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Original article
Forecasting the disease burden of chronic hepatitis C virus in Poland Robert Flisiaka, Waldemar Halotab, Krzysztof Tomasiewiczc, Kaja Kostrzewskad, Homie A. Razavie and Erin E. Gowere Background and aims Chronic hepatitis C virus infection is prevalent among 200 000 individuals in Poland; however, few are aware of their condition (30 000 diagnosed) and even fewer are treated (2490 in 2014). This analysis projected future disease burden and developed two treatment scenarios to control or eliminate hepatitis C virusrelated disease in Poland. Methods Using a modeling approach, the infected population and future disease progression were quantified. Baseline variables included viremic prevalence, age and sex, diagnosis rate, treatment rate, disease progression, and sustained virologic response rates. Data were collected from the literature and through expert interviews. Results The number of prevalent hepatitis C virus infections is projected to decrease (5%) by 2030. However, the numbers of individuals with compensated and decompensated cirrhosis, and hepatocellular carcinoma are estimated to increase by 40, 55, and 60%, respectively. By increasing sustained virologic response rates to 95% from 2015 onward, and the number of treated cases (from 2490 to 5000), the number of individuals with cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma is projected to remain constant until 2030. A strategy
Introduction It is estimated that ∼ 200 000 individuals are infected with the hepatitis C virus (HCV) in Poland, but the future disease burden of HCV has not been quantified. Chronic hepatitis C is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation [1–3]. In addition, a number of studies have shown that the number of individuals who will progress to endstage liver disease will increase as the HCV-infected population ages [4–7]. A notifiable disease registry for HCV was implemented in the late 1990s, carried out by the National Institute of Public Health-National Institute of Hygiene (NIPHNIH) [8]. Although there is no national screening program, recently, two large surveillance studies were carried out on more than 23 000 inhabitants to estimate HCV burden. It was estimated that 200 000 inhabitants were actively infected (HCV RNA positive), with 0.9–1.9% of the population being anti-HCV positive [9,10]. The majority of patients were infected with genotype (G) 1b (77%), followed by G3 (14%) and G4 (5%) [11]. It is 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
to eliminate chronic hepatitis C virus infection was also considered. To reduce total infections by 90% and mortality by 80%, treatment was increased to 15 000 patients annually. This scenario required the diagnosis of 15 000 new cases (compared with 3000 today). Conclusion A marked reduction in hepatitis C virus-related disease burden is possible, with increased diagnosis and treatment. The results could inform the development of effective disease management in Poland. Eur J Gastroenterol Hepatol 27:70–76 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2015, 27:70–76 Keywords: diagnosis, disease burden, epidemiology, hepatitis C virus, hepatitis C, Poland, treatment a Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, bDepartment of Infectious Diseases and Hepatology, CMUMK Bydgoszcz, Bydgoszcz, cDepartment of Infectious Diseases, Medical University of Lublin, Lublin, dHTA Consulting, Krakow, Poland and eCenter for Disease Analysis, Louisville, Colorado, USA
Correspondence to Robert Flisiak, MD, Department of Infectious Diseases and Hepatology, Medical University of Bialystok, ul. Zurawia 14, 15-540 Bialystok, Poland Tel: + 48 60 5203525; fax: + 48 85 7416921; e-mail: [email protected] Received 6 July 2014 Accepted 6 October 2014
estimated that only 15% of infected individuals have been diagnosed and treated to date (unpublished data). Infection with chronic HCV infection has been called a silent pandemic [12]. The lack of screening programs has resulted in the accumulation of a hidden HCV-infected population at risk for advanced disease, and, moreover, a potential reservoir for uncontrolled spread of the infection. Treatment in Poland is limited to ∼ 3000 patients annually and the majority of these patients receive dual therapy based on pegylated interferon-α and ribavirin. According to the Polish National Health Fund (NFZ) reimbursement policy, only 20% of HCV-infected patients are currently eligible to receive a triple therapy regimen based on the first-generation direct-acting antivirals boceprevir or telaprevir. With the availability of second-generation therapies (e.g. sofosbuvir, simeprevir, and daclatasvir), and possible interferon-free regimens expected in Poland in 2015 or later, the costefficacy of these innovative regimens and prediction of HCV control and eradication in Poland should be strongly supported for more efficient reimbursement policy. DOI: 10.1097/MEG.0000000000000237
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Chronic hepatitis C virus burden in Poland Flisiak et al. 71
A detailed description of the model and methodology has been described previously [6]. The historical epidemiology of HCV was gathered through a literature search, analysis of unpublished data, and discussion with an expert panel. Because HCV epidemiology was reported in different years, a mathematical disease progression model was used to estimate the 2013 HCV-infected population. The model was constructed in Microsoft Excel (Microsoft Corp., Redmond, Washington, USA) and designed to quantify the size of the HCV-infected population, by the liver disease stages, from 1950 to 2030. The model started with the annual number of acute infections that progressed to chronic HCV (viremic) infection, accounting for spontaneous clearance of the virus. The progression of new cases was followed along with all chronic infections from previous years using previously published transition probabilities [6] after taking into account mortality and cured patients. The total number of cases at each stage of the disease was tracked by age and sex. Five-year age cohorts were used through age 84, and those aged 85 years and older were treated as one cohort. Baseline population characteristics
There are a number of studies reporting anti-HCV prevalence in Poland [2,3,7–15]. The largest study determined a viremic (RNA positive) rate of 0.60% [2]. However, it also determined an antibody-positive prevalence of 1.94% with a single fourth-generation ELISA test [2]. Another study found an antibody prevalence of 1.91 and 0.86% with repeatedly reactive ELISA and western blot confirmatory tests [3]. Thus, in 2009, the anti-HCV prevalence in the adult population (18 + ) in Poland was estimated to be 0.86%, with an estimated prevalence of 0.72% for all ages. The viremic prevalence was estimated to be 0.60% in adults. For the purpose of this analysis, it was estimated that there were 200 000 viremic infections in 2009 (for all ages), corresponding to a prevalence of 0.52% (Table 2). The age and sex distribution was developed using diagnosed data from the NIPH-NIH (Fig. 1) [1]. The number of RNA-positive diagnosed cases was available from 1999 to 2012. The diagnosed population was adjusted for mortality and cured, by year, and was aged to 2012. It was assumed that the age and sex distribution of the diagnosed population was reflective of the current distribution in Poland. According to the most recent data published by the NIPH-NIH, there were 30 200 patients living with a diagnosis [1]. In 2012, 2290 individuals were newly diagnosed. For the purpose of this analysis, 3000 newly diagnosed were assumed per
1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0
0– 4 5 10 –9 – 15 14 20–19 – 25 24 – 30 29 –3 35 4 – 40 39 –4 45 4 50–49 – 55 54 60–59 – 65 64 – 70 69 – 75 74 – 80 79 –8 85 4 +
Materials and methods
Fig. 1
HCV prevalence (%)
The aim of this study was to assess baseline epidemiology, project HCV-related disease burden, and develop treatment strategies that consider the actions necessary to control or eliminate HCV infection.
