Abstract
Background:
The high cost of new hepatitis C (HCV) treatments has resulted in “watchful waiting” strategies being developed to safely delay treatment, which will in turn delay viral load suppression (VLS).
Objective:
To document if delayed VLS adversely impacted patient risk for adverse events and death.
Methods:
187,860 patients were selected from the Veterans Administration’s (VA) clinical registry (CCR), a longitudinal compilation of electronic medical records (EMR) data for 1999–2010. Inclusion criteria required at least 6 months of CCR/EMR data prior to their HCV diagnosis and sufficient data post-diagnosis to calculate one or more FIB-4 scores. Primary outcome measures were time-to-death and time-to-a composite of liver-related clinical events. Cox proportional hazards models were estimated separately using three critical FIB-4 levels to define early and late viral response.
Results:
Achieving an undetectable viral load before the patient’s FIB-4 level exceed pre-specified critical values (1.00, 1.45 and 3.25) effectively reduced the risk of an adverse clinical events by 33–35% and death by 21–26%. However, achieving VLS after FIB-4 exceeds 3.25 significantly reduced the benefit of viral response.
Conclusions:
Delaying VLS until FIB-4 >3.25 reduces the benefits of VLS in reducing patient risk.
Conflict of interest: Financial support for the development of the database used in this research was provided by Bristol-Myers Squibb [BMS]. The University of Southern California maintained all rights to publication. The University sub-contracted with the Veterans Affairs Department for access to the data. Conflict of Interest Disclosures: Drs. McCombs and Fox received salary and travel support under the terms of the research grant between Abbvie Pharmaceuticals and USC designed to continue previous research. Tara Matsuda and Justin McGinnis were supported as a USC graduate research assistant under the terms of the grant. Dr. Ivy Tonnu-Mihara is employed by the VA. Employees of BMS and Abbvie were not involved with the analyses included in this research or in the drafting of this manuscript. BMS employees were involved as co-authors of earlier publications and manuscripts using the same database. The research did not involve specific drugs or drugs marketed by BMS.
Research funding: This research used a database developed under a previous study funded by BMS.
Author statement: Drs. McCombs and Fox received salary and travel support under the terms of the research grant between Abbvie Pharmaceuticals and USC designed to continue previous research. Tara Matsuda and Justin McGinnis were supported as a USC graduate research assistant under the terms of the grant. Dr. Ivy Tonnu-Mihara is employed by the VA.
References
American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. When and in whom to initiate HCV therapy. Available at: http://hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy. Accessed August 14, 2014.Search in Google Scholar
Backus, L. I., S. Gavrilov, T. P. Loomis, J. P. Halloran, B. R. Phillips, P. S. Belperio and L. A. Mole (2009) “Clinical Case Registries: Simultaneous Local and National Disease Registries for Population Quality Management,” Journal of the American Medical Informatics Association, 16(6):775–783.10.1197/jamia.M3203Search in Google Scholar
Backus, L. I., D. B. Boothroyd, B. R. Phillips, P. Belperio, J. Halloran and L. A. Mole (2011) “A Sustained Virologic Response Reduces Risk of All-Cause Mortality in Patients with Hepatitis C,” Clinical Gastroenterology and Hepatology, 9:509–516.e1.10.1016/j.cgh.2011.03.004Search in Google Scholar
