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Prognosis of patients with chronic hepatitis B in France (2008–2013): A nationwide, observational and hospital-based study
Accepted Manuscript Prognosis of Patients with Chronic Hepatitis B in France (2008-2013): A Nationwide, Observational and Hospital-based Study Vincent Mallet, Kamal Hamed, Michaël Schwarzinger PII: DOI: Reference:
S0168-8278(16)30642-0 http://dx.doi.org/10.1016/j.jhep.2016.10.031 JHEPAT 6316
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
4 June 2016 27 October 2016 27 October 2016
Please cite this article as: Mallet, V., Hamed, K., Schwarzinger, M., Prognosis of Patients with Chronic Hepatitis B in France (2008-2013): A Nationwide, Observational and Hospital-based Study, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.10.031
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Prognosis of Patients with Chronic Hepatitis B in France (2008-2013): A Nationwide, Observational and Hospitalbased Study Running title: Prognosis of CHB Patients in France 2008-2013 Vincent Mallet, MD, PhD;1 Kamal Hamed, MD, MPH;2 Michaël Schwarzinger, MD, PhD3,4 1. Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (Inserm), Unité 1223 - Paris, France; Hepatology service, Assistance Publique — Hôpitaux de Paris (AP—HP), Groupe Hospitalier Cochin Port-Royal, Paris, France 2. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA 3. Translational Health Economics Network (THEN), Paris, France 4. Infection Antimicrobials Modeling & Evolution (IAME), UMR 1137, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Diderot, Sorbonne Paris Cité, France Contact details for corresponding author: Vincent Mallet, MD, PhD, Assistance Publique — Hôpitaux de Paris, Groupe Hospitalier Cochin Port-Royal, Hepatology service, 27 rue du faubourg Saint Jacques, 75014, Paris, France. Phone: + 33 6 14 08 20 96. Email: [email protected] Key words Hepatitis B Virus; Carcinoma, Hepatocellular/Epidemiology ; Disease Progression ; Endstage Liver Disease; Prognosis; Risk factors Abbreviations
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aHR=adjusted hazard ratio; AIDS: acquired immune deficiency syndrome; CHB=chronic hepatitis B; CKD=chronic kidney disease; HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCV=hepatitis C virus; HDV=hepatitis D virus; HIV=human immunodeficiency virus; IQR=interquartile range Word count: 2784 of 3000; 5 of 5 tables or figures
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Conflicts of Interest Statement: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare that: VM is a speaker for BMS, Gilead, Janssen, Merck and co., Roche; a board member of Gilead, Janssen, Merck and co.; and a consultant for Translational Health Economics Network (THEN); KH is an employee of Novartis Pharmaceuticals Corporation; MS is an employee of Translational Health Economics Network (THEN). Contributorship Statement: VM initiated and conceptualized the study, contributed to the interpretation of the data, and wrote the first draft of the paper. He is the guarantor. KH contributed to the conceptualization of the study, interpretation of the data, and drafting of the paper. MS initiated and conceptualized the study, performed the primary data analysis, and contributed to the interpretation of the data and drafting of the paper. All authors gave final approval of this version to be submitted. Transparency Declaration: The lead author (VM) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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Abstract Background and aims: How risk factors associated with chronic hepatitis B (CHB) modify liver disease progression and mortality has been scarcely reported outside of Asia. Methods: All individuals discharged with CHB from acute and post-acute care hospitals in Metropolitan France between January 2008 and December 2013 were selected. Associations between liver- and non-liver-related risk factors and both liver disease progression (end-stage liver disease or hepatocellular carcinoma) and mortality were assessed by multivariate Cox proportional hazard models. Results: Overall, liver disease progression, liver transplantation and death were recorded in 7479 (15.5%), 433 (8.2%) and 5299 (11.0%) patients, respectively. An additional liver-related risk factor was recorded in 5426 (72.6%) patients with liver disease progression and 2699 (75.5%) patients with liver transplantation or liver death. Adjusted hazard ratios (95% confidence interval) for liver disease progression of hepatitis D virus co-infection, hepatitis C virus co-infection, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease were 1.44 (1.35–1.53), 1.77 (1.68–1.87), 3.37 (3.20–3.55), 1.40 (1.32–1.48), and 2.19 (1.98–2.42), respectively. All liver-related risk factors increased the risk of all-cause mortality, especially after liver disease progression. Adjusted hazard ratios for liver disease progression and inhospital mortality of HIV co-infection without acquired immune deficiency syndrome (AIDS) were 0.60 (0.52–0.70) and 0.63 (0.51–0.78), respectively.
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Conclusions and Relevance: In France, 2008-2013, liver disease progression among CHB patients was closely related to other risk factors. HIV co-infected patients without AIDS had better outcomes, suggesting better care in this group of patients. Word count: 250/250
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Lay summary In France, 2008-2013, about three-quarters of patients with chronic hepatitis B who progressed to a liver-related complication, including liver transplantation and liverrelated death, had an additional liver-related risk factor. Despite a higher prevalence of liver-related risk factors, HIV co-infected patients without AIDS had better outcomes. Prognosis of patients with chronic hepatitis B is closely related to other risk factors. Treatment of chronic hepatitis B patients, including control of chronic hepatitis Bassociated risk factors, is more efficient in HIV co-infected patients.
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Introduction Approximately 3.61% of the global population is chronically infected with hepatitis B virus (HBV).(1) A fraction will progress to a liver-related complication, including endstage liver disease (ESLD) and hepatocellular carcinoma (HCC), and will contribute to more than half of liver deaths worldwide.(2, 3) Male gender, older age, genetic susceptibility, HBV replication level, co-infections with HDV or HCV, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease have all been associated with liver disease progression in patients with chronic hepatitis B (CHB).(4-9) Non-liver-related risk factors, including chronic kidney disease (CKD), cardiovascular disease, respiratory disease, and extrahepatic cancer, may alter the course of CHB by increasing the competing risk of death from non-liver causes.(10) Acquired immune deficiency syndrome (AIDS) was historically associated with liver disease progression in patients co-infected with human immunodeficiency virus (HIV),(11) but recent studies conducted in the era of effective antiviral treatment for both HIV and HBV infections suggested that liver outcomes improved over the past 10 years.(12) Finally, most population studies on CHB were conducted in Asia and it is not clear whether risk factors of liver disease progression identified in these cohorts pertain to Western patients. Risks of liver disease progression and all-cause hospital mortality associated with liverand non-liver-related risk factors were evaluated among all patients discharged with CHB from French hospitals in 2008-2013.
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Methods Data source The Programme de Médicalisation des Systèmes d’Information (PMSI) database contains information on all public and private hospital billing claims for acute and post-acute care in France. Using unique anonymous identifiers, it is possible to trace the hospital trajectory of each selected patient and observe the progression of his/her conditions over time. Standardized hospital discharge summaries include patient demographics, as well as primary and associated discharge diagnosis codes (WHO International Classification of Diseases, 10th revision [ICD-10], French version), medical procedures performed (French Medical Common Procedure Coding System), length of stay, and inhospital mortality, which accounted for 57.4% of all adult deaths recorded in Metropolitan France during the study period.(13) The study was approved by the French National Commission for Data Protection (CNIL DE-2013-068). The requirement for informed consent was waived because the study used anonymized data.
Study population The study population comprised all adult patients in Metropolitan France who were discharged with a primary or associated diagnosis of CHB (ICD-10 B18.0 or B18.1 codes) between January 2008 and December 2013. As immunosuppression is a risk factor of liver disease progression in patients with CHB,(14) recipients of solid organ transplant (liver, heart, lung, pancreas, or bowel) or allogeneic stem cell transplant before January 2008 were excluded. However, the roles of HIV co-infection and former kidney
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transplant in CHB progression were evaluated. The codes of the medical conditions and events tracked in this retrospective cohort study are provided in eTable 1.
