Open Forum Infectious Diseases BRIEF REPORT for care” (LP) of chronic hepatitis to improve the ability to find Late Presentation for Care Among patients before they develop advanced fibrosis and improve sur - Patients With Chronic Hepatitis C: veillance within this group as well. Late presentation for care Prevalence and Risk Factors of chronic hepatitis was defined as a liver stiffness measure- 1,2 3 1,2 ment (LSM) ≥9.5 kPa, aspartate aminotransferase-to-platelet Janne Fuglsang Hansen, Sofie Hallager , Anne Øvrehus, 3,4 1,2 1,2 Nina Weis, Peer Brehm Christensen, and Court Pedersen ratio index score >1.5, FIB-4 >3.25, Fibrotest >0.59, or a biopsy 1 2 Department of Infectious Diseases, Odense University Hospital, Denmark; Clinical Institute, with Metavir score F3 with no previous antiviral treatment. University of Southern Denmark, Odense; Department of Infectious Diseases, Copenhagen “Presentation with late-stage liver disease” (LSLD) was defined University Hospital, Hvidovre, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark as the presence of HCC or decompensated cirrhosis at first con- sultation . e Th purpose of this study was to (1) investigate Patients with chronic hepatitis C may have advanced fibrosis at the prevalence of LP/LSLD at first consultation at a treatment first evaluation. Using the European Association for the Study facility in a country with low CHC prevalence and (2) describe of the Liver (EASL) definition (FibroScan® >9.5 kPa) for “late associated risk factors. presenter for care” (LP), we found that 32% (169 of 527) of patients were LP. Being a LP was associated with increasing age MATERIAL AND METHODS and a history of alcohol overuse. This study included all adult (age ≥18 years) CHC patients with Keywords. chronic hepatitis C; cirrhosis; fibrosis; late pres- a first consultation for CHC at Odense University Hospital, entation; liver stiffness measurement. Denmark, from May 2007 to January 2016. Patients were identi- fied through the Danish Database for Hepatitis B and Hepatitis Living with untreated chronic hepatitis C (CHC) may lead to C (DANHEP), a national clinical database including all patients liver cirrhosis, consequently increasing the risk of hepatocel- with chronic hepatitis B or CHC admitted to hospitals in lular carcinoma (HCC) and hepatic decompensation . New Denmark . Missing information was supplemented with data treatment regimens with directly acting antivirals (DAAs) cure from InfCare, a local quality control database, or extracted from most patients with CHC and reduce the risk of complications, patient records. Liver stiffness measurement was extracted from especially if treatment is initiated before advanced bfi rosis the FibroScan device (Echosens, France). Data from the differ- occurs . Finding the patients at an earlier stage is crucial to ent registries were linked using the national, unique 10-digit achieve the World Health Organization Global Health Sector personal identification number. target of reducing liver-related mortality and morbidity by 65% Late presentation for care was defined as a reliable LSM ≥9.5 by 2030 . Patients with CHC may have been infected many kPa within 180 days of first consultation. Reliability was defined years before contact with a treatment facility, and linkage to care as 10 valid measurements and an interquartile range (IQR)/ has been identified as a major obstacle to receiving treatment median <30% if LSM was ≥7.1 kPa [8, 9]. Presenting with LSLD and follow-up for liver disease . was defined as HCC or decompensation within 180 days of ini- A definition of “late presentation” has aided the surveillance tial consultation. and identification of risk factors for presenting with advanced A history of alcohol overuse was defined as ever having a human immunodeficiency virus (HIV) at the time of diagnosis self-reported use above 3/2 units per day (male/female) for . Therefore, the European Association for the Study of the more than 1 year. A history of intravenous drug use (IDU) was Liver (EASL) and HIV in Europe defined “late presentation defined as ever having a self-reported episode of injecting. The project was approved by The Danish Patient Safety Authority (j.nr 3-3013-2243/1) and the Danish Data Protection Agency (j.nr 2008-58-0035). Received 18 August 2017; editorial decision 18 November 2017; accepted 21 November 2017. Correspondence: J.F. Hansen, MD, Department of Infectious Diseases, Odense University Hospital, Q Statistical Analysis Entrance 20, penthouse, J.B. Winsløwsvej 4, 5000 Odense, Denmark (email@example.com). Comparison of proportions was done using Pearson’s χ test Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases and comparison of median values with Kruskal-Wallis test. Society of America. This is an Open Access article distributed under the terms of the Creative Logistic regression models included age groups, sex, origin Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any and history of alcohol overuse, or IDU. There were no statisti- medium, provided the original work is not altered or transformed in any way, and