Bonnard, P., A. Elsharkawy, K. Zalata, E. Delarocque-Astagneau, L. Biard, L. Le Fouler, A. B. Hassan, M. Abdel-Hamid, M. El-Daly, M. E. Gamal, M. El Kassas, P. Bedossa, F. Carrat, A. Fontanet and G. Esmat (2015) “Comparison of Liver Biopsy and Noninvasive Techniques for Liver Fibrosis Assessment in Patients Infected with HCV-genotype 4 in Egypt,” Journal of Viral Hepatitis, 22:245–253.10.1111/jvh.12285Search in Google Scholar
Butt, A. A., X. Wang and C. G. Moore (2009) “Effect of Hepatitis C Virus and Its Treatment on Survival,” Hepatology, 50(8):387–392.10.1002/hep.23000Search in Google Scholar
Butt, A. A., P. Yan, V. Lo Re, 3rd, D. Rimland, M. B. Goetz, D. Leaf, M. S. Freiberg, M. B. Klein, A. C. Justice and K. E. Sherman; ERCHIVES (Electronically Retrieved Cohort of HCV Infected Veterans) Study Team (2015) “Liver Fibrosis Progression in Hepatitis C Virus Infection After Seroconversion,” Journal of the American Medical Association Internal Medicine, 172(2):178–185.10.1001/jamainternmed.2014.6502Search in Google Scholar
Center for Quality Management in Public Health (2010) “The State of Care for Veterans with Chronic Hepatitis C.” US Department of Veteran Affairs, Public Health Strategic Health Care Group, Center for Quality Management in Public Health, Palo Alto, CA.Search in Google Scholar
Chen, S. L. and T. R. Morgan (2006) “The Natural History of Hepatitis C Virus (HCV) Infection. International Journal of Medical Sciences, 3(2):47–52.10.7150/ijms.3.47Search in Google Scholar
Chen, J., J. Florian, W. Carter, R. D. Fleischer, T. S. Hammerstrom, P. R. Jadhav, W. Zeng, J. Murray and D. Birnkrant (2013) Earlier Sustained Virologic Response End Points for Regulatory Approval and dose Selection of Hepatitis C Therapies,” Gastroenterology, 144(7):1450–1455.e2.10.1053/j.gastro.2013.02.039Search in Google Scholar
Crosse, K., O. G. Umeadi, F. A. Anania, J. Laurin, J. Papadimitriou, C. Drachenberg and C. D. Howell (2004) “Racial Differences in Liver Inflammation and Fibrosis Related to Chronic Hepatitis C,” Clinical Gastroenterology and Hepatology, 2(6):463–468.10.1016/S1542-3565(04)00162-4Search in Google Scholar
Davis, G. L., J. E. Albright, S. F. Cook and D. M. Rosenberg (2003) “Projecting Future Complications of Chronic Hepatitis C in the United States,” Liver Transplantation, 9(4):331–338.10.1053/jlts.2003.50073Search in Google Scholar
Denniston, M. M., R. B. Jiles, J. Drobeniuc, R. M. Klevens, J. W. Ward, G. M. McQuillan and S. D. Holmberg (2014) “Chronic Hepatitix C Virus Infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010,” Annals of Internal Medicine, 160(5):293–300.10.7326/M13-1133Search in Google Scholar
Ditah, I., F. Ditah, P. Devaki, O. Ewelukwa, C. Ditah, B. Njei, H. N. Luma and M. Charlton (2014) “The Changing Epidemiology of Hepatitis C Virus Infection in the United States: National Health and Nutrition Examination Survey 2001 to 2010,” Journal of Hepatology, 60(4):691–698.10.1016/j.jhep.2013.11.014Search in Google Scholar
El-Serag, H. B. and A. C. Mason (2000) “Risk Factors for the Rising Rates of Primary Liver Cancer in the United Stats,” Archives of Internal Medicine, 160(21):3227–3230.10.1001/archinte.160.21.3227Search in Google Scholar
Fried, Michael W., M. L. Shiffman, K. R. Reddy, C. Smith, G. Marinos, F. L. Gonçales Jr, D. Häussinger, M. Diago, G. Carosi, D. Dhumeaux, A. Craxi, A. Lin, J. Hoffman and J. Yu (2002) “Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C Virus Infection,” New England Journal of Medicine, 347(13):975–982.10.1056/NEJMoa020047Search in Google Scholar
Ghany, M. G., A. S. Lok, J. E. Everhart, G. T. Everson, W. M. Lee, T. M. Curto, E. C. Wright, A. M. Stoddard, R. K. Sterling, A. M. Di Bisceglie, H. L. Bonkovsky, C. Morishima, T. R. Morgan and J. L. Dienstag; HALT-C Trial Group (2010) “Predicting Clinical and Histologic Outcomes Based on Standard Laboratory Tests in Advanced Chronic Hepatitis C,” Gastroenterology, 138:136–146.10.1053/j.gastro.2009.09.007Search in Google Scholar
