictive value of early viral dynamics on SVR offers a brand new perspective: a response-guided schedule may be a viable option for patients with HCV-5 infection. More intuitively, a 24-week course may be enough for those achieving a negative viral load by week 4 of treatment, as indicated by the high positive predictive value (93.8%) of this variable on sustained virological response.3 Contrarily, adoption of a stopping rule may be the most reasonable option for patients in whom HCV-RNA remains positive by week 12 of therapy, as these patients are unlikely to respond to the 48-week treatment.3 In conclusion, before attempting to evaluate the newly approved (but costly) protease inhibitors boceprevir and telaprevir or newer agents with pan-genotypic activities (such as sofosbuvir) against HCV-5, a response-guided approach based on the standard dual (PegIFN and ribavirin) regimen merits appropriate consideration in randomised trials targeting to establish a cost-effective treatment for HCV-5. This is important as the HCV-5 infected population is mainly based in developing countries with limited financial resources. Thus, we are ready to share our data in multicentric efforts.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None.
AP&T invited commentary and correspondence columns are restricted to letters discussing papers that have been published in the journal. A letter must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt.
ª 2014 John Wiley & Sons Ltd
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Letters to the Editors REFERENCES 1. Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014; 39: 137–47. 2. Karatapanis S, Tsoplou P, Papastergiou V, et al. Hepatitis C virus genotyping in Greece: unexpected high prevalence of genotype 5a in a Greek island. J Med Virol 2012; 84: 223–8. 3. Papastergiou V, Skorda L, Lisgos P, et al. Hepatitis C virus genotype 5: prospective evaluation of peginterferon/ribavirin treatment efficacy and predictive value of on-treatment virological
Letter: response-guided treatment of hepatitis C virus genotype 5 may be feasible – authors’ reply J. M. Wantuck* & M. H. Nguyen† *Department of Medicine, Veteran’s Affairs Palo Alto Health Care System, Palo Alto, PA, USA. † Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA. E-mail: [email protected] doi:10.1111/apt.12747
SIRS, We appreciate the interests by Papastergiou et al. regarding our recent article on HCV genotypes 4, 5, and 6.1, 2 We agree that none of the HCV-5 studies to date has been a multicentre randomised trial, but almost all have also only examined the 48-week therapy duration, providing no basis for alternative recommendation of a shorter treatment course.2, 3 With regard to response-guided therapy, the letter advocated that 24-week therapy may be sufficient for those with rapid virological response (RVR) with its high positive predictive value (PPV) of 93.8% (95% CI = 69.8– 99.8%) and that early virological response (EVR) can be used as a stopping rule with its high negative predictive value of 100% (95% CI =15.8–100%) based on a small study (n = 27).4 The lower limits of these values were, however, not sufficiently robust to truncate treatment duration in ‘good responders’ or to discontinue early in ‘poor responders’. In addition, this study did not include patients treated for 24 weeks and thus no direct evidence to support this shorter treatment course. A recent meta-analysis inclusive of 10 studies and 423 treatment-naive HCV-5 patients treated with either IFN or PEG-IFN + RBV found insufficient data to support proper analysis of RVR, EVR, ethnicity or IL28B polymorphisms as predictors of sustained virological response (SVR).3 Therefore, while the response-guided approach may indeed be valuable, additional studies are needed.
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responses for sustained virological response. J Clin Gastroenterol 2014; 48: 160–5. 4. Papastergiou V, Dimitroulopoulos D, Skorda L, et al. Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: does ethnicity matter? J Med Virol 2012; 84: 1217–23. 5. Antaki N, Bibert S, Kebbewar K, et al. IL28B polymorphisms do not predict response to therapy in chronic hepatitis C with HCV genotype 5. Gut 2012; 61: 1640–1.
With regard to cost, we agree that PEG-IFN + RBV may remain the cost-effective option for most HCV-5 patients for some time, given the high cost of newer agents and relatively high SVR for HCV-5. Another recent meta-analysis reported pooled SVR of 59.1% for PEF IFN + RBV in HCV-5 vs. 41.6% in HCV-1 and 68.6% in HCV 2/3.5 Hopefully, with time, the newer and more efficacious agents can be made accessible for developing countries as have been done for HIV infection.6, 7
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.1 REFERENCES 1. Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014; 39: 137–47. 2. Papastergiou V, Karatapanis S. Letter: response-guided treatment of hepatitis C virus genotype 5 may be feasible. Aliment Pharmacol Ther 2014; 39: 1337–8. 3. Devaki P, Jencks DS, Marupakula V, Nangia S, Nguyen MH. Sustained virological response (SVR) to standard interferon (IFN) or pegylated interferon (PEG IFN) and ribavirin (RBV) in patients with hepatitis C virus genotype 5 (HCV-5): results of a meta-analysis of 423 patients from 10 individual studies. Gastroenterology 2014, in press. 4. Papastergiou V, Skorda L, Lisgos P, et al. Hepatitis C virus genotype 5: prospective evaluation of peginterferon/ribavirin treatment efficacy and predictive value of on-treatment virological responses for sustained virological response. J Clin Gastroenterol 2014; 48: 160–5. 5. Devaki P, Jencks DS, Nangia S, Marupakula V, Nguyen MH. Meta-analysis: sustained virologic response (SVR) in patients with infection with hepatitis C virus genotype 5 (HCV-5) versus genotype 1 (HCV-1) and HCV genotype 2/3(HCV -2/3) treated with interferon or pegylated interferon and ribavirin (PEG IFN+RBV). Gastroenterology 2014, in press. 6. Jayakesera C, Barry M, Roberts L, Nguyen MH. Access to novel therapeutics for chronic hepatitis C infection in low- and middleincome countries is not only needed but also possible. N Engl J Med 2014, in press. 7. Farmer PE. Chronic infectious disease and the future of health care delivery. N Engl J Med 2013; 369: 2424–36.