that the work cal significant interactions. Chronic hepatitis B and HIV were is properly cited. For commercial re-use, please contact firstname.lastname@example.org excluded in the multivariate models due to small numbers DOI: 10.1093/ofid/ofx257 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx257/4655183 by Ed 'DeepDyve' Gillespie user on 16 March 2018 using backward elimination. Goodness of fit was examined 32.1% were LP and 5.3% presented with LSLD. Late presenta- using the Hosmer and Lemeshow’s method with 6 groups. The tion for care was associated with increasing age and having a significance level was set to <0.05. Data were analyzed using history of alcohol overuse. The exclusion of 43 patients with STATA, version 14. missing LSM that had indicators associated with less severe disease (young and a history of IDU) could have overestimated RESULTS the proportion of LP, but even if all the excluded patients had a LSM <9.5 kPa, the percentage of LP would still be 29.6%. In From May 2007 to January 2016, 570 patients had a first con- a 5-year follow-up study of CHC, it was shown that LSM >9.5 sultation for CHC. Of the 570 patients, 43 (7.5%) did not have kPa was associated with significantly higher mortality . any data available for evaluation of the degree of fibrosis. These This makes the high proportion of LP a significant health patients were a median 4.3 years younger (P < .005) and more problem. likely to have a history of alcohol overuse or IDU (P < .005) than A recently published study from New Zealand reported 17%– the included patients. 22% “late hepatitis notifications”, defined as decompensation or Late Presentation for Care HCC before or within 2 years of a reported diagnosis of CHC There were 169 (32.1%) late presenters for care with no statis- to the health authorities . Compared with our 5% within tically significant change during the 9-year study period. The 6 months of presentation, their numbers are high. However, the year 2007 had the highest number of first consultations due to results are difficult to compare because we have no informa- the implementation of a drug center outreach program. Patients tion on whether the patients in the study had a consultation at with LP were a median of 7 years older than patients with base- a treatment facility at the time of diagnosis. The patients in our line LSM <9.5 kPa (P < .005). In univariate analysis, age and a study may have been infected many years previous to their first history of alcohol overuse were strongly associated with LP, and contact with care. The time span from infection to testing and this remained significant in multivariable analysis (Table 1). from diagnosis and linkage to care is also unknown. Some of the Presentation With Late Stage Liver Disease delay in our study may have been due to the limited treatment There were 28 (5.3%) patients presenting with LSLD (28 of 169 options of the past, and with the introduction of the highly ef- of the LP patients). Their median LSM was 51.4 kPa (IQR, 25.8– fective DAA treatment, the delay may be reduced the coming 69.1) and median age was 50.9 years (IQR, 45.7–56.1). None years. It is also likely that the increased screening in asymptom- of the LSLD patients were under 30 years of age. Among the atic patients such as the US baby boomer testing  will re- patients above 30 years of age, a history of IDU was significantly duce LP in the near future. associated with reduced risk of presenting with LSLD (Table 1). Late presentation for care was associated with increasing age and alcohol overuse, factors that previously have been linked DISCUSSION to a high risk of cirrhosis [13, 14]. In our setting, drug users in In this single-center study including CHC patients in Denmark treatment (opiate substitution therapy) have in the past decade presenting to specialized care for the first time, we found that been targeted for hepatitis C virus screening and evaluation for Table 1. Odds Ratios for Late Presentation for Care and for Having Late-Stage Liver Disease at Initial Consultation Model for Late Presentation for Care Model for Presenting With Late-Stage Liver Disease Univariate OR Multivariate OR Univariate OR Multivariate OR Baseline predictor |(95% CI) P Value (95% CI) P Value (95% CI) P Value (95% CI) P Value Western European 0.9 (0.5–1.6) .814 0.8 (0.4–1.5) .549 0.6 (0.2–1.7) .384 0.8 (0.2–2.6) .704 Male sex 1.3 (0.9–1.9) .211 1.4 (0.9–2.1) .171 1.2 (0.5–2.7) .732 1.3 (0.5–3.3) .563 Age (years) a a <30 1 N/A N/A 30–39 3.7 (0.9–16.5) .081 3.8 (0.9–16.8) .080 1 1 40–49 8.9 (2.1–38) .003 8.6 (2–37.2) .005 1.9 (0.6–6.4) .278 1.8 (0.5–5.9) .352 50–59 17.3 (4–74.8) <.005 16.5 (3.8–71.9) <.005 3.8 (1.2–12.1) .024 3 (0.9–9.8) .071 60+ 15.5 (2.9–81.6) .001 14.3 (2.7–77) .002 6.3 (1.3–30.4) .022 4 (0.8–20.9) .099 b b Hepatitis B coinfection 0.8 (0.3–2) .656 2.6 (0.7–9.3) .141 b b b HIV coinfection 2.1 (0.4–10.7) .355 3.7 (0.4–32.4) .244 History of alcohol use 1.82 (1.2–2.7) .003 1.7 (1.1–2.7) .018 2 (0.8–4.7) .130 2.6 (1–7) .062 History of intravenous drug use 0.8 (0.4–0.9) .275 0.8 (0.4–1.4) .387 0.3 (0.2–0.8) .008 0.3 (0.1–0.8) .016 Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio. No patients in this age group presented with late-stage liver disease. Coinfection with hepatitis B and HIV was omitted from the multivariate models due to small numbers with insignificant contribution. 