Outcome measures The primary outcome was liver disease progression to a composite outcome of ESLD or HCC before liver transplantation or death. Secondary outcomes included liver transplantation and all-cause in-hospital mortality. In patients without liver transplantation, liver death was defined as death after liver disease progression and competing mortality was defined as death before liver disease progression.(15)
Risk factors Liver-related risk factors included co-infections with HDV or HCV, alcohol use disorders (including alcoholic liver disease), diabetes mellitus, obesity (body mass index ≥30 kg/m2), and other primary causes of cirrhosis (congenital malformations, inherited metabolic liver disease, primary Budd-Chiari syndrome, or autoimmune hepatitis). Non-liver-related risk factors were recorded before liver disease progression and included co-infection with HIV, CKD, cancer other than HCC, cardiovascular disease, and respiratory disease.(2) Co-infection with HIV was staged into three categories depending on HIV control: at least one hospitalization for AIDS defining conditions before liver disease progression; any record of former AIDS (before 2008); and no AIDS recorded otherwise. CKD was staged into three categories at cohort inception: kidney transplant recipient before January 2008; on dialysis; and CKD otherwise. Patients who underwent kidney transplantation during the study period were censored at the time of kidney transplantation. Cardiovascular and respiratory diseases were defined according to causes of death retained in the Global Burden of Disease study.(2)
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Statistical analysis Age and categorical variables were compared using Kruskal-Wallis tests and χ2 tests, respectively. Multivariate associations were analyzed by adjusted hazard ratios (aHRs) using Cox proportional hazard models with age as the underlying time variable.(16, 17) Follow-up depended on the study outcome. For liver disease progression (ESLD or HCC), follow-up was measured from January 2008 to liver disease progression or last hospital discharge in 2008-2013. For overall mortality, follow-up was measured from January 2008 to in-hospital death or last hospital discharge in 2008-2013. For the composite outcome of liver transplantation or death versus non-liver death, follow-up was measured from January 2008 to liver transplantation, liver death, or non-liver death, whichever came first in the study period. The proportionality of hazards was evaluated by plots of Schoenfeld residuals for all explanatory variables. Accordingly, all multivariate Cox models were stratified by gender, obesity status, and patient residency area across five main French regions. All analyses were performed with SAS 9.4 (Statistical Analysis System, Cary, NC, USA).
Sensitivity analyses Three sensitivity analyses on selected samples were conducted to explore possible limitations of the main study results on liver disease progression. First, a possible coding bias of CHB was examined and all patients with at least two hospitalizations recording CHB among discharge diagnosis codes were selected. Second, a possible classification bias of ESLD in liver disease staging in 2008-2013 (see eTable 1) was examined and all patients recorded with cirrhosis were selected. Finally, as CHB treatment is not included in the National Hospital Formulary and therefore CHB treatment is not recorded in the PMSI hospital discharge database, all patients with co-primary discharge diagnosis
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codes indicating CHB treatment at the hospital before liver disease progression (i.e., administration (ICD-10 Z51.2) or monitoring (ICD-10 Z51.2, Z51.4, Z09.2, Z09.7-9) of treatment for CHB) were selected.
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Results Cohort characteristics A total of 48,189 patients with CHB constituted the hospital cohort for the main analysis (see Figure 1). Patients were 58.6% male with a median (IQR) age of 44 (32-57) years at cohort inception. Overall, 29,811 (61.8%) patients had at least one risk factor associated with CHB, including 20,355 (42.2%) and 21,984 (45.6%) patients with liver-related risk factors and non-liver-related risk factors, respectively (see Table 1). Screening for HBV is mandatory for pregnant women in France and CHB was recorded in 4928 (24.7%) of 19,933 women delivering at hospital at a median (IQR) age of 29 (2634) years. All risk factors, except obesity, were more prevalent in male than in female patients (see eTable 2). HIV co-infection was recorded in 5757 (12.0%) patients with CHB (see Table 2). HIV/HBV co-infected patients were more frequently male (73.0% vs. 56.7%). HIV/HBV co-infected patients had more liver-related risk factors (52.5% vs. 40.8%) due to primarily increased HCV co-infection (34.1% vs. 12.6%) as diabetes mellitus and obesity were less frequent. HIV/HBV patients also had more non-liver-related risk factors (45.7% vs. 38.2%) including CKD, cancer other than HCC, and respiratory disease.
Liver disease progression and mortality Liver disease progression was recorded in 7479 (15.5%) patients (Table 1). Patients with liver disease progression were older and more frequently of male gender than those censored without liver disease progression. Liver-related risk factors were recorded in about three-quarters (72.6%) and one-third (36.7%) of patients with or without liver disease progression, respectively. HIV co-infection without AIDS was less
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frequently recorded among patients with liver disease progression. In contrast, all other non-liver-related risk factors were more frequently recorded among patients with liver disease progression. Similar results were found for 6226 (12.9%) and 3145 (6.5%) patients recorded with ESLD and HCC, respectively (see eTable 3). Overall, 433 (0.9%) patients underwent liver transplantation and 5299 (11.0%) patients died at hospital in 2008-2013. All risk factors, except HIV co-infection without AIDS, were more prevalent among CHB patients who underwent liver transplantation or died at hospital during the study period. Liver transplantation or liver death were recorded in 3573 (63.5%) patients; otherwise, 2055 (36.5%) patients died at hospital from non-liver causes (see eTable 3). About three-quarters (75.5%) of liver transplantations and liver deaths were associated with liver-related risk factors. Almost all (97.0%) non-liver deaths were associated with nonliver-related risk factors. Liver transplantation, liver death and competing non-liver death were recorded in 19 (4.4%), 357 (11.4%) and 34 (1.7%) patients without any risk factor other than CHB.
Multivariate associations of liver-related risk factors with liver disease progression The adjusted hazard ratios (aHR) of liver disease progression for HDV co-infection, HCV co-infection, alcohol use disorders, diabetes mellitus, and other primary causes of cirrhosis were 1.44 (95% confidence interval [CI], 1.35 to 1.53), 1.77 (95% CI, 1.68 to 1.87), 3.37 (95% CI, 3.20 to 3.55), 1.40 (95% CI, 1.32 to 1.48), and 2.19 (95% CI, 1.98 to 2.42), respectively (Top panel of Figure 2; see eTable 4). Patients co-infected with HDV or HCV progressed at faster rates towards HCC than ESLD, while patients with alcohol
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use disorders or diabetes mellitus progressed at faster rates towards ESLD than HCC (see eTable 5). All non-liver related risk factors were associated with lower risks of liver disease progression except kidney transplant recipients and patients on dialysis (see bottom panel of Figure 2). The aHR of liver disease progression for HIV co-infection was overall 0.77 (95% CI, 0.71 to 0.83), but depended on HIV/AIDS stage: 0.60 (95% CI, 0.52 to 0.70) without AIDS recorded; 0.96 (95% CI, 0.85 to 1.08) with AIDS recorded before 2008; and 0.73 (95% CI, 0.65 to 0.83) with AIDS defining condition recorded in 20082013. The strength of the association between HIV co-infection and liver disease progression was overall more marked for HCC (aHR = 0.47 [95% CI, 0.41 to 0.54]) than for ESLD (aHR = 0.82 [95% CI, 0.76 to 0.90]) (see eTable 5 for details).
Multivariate associations of risk factors with liver transplantation or liver death versus competing death from non-liver causes All risk factors were associated with increased risks of in-hospital death (Figure 3), except HIV co-infection without AIDS recorded (aHR=0.63 [95% CI, 0.51-0.78]). All liver-related risk factors were independently associated with higher risks of liver transplantation or liver death (top panel of Figure 3; see eTable 4), with alcohol use disorders associated with the highest risk (aHR=3.18 [95%CI, 2.95 to 3.42]). HDV and HCV co-infections were also independently associated with higher risks of non-liver death. All non-liver-related risk factors, except HIV co-infection by stage, were independently associated with higher risks of non-liver death (see bottom panel of Figure 3; see eTable 4). Patients with cancer other than HCC (aHR = 1.14 [95% CI 1.04 to 1.25]) and
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kidney transplant recipients (aHR = 1.43 [95% CI, 1.14 to 1.79]) were also at risk of liver transplantation or liver death. HIV co-infection exhibited opposite risks of non-liver death depending on HIV/AIDS stage: higher risks in patients with AIDS-defining condition recorded in 2008-2013 versus lower risks in patients with no AIDS recorded or former AIDS recorded before 2008. Accordingly, the association of HIV co-infection at an early stage (i.e., without AIDS recorded) with lower risks of liver transplantation or liver death (aHR= 0.52 (95% CI, 0.41 to 0.66]) could not be explained by higher risks of competing non-liver death.