Holmberg, S. D., M. Lu, L. B. Rupp, L. E. Lamerato, A. C. Moorman, V. Vijayadeva, J. A. Boscarino, E. M. Henkle and S. C. Gordon; Chronic Hepatitis Cohort Study (CHeCS) Investigators (2013) “Noninvasive Serum Fibrosis Markers for Screening and Staging Chronic Hepatitis C Virus Patients in a Large US Cohort,” Clinical Infectious Diseases, 57:240–246.10.1093/cid/cit245Search in Google Scholar
Kallwitz, E. R., J. Layden-Almer, M. Dhamija, J. Berkes, G. Guzman, R. Lepe, S. J. Cotler and T. J. Layden (2010) “Ethnicity and Body Mass Index are Associated with Hepatitis C Presentation and Progression,” Clinical Gastroenterology and Hepatology, 8(1):72–78.10.1016/j.cgh.2009.08.009Search in Google Scholar
Kanwal, F., J. R. Kramer, J. Ilyas, Z. Duan and H. B. El-Serag (2014) “HCV Genotype 3 is Associated with an Increased Risk of Cirrhosis and Hepatocellular Cancer in a National Sample of U.S. Veterans with HCV,” Hepatology, 60:98–105.10.1002/hep.27095Search in Google Scholar
Klevens, R. M., D. J. Hu, R. Jiles and S. D. Holmberg (2012) “Evolving Epidemiology of Hepatitis C Virus in the United States,” Clinical Infectious Diseases, 55(Suppl 1):S3–S9.10.1093/cid/cis393Search in Google Scholar
Kobayashi, M., E. Tanaka, T. Sodeyama, A. Urushihara, A. Matsumoto and K. Kiyosawa (1996) “The Natural Course of Chronic Hepatitis C: A Comparison Between Patients with Genotypes 1 and 2 Hepatitis C Viruses,” Hepatology, 23:695–699.10.1002/hep.510230406Search in Google Scholar
Larsen, C., V. Bousquet, E. Delarocque-Astagneau, C. Pioche, F. Roudot-Thoraval; HCV Surveillance Steering Committee; HCV Surveillance Group and J. C. Desenclos (2010) “Hepatitis C Virus Genotype 3 and the Risk of Severe Liver Disease in a Large Population of Drug Users in France,” Journal of Medical Virology, 82(10):1647–1654.10.1002/jmv.21850Search in Google Scholar
Lavanchy, D. (2009) “The Global Burden of Hepatitis C,” Liver International, 29(Suppl 1):74–81.10.1111/j.1478-3231.2008.01934.xSearch in Google Scholar
Lee, M. H., H. I. Yang, S. N. Lu, C. L. Jen, S. L. You, L. Y. Wang, C. H. Wang, W. J. Chen and C. J. Chen; R.E.V.E.A.L.-HCV Study Group (2012) “Chronic Hepatitic C Virus Infection Increases Mortality from Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prosepctive Study,” The Journal of Infectious Diseases, 206:469–477.10.1093/infdis/jis385Search in Google Scholar
Loftus, P. (2013) “Patient Dilemma: Treat Hepatitic C Now or Hold Out?” Wall Street Journal. Available at: http://www.wsj.com/articles/SB10001424127887323293704578330712442353712. Accessed May 30, 2015.Search in Google Scholar
McCombs, J., T. Matsuda, I. Tonnu-Mihara, S. Saab, P. Hines, G. L’italien, T. Juday and Y. Yuan (2014) “The Risk of Long-Term Morbidity and Mortality in Patients with Chronic Hepatitis C: Results from an Analysis of Data from a Department of Veterans Affairs Clinical Registry,” Journal of the American Medical Association Internal Medicine, 174:204–212.10.1001/jamainternmed.2013.12505Search in Google Scholar
Ng, V. and S. Saab (2011) “Effects of a Sustained Virologic Response on Outcomes of Patients with Chronic Hepatitis C,” Clinical Gastroenterology and Hepatology, 9(11):923–930.10.1016/j.cgh.2011.05.028Search in Google Scholar
Rein, D. B., J. S. Wittenborn, C. M. Weinbaum, M. Sabin, B. D. Smith and S. B. Lesesne (2011) “Forecasting the Morbidity and Mortality Associated with Prevalent Cases of Pre-Cirrhotic Chronic Hepatitis C in the United States,” Digestive and Liver Disease, 43(1):66–72.10.1016/j.dld.2010.05.006Search in Google Scholar