Males (2012)
Females (2012)
Age and sex distribution of antihepatitis C virus prevalence in Poland, 2012.
year, beginning in 2013. Treatment and diagnosis estimates for 2013 are shown in Table 2. According to the NFZ, an average number of 2490 individuals were treated per year from 2008 to 2012. In 2013, the number of treated patients increased to 2990 individuals in light of increased triple therapy treatment for previously warehoused patients. It is anticipated that the number of treated patients will decrease to the 2008–2012 average, with an estimated 2500 individuals treated in 2014. Polish population data were obtained by 5-year age and sex cohorts from the United Nations population database [16]. The genotype distribution (Table 1) was developed using data from an analysis of more than 14 600 patients from 22 centers from 2003 to 2012 [4]. It is estimated, from 1998 to 2001, that transfusion accounted for 9.0% of the transmission of HCV infection [17], whereas, in 2013, it was estimated that active intravenous drug usage accounted for 5% of transmission. Estimates for 2013 are shown in Table 2. There were limited data available on the incidence of new cases of HCV in Poland. The number of new HCV infections was back-calculated. Eq. (1) shows that, at any point in time, the total number of HCV infections equals the sum of all new infections minus the number of Hepatitis C virus genotype distribution in Poland, 2003–2012
Table 1
Genotype 1a 1b 2 3 4 5 6 Mixed
% 2.0 77.4 0.1 13.8 4.9 0.0 0.1 1.6
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72 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
Table 2
Model inputs and 2013 estimations Historical (minimum–maximum uncertainty interval)
HCV-infected cases Number of anti-HCV cases Anti-HCV prevalence Number of viremic cases Viremic prevalence Viremic rate HCV diagnosed (viremic) Viremic diagnosed up to now Viremic diagnosis rate Annual newly diagnosed New infections New infections New infection rate (per 100k) Treated Number treated Risk factors Number of active IDUs with HCV (%) Previous blood transfusion (%)
286 000 0.8% 200 000 0.5%
(197 000–380 000) (0.5–1.0%) (138 000–266 000) (0.4–0.8%) 70.0%
Year [references] 2009 [2] – 2009 [1,2] –
2013 (95% uncertainty interval) 286 000 0.7% 201 000 0.5%
2012 [1,2]
(203 000–286 000) (0.5–0.9%) (142 000–235 000) (0.4–0.6%) 70%
30 000 – 3000
2012 [unpublished data] – 2012 [unpublished data]
30 400 15.2% 3000
– –
– –
5420 14.1
2490 – –
2008–2012 [4] 2009 [16] 2013 [unpublished data]
2990 10 000 (5%) 18 000 (9%)
HCV, hepatitis C virus; IDUs, injection drug users.
spontaneously cleared cases, all-cause, and liver-related mortality, and cured cases: Using the known number of total HCV infections in 2009, the annual number of all-cause mortality, liver-
Total HCV infectionsYear x ¼
x X
annually. Treatment in this scenario focused on patients 20–69 years of age with a METAVIR score ≥ F1. Estimates of sustained virologic response (SVR) rates were based on SVR observed among treated patients, clinical studies, and expert opinion [28–30]. SVR rates of
ðNew infectionst spontaneously curedt mortalityt treated & curedt Þ
ð1Þ
t¼1950
related deaths, and cured cases, the annual numbers of new infections were estimated [Eq. (1)] [6]. According to this calculation, there were an estimated 5420 new cases of HCV in Poland in 2013. Mortality and liver transplants
All-cause mortality for the years 1958–2009 was estimated by 5-year age and sex cohorts using data from the Max Planck Institute for Demographic Research [18]. Increased mortality among the transfused and injection drug user populations was accounted for by applying a standard mortality ratio of 2.1 and 10.0, respectively, for the affected age groups [19–25]. Liver transplant data were available through Poltransplant, the Center for Organizational and Coordination for Transplantation. In 2013, 318 liver transplants were performed in Poland [26]. It is estimated that 27.8% of transplants are attributable to HCV [27]. Scenarios
A baseline scenario and two scenarios with improved diagnosis and treatment were modeled in Poland. Baseline scenario
The baseline scenario assumed a continued diagnosis of 3000 infections and treatment of 2500 infections
40% (G1/4), 75% (G2), and 70% (G3) were assumed. The current standard of care in Poland allows for the treatment of patients with any histological changes typical for hepatitis in individuals from 3 years of age independent of genotype. However, triple (boceprevir or telaprevir based) therapy reimbursement among treatment-naive patients is limited to G1-infected adults with fibrosis ≥ F2 and the IL28B TT genotype, reducing the availability of triple therapy to about 20% of the infected, diagnosed population.