Sensitivity analyses The main study results on liver disease progression were robust in all sensitivity analyses conducted on selected samples. Multivariate associations were similar among patients with at least two hospitalizations recording CHB among discharge diagnosis codes (see eFigure 1). Multivariate associations were also similar among patients recorded with cirrhosis (see eFigure 2 and eFigure 3). In particular, HIV co-infection without AIDS remained associated with a better outcome. Finally, multivariate associations for liver disease progression, ESLD, HCC, and mortality before liver disease progression were similar among patients identified with a treatment for CHB (n=4099) (see eTable 6 and eFigure 4). Specifically, HIV co-infection remained associated with significantly lower risks of liver disease progression and of in-hospital mortality.
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Discussion A total of 7479 patients with CHB progressed to a liver-related complication, including ESLD or HCC, 433 underwent liver transplantation, and 5299 died at hospital in 20082013 in France. Liver-related risk factors other than CHB were recorded in 72.6% patients with liver disease progression and increased the risk of all-cause mortality, especially after ESLD or HCC. Non-liver-related risk factors increased the risk of competing mortality before liver disease progression. Kidney transplant recipients and patients with cancer other than HCC remained at higher risk of liver death despite higher risks of competing mortality. Co-infection with HIV was independently associated with about 20% reduction of the risk of liver disease progression and reduced the risk of dying at hospital by about 40%. To our knowledge, this is the largest Western cohort study on the prognosis of patients with CHB.(18) Selection bias is limited because all residents in France have universal access to hospital care. The French National Hospital Discharge (PMSI) database and the ICD-10 classification have been previously validated for “hard outcomes”, including inhospital death, and the risk factors under study.(2, 19-21) In addition, similar multivariate associations were found in the main analysis and two sensitivity analyses, one by selecting patients with at least two hospital stays with a diagnosis of CHB and the second by selecting patients with a diagnosis of cirrhosis at study entry, before disease progression. Liver- and non-liver-related risk factors have rarely been taken into account together to model liver disease progression in patients with CHB, especially outside of the Asian setting.(8, 22, 23) As previously reported, we found that co-infection with HDV and HCV,
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and alcohol use disorders were independent risk factors of liver disease progression, liver transplantation and liver death. Alcohol use disorders were associated with threefold greater risk of liver disease progression and faster progression towards ESLD than HCC.(4, 6, 24, 25) The results also highlight the independent association of diabetes mellitus with liver disease progression (aHR = 1.40, 95% CI 1.32 to 1.48).(26, 27) Overall, the results suggest that liver disease progression, liver transplantation, or liver death are primarily accounted for by liver-related risk factors other than CHB in a setting with universal access to hospital care. The study also highlights the burden of non-liver related risk factors in patients with CHB. Except for HIV co-infection, non-liver-related risk factors were all associated with higher risks of competing non-liver death and accounted for about all (97%) non-liver deaths. As a consequence, patients with non-liver risk factors were at significantly lower risk of liver disease progression. The absence of information on CHB treatment is a limitation. However, CHB treatment generally follows clinical practice guidelines in France as CHB treatment is free of charge from the patient’s perspective.(28, 29) In a sensitivity analysis, multivariate associations remained similar in the sample of 4099 patients identified with discharge diagnosis codes indicating CHB treatment. In this respect, the study findings on HIV/HBV co-infection are of interest as standardof-care of co-infected patients includes effective antivirals to control both HIV and HBV replication and close follow-up.(29) About all HIV/HBV co-infected patients received standard-of-care in a recent multicenter observational study conducted in France.(12) In turn, HIV/HBV co-infection was independently associated with lower risks of liver disease progression (aHR=0.77 [95% CI, 0.71 to 0.83]) and reduced in-hospital death. Prognosis of CHB Patients in France 2008-2013
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Several findings suggest that CHB treatment is not strictly related to antivirals but also involves closer follow-up with better control of liver-related risk factors. First, it is noteworthy that HIV co-infection was associated with higher rates of liver-related risk factors, although their confounding effect on HIV co-infection was taken into account in all multivariate analyses. Second, patients co-infected with HIV were disentangled by stage to limit heterogeneity and patients with AIDS-defining conditions in 2008-2013 were at higher risk of non-liver (AIDS) death, and therefore lower risk of liver disease progression. Finally, patients without AIDS recorded had a similar risk of non-liver death than mono-infected patients but significantly lower risk of liver disease progression (aHR=0.60, [95% CI, 0.52-0.70]). These patients remained at a lower risk of liver disease progression in the sample of 4099 patients identified with discharge diagnosis codes indicating CHB treatment. Overall, the study results suggest that CHB treatment strategies recommended in patients co-infected with HIV should be investigated in HBV mono-infected patients. In conclusion, our results suggest that the prognosis of patients with CHB is primarily driven by liver-related and non-liver-related risk factors other than CHB in Western settings. Besides the potential benefits of expanding antivirals in mono-infected CHB patients, liver prognosis would be substantially improved by a more stringent control of liver-related risk factors including alcohol abstinence and eradication of HCV.
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Acknowledgements Novartis Pharmaceuticals Corporation funded the study. Vincent Mallet is funded by la Fondation ARC pour la recherche sur le cancer. The authors would like to thank Professors Philippe Sogni, Dominique Salmon, and Stanislas Pol for their comments on the manuscript; and Dr. Aldo Trylesinski for his help in the development of the study.
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Legends to figures Figure 1: study flowchart Figure 2: Risk factors of liver disease progression of CHB patients in the 2008-2013 French hospital database (N=48,189) Follow-up was from January 2008 to liver disease progression, a composite outcome of end-stage liver disease and/or hepatocellular carcinoma, or to last discharge. Patients with chronic kidney disease were censored at kidney transplantation (n = 253) in 2008–2013. All risk factors under study were recorded before liver disease progression. Note: aHR = adjusted hazard ratio; CI = confidence interval; CKD = chronic kidney disease; HCC = hepatocellular carcinoma; HDV = hepatitis D virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus.
Figure 3: Prognostic factors of CHB patients in the 2008-2013 French hospital database (N=48,189) Follow-up was from January 2008 to liver transplantation, death after liver disease progression, competing mortality before liver disease progression or last discharge. In-hospital mortality includes 86/433 and 18/253 patients who died after liver and renal transplantation, respectively; otherwise patients were censored at kidney transplant. All risk factors under study were recorded before outcome. Note: aHR = adjusted hazard ratio; CI = confidence interval; CKD = chronic kidney disease; HCC = hepatocellular carcinoma; HDV = hepatitis D virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus.