Aliment Pharmacol Ther 2014; 39: 1337-1344 ª 2014 John Wiley & Sons Ltd
Letters to the Editors Letter: response-guided treatment of hepatitis C virus genotype 5 may be feasible V. Papastergiou & S. Karatapanis First Department of Internal Medicine, General Hospital of Rhodes, Rhodes, Greece. E-mail: [email protected] doi:10.1111/apt.12702
SIRS, We read with great interest the review article by Wantuck et al. discussing the epidemiology and treatment outcomes of hepatitis C virus (HCV) genotypes 4 through 6.1 HCV genotype 5 (HCV-5) is an uncommon genotype with few reports outside South Africa, including a cluster of the infection described in Greece.2 Although a fixed 48-week course of pegylated interferon (PegIFN) and ribavirin is currently recommended, this suggestion is not based on solid evidence.1 Indeed, most therapeutic data come from retrospective studies with small sample sizes and extreme heterogeneity regarding treatment modalities (e.g. use of standard interferon) and patient sampling (e.g. inclusion of relapsers). As stated by Wantuck et al., HCV-5 has been claimed to be an easier to treat genotype (as compared with HCV genotype 1), showing response rates similar to genotypes 2 and 3. However, this has been questioned by other reports showing an overall response more similar to genotype 1.3 Clearly, comparison with other HCV genotypes is not a solid basis for standardising treatment of HCV-5. Prospective trials, to date hampered by obvious difficulties in patient sampling, are urgently needed to establish the optimal therapeutic strategy for HCV-5. This includes assessment of the potential cost utility of a response-guided approach, as originally adopted for HCV genotype 1 and recently proposed for genotype 6.1 Including 27 treatment-na€ıve patients with HCV-5 infection, we have prospectively assessed the efficacy of combined anti-viral treatment showing a sustained viral
response (SVR) of 63%.3 Congruently with previous reports, our patients were more frequently females of advanced age, characterised by high baseline viraemia and advanced hepatic fibrosis. Albeit adequately powered studies are warranted for definitive conclusions, it seems that neither these factors nor IL-28B polymorphisms, known to adversely affect treatment of other HCV genotypes,4 impact therapy of HCV-5.5 In our study, 16/27 patients (59.3%) had undetectable HCV-RNA by week 24, all but one of whom (85.2%) went on to achieve a 48-week response.3 Nevertheless, a substantial relapse rate, in our setting as high as 26.1%, may decisively discourage a fixed shortening of treatment duration to 24 weeks. However, our finding of an excellent predictive value of early viral dynamics on SVR offers a brand new perspective: a response-guided schedule may be a viable option for patients with HCV-5 infection. More intuitively, a 24-week course may be enough for those achieving a negative viral load by week 4 of treatment, as indicated by the high positive predictive value (93.8%) of this variable on sustained virological response.3 Contrarily, adoption of a stopping rule may be the most reasonable option for patients in whom HCV-RNA remains positive by week 12 of therapy, as these patients are unlikely to respond to the 48-week treatment.3 In conclusion, before attempting to evaluate the newly approved (but costly) protease inhibitors boceprevir and telaprevir or newer agents with pan-genotypic activities (such as sofosbuvir) against HCV-5, a response-guided approach based on the standard dual (PegIFN and ribavirin) regimen merits appropriate consideration in randomised trials targeting to establish a cost-effective treatment for HCV-5. This is important as the HCV-5 infected population is mainly based in developing countries with limited financial resources. Thus, we are ready to share our data in multicentric efforts.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None.
AP&T invited commentary and correspondence columns are restricted to letters discussing papers that have been published in the journal. A letter must have a maximum of 300 words, may contain one table or figure, and should have no more than 10 references. It should be submitted electronically to the Editors via http://mc.manuscriptcentral.com/apt.