Control disease burden scenario
A second scenario was developed to control disease burden. This scenario assumed increased treatment efficacy and uptake. In 2015, it was projected that SVR could increase to 95% (G1/2/4) and 90% (G3). Treatment was limited to individuals with fibrosis staging of F1 or greater. SVR rates applied in 2015 were held constant through 2030. In addition, annual diagnosis increased by 30% to 3900 individuals (from 3000) and treatment increased 100% across genotypes to 5000 individuals (from 2490). To maintain the treatment level, diagnosis was increased by 30% to 5000 individuals annually in 2016. Treatment of 5000 patients annually and diagnosis of 5000 individuals annually were held constant through 2030. Beginning in 2020, treatment was not limited on the basis of fibrosis stage.
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Chronic hepatitis C virus burden in Poland Flisiak et al. 73
Elimination scenario
Results
A third scenario was created to assess the actions necessary to achieve elimination of chronic HCV infection by 2030. Increases in SVR as stated above were applied for this strategy. Treatment was limited to individuals with fibrosis staging of F1 or greater. Beginning in 2015, diagnosis was increased 150% to 7500 individuals annually whereas treatment was increased 100% across genotypes to 5000 individuals. In 2016, age restrictions were expanded to include patients up to 74 years of age and treatment was considered for individuals irrespective of fibrosis stage. Further, diagnosis and treatment were increased to 15 000 and 10 000 individuals annually. In 2018, diagnosis was held constant and treatment was increased to 15 000 individuals annually. Annual diagnosis of 15 000 individuals and treatment of 15 000 individuals were held constant through 2030.
Baseline
Fig. 2
(a)
In 2013, there were an estimated 201 000 (95% uncertainty interval: 142 000–235 000) viremic individuals in Poland (Fig. 2b). The viremic age distribution is shown in Fig. 2a. The total number of viremic cases is projected to decrease to 191 000 by 2030 because of reduced incidence since the peak in 1990 and greater mortality as the infected population ages (Fig. 2c). Although the overall prevalence is projected to decrease, the number of individuals with more advanced liver disease is projected to increase. The number of individuals with compensated cirrhosis is projected to increase by 40% to 23 000 in 2030 (from 16 300 in 2013), and the population with decompensated cirrhosis will increase by 55% to 2460 in 2030 (from 1590 in 2013). The number of individuals with HCV-related HCC will increase to 1250 individuals in 2030, a 60% increase from 2013. Finally, liver-related mortality will increase 65%, corresponding to 1100 individuals, in 2030 (Fig. 3).
Prevalence (× 1000)
250
Control disease burden
200 150 100 50
20
30
20 20
10 20
00 20
90 19
80 19
60
19 70
19
19
50
0
In addition, by 2030, the number of individuals with compensated cirrhosis will decrease to 15 600 individuals and the population with decompensated cirrhosis will decrease to 1590 individuals (30% decrease and 35% decrease from baseline) (Fig. 3). The number of individuals with HCV-related HCC will decrease to 890 cases relative to an increase in the baseline.
25 000 20 000 15 000 10 000 5 000 0
Elimination
0– 54 10 –9 15–14 – 20 19 – 25 24 30–29 35–34 40–39 45–44 5 0 –4 9 – 55 54 – 60 59 65–64 – 70 69 – 75 74 – 80 79 – 8584 +
Total viremic infected
(b)
Under an increased diagnosis and treatment strategy, where by 2030 up to 15 000 are treated annually, there was a 90% reduction in viremic infections relative to 2013 (21 600 remaining cases in 2030). This strategy would result in an 80% decrease in HCV-related mortality, avoiding 6540 liver-related deaths.
90 000 80 000 70 000 60 000 50 000 40 000 30 000 20 000 10 000
250 000 200 000 150 000 100 000 50 000
–
Total viremic infections
(c) Viremic infections (by disease stage)
Under increased treatment efficacy and increased treatment, the number of viremic infected individuals is projected to decrease at a faster rate than in the baseline scenario (Fig. 3), with 141 000 viremic individuals remaining in 2030. In this scenario, HCV-related mortality is projected to decrease 30% from the base case, a reduction of 2840 liver-related deaths.
19 50 19 60 19 70 19 80 19 90 20 00 20 10 20 20 20 30 20 40 20 50
–
F0 F2 F4/compensated cirrhosis HCC
F1 F3 Decompensated cirrhosis Total viremic
Baseline scenario outputs. (a) Total viremic cases, by year, 1950–2030. (b) Total viremic cases, by age, 2013. (c) Number of viremic cases, in total, and by disease stage, 1950–2050.
In addition, by 2030, the number of individuals with compensated cirrhosis will decrease to 3220 individuals and the population with decompensated cirrhosis will decrease to less than 350 individuals (Fig. 3). Further, HCC cases would reduce to a projected 240 individuals relative to the baseline.
Discussion It is expected that the second wave of direct-acting antiviral-based therapy, and, more importantly, the implementation of IFN-free and ribavirin-free regimens, will yield a chance for HCV cure rates close to 95%.