Prognosis of CHB Patients in France 2008-2013
24
Table 1. Risk Factors and Outcomes of Patients with Chronic Hepatitis B Virus Infection (2008-2013) Overall population N (%) = 48,189 (100)
Male gender, n (%) Age at cohort inception, at first event or last discharge without event, median (IQR) years Region of residency in Metropolitan France, n (%) Greater Paris area North-West North-East South-West South-East Liver-related risk factors,c n (%) Co-infection with HDV Co-infection with HCV Alcohol use disorders Diabetes mellitus Obesity (≥30 kg/m2) Other cause of cirrhosis Non-liver-related risk factors,c n (%) Co-infection with HIV AIDS in 2008-2013 AIDS before 2008 No AIDS CKD (all) Kidney transplant recipient at cohort inception On dialysis at cohort inception CKD without kidney transplantation or dialysis Cancer other than HCC
With liver disease progression
28,256 (58.6) 44 (32–57)
n (%) = 7479 (15.5) 5706 (76.3) 58 (48–68)
Censored without liver disease progression n (%) = 40,710 (84.5%) 22,550 (55.4) 46 (35-59)
20,212 (42.0) 5613 (11.7) 7324 (15.2) 3888 (8.1) 11,152 (23.1) 20,355 (42.2) 5143 (10.7) 7297 (15.1) 6383 (13.3) 6378 (13.2) 4287 (8.9) 839 (1.7) 21,984 (45.6) 5757 (12.0) 2,039 (4.2) 1,697 (3.5) 2,021 (4.2) 4139 (8.6) 603 (1.3) 573 (1.2) 2963 (6.2) 5361 (11.1)
2985 (39.9) 840 (11.2) 1180 (15.8) 582 (7.8) 1892 (25.3) 5426 (72.6) 1199 (16.0) 2308 (30.9) 2989 (40.0) 1941 (26.0) 793 (10.6) 443 (5.9) 4199 (56.1) 802 (10.7) 294 (3.9) 328 (4.4) 180 (2.4) 755 (10.1) 125 (1.7) 89 (1.2) 541 (7.2) 1089 (14.6)
17,227 (42.3) 4773 (11.7) 6144 (15.1) 3306 (8.1) 9260 (22.8) 14,929 (36.7) 3944 (9.7) 4989 (12.3) 3394 (8.3) 4437 (10.9) 3494 (8.6) 396 (1.0) 17,785 (423) 4955 (12.2) 1,745 (4.3) 1,369 (3.4) 1,841 (4.5) 3384 (8.3) 478 (1.2) 484 (1.2) 2422 (6.0) 4272 (10.5)
a
Prognosis of CHB Patients in France 2008-2013
P-value
In-hospital mortalityb n (%) = 5299 (11.0)
Alive at last discharge n (%) = 42,890 (89.0)
Pvalue
<0.001
3,885 (73.3) 62 (52-74)
24,371 (56.8) 46 (35-59)
<0.001
1,848 (34.9) 665 (12.6) 899 (17.0) 494 (9.3) 1,393 (26.3) 3,676 (69.4) 829 (15.6) 1,485 (28.0) 1,685 (31.8) 1,376 (26.0) 530 (10.0) 252 (4.8) 3,949 (74.5) 603 (11.4) 340 (6.4) 171 (3.2) 92 (1.7) 1,076 (20.3) 161 (3.0) 212 (4.0) 703 (12.3) 1,772 (33.4)
18,364 (42.8) 4,948 (11.5) 6,425 (15.0) 3,394 (7.9) 9,759 (22.8) 16,679 (38.9) 4,314 (10.1) 5,812 (13.6) 4,698 (11.0) 5,002 (11.7) 3,757 (8.8) 587 (1.4) 18,035 (42.1) 5,154 (12.0) 1,699 (4.0) 1,526 (3.6) 1,929 (4.5) 3,063 (7.1) 442 (1.0) 361 (0.8) 2,260 (5.3) 3,589 (8.4)
<0.001
<0.001
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
<0.001
<0.001
<0.001
<0.001
25
<0.001
<0.001
<0.001 <0.001 <0.001 <0.001 <0.001 <0.01 <0.001 <0.001 0.18
<0.001
<0.001
<0.001
<0.001
Cardiovascular disease Respiratory disease
12,649 (26.3) 7404 (15.4)
2694 (36.0) 1287 (17.2)
9955 (24.5) 6117 (15.0)
<0.001 <0.001
2,740 (51.7) 1,682 (31.7)
9,909 (23.1) 5,722 (13.3)
aAmong
<0.001 <0.001
7479 patients with liver disease progression, 1892 (25.3%) had both decompensated cirrhosis and hepatocellular carcinoma. bincludes 86/433 and 18/253 patients who died after liver and renal transplantation, respectively. cRisk factors are recorded before disease progression. dIncludes 40 congenital malformations; 239 hemochromatosis; 10 cystic fibrosis; 3 Wilson disease; 34 primary Budd-Chiari syndrome; 111 primary biliary cirrhosis; 81 autoimmune hepatitis; 350 primary sclerosing cholangitis. AIDS = acquired immune deficiency syndrome. CKD = chronic kidney disease. HCC = hepatocellular carcinoma HCV = hepatitis C virus. HDV = hepatitis D virus. HIV = human immunodeficiency virus. IQR = interquartile range
Prognosis of CHB Patients in France 2008-2013
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Table 2: Risk factors of Patients with Chronic Hepatitis B Virus Infection, by HIV coinfection status All N (%) = 48,189 (100)
HIV-positive n (%) = 5757 (12.0)
28,256 (58.6) 44 (32–57)
4202 (73.0) 43 (37–49)
HIVnegative n (%) = 42,432 (88.0) 24,054 (56.7) 44 (32–58)
20,212 (42.0) 5613 (11.7) 7324 (15.2) 3888 (8.1) 11,152 (23.1) 20,355 (42.2) 5143 (10.7) 7297 (15.1) 6383 (13.3) 6378 (13.2) 4287 (8.9) 839 (1.7)
3142 (54.6) 519 (9.0) 548 (9.5) 435 (7.6) 1113 (19.3) 3,024 (52.5) 829 (14.4) 1965 (34.1) 927 (16.1) 499 (8.7) 269 (4.7) 76 (1.3)
17,070 (40.0) 5094 (12.0) 6776 (16.0) 3453 (8.1) 10,039 (23.7) 17,331 (40.8) 4314 (10.2) 5332 (12.6) 5456 (12.9) 5879 (13.9) 4018 (9.5) 763 (1.8)
18,855 (39.1) 4139 (8.6)
2,628 (45.7) 592 (10.3)
16,227 (38.2) 3547 (8.4)
Kidney transplant recipient at cohort inception
603 (1.3)
36 (0.5)
577 (1.4)
On dialysis at cohort inceptionc
573 (1.2)
58 (1.0)
515 (1.2)
CKD without kidney transplantation or dialysis
2963 (6.2)
508 (8.8)
2455 (5.8)
Cancer other than HCC
5361 (11.1)
864 (15.0)
Cardiovascular disease
12,649 (26.3) 7404 (15.4)
1482 (25.7) 1074 (18.7)
Male gender, n (%) Age at cohort inception, median (IQR) years Region of residency in Metropolitan France, n (%) Greater Paris area North-West North-East South-West South-East Liver-related risk factorsa, n (%) Co-infection with HDV Co-infection with HCV Alcohol use disorders Diabetes mellitus Obesity (≥30 kg/m2) Other cause of cirrhosisb
Pvalue
<0.001 <0.001
<0.001
<.001
<.001
<0.001
<.001
<0.001
<.001
<0.001
0.37
<0.001
<.001
<0.001
<.001
<0.01
<.05
<.0001
<.0001
<0.001
<.0001
<0.001
<0.001
4497 (10.6)
<0.001
<0.001
11,167 (26.3) 6330 (14.9)
0.35
<0.001
<0.001
<0.001
Non-liver-related risk factorsa, n (%) CKD (all), n (%)
Respiratory disease
Prognosis of CHB Patients in France 2008-2013
Pvalueb
27
aRisk
factors are recorded before liver disease progression. bIncludes: 40 congenital malformations; 239 hemochromatosis; 10 cystic fibrosis; 3 Wilson disease; 34 primary Budd-Chiari syndrome; 111 primary biliary cirrhosis; 81 autoimmune hepatitis; 350 primary sclerosing cholangitis. cCensored at kidney transplantation in 2008– 2013 (N = 253). AIDS = acquired immune deficiency syndrome. CKD = chronic kidney disease. HCC = hepatocellular carcinoma HCV = hepatitis C virus. HDV = hepatitis D virus. HIV = human immunodeficiency virus. IQR = interquartile range
Prognosis of CHB Patients in France 2008-2013
28
Prognosis of CHB Patients in France 2008-2013
29
Prognosis of CHB Patients in France 2008-2013
30
Prognosis of CHB Patients in France 2008-2013
31
Prognosis of CHB Patients in France 2008-2013
32
S0168-8278(16)30642-0 http://dx.doi.org/10.1016/j.jhep.2016.10.031 JHEPAT 6316
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
4 June 2016 27 October 2016 27 October 2016
Please cite this article as: Mallet, V., Hamed, K., Schwarzinger, M., Prognosis of Patients with Chronic Hepatitis B in France (2008-2013): A Nationwide, Observational and Hospital-based Study, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.10.031
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Prognosis of Patients with Chronic Hepatitis B in France (2008-2013): A Nationwide, Observational and Hospitalbased Study Running title: Prognosis of CHB Patients in France 2008-2013 Vincent Mallet, MD, PhD;1 Kamal Hamed, MD, MPH;2 Michaël Schwarzinger, MD, PhD3,4 1. Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (Inserm), Unité 1223 - Paris, France; Hepatology service, Assistance Publique — Hôpitaux de Paris (AP—HP), Groupe Hospitalier Cochin Port-Royal, Paris, France 2. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA 3. Translational Health Economics Network (THEN), Paris, France 4. Infection Antimicrobials Modeling & Evolution (IAME), UMR 1137, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Diderot, Sorbonne Paris Cité, France Contact details for corresponding author: Vincent Mallet, MD, PhD, Assistance Publique — Hôpitaux de Paris, Groupe Hospitalier Cochin Port-Royal, Hepatology service, 27 rue du faubourg Saint Jacques, 75014, Paris, France. Phone: + 33 6 14 08 20 96. Email: [email protected] Key words Hepatitis B Virus; Carcinoma, Hepatocellular/Epidemiology ; Disease Progression ; Endstage Liver Disease; Prognosis; Risk factors Abbreviations