Sanchez-Conde, M., M. L. Montes-Ramirez, P. Miralles, J. M. Alvarez, J. M. Bellón, M. Ramírez, J. R. Arribas, I. Gutiérrez, J. C. López, J. Cosín, E. Alvarez, J. González and J. Berenguer (2010) “Comparison of Transient Elastography and Liver Biopsy for the Assessment of Liver Fibrosis in HIV/Hepatitis C Virus-Coinfected Patients and Correlation with Noninvasive Serum Markers,” Journal of Viral Hepatitis, 17:280–286.10.1111/j.1365-2893.2009.01180.xSearch in Google Scholar
Seeff, L. B. (2009) “The History of the ‘Natural History’ of Hepatitis C (1968–2009),” Liver International, 29(Suppl 1):89–99.10.1111/j.1478-3231.2008.01927.xSearch in Google Scholar
Sterling, R. K., R. T. Stravitz, V. A. Luketic, A. J. Sanyal, M. J. Contos, A. S. Mills and M. L. Shiffman (2004) “A Comparison of the Spectrum of Chronic Hepatitis C Virus Between Caucasians and African Americans,” Clinical Gastroenterology and Hepatology, 2(6):469–473.10.1016/S1542-3565(04)00164-8Search in Google Scholar
Sterling, R. K., E. Lissen, N. Clumeck, R. Sola, M. C. Correa, J. Montaner, M. S. Sulkowski, F. J. Torriani, D. T. Dieterich, D. L. Thomas, D. Messinger and M. Nelson; APRICOT Clinical Investigators (2006) “Development of a Simple Noninvasive Index to Predict Significant Fibrosis in Patients with HIV/HCV Coinfection,” Hepatology, 43:1317–1325.10.1002/hep.21178Search in Google Scholar
Vallet-Pichard, A., V. Mallet, B. Nalpas, V. Verkarre, A. Nalpas, V. Dhalluin-Venier, H. Fontaine and S. Pol (2007) “FIB-4: An Inexpensive and Accurate Marker of Fibrosis in HCV Infection. Comparison with Liver Biopsy and Fibrotest,” Hepatology, 46(1):32–36.10.1002/hep.21669Search in Google Scholar
van der Meer, A. J., B. J. Veldt, J. J. Feld, H. Wedemeyer, J. F. Dufour, F. Lammert, A. Duarte-Rojo, E. Heathcote, M. P. Manns, L. Kuske, S. Zeuzem, W. P. Hofmann, R. J. de Knegt, B. E. Hansen and H. L. Janssen (2012) “Association Between Sustained Virological Response and All-Cause Mortality Among Patients with Chronic Hepatitis C and Advanced Hepatic Fibrosis,” Journal of the American Medical Association, 308(24):2584–2593.10.1001/jama.2012.144878Search in Google Scholar
van der Meer, A. J., B. E. Hansen, G. Fattovich, J. J. Feld, H. Wedemeyer, J. F. Dufour, F. Lammert, A. Duarte-Rojo, M. P. Manns, D. Ieluzzi, S. Zeuzem, W. P. Hofmann, R. J. de Knegt, B. J. Veldt and H. L. Janssen (2015) “Reliable Prediction of Clinical Outcome in Patients with Chronic HCV Infection and Compensated Advanced Hepatic Fibrosis: A Validated Model Using Objective and Readily Available Clinical Parameters,” Gut, 64(2):322–331.10.1136/gutjnl-2013-305357Search in Google Scholar
Vergniol, J., J. Foucher, E. Terrebonne, P. H. Bernard, B. le Bail, W. Merrouche, P. Couzigou and V. de Ledinghen (2011) “Noninvasive Tests for Fibrosis and Liver Stiffness Predict 5-year Outcomes of Patients with Chronic Hepatitis C,” Gastroenterology, 140:1970–1979.e3.10.1053/j.gastro.2011.02.058Search in Google Scholar
Xu, F., J. Xing, A. C. Moorman, S. C. Gordon, L. B. Rupp, M. Lu, P. R. Spradling, E. H. Teshale, J. A. Boscarino, V. Vijayadeva, M. A. Schmidt (2014) FIB-4 Score and Gender Predict the Incidence of Hepatocellular Carcinoma (HCC) among Patients with Chronic Hepatitis C Virus (HCV) Infection: Chronic Hepatitis Cohort Study (CHeCS) 65th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA.Search in Google Scholar
Zhou, S., N. A. Terrault, L. Ferrell, J. A. Hahn, J. Y. Lau, P. Simmonds, J. P. Roberts, J. R. Lake, N. L. Ascher and T. L. Wright (1996) “Severity of Liver Disease in Liver Transplantation Recipients with Hepatitis C Virus Infection: Relationship to Genotype and Level of Viremia,” Hepatology, 24(5):1041–1046.10.1002/hep.510240510Search in Google Scholar
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