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74 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
Fig. 3
(a)
(b) Total infected cases (viremic)
250 000 200 000 150 000 100 000 50 000
Control disease burden
20 1 20 3 1 20 4 1 20 5 1 20 6 2017 2018 1 20 9 2 20 0 2 20 1 2022 2 20 3 2 20 4 2025 2 20 6 2027 2028 2029 30
20 1 20 3 1 20 4 1 20 5 1 20 6 2017 1 20 8 1 20 9 2 20 0 2021 2022 2 20 3 2 20 4 2025 2 20 6 2027 2028 2 20 9 30
–
Baseline
Noncirrhotic fibrosis
200 000 175 000 150 000 125 000 100 000 75 000 50 000 25 000 –
Baseline
Elimination
Control disease burden
Elimination
(d)
(c) F4/compensated cirrhosis
Decompensated cirrhosis
25 000
3000 2500 2000 1500 1000 500 –
20 000 15 000 10 000 5000
Baseline
Control disease burden
20 1 20 3 1 20 4 2015 1 20 6 1 20 7 18 20 2019 2 20 0 2 20 1 2022 2 20 3 2024 2 20 5 2 20 6 2 20 7 28 20 2029 30
20 1 20 3 14 20 1 20 5 1 20 6 2017 1 20 8 2019 2 20 0 2 20 1 2022 2 20 3 2 20 4 2 20 5 26 20 2027 2 20 8 2029 30
–
Baseline
Elimination
(e)
Control disease burden
Elimination
(f) Liver-related deaths
HCC
1400 1200 1000 800 600 400 200 –
Baseline
Control disease burden
Elimination
1 20 3 1 20 4 1 20 5 16 20 2017 1 20 8 1 20 9 2 20 0 2 20 1 2 20 2 2 20 3 2 20 4 2 20 5 2 20 6 2 20 7 2 20 8 2 20 9 30
20
20 1 20 3 1 20 4 15 20 1 20 6 1 20 7 18 20 1 20 9 2 20 0 21 20 2 20 2 2 20 3 2 20 4 25 20 2 20 6 2 20 7 2 20 8 2 20 9 30
1200 1000 800 600 400 200 –
Baseline
Control disease burden
Elimination
Morbidity (a–e) and mortality (f), by scenario, by year, 2013–2030.
According to current predictions, the number of treated patients will exceed eligible patients in 2024 (results not shown). Thus, to mitigate HCV-related liver disease in the coming years, an increase in both diagnosis and treatment is needed. In this model, the diagnosis rate was increased to provide a sufficient patient pool to achieve the two scenarios. It is assumed that undiagnosed patients will be captured at the rate needed to maintain treatment; however, because of various risk factors (e.g. transfusion before blood screening protocols, injection drug use, etc.) diagnosis at the population level may be inefficient, expensive, and fail to target the appropriate populations without a country-specific screening strategy. In the USA, the Center for Disease Control and Prevention has recommended birth year-based screening for the efficient use
of resources [31,32]. By focusing on age cohorts with a high HCV prevalence, potential undiagnosed cases may be identified in a more efficient manner. In Poland, there is a birth cohort effect wherein 76% of the infected population (58% of the total country population) in 2013 is between 25 and 64 years of age. In both sexes, this analysis suggests a pooling of patients infected through transfusion or hospital procedures before implementation of current infection control practices. Further, in men, there is a noticeable peak in younger age groups, likely attributable to injection drug use (Fig. 1). In addition to increased diagnosis, these scenarios incorporate increases in the number of treated patients and a change in restrictions of fibrotic stages eligible for treatment. To achieve steady-state mortality and morbidity under forecasted trends, an increase in treatment
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Chronic hepatitis C virus burden in Poland Flisiak et al. 75
of 80% (5000 patients annually) would be required beginning in 2015. Although new treatments are expected to be more tolerable with a shorter duration of treatment, it is assumed that the health care system can support an increase in patients treated. Additional factors may be required to achieve these suggestions. It is understood that elimination of HCV by 2030 in Poland is unlikely. However, this analysis suggests that elimination could be achieved by increasing treatment to 15 000 patients, highlighting that increased diagnosis will be necessary to mitigate impending increases in disease burden in Poland. There are several limitations to this analysis that could impact outcomes. First, the published data applied in this model represent the best data available in Poland; however, it is understood that each input is subject to limitations. Second, it is assumed that the number of new cases of HCV will remain constant after 2013. A higher number of new infections could result in a higher total number of infections in 2030. Further, the forecasts assume that sufficient numbers of diagnosed patients will be available for treatment. However, as the diagnosis rate increases, it will become more difficult to identify undiagnosed patients. Moreover, the ability of a country to treat its HCV-infected population may be limited by the number of available diagnosed and eligible patients. Finally, the model does not consider the progression of cured HCV patients. Studies have shown that more advanced patients may experience disease progression after achieving SVR, although at a slower rate [33]. In turn, the data presented may overestimate the reduction in HCC and decompensated cirrhosis cases because the scope of the forecast was limited to viremic cases.
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Conclusion
A reduction in HCV burden in Poland is possible with increased diagnosis and increased treatment efficacy. Depending on the scenario, a reduction of total HCV cases by 30–90% and a reduction in mortality of 30–80% were modeled. The analysis shows possible elimination of HCV in the Polish population by 2030 with an increase in the number of diagnosed and treated individuals up to 15 000 annually.
Acknowledgements
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This project was supported by Gilead Sciences. 21
Conflicts of interest
Robert Flisiak has served as a speaker or advisor for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, MSD, Novartis, and Roche. Waldemar Halota and Krzysztof Tomasiewicz have served as a speaker or advisor for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, MSD, and Roche. Kaja Kostrzewska is an employee with HTA Consulting. Homie Razavi and Erin Gower are employees with the Center for Disease Analysis.