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aHR=adjusted hazard ratio; AIDS: acquired immune deficiency syndrome; CHB=chronic hepatitis B; CKD=chronic kidney disease; HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCV=hepatitis C virus; HDV=hepatitis D virus; HIV=human immunodeficiency virus; IQR=interquartile range Word count: 2784 of 3000; 5 of 5 tables or figures
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Conflicts of Interest Statement: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare that: VM is a speaker for BMS, Gilead, Janssen, Merck and co., Roche; a board member of Gilead, Janssen, Merck and co.; and a consultant for Translational Health Economics Network (THEN); KH is an employee of Novartis Pharmaceuticals Corporation; MS is an employee of Translational Health Economics Network (THEN). Contributorship Statement: VM initiated and conceptualized the study, contributed to the interpretation of the data, and wrote the first draft of the paper. He is the guarantor. KH contributed to the conceptualization of the study, interpretation of the data, and drafting of the paper. MS initiated and conceptualized the study, performed the primary data analysis, and contributed to the interpretation of the data and drafting of the paper. All authors gave final approval of this version to be submitted. Transparency Declaration: The lead author (VM) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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Abstract Background and aims: How risk factors associated with chronic hepatitis B (CHB) modify liver disease progression and mortality has been scarcely reported outside of Asia. Methods: All individuals discharged with CHB from acute and post-acute care hospitals in Metropolitan France between January 2008 and December 2013 were selected. Associations between liver- and non-liver-related risk factors and both liver disease progression (end-stage liver disease or hepatocellular carcinoma) and mortality were assessed by multivariate Cox proportional hazard models. Results: Overall, liver disease progression, liver transplantation and death were recorded in 7479 (15.5%), 433 (8.2%) and 5299 (11.0%) patients, respectively. An additional liver-related risk factor was recorded in 5426 (72.6%) patients with liver disease progression and 2699 (75.5%) patients with liver transplantation or liver death. Adjusted hazard ratios (95% confidence interval) for liver disease progression of hepatitis D virus co-infection, hepatitis C virus co-infection, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease were 1.44 (1.35–1.53), 1.77 (1.68–1.87), 3.37 (3.20–3.55), 1.40 (1.32–1.48), and 2.19 (1.98–2.42), respectively. All liver-related risk factors increased the risk of all-cause mortality, especially after liver disease progression. Adjusted hazard ratios for liver disease progression and inhospital mortality of HIV co-infection without acquired immune deficiency syndrome (AIDS) were 0.60 (0.52–0.70) and 0.63 (0.51–0.78), respectively.
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Conclusions and Relevance: In France, 2008-2013, liver disease progression among CHB patients was closely related to other risk factors. HIV co-infected patients without AIDS had better outcomes, suggesting better care in this group of patients. Word count: 250/250
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Lay summary In France, 2008-2013, about three-quarters of patients with chronic hepatitis B who progressed to a liver-related complication, including liver transplantation and liverrelated death, had an additional liver-related risk factor. Despite a higher prevalence of liver-related risk factors, HIV co-infected patients without AIDS had better outcomes. Prognosis of patients with chronic hepatitis B is closely related to other risk factors. Treatment of chronic hepatitis B patients, including control of chronic hepatitis Bassociated risk factors, is more efficient in HIV co-infected patients.
Prognosis of CHB Patients in France 2008-2013
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Introduction Approximately 3.61% of the global population is chronically infected with hepatitis B virus (HBV).(1) A fraction will progress to a liver-related complication, including endstage liver disease (ESLD) and hepatocellular carcinoma (HCC), and will contribute to more than half of liver deaths worldwide.(2, 3) Male gender, older age, genetic susceptibility, HBV replication level, co-infections with HDV or HCV, alcohol use disorders, diabetes mellitus, and other rare causes of chronic liver disease have all been associated with liver disease progression in patients with chronic hepatitis B (CHB).(4-9) Non-liver-related risk factors, including chronic kidney disease (CKD), cardiovascular disease, respiratory disease, and extrahepatic cancer, may alter the course of CHB by increasing the competing risk of death from non-liver causes.(10) Acquired immune deficiency syndrome (AIDS) was historically associated with liver disease progression in patients co-infected with human immunodeficiency virus (HIV),(11) but recent studies conducted in the era of effective antiviral treatment for both HIV and HBV infections suggested that liver outcomes improved over the past 10 years.(12) Finally, most population studies on CHB were conducted in Asia and it is not clear whether risk factors of liver disease progression identified in these cohorts pertain to Western patients. Risks of liver disease progression and all-cause hospital mortality associated with liverand non-liver-related risk factors were evaluated among all patients discharged with CHB from French hospitals in 2008-2013.
Prognosis of CHB Patients in France 2008-2013
7
Methods Data source The Programme de Médicalisation des Systèmes d’Information (PMSI) database contains information on all public and private hospital billing claims for acute and post-acute care in France. Using unique anonymous identifiers, it is possible to trace the hospital trajectory of each selected patient and observe the progression of his/her conditions over time. Standardized hospital discharge summaries include patient demographics, as well as primary and associated discharge diagnosis codes (WHO International Classification of Diseases, 10th revision [ICD-10], French version), medical procedures performed (French Medical Common Procedure Coding System), length of stay, and inhospital mortality, which accounted for 57.4% of all adult deaths recorded in Metropolitan France during the study period.(13) The study was approved by the French National Commission for Data Protection (CNIL DE-2013-068). The requirement for informed consent was waived because the study used anonymized data.
Study population The study population comprised all adult patients in Metropolitan France who were discharged with a primary or associated diagnosis of CHB (ICD-10 B18.0 or B18.1 codes) between January 2008 and December 2013. As immunosuppression is a risk factor of liver disease progression in patients with CHB,(14) recipients of solid organ transplant (liver, heart, lung, pancreas, or bowel) or allogeneic stem cell transplant before January 2008 were excluded. However, the roles of HIV co-infection and former kidney
Prognosis of CHB Patients in France 2008-2013
8
transplant in CHB progression were evaluated. The codes of the medical conditions and events tracked in this retrospective cohort study are provided in eTable 1.