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx257/4655183 by Ed 'DeepDyve' Gillespie user on 16 March 2018 submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. liver disease. The examinations have been performed in an out- Conflicts that the editors consider relevant to the content of the manuscript reach setting making linkage to care easy. This is probably the have been disclosed. main factor why few patients with IDU were LP in our study. The association with age was expected but illustrates the References missed opportunity to diagnose CHC, especially among for- 1. Mühlberger N, Schwarzer R, Lettmeier B, et al. HCV-related burden of disease in mer intravenous drug users outside drug treatment centers. Europe: a systematic assessment of incidence, prevalence, morbidity, and mortal- ity. BMC Public Health 2009; 9:34. None of the patients younger than 30 years of age had LSLD, 2. EASL. EASL recommendations on treatment of Hepatitis C 2016. J Hepatol 2016. probably due to infection in their 20s with less time to develop Available at: http://dx.doi.org/10.1016/j.jhep.2016.09.001. Accessed 20 July 2017. 3. World Health Organization. Combating hepatitis B and C to reach elimination fibrosis. The association of LSLD to not having a history of by 2030. May 2016. Available at: http://www.who.int/hepatitis/publications/hep- IDU among the patients above 30 years of age may reflect elimination-by-2030-brief/en/. Accessed 1 July 2017. the higher number of patients acquiring CHC from other 4. Lin M, Kramer J, White D, et al. Barriers to hepatitis C treatment in the era of direct-acting anti-viral agents. Aliment Pharmacol Ther 2017; 46:992–1000. sources (primarily nosocomial transmission) in the 1970s and 5. Montlahuc C, Guiguet M, Abgrall S, et al. Impact of late presentation on the risk 1980s before hepatitis C screening of blood products were of death among HIV-infected people in France (2003-2009). J Acquir Immune Defic Syndr 2013; 64:197–203. introduced. 6. Mauss S, Pol S, Buti M, et al. Late presentation of chronic viral hepatitis for med- ical care: a consensus definition. BMC Med 2017; 15:92. CONCLUSIONS 7. Weis N, Thomsen RW. The Danish database for hepatitis B and C. Ugeskr Laeger 2012; 174:2521. Because a history of IDU accounts for the majority of the 8. Schwabl P, Bota S, Salzl P, et al. New reliability criteria for transient elastography increase the number of accurate measurements for screening of cirrhosis and por- Danish CHC population , testing for CHC in the popula- tal hypertension. Liver Int 2015; 35:381–90. tion with a former or present IDU remains the most important 9. Boursier J, Zarski JP, de Ledinghen V, et al. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology 2013; 57:1182–91. initiative for earlier diagnosis and timely treatment. However, 10. Vergniol J, Foucher J, Terrebonne E, et al. Noninvasive tests for fibrosis and our data also suggest that screening for CHC and liver disease liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. among persons born before 1970 or with an overuse of alcohol Gastroenterology 2011; 140:1970–9, 1979.e1–3. 11. Alavi M, Law MG, Grebely J, et al. Time to decompensated cirrhosis and hepato- may reduce the risk of LP and presenting with LSLD. cellular carcinoma after an HBV or HCV notification: a population-based study. J Hepatol 2016; 65:879–87. Acknowledgments 12. Younossi ZM, LaLuna LL, Santoro JJ, et al. Implementation of baby boomer hep- atitis C screening and linking to care in gastroenterology practices: a multi-center Financial support. This work was funded by the Region of Southern pilot study. BMC Gastroenterol 2016; 16:45. Denmark (grant j. nr. 14/24378), Gilead Sciences Nordic Fellowship 13. Federico A, Dallio M, Ormando VM, et al. Alcoholic liver disease and hepatitis C Programme 2014 (grant FP 2013-03), and The Innovation Found Denmark. chronic infection. Rev Recent Clin Trials 2016; 11:201–7. Potential conifl cts of interests. A. Ø. has done consultant work for 14. Marcellin P, Grotzinger K, Theodore D, et al. Severity of liver disease among Abbvie and Gilead. P. B. C. has received unrestricted grants for research chronic hepatitis C patients: an observational study of 4594 patients in five from Gilead, Abbvie, and Merck Sharp Dohme. N. W. has done consultant European countries. J Gastroenterol Hepatol 2015; 30:364–71. work for Bristol-Meyrs Squibb, Abbvie, Gilead, and Merck Sharp Dohme. 15. Christensen PB, Hay G, Jepsen P, et al. Hepatitis C prevalence in Denmark - an C. P. has received an unrestricted grant from Gilead. All authors have estimate based on multiple national registers. BMC Infect Dis 2012; 12:178. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx257/4655183 by Ed 'DeepDyve' Gillespie user on 16 March 2018
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