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Original article
Forecasting the disease burden of chronic hepatitis C virus in Poland Robert Flisiaka, Waldemar Halotab, Krzysztof Tomasiewiczc, Kaja Kostrzewskad, Homie A. Razavie and Erin E. Gowere Background and aims Chronic hepatitis C virus infection is prevalent among 200 000 individuals in Poland; however, few are aware of their condition (30 000 diagnosed) and even fewer are treated (2490 in 2014). This analysis projected future disease burden and developed two treatment scenarios to control or eliminate hepatitis C virusrelated disease in Poland. Methods Using a modeling approach, the infected population and future disease progression were quantified. Baseline variables included viremic prevalence, age and sex, diagnosis rate, treatment rate, disease progression, and sustained virologic response rates. Data were collected from the literature and through expert interviews. Results The number of prevalent hepatitis C virus infections is projected to decrease (5%) by 2030. However, the numbers of individuals with compensated and decompensated cirrhosis, and hepatocellular carcinoma are estimated to increase by 40, 55, and 60%, respectively. By increasing sustained virologic response rates to 95% from 2015 onward, and the number of treated cases (from 2490 to 5000), the number of individuals with cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma is projected to remain constant until 2030. A strategy
Introduction It is estimated that ∼ 200 000 individuals are infected with the hepatitis C virus (HCV) in Poland, but the future disease burden of HCV has not been quantified. Chronic hepatitis C is the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation [1–3]. In addition, a number of studies have shown that the number of individuals who will progress to endstage liver disease will increase as the HCV-infected population ages [4–7]. A notifiable disease registry for HCV was implemented in the late 1990s, carried out by the National Institute of Public Health-National Institute of Hygiene (NIPHNIH) [8]. Although there is no national screening program, recently, two large surveillance studies were carried out on more than 23 000 inhabitants to estimate HCV burden. It was estimated that 200 000 inhabitants were actively infected (HCV RNA positive), with 0.9–1.9% of the population being anti-HCV positive [9,10]. The majority of patients were infected with genotype (G) 1b (77%), followed by G3 (14%) and G4 (5%) [11]. It is 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
to eliminate chronic hepatitis C virus infection was also considered. To reduce total infections by 90% and mortality by 80%, treatment was increased to 15 000 patients annually. This scenario required the diagnosis of 15 000 new cases (compared with 3000 today). Conclusion A marked reduction in hepatitis C virus-related disease burden is possible, with increased diagnosis and treatment. The results could inform the development of effective disease management in Poland. Eur J Gastroenterol Hepatol 27:70–76 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2015, 27:70–76 Keywords: diagnosis, disease burden, epidemiology, hepatitis C virus, hepatitis C, Poland, treatment a Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, bDepartment of Infectious Diseases and Hepatology, CMUMK Bydgoszcz, Bydgoszcz, cDepartment of Infectious Diseases, Medical University of Lublin, Lublin, dHTA Consulting, Krakow, Poland and eCenter for Disease Analysis, Louisville, Colorado, USA
Correspondence to Robert Flisiak, MD, Department of Infectious Diseases and Hepatology, Medical University of Bialystok, ul. Zurawia 14, 15-540 Bialystok, Poland Tel: + 48 60 5203525; fax: + 48 85 7416921; e-mail: [email protected] Received 6 July 2014 Accepted 6 October 2014
estimated that only 15% of infected individuals have been diagnosed and treated to date (unpublished data). Infection with chronic HCV infection has been called a silent pandemic [12]. The lack of screening programs has resulted in the accumulation of a hidden HCV-infected population at risk for advanced disease, and, moreover, a potential reservoir for uncontrolled spread of the infection. Treatment in Poland is limited to ∼ 3000 patients annually and the majority of these patients receive dual therapy based on pegylated interferon-α and ribavirin. According to the Polish National Health Fund (NFZ) reimbursement policy, only 20% of HCV-infected patients are currently eligible to receive a triple therapy regimen based on the first-generation direct-acting antivirals boceprevir or telaprevir. With the availability of second-generation therapies (e.g. sofosbuvir, simeprevir, and daclatasvir), and possible interferon-free regimens expected in Poland in 2015 or later, the costefficacy of these innovative regimens and prediction of HCV control and eradication in Poland should be strongly supported for more efficient reimbursement policy. DOI: 10.1097/MEG.0000000000000237
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Chronic hepatitis C virus burden in Poland Flisiak et al. 71
A detailed description of the model and methodology has been described previously [6]. The historical epidemiology of HCV was gathered through a literature search, analysis of unpublished data, and discussion with an expert panel. Because HCV epidemiology was reported in different years, a mathematical disease progression model was used to estimate the 2013 HCV-infected population. The model was constructed in Microsoft Excel (Microsoft Corp., Redmond, Washington, USA) and designed to quantify the size of the HCV-infected population, by the liver disease stages, from 1950 to 2030. The model started with the annual number of acute infections that progressed to chronic HCV (viremic) infection, accounting for spontaneous clearance of the virus. The progression of new cases was followed along with all chronic infections from previous years using previously published transition probabilities [6] after taking into account mortality and cured patients. The total number of cases at each stage of the disease was tracked by age and sex. Five-year age cohorts were used through age 84, and those aged 85 years and older were treated as one cohort. Baseline population characteristics
There are a number of studies reporting anti-HCV prevalence in Poland [2,3,7–15]. The largest study determined a viremic (RNA positive) rate of 0.60% [2]. However, it also determined an antibody-positive prevalence of 1.94% with a single fourth-generation ELISA test [2]. Another study found an antibody prevalence of 1.91 and 0.86% with repeatedly reactive ELISA and western blot confirmatory tests [3]. Thus, in 2009, the anti-HCV prevalence in the adult population (18 + ) in Poland was estimated to be 0.86%, with an estimated prevalence of 0.72% for all ages. The viremic prevalence was estimated to be 0.60% in adults. For the purpose of this analysis, it was estimated that there were 200 000 viremic infections in 2009 (for all ages), corresponding to a prevalence of 0.52% (Table 2). The age and sex distribution was developed using diagnosed data from the NIPH-NIH (Fig. 1) [1]. The number of RNA-positive diagnosed cases was available from 1999 to 2012. The diagnosed population was adjusted for mortality and cured, by year, and was aged to 2012. It was assumed that the age and sex distribution of the diagnosed population was reflective of the current distribution in Poland. According to the most recent data published by the NIPH-NIH, there were 30 200 patients living with a diagnosis [1]. In 2012, 2290 individuals were newly diagnosed. For the purpose of this analysis, 3000 newly diagnosed were assumed per
1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0
0– 4 5 10 –9 – 15 14 20–19 – 25 24 – 30 29 –3 35 4 – 40 39 –4 45 4 50–49 – 55 54 60–59 – 65 64 – 70 69 – 75 74 – 80 79 –8 85 4 +
Materials and methods
Fig. 1
HCV prevalence (%)
The aim of this study was to assess baseline epidemiology, project HCV-related disease burden, and develop treatment strategies that consider the actions necessary to control or eliminate HCV infection.