ª 2014 John Wiley & Sons Ltd
1337
Letters to the Editors REFERENCES 1. Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014; 39: 137–47. 2. Karatapanis S, Tsoplou P, Papastergiou V, et al. Hepatitis C virus genotyping in Greece: unexpected high prevalence of genotype 5a in a Greek island. J Med Virol 2012; 84: 223–8. 3. Papastergiou V, Skorda L, Lisgos P, et al. Hepatitis C virus genotype 5: prospective evaluation of peginterferon/ribavirin treatment efficacy and predictive value of on-treatment virological
Letter: response-guided treatment of hepatitis C virus genotype 5 may be feasible – authors’ reply J. M. Wantuck* & M. H. Nguyen† *Department of Medicine, Veteran’s Affairs Palo Alto Health Care System, Palo Alto, PA, USA. † Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA. E-mail: [email protected] doi:10.1111/apt.12747
SIRS, We appreciate the interests by Papastergiou et al. regarding our recent article on HCV genotypes 4, 5, and 6.1, 2 We agree that none of the HCV-5 studies to date has been a multicentre randomised trial, but almost all have also only examined the 48-week therapy duration, providing no basis for alternative recommendation of a shorter treatment course.2, 3 With regard to response-guided therapy, the letter advocated that 24-week therapy may be sufficient for those with rapid virological response (RVR) with its high positive predictive value (PPV) of 93.8% (95% CI = 69.8– 99.8%) and that early virological response (EVR) can be used as a stopping rule with its high negative predictive value of 100% (95% CI =15.8–100%) based on a small study (n = 27).4 The lower limits of these values were, however, not sufficiently robust to truncate treatment duration in ‘good responders’ or to discontinue early in ‘poor responders’. In addition, this study did not include patients treated for 24 weeks and thus no direct evidence to support this shorter treatment course. A recent meta-analysis inclusive of 10 studies and 423 treatment-naive HCV-5 patients treated with either IFN or PEG-IFN + RBV found insufficient data to support proper analysis of RVR, EVR, ethnicity or IL28B polymorphisms as predictors of sustained virological response (SVR).3 Therefore, while the response-guided approach may indeed be valuable, additional studies are needed.
1338
responses for sustained virological response. J Clin Gastroenterol 2014; 48: 160–5. 4. Papastergiou V, Dimitroulopoulos D, Skorda L, et al. Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: does ethnicity matter? J Med Virol 2012; 84: 1217–23. 5. Antaki N, Bibert S, Kebbewar K, et al. IL28B polymorphisms do not predict response to therapy in chronic hepatitis C with HCV genotype 5. Gut 2012; 61: 1640–1.
With regard to cost, we agree that PEG-IFN + RBV may remain the cost-effective option for most HCV-5 patients for some time, given the high cost of newer agents and relatively high SVR for HCV-5. Another recent meta-analysis reported pooled SVR of 59.1% for PEF IFN + RBV in HCV-5 vs. 41.6% in HCV-1 and 68.6% in HCV 2/3.5 Hopefully, with time, the newer and more efficacious agents can be made accessible for developing countries as have been done for HIV infection.6, 7
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.1 REFERENCES 1. Wantuck JM, Ahmed A, Nguyen MH. Review article: the epidemiology and therapy of chronic hepatitis C genotypes 4, 5 and 6. Aliment Pharmacol Ther 2014; 39: 137–47. 2. Papastergiou V, Karatapanis S. Letter: response-guided treatment of hepatitis C virus genotype 5 may be feasible. Aliment Pharmacol Ther 2014; 39: 1337–8. 3. Devaki P, Jencks DS, Marupakula V, Nangia S, Nguyen MH. Sustained virological response (SVR) to standard interferon (IFN) or pegylated interferon (PEG IFN) and ribavirin (RBV) in patients with hepatitis C virus genotype 5 (HCV-5): results of a meta-analysis of 423 patients from 10 individual studies. Gastroenterology 2014, in press. 4. Papastergiou V, Skorda L, Lisgos P, et al. Hepatitis C virus genotype 5: prospective evaluation of peginterferon/ribavirin treatment efficacy and predictive value of on-treatment virological responses for sustained virological response. J Clin Gastroenterol 2014; 48: 160–5. 5. Devaki P, Jencks DS, Nangia S, Marupakula V, Nguyen MH. Meta-analysis: sustained virologic response (SVR) in patients with infection with hepatitis C virus genotype 5 (HCV-5) versus genotype 1 (HCV-1) and HCV genotype 2/3(HCV -2/3) treated with interferon or pegylated interferon and ribavirin (PEG IFN+RBV). Gastroenterology 2014, in press. 6. Jayakesera C, Barry M, Roberts L, Nguyen MH. Access to novel therapeutics for chronic hepatitis C infection in low- and middleincome countries is not only needed but also possible. N Engl J Med 2014, in press. 7. Farmer PE. Chronic infectious disease and the future of health care delivery. N Engl J Med 2013; 369: 2424–36.
Aliment Pharmacol Ther 2014; 39: 1337-1344 ª 2014 John Wiley & Sons Ltd