Outcome measures The primary outcome was liver disease progression to a composite outcome of ESLD or HCC before liver transplantation or death. Secondary outcomes included liver transplantation and all-cause in-hospital mortality. In patients without liver transplantation, liver death was defined as death after liver disease progression and competing mortality was defined as death before liver disease progression.(15)
Risk factors Liver-related risk factors included co-infections with HDV or HCV, alcohol use disorders (including alcoholic liver disease), diabetes mellitus, obesity (body mass index ≥30 kg/m2), and other primary causes of cirrhosis (congenital malformations, inherited metabolic liver disease, primary Budd-Chiari syndrome, or autoimmune hepatitis). Non-liver-related risk factors were recorded before liver disease progression and included co-infection with HIV, CKD, cancer other than HCC, cardiovascular disease, and respiratory disease.(2) Co-infection with HIV was staged into three categories depending on HIV control: at least one hospitalization for AIDS defining conditions before liver disease progression; any record of former AIDS (before 2008); and no AIDS recorded otherwise. CKD was staged into three categories at cohort inception: kidney transplant recipient before January 2008; on dialysis; and CKD otherwise. Patients who underwent kidney transplantation during the study period were censored at the time of kidney transplantation. Cardiovascular and respiratory diseases were defined according to causes of death retained in the Global Burden of Disease study.(2)
Prognosis of CHB Patients in France 2008-2013
9
Statistical analysis Age and categorical variables were compared using Kruskal-Wallis tests and χ2 tests, respectively. Multivariate associations were analyzed by adjusted hazard ratios (aHRs) using Cox proportional hazard models with age as the underlying time variable.(16, 17) Follow-up depended on the study outcome. For liver disease progression (ESLD or HCC), follow-up was measured from January 2008 to liver disease progression or last hospital discharge in 2008-2013. For overall mortality, follow-up was measured from January 2008 to in-hospital death or last hospital discharge in 2008-2013. For the composite outcome of liver transplantation or death versus non-liver death, follow-up was measured from January 2008 to liver transplantation, liver death, or non-liver death, whichever came first in the study period. The proportionality of hazards was evaluated by plots of Schoenfeld residuals for all explanatory variables. Accordingly, all multivariate Cox models were stratified by gender, obesity status, and patient residency area across five main French regions. All analyses were performed with SAS 9.4 (Statistical Analysis System, Cary, NC, USA).
Sensitivity analyses Three sensitivity analyses on selected samples were conducted to explore possible limitations of the main study results on liver disease progression. First, a possible coding bias of CHB was examined and all patients with at least two hospitalizations recording CHB among discharge diagnosis codes were selected. Second, a possible classification bias of ESLD in liver disease staging in 2008-2013 (see eTable 1) was examined and all patients recorded with cirrhosis were selected. Finally, as CHB treatment is not included in the National Hospital Formulary and therefore CHB treatment is not recorded in the PMSI hospital discharge database, all patients with co-primary discharge diagnosis
Prognosis of CHB Patients in France 2008-2013
10
codes indicating CHB treatment at the hospital before liver disease progression (i.e., administration (ICD-10 Z51.2) or monitoring (ICD-10 Z51.2, Z51.4, Z09.2, Z09.7-9) of treatment for CHB) were selected.
Prognosis of CHB Patients in France 2008-2013
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Results Cohort characteristics A total of 48,189 patients with CHB constituted the hospital cohort for the main analysis (see Figure 1). Patients were 58.6% male with a median (IQR) age of 44 (32-57) years at cohort inception. Overall, 29,811 (61.8%) patients had at least one risk factor associated with CHB, including 20,355 (42.2%) and 21,984 (45.6%) patients with liver-related risk factors and non-liver-related risk factors, respectively (see Table 1). Screening for HBV is mandatory for pregnant women in France and CHB was recorded in 4928 (24.7%) of 19,933 women delivering at hospital at a median (IQR) age of 29 (2634) years. All risk factors, except obesity, were more prevalent in male than in female patients (see eTable 2). HIV co-infection was recorded in 5757 (12.0%) patients with CHB (see Table 2). HIV/HBV co-infected patients were more frequently male (73.0% vs. 56.7%). HIV/HBV co-infected patients had more liver-related risk factors (52.5% vs. 40.8%) due to primarily increased HCV co-infection (34.1% vs. 12.6%) as diabetes mellitus and obesity were less frequent. HIV/HBV patients also had more non-liver-related risk factors (45.7% vs. 38.2%) including CKD, cancer other than HCC, and respiratory disease.
Liver disease progression and mortality Liver disease progression was recorded in 7479 (15.5%) patients (Table 1). Patients with liver disease progression were older and more frequently of male gender than those censored without liver disease progression. Liver-related risk factors were recorded in about three-quarters (72.6%) and one-third (36.7%) of patients with or without liver disease progression, respectively. HIV co-infection without AIDS was less
Prognosis of CHB Patients in France 2008-2013
12
frequently recorded among patients with liver disease progression. In contrast, all other non-liver-related risk factors were more frequently recorded among patients with liver disease progression. Similar results were found for 6226 (12.9%) and 3145 (6.5%) patients recorded with ESLD and HCC, respectively (see eTable 3). Overall, 433 (0.9%) patients underwent liver transplantation and 5299 (11.0%) patients died at hospital in 2008-2013. All risk factors, except HIV co-infection without AIDS, were more prevalent among CHB patients who underwent liver transplantation or died at hospital during the study period. Liver transplantation or liver death were recorded in 3573 (63.5%) patients; otherwise, 2055 (36.5%) patients died at hospital from non-liver causes (see eTable 3). About three-quarters (75.5%) of liver transplantations and liver deaths were associated with liver-related risk factors. Almost all (97.0%) non-liver deaths were associated with nonliver-related risk factors. Liver transplantation, liver death and competing non-liver death were recorded in 19 (4.4%), 357 (11.4%) and 34 (1.7%) patients without any risk factor other than CHB.
Multivariate associations of liver-related risk factors with liver disease progression The adjusted hazard ratios (aHR) of liver disease progression for HDV co-infection, HCV co-infection, alcohol use disorders, diabetes mellitus, and other primary causes of cirrhosis were 1.44 (95% confidence interval [CI], 1.35 to 1.53), 1.77 (95% CI, 1.68 to 1.87), 3.37 (95% CI, 3.20 to 3.55), 1.40 (95% CI, 1.32 to 1.48), and 2.19 (95% CI, 1.98 to 2.42), respectively (Top panel of Figure 2; see eTable 4). Patients co-infected with HDV or HCV progressed at faster rates towards HCC than ESLD, while patients with alcohol
Prognosis of CHB Patients in France 2008-2013
13
use disorders or diabetes mellitus progressed at faster rates towards ESLD than HCC (see eTable 5). All non-liver related risk factors were associated with lower risks of liver disease progression except kidney transplant recipients and patients on dialysis (see bottom panel of Figure 2). The aHR of liver disease progression for HIV co-infection was overall 0.77 (95% CI, 0.71 to 0.83), but depended on HIV/AIDS stage: 0.60 (95% CI, 0.52 to 0.70) without AIDS recorded; 0.96 (95% CI, 0.85 to 1.08) with AIDS recorded before 2008; and 0.73 (95% CI, 0.65 to 0.83) with AIDS defining condition recorded in 20082013. The strength of the association between HIV co-infection and liver disease progression was overall more marked for HCC (aHR = 0.47 [95% CI, 0.41 to 0.54]) than for ESLD (aHR = 0.82 [95% CI, 0.76 to 0.90]) (see eTable 5 for details).
Multivariate associations of risk factors with liver transplantation or liver death versus competing death from non-liver causes All risk factors were associated with increased risks of in-hospital death (Figure 3), except HIV co-infection without AIDS recorded (aHR=0.63 [95% CI, 0.51-0.78]). All liver-related risk factors were independently associated with higher risks of liver transplantation or liver death (top panel of Figure 3; see eTable 4), with alcohol use disorders associated with the highest risk (aHR=3.18 [95%CI, 2.95 to 3.42]). HDV and HCV co-infections were also independently associated with higher risks of non-liver death. All non-liver-related risk factors, except HIV co-infection by stage, were independently associated with higher risks of non-liver death (see bottom panel of Figure 3; see eTable 4). Patients with cancer other than HCC (aHR = 1.14 [95% CI 1.04 to 1.25]) and
Prognosis of CHB Patients in France 2008-2013
14
kidney transplant recipients (aHR = 1.43 [95% CI, 1.14 to 1.79]) were also at risk of liver transplantation or liver death. HIV co-infection exhibited opposite risks of non-liver death depending on HIV/AIDS stage: higher risks in patients with AIDS-defining condition recorded in 2008-2013 versus lower risks in patients with no AIDS recorded or former AIDS recorded before 2008. Accordingly, the association of HIV co-infection at an early stage (i.e., without AIDS recorded) with lower risks of liver transplantation or liver death (aHR= 0.52 (95% CI, 0.41 to 0.66]) could not be explained by higher risks of competing non-liver death.