Males (2012)
Females (2012)
Age and sex distribution of antihepatitis C virus prevalence in Poland, 2012.
year, beginning in 2013. Treatment and diagnosis estimates for 2013 are shown in Table 2. According to the NFZ, an average number of 2490 individuals were treated per year from 2008 to 2012. In 2013, the number of treated patients increased to 2990 individuals in light of increased triple therapy treatment for previously warehoused patients. It is anticipated that the number of treated patients will decrease to the 2008–2012 average, with an estimated 2500 individuals treated in 2014. Polish population data were obtained by 5-year age and sex cohorts from the United Nations population database [16]. The genotype distribution (Table 1) was developed using data from an analysis of more than 14 600 patients from 22 centers from 2003 to 2012 [4]. It is estimated, from 1998 to 2001, that transfusion accounted for 9.0% of the transmission of HCV infection [17], whereas, in 2013, it was estimated that active intravenous drug usage accounted for 5% of transmission. Estimates for 2013 are shown in Table 2. There were limited data available on the incidence of new cases of HCV in Poland. The number of new HCV infections was back-calculated. Eq. (1) shows that, at any point in time, the total number of HCV infections equals the sum of all new infections minus the number of Hepatitis C virus genotype distribution in Poland, 2003–2012
Table 1
Genotype 1a 1b 2 3 4 5 6 Mixed
% 2.0 77.4 0.1 13.8 4.9 0.0 0.1 1.6
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72 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
Table 2
Model inputs and 2013 estimations Historical (minimum–maximum uncertainty interval)
HCV-infected cases Number of anti-HCV cases Anti-HCV prevalence Number of viremic cases Viremic prevalence Viremic rate HCV diagnosed (viremic) Viremic diagnosed up to now Viremic diagnosis rate Annual newly diagnosed New infections New infections New infection rate (per 100k) Treated Number treated Risk factors Number of active IDUs with HCV (%) Previous blood transfusion (%)
286 000 0.8% 200 000 0.5%
(197 000–380 000) (0.5–1.0%) (138 000–266 000) (0.4–0.8%) 70.0%
Year [references] 2009 [2] – 2009 [1,2] –
2013 (95% uncertainty interval) 286 000 0.7% 201 000 0.5%
2012 [1,2]
(203 000–286 000) (0.5–0.9%) (142 000–235 000) (0.4–0.6%) 70%
30 000 – 3000
2012 [unpublished data] – 2012 [unpublished data]
30 400 15.2% 3000
– –
– –
5420 14.1
2490 – –
2008–2012 [4] 2009 [16] 2013 [unpublished data]
2990 10 000 (5%) 18 000 (9%)
HCV, hepatitis C virus; IDUs, injection drug users.
spontaneously cleared cases, all-cause, and liver-related mortality, and cured cases: Using the known number of total HCV infections in 2009, the annual number of all-cause mortality, liver-
Total HCV infectionsYear x ¼
x X
annually. Treatment in this scenario focused on patients 20–69 years of age with a METAVIR score ≥ F1. Estimates of sustained virologic response (SVR) rates were based on SVR observed among treated patients, clinical studies, and expert opinion [28–30]. SVR rates of
ðNew infectionst spontaneously curedt mortalityt treated & curedt Þ
ð1Þ
t¼1950
related deaths, and cured cases, the annual numbers of new infections were estimated [Eq. (1)] [6]. According to this calculation, there were an estimated 5420 new cases of HCV in Poland in 2013. Mortality and liver transplants
All-cause mortality for the years 1958–2009 was estimated by 5-year age and sex cohorts using data from the Max Planck Institute for Demographic Research [18]. Increased mortality among the transfused and injection drug user populations was accounted for by applying a standard mortality ratio of 2.1 and 10.0, respectively, for the affected age groups [19–25]. Liver transplant data were available through Poltransplant, the Center for Organizational and Coordination for Transplantation. In 2013, 318 liver transplants were performed in Poland [26]. It is estimated that 27.8% of transplants are attributable to HCV [27]. Scenarios
A baseline scenario and two scenarios with improved diagnosis and treatment were modeled in Poland. Baseline scenario
The baseline scenario assumed a continued diagnosis of 3000 infections and treatment of 2500 infections
40% (G1/4), 75% (G2), and 70% (G3) were assumed. The current standard of care in Poland allows for the treatment of patients with any histological changes typical for hepatitis in individuals from 3 years of age independent of genotype. However, triple (boceprevir or telaprevir based) therapy reimbursement among treatment-naive patients is limited to G1-infected adults with fibrosis ≥ F2 and the IL28B TT genotype, reducing the availability of triple therapy to about 20% of the infected, diagnosed population.
Control disease burden scenario
A second scenario was developed to control disease burden. This scenario assumed increased treatment efficacy and uptake. In 2015, it was projected that SVR could increase to 95% (G1/2/4) and 90% (G3). Treatment was limited to individuals with fibrosis staging of F1 or greater. SVR rates applied in 2015 were held constant through 2030. In addition, annual diagnosis increased by 30% to 3900 individuals (from 3000) and treatment increased 100% across genotypes to 5000 individuals (from 2490). To maintain the treatment level, diagnosis was increased by 30% to 5000 individuals annually in 2016. Treatment of 5000 patients annually and diagnosis of 5000 individuals annually were held constant through 2030. Beginning in 2020, treatment was not limited on the basis of fibrosis stage.
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Chronic hepatitis C virus burden in Poland Flisiak et al. 73
Elimination scenario
Results
A third scenario was created to assess the actions necessary to achieve elimination of chronic HCV infection by 2030. Increases in SVR as stated above were applied for this strategy. Treatment was limited to individuals with fibrosis staging of F1 or greater. Beginning in 2015, diagnosis was increased 150% to 7500 individuals annually whereas treatment was increased 100% across genotypes to 5000 individuals. In 2016, age restrictions were expanded to include patients up to 74 years of age and treatment was considered for individuals irrespective of fibrosis stage. Further, diagnosis and treatment were increased to 15 000 and 10 000 individuals annually. In 2018, diagnosis was held constant and treatment was increased to 15 000 individuals annually. Annual diagnosis of 15 000 individuals and treatment of 15 000 individuals were held constant through 2030.
Baseline
Fig. 2
(a)
In 2013, there were an estimated 201 000 (95% uncertainty interval: 142 000–235 000) viremic individuals in Poland (Fig. 2b). The viremic age distribution is shown in Fig. 2a. The total number of viremic cases is projected to decrease to 191 000 by 2030 because of reduced incidence since the peak in 1990 and greater mortality as the infected population ages (Fig. 2c). Although the overall prevalence is projected to decrease, the number of individuals with more advanced liver disease is projected to increase. The number of individuals with compensated cirrhosis is projected to increase by 40% to 23 000 in 2030 (from 16 300 in 2013), and the population with decompensated cirrhosis will increase by 55% to 2460 in 2030 (from 1590 in 2013). The number of individuals with HCV-related HCC will increase to 1250 individuals in 2030, a 60% increase from 2013. Finally, liver-related mortality will increase 65%, corresponding to 1100 individuals, in 2030 (Fig. 3).
Prevalence (× 1000)
250
Control disease burden
200 150 100 50
20
30
20 20
10 20
00 20
90 19
80 19
60
19 70
19
19
50
0
In addition, by 2030, the number of individuals with compensated cirrhosis will decrease to 15 600 individuals and the population with decompensated cirrhosis will decrease to 1590 individuals (30% decrease and 35% decrease from baseline) (Fig. 3). The number of individuals with HCV-related HCC will decrease to 890 cases relative to an increase in the baseline.
25 000 20 000 15 000 10 000 5 000 0
Elimination
0– 54 10 –9 15–14 – 20 19 – 25 24 30–29 35–34 40–39 45–44 5 0 –4 9 – 55 54 – 60 59 65–64 – 70 69 – 75 74 – 80 79 – 8584 +
Total viremic infected
(b)
Under an increased diagnosis and treatment strategy, where by 2030 up to 15 000 are treated annually, there was a 90% reduction in viremic infections relative to 2013 (21 600 remaining cases in 2030). This strategy would result in an 80% decrease in HCV-related mortality, avoiding 6540 liver-related deaths.
90 000 80 000 70 000 60 000 50 000 40 000 30 000 20 000 10 000
250 000 200 000 150 000 100 000 50 000
–
Total viremic infections
(c) Viremic infections (by disease stage)
Under increased treatment efficacy and increased treatment, the number of viremic infected individuals is projected to decrease at a faster rate than in the baseline scenario (Fig. 3), with 141 000 viremic individuals remaining in 2030. In this scenario, HCV-related mortality is projected to decrease 30% from the base case, a reduction of 2840 liver-related deaths.
19 50 19 60 19 70 19 80 19 90 20 00 20 10 20 20 20 30 20 40 20 50
–
F0 F2 F4/compensated cirrhosis HCC
F1 F3 Decompensated cirrhosis Total viremic
Baseline scenario outputs. (a) Total viremic cases, by year, 1950–2030. (b) Total viremic cases, by age, 2013. (c) Number of viremic cases, in total, and by disease stage, 1950–2050.
In addition, by 2030, the number of individuals with compensated cirrhosis will decrease to 3220 individuals and the population with decompensated cirrhosis will decrease to less than 350 individuals (Fig. 3). Further, HCC cases would reduce to a projected 240 individuals relative to the baseline.
Discussion It is expected that the second wave of direct-acting antiviral-based therapy, and, more importantly, the implementation of IFN-free and ribavirin-free regimens, will yield a chance for HCV cure rates close to 95%.