Sensitivity analyses The main study results on liver disease progression were robust in all sensitivity analyses conducted on selected samples. Multivariate associations were similar among patients with at least two hospitalizations recording CHB among discharge diagnosis codes (see eFigure 1). Multivariate associations were also similar among patients recorded with cirrhosis (see eFigure 2 and eFigure 3). In particular, HIV co-infection without AIDS remained associated with a better outcome. Finally, multivariate associations for liver disease progression, ESLD, HCC, and mortality before liver disease progression were similar among patients identified with a treatment for CHB (n=4099) (see eTable 6 and eFigure 4). Specifically, HIV co-infection remained associated with significantly lower risks of liver disease progression and of in-hospital mortality.
Prognosis of CHB Patients in France 2008-2013
15
Discussion A total of 7479 patients with CHB progressed to a liver-related complication, including ESLD or HCC, 433 underwent liver transplantation, and 5299 died at hospital in 20082013 in France. Liver-related risk factors other than CHB were recorded in 72.6% patients with liver disease progression and increased the risk of all-cause mortality, especially after ESLD or HCC. Non-liver-related risk factors increased the risk of competing mortality before liver disease progression. Kidney transplant recipients and patients with cancer other than HCC remained at higher risk of liver death despite higher risks of competing mortality. Co-infection with HIV was independently associated with about 20% reduction of the risk of liver disease progression and reduced the risk of dying at hospital by about 40%. To our knowledge, this is the largest Western cohort study on the prognosis of patients with CHB.(18) Selection bias is limited because all residents in France have universal access to hospital care. The French National Hospital Discharge (PMSI) database and the ICD-10 classification have been previously validated for “hard outcomes”, including inhospital death, and the risk factors under study.(2, 19-21) In addition, similar multivariate associations were found in the main analysis and two sensitivity analyses, one by selecting patients with at least two hospital stays with a diagnosis of CHB and the second by selecting patients with a diagnosis of cirrhosis at study entry, before disease progression. Liver- and non-liver-related risk factors have rarely been taken into account together to model liver disease progression in patients with CHB, especially outside of the Asian setting.(8, 22, 23) As previously reported, we found that co-infection with HDV and HCV,
Prognosis of CHB Patients in France 2008-2013
16
and alcohol use disorders were independent risk factors of liver disease progression, liver transplantation and liver death. Alcohol use disorders were associated with threefold greater risk of liver disease progression and faster progression towards ESLD than HCC.(4, 6, 24, 25) The results also highlight the independent association of diabetes mellitus with liver disease progression (aHR = 1.40, 95% CI 1.32 to 1.48).(26, 27) Overall, the results suggest that liver disease progression, liver transplantation, or liver death are primarily accounted for by liver-related risk factors other than CHB in a setting with universal access to hospital care. The study also highlights the burden of non-liver related risk factors in patients with CHB. Except for HIV co-infection, non-liver-related risk factors were all associated with higher risks of competing non-liver death and accounted for about all (97%) non-liver deaths. As a consequence, patients with non-liver risk factors were at significantly lower risk of liver disease progression. The absence of information on CHB treatment is a limitation. However, CHB treatment generally follows clinical practice guidelines in France as CHB treatment is free of charge from the patient’s perspective.(28, 29) In a sensitivity analysis, multivariate associations remained similar in the sample of 4099 patients identified with discharge diagnosis codes indicating CHB treatment. In this respect, the study findings on HIV/HBV co-infection are of interest as standardof-care of co-infected patients includes effective antivirals to control both HIV and HBV replication and close follow-up.(29) About all HIV/HBV co-infected patients received standard-of-care in a recent multicenter observational study conducted in France.(12) In turn, HIV/HBV co-infection was independently associated with lower risks of liver disease progression (aHR=0.77 [95% CI, 0.71 to 0.83]) and reduced in-hospital death. Prognosis of CHB Patients in France 2008-2013
17
Several findings suggest that CHB treatment is not strictly related to antivirals but also involves closer follow-up with better control of liver-related risk factors. First, it is noteworthy that HIV co-infection was associated with higher rates of liver-related risk factors, although their confounding effect on HIV co-infection was taken into account in all multivariate analyses. Second, patients co-infected with HIV were disentangled by stage to limit heterogeneity and patients with AIDS-defining conditions in 2008-2013 were at higher risk of non-liver (AIDS) death, and therefore lower risk of liver disease progression. Finally, patients without AIDS recorded had a similar risk of non-liver death than mono-infected patients but significantly lower risk of liver disease progression (aHR=0.60, [95% CI, 0.52-0.70]). These patients remained at a lower risk of liver disease progression in the sample of 4099 patients identified with discharge diagnosis codes indicating CHB treatment. Overall, the study results suggest that CHB treatment strategies recommended in patients co-infected with HIV should be investigated in HBV mono-infected patients. In conclusion, our results suggest that the prognosis of patients with CHB is primarily driven by liver-related and non-liver-related risk factors other than CHB in Western settings. Besides the potential benefits of expanding antivirals in mono-infected CHB patients, liver prognosis would be substantially improved by a more stringent control of liver-related risk factors including alcohol abstinence and eradication of HCV.
Prognosis of CHB Patients in France 2008-2013
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Acknowledgements Novartis Pharmaceuticals Corporation funded the study. Vincent Mallet is funded by la Fondation ARC pour la recherche sur le cancer. The authors would like to thank Professors Philippe Sogni, Dominique Salmon, and Stanislas Pol for their comments on the manuscript; and Dr. Aldo Trylesinski for his help in the development of the study.
Prognosis of CHB Patients in France 2008-2013
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Legends to figures Figure 1: study flowchart Figure 2: Risk factors of liver disease progression of CHB patients in the 2008-2013 French hospital database (N=48,189) Follow-up was from January 2008 to liver disease progression, a composite outcome of end-stage liver disease and/or hepatocellular carcinoma, or to last discharge. Patients with chronic kidney disease were censored at kidney transplantation (n = 253) in 2008–2013. All risk factors under study were recorded before liver disease progression. Note: aHR = adjusted hazard ratio; CI = confidence interval; CKD = chronic kidney disease; HCC = hepatocellular carcinoma; HDV = hepatitis D virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus.
Figure 3: Prognostic factors of CHB patients in the 2008-2013 French hospital database (N=48,189) Follow-up was from January 2008 to liver transplantation, death after liver disease progression, competing mortality before liver disease progression or last discharge. In-hospital mortality includes 86/433 and 18/253 patients who died after liver and renal transplantation, respectively; otherwise patients were censored at kidney transplant. All risk factors under study were recorded before outcome. Note: aHR = adjusted hazard ratio; CI = confidence interval; CKD = chronic kidney disease; HCC = hepatocellular carcinoma; HDV = hepatitis D virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus.