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74 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
Fig. 3
(a)
(b) Total infected cases (viremic)
250 000 200 000 150 000 100 000 50 000
Control disease burden
20 1 20 3 1 20 4 1 20 5 1 20 6 2017 2018 1 20 9 2 20 0 2 20 1 2022 2 20 3 2 20 4 2025 2 20 6 2027 2028 2029 30
20 1 20 3 1 20 4 1 20 5 1 20 6 2017 1 20 8 1 20 9 2 20 0 2021 2022 2 20 3 2 20 4 2025 2 20 6 2027 2028 2 20 9 30
–
Baseline
Noncirrhotic fibrosis
200 000 175 000 150 000 125 000 100 000 75 000 50 000 25 000 –
Baseline
Elimination
Control disease burden
Elimination
(d)
(c) F4/compensated cirrhosis
Decompensated cirrhosis
25 000
3000 2500 2000 1500 1000 500 –
20 000 15 000 10 000 5000
Baseline
Control disease burden
20 1 20 3 1 20 4 2015 1 20 6 1 20 7 18 20 2019 2 20 0 2 20 1 2022 2 20 3 2024 2 20 5 2 20 6 2 20 7 28 20 2029 30
20 1 20 3 14 20 1 20 5 1 20 6 2017 1 20 8 2019 2 20 0 2 20 1 2022 2 20 3 2 20 4 2 20 5 26 20 2027 2 20 8 2029 30
–
Baseline
Elimination
(e)
Control disease burden
Elimination
(f) Liver-related deaths
HCC
1400 1200 1000 800 600 400 200 –
Baseline
Control disease burden
Elimination
1 20 3 1 20 4 1 20 5 16 20 2017 1 20 8 1 20 9 2 20 0 2 20 1 2 20 2 2 20 3 2 20 4 2 20 5 2 20 6 2 20 7 2 20 8 2 20 9 30
20
20 1 20 3 1 20 4 15 20 1 20 6 1 20 7 18 20 1 20 9 2 20 0 21 20 2 20 2 2 20 3 2 20 4 25 20 2 20 6 2 20 7 2 20 8 2 20 9 30
1200 1000 800 600 400 200 –
Baseline
Control disease burden
Elimination
Morbidity (a–e) and mortality (f), by scenario, by year, 2013–2030.
According to current predictions, the number of treated patients will exceed eligible patients in 2024 (results not shown). Thus, to mitigate HCV-related liver disease in the coming years, an increase in both diagnosis and treatment is needed. In this model, the diagnosis rate was increased to provide a sufficient patient pool to achieve the two scenarios. It is assumed that undiagnosed patients will be captured at the rate needed to maintain treatment; however, because of various risk factors (e.g. transfusion before blood screening protocols, injection drug use, etc.) diagnosis at the population level may be inefficient, expensive, and fail to target the appropriate populations without a country-specific screening strategy. In the USA, the Center for Disease Control and Prevention has recommended birth year-based screening for the efficient use
of resources [31,32]. By focusing on age cohorts with a high HCV prevalence, potential undiagnosed cases may be identified in a more efficient manner. In Poland, there is a birth cohort effect wherein 76% of the infected population (58% of the total country population) in 2013 is between 25 and 64 years of age. In both sexes, this analysis suggests a pooling of patients infected through transfusion or hospital procedures before implementation of current infection control practices. Further, in men, there is a noticeable peak in younger age groups, likely attributable to injection drug use (Fig. 1). In addition to increased diagnosis, these scenarios incorporate increases in the number of treated patients and a change in restrictions of fibrotic stages eligible for treatment. To achieve steady-state mortality and morbidity under forecasted trends, an increase in treatment
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Chronic hepatitis C virus burden in Poland Flisiak et al. 75
of 80% (5000 patients annually) would be required beginning in 2015. Although new treatments are expected to be more tolerable with a shorter duration of treatment, it is assumed that the health care system can support an increase in patients treated. Additional factors may be required to achieve these suggestions. It is understood that elimination of HCV by 2030 in Poland is unlikely. However, this analysis suggests that elimination could be achieved by increasing treatment to 15 000 patients, highlighting that increased diagnosis will be necessary to mitigate impending increases in disease burden in Poland. There are several limitations to this analysis that could impact outcomes. First, the published data applied in this model represent the best data available in Poland; however, it is understood that each input is subject to limitations. Second, it is assumed that the number of new cases of HCV will remain constant after 2013. A higher number of new infections could result in a higher total number of infections in 2030. Further, the forecasts assume that sufficient numbers of diagnosed patients will be available for treatment. However, as the diagnosis rate increases, it will become more difficult to identify undiagnosed patients. Moreover, the ability of a country to treat its HCV-infected population may be limited by the number of available diagnosed and eligible patients. Finally, the model does not consider the progression of cured HCV patients. Studies have shown that more advanced patients may experience disease progression after achieving SVR, although at a slower rate [33]. In turn, the data presented may overestimate the reduction in HCC and decompensated cirrhosis cases because the scope of the forecast was limited to viremic cases.
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Conclusion
A reduction in HCV burden in Poland is possible with increased diagnosis and increased treatment efficacy. Depending on the scenario, a reduction of total HCV cases by 30–90% and a reduction in mortality of 30–80% were modeled. The analysis shows possible elimination of HCV in the Polish population by 2030 with an increase in the number of diagnosed and treated individuals up to 15 000 annually.
Acknowledgements
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This project was supported by Gilead Sciences. 21
Conflicts of interest
Robert Flisiak has served as a speaker or advisor for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, MSD, Novartis, and Roche. Waldemar Halota and Krzysztof Tomasiewicz have served as a speaker or advisor for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, MSD, and Roche. Kaja Kostrzewska is an employee with HTA Consulting. Homie Razavi and Erin Gower are employees with the Center for Disease Analysis.
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