Prognosis of CHB Patients in France 2008-2013
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Table 1. Risk Factors and Outcomes of Patients with Chronic Hepatitis B Virus Infection (2008-2013) Overall population N (%) = 48,189 (100)
Male gender, n (%) Age at cohort inception, at first event or last discharge without event, median (IQR) years Region of residency in Metropolitan France, n (%) Greater Paris area North-West North-East South-West South-East Liver-related risk factors,c n (%) Co-infection with HDV Co-infection with HCV Alcohol use disorders Diabetes mellitus Obesity (≥30 kg/m2) Other cause of cirrhosis Non-liver-related risk factors,c n (%) Co-infection with HIV AIDS in 2008-2013 AIDS before 2008 No AIDS CKD (all) Kidney transplant recipient at cohort inception On dialysis at cohort inception CKD without kidney transplantation or dialysis Cancer other than HCC
With liver disease progression
28,256 (58.6) 44 (32–57)
n (%) = 7479 (15.5) 5706 (76.3) 58 (48–68)
Censored without liver disease progression n (%) = 40,710 (84.5%) 22,550 (55.4) 46 (35-59)
20,212 (42.0) 5613 (11.7) 7324 (15.2) 3888 (8.1) 11,152 (23.1) 20,355 (42.2) 5143 (10.7) 7297 (15.1) 6383 (13.3) 6378 (13.2) 4287 (8.9) 839 (1.7) 21,984 (45.6) 5757 (12.0) 2,039 (4.2) 1,697 (3.5) 2,021 (4.2) 4139 (8.6) 603 (1.3) 573 (1.2) 2963 (6.2) 5361 (11.1)
2985 (39.9) 840 (11.2) 1180 (15.8) 582 (7.8) 1892 (25.3) 5426 (72.6) 1199 (16.0) 2308 (30.9) 2989 (40.0) 1941 (26.0) 793 (10.6) 443 (5.9) 4199 (56.1) 802 (10.7) 294 (3.9) 328 (4.4) 180 (2.4) 755 (10.1) 125 (1.7) 89 (1.2) 541 (7.2) 1089 (14.6)
17,227 (42.3) 4773 (11.7) 6144 (15.1) 3306 (8.1) 9260 (22.8) 14,929 (36.7) 3944 (9.7) 4989 (12.3) 3394 (8.3) 4437 (10.9) 3494 (8.6) 396 (1.0) 17,785 (423) 4955 (12.2) 1,745 (4.3) 1,369 (3.4) 1,841 (4.5) 3384 (8.3) 478 (1.2) 484 (1.2) 2422 (6.0) 4272 (10.5)
a
Prognosis of CHB Patients in France 2008-2013
P-value
In-hospital mortalityb n (%) = 5299 (11.0)
Alive at last discharge n (%) = 42,890 (89.0)
Pvalue
<0.001
3,885 (73.3) 62 (52-74)
24,371 (56.8) 46 (35-59)
<0.001
1,848 (34.9) 665 (12.6) 899 (17.0) 494 (9.3) 1,393 (26.3) 3,676 (69.4) 829 (15.6) 1,485 (28.0) 1,685 (31.8) 1,376 (26.0) 530 (10.0) 252 (4.8) 3,949 (74.5) 603 (11.4) 340 (6.4) 171 (3.2) 92 (1.7) 1,076 (20.3) 161 (3.0) 212 (4.0) 703 (12.3) 1,772 (33.4)
18,364 (42.8) 4,948 (11.5) 6,425 (15.0) 3,394 (7.9) 9,759 (22.8) 16,679 (38.9) 4,314 (10.1) 5,812 (13.6) 4,698 (11.0) 5,002 (11.7) 3,757 (8.8) 587 (1.4) 18,035 (42.1) 5,154 (12.0) 1,699 (4.0) 1,526 (3.6) 1,929 (4.5) 3,063 (7.1) 442 (1.0) 361 (0.8) 2,260 (5.3) 3,589 (8.4)
<0.001
<0.001
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
<0.001
<0.001
<0.001
<0.001
25
<0.001
<0.001
<0.001 <0.001 <0.001 <0.001 <0.001 <0.01 <0.001 <0.001 0.18
<0.001
<0.001
<0.001
<0.001
Cardiovascular disease Respiratory disease
12,649 (26.3) 7404 (15.4)
2694 (36.0) 1287 (17.2)
9955 (24.5) 6117 (15.0)
<0.001 <0.001
2,740 (51.7) 1,682 (31.7)
9,909 (23.1) 5,722 (13.3)
aAmong
<0.001 <0.001
7479 patients with liver disease progression, 1892 (25.3%) had both decompensated cirrhosis and hepatocellular carcinoma. bincludes 86/433 and 18/253 patients who died after liver and renal transplantation, respectively. cRisk factors are recorded before disease progression. dIncludes 40 congenital malformations; 239 hemochromatosis; 10 cystic fibrosis; 3 Wilson disease; 34 primary Budd-Chiari syndrome; 111 primary biliary cirrhosis; 81 autoimmune hepatitis; 350 primary sclerosing cholangitis. AIDS = acquired immune deficiency syndrome. CKD = chronic kidney disease. HCC = hepatocellular carcinoma HCV = hepatitis C virus. HDV = hepatitis D virus. HIV = human immunodeficiency virus. IQR = interquartile range
Prognosis of CHB Patients in France 2008-2013
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Table 2: Risk factors of Patients with Chronic Hepatitis B Virus Infection, by HIV coinfection status All N (%) = 48,189 (100)
HIV-positive n (%) = 5757 (12.0)
28,256 (58.6) 44 (32–57)
4202 (73.0) 43 (37–49)
HIVnegative n (%) = 42,432 (88.0) 24,054 (56.7) 44 (32–58)
20,212 (42.0) 5613 (11.7) 7324 (15.2) 3888 (8.1) 11,152 (23.1) 20,355 (42.2) 5143 (10.7) 7297 (15.1) 6383 (13.3) 6378 (13.2) 4287 (8.9) 839 (1.7)
3142 (54.6) 519 (9.0) 548 (9.5) 435 (7.6) 1113 (19.3) 3,024 (52.5) 829 (14.4) 1965 (34.1) 927 (16.1) 499 (8.7) 269 (4.7) 76 (1.3)
17,070 (40.0) 5094 (12.0) 6776 (16.0) 3453 (8.1) 10,039 (23.7) 17,331 (40.8) 4314 (10.2) 5332 (12.6) 5456 (12.9) 5879 (13.9) 4018 (9.5) 763 (1.8)
18,855 (39.1) 4139 (8.6)
2,628 (45.7) 592 (10.3)
16,227 (38.2) 3547 (8.4)
Kidney transplant recipient at cohort inception
603 (1.3)
36 (0.5)
577 (1.4)
On dialysis at cohort inceptionc
573 (1.2)
58 (1.0)
515 (1.2)
CKD without kidney transplantation or dialysis
2963 (6.2)
508 (8.8)
2455 (5.8)
Cancer other than HCC
5361 (11.1)
864 (15.0)
Cardiovascular disease
12,649 (26.3) 7404 (15.4)
1482 (25.7) 1074 (18.7)
Male gender, n (%) Age at cohort inception, median (IQR) years Region of residency in Metropolitan France, n (%) Greater Paris area North-West North-East South-West South-East Liver-related risk factorsa, n (%) Co-infection with HDV Co-infection with HCV Alcohol use disorders Diabetes mellitus Obesity (≥30 kg/m2) Other cause of cirrhosisb
Pvalue
<0.001 <0.001
<0.001
<.001
<.001
<0.001
<.001
<0.001
<.001
<0.001
0.37
<0.001
<.001
<0.001
<.001
<0.01
<.05
<.0001
<.0001
<0.001
<.0001
<0.001
<0.001
4497 (10.6)
<0.001
<0.001
11,167 (26.3) 6330 (14.9)
0.35
<0.001
<0.001
<0.001
Non-liver-related risk factorsa, n (%) CKD (all), n (%)
Respiratory disease
Prognosis of CHB Patients in France 2008-2013
Pvalueb
27
aRisk
factors are recorded before liver disease progression. bIncludes: 40 congenital malformations; 239 hemochromatosis; 10 cystic fibrosis; 3 Wilson disease; 34 primary Budd-Chiari syndrome; 111 primary biliary cirrhosis; 81 autoimmune hepatitis; 350 primary sclerosing cholangitis. cCensored at kidney transplantation in 2008– 2013 (N = 253). AIDS = acquired immune deficiency syndrome. CKD = chronic kidney disease. HCC = hepatocellular carcinoma HCV = hepatitis C virus. HDV = hepatitis D virus. HIV = human immunodeficiency virus. IQR = interquartile range
Prognosis of CHB Patients in France 2008-2013
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Prognosis of CHB Patients in France 2008-2013
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Prognosis of CHB Patients in France 2008-2013
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Prognosis of CHB Patients in France 2008-2013
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