Modeling the Health Economic Burden of Hepatitis C Virus Infection in Turkey: Cost-Effectiveness of Targeted Screening

Background/Aims: In 2016, World Health Organization introduced global goals to eliminate hepatitis C virus by 2030. The aim of this study is to analyze the epidemiologic and economic burden of hepatitis C virus in Turkey and compare current practice (regular care) with a hypothetical active screening and treatment approach (active scenario). Materials and Methods: A Markov model was used to analyze and compare regular care with a scenario developed by experts including the screening and treatment of all acute and chronic hepatitis C virus infections between 2020 and 2050. General and targeted populations were focused. The model reflected the natural history of the disease, and the inputs were based on a literature review and expert opinions. Costs were provided by previous studies and national regulations. Results: The active scenario resulted in higher spending for all groups compared with regular care in the first year. Cumulative costs were equalized in the 8th, 12th, 13th, and 16th year and followed by cost-savings of 49.7 million, 1.1 billion, 288.6 million, and 883.4 million Turkish liras in 20 years for prisoners, refugees, people who inject drugs (PWID), and all population, respectively. In all groups, the mortality was found to be lower with the active scenario. In total, 62.8% and 50.6% of expected deaths with regular care in 5 and 20 years, respectively, were prevented with the active scenario. Conclusions: An active screening and treatment approach for hepatitis C virus infection could be cost-effective for PWID, prisoners, and refugees. Almost two-thirds of deaths in regular care could be prevented in 5 years’ time with this approach.


INTRODUCTION
Globally, an estimated 71 million people have chronic hepatitis C virus (HCV) infection, and the risk for cirrhosis in people with chronic HCV infection is 15%-30% within 20 years.The World Health Organization (WHO) also estimated that in 2016, approximately 399 000 people died from HCV, mostly owing to complications of cirrhosis and hepatocellular carcinoma. 1bstantial progress in the treatment of HCV has been made since the introduction of direct-acting antivirals (DAAs) in 2013, resulting in improved efficacy and tolerance and a shorter duration of treatment compared with previous treatments. 2However, challenges in the treatment of HCV remain.Underdiagnosis of HCV infection is still a concern: it is estimated that only 20% of people with HCV worldwide have been diagnosed. 2dditionally, particular attention needs to be focused on those population groups with a higher prevalence of HCV, such as people who inject drugs (PWID), prisoners, refugees, and men who have sex with men (MSM).Preventing transfusion-related HCV transmission has been identified as a priority, and blood transfusion safety has improved since 2000. 2,3In 2016, with the success of DAAs, WHO introduced global goals for the care and management of HCV: a 90% reduction in new cases of chronic HCV, a 65% reduction in HCV-related deaths, and treatment of 80% of eligible people with chronic HCV infection by 2030. 4 Unfortunately, current levels of testing and treatment are generally insufficient to achieve these goals in most settings.[7] In this study, our aim was to analyze the epidemiologic and economic burden of HCV in Turkey and compare current practice with a hypothetical active screening and treatment approach.

MATERIALS AND METHODS
Analyses of the disease burden of HCV in Turkey were based on a Markov model built in Microsoft Excel ® . 8Our primary objective was to analyze the cost-effectiveness of an active screening and treatment approach (referred as the active scenario) in targeted populations, which comprised blood transfusion recipients before 2000, PWID, MSM, prisoners, and refugees.Secondary objectives were to investigate the cost-effectiveness of the active scenario in the general population (defined as the nonhigh-risk population that remains after exclusion of the targeted populations) and the reduction of mortality in the general as well as targeted populations, with the active scenario compared with current practices (referred to as regular care).A panel meeting was held in Ankara in December 2019 and an online meeting in December 2020 consisting of 5 physicians from infectious disease and gastroenterology specialties and one model/analysis specialist to reach a consensus on all inputs of the model.Regular care represented the treatments currently used to manage HCV infection.The disease model reflected the natural history of acute and chronic HCV infection. 9he active scenario, which was created by panel participants, comprised the following criteria: (i) anti-HCV antibody testing for all patients with acute HCV infection, (ii) HCV-RNA testing for all those with positive anti-HCV antibody tests, (iii) treatment for all patients with positive HCV-RNA tests, and (iv) diagnosis and (v) treatment of all chronic HCV infections.Data for the total adult population were obtained from the United Nations Department of Economic and Social Affairs, 10 and the ratio of blood transfusion recipients was estimated by panel participants.The PWID prevalence data were gathered from the 2019 Turkish Drug Report 11 and data regarding the number of prisoners were from Turkish Statistical Institute reports. 12Population of MSM was calculated based on Marcus et al, 13 and the number of refugees was obtained from the United Nations Refugee Agency. 14Mortality calculations were based on the number of individuals with chronic HCV and estimates for progression rates to cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation.Estimations used as model input for current acute and chronic HCV infection are presented in Tables 1 and 2 with references.  Healre service costs were calculated using the Official Health Notification (December 2020) of the Social Security Institution of Turkey. 60These services included diagnostic tests, such as anti-HCV antibody, HCV-RNA, and HCV genotyping tests.Medication costs were estimated by panel participants, and costs of other health states (chronic hepatitis, cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation) were based on previous studies 61,62 and used with currency and inflation adjustments.Costs of diagnostic tests were calculated as 8.62 Turkish liras (TL) for an anti-HCV antibody test, 111.87 TL for an HCV-RNA test, and 109.59TL for an HCV genotyping test.Annual medication cost was estimated at 15,000 TL.Other annual medical cost estimates were 1502 TL for chronic hepatitis, 1546 TL for cirrhosis, 12,512 TL for decompensated cirrhosis, 39,749 TL for hepatocellular carcinoma, and 169,350 TL for liver transplantation.
The cost of tests for screening purposes, the cost of medication for patients receiving treatment, and other treatment costs for patients who were non-responders or non-compliant with the treatment or who did not receive any treatment were collected, and a total cost calculation was made.Incremental cost-effectiveness ratios were calculated in terms of death averted.The model was projected between 2020 and 2050.

RESULTS
The total adult population of Turkey in 2019 was 62 million.Individuals with HCV are shown in Table 3 along with

Main Points
• Underdiagnosis of hepatitis C virus (HCV) infection is a concern.Particular attention needs to be focused on population groups with a higher prevalence of HCV, such as people who inject drugs, prisoners, refugees, and people with risky sexual behavior.

•
We analyzed the epidemiologic and economic burden of HCV in Turkey and compared current practice with a hypothetical active scenario which included the screening and treatment of all acute and chronic HCV-infected patients.

•
Active scenario was found to be cost-effective for people who inject drugs, prisoners, and refugees.Almost twothirds of HCV-related deaths could be prevented in 5 years' time with this approach.HCV, hepatitis C virus; MSM, men who have sex with men; PWID, people who inject drugs.All numbers were given as sum of people with acute and chronic HCV infection.
their treatment status.It was calculated that there were 1029 people with acute and 592 970 with chronic HCV infection.Of these 1029 people with acute HCV infection, 23 (2.24%) were estimated to receive treatment, whereas 213 469 (36.0%) people with chronic infection were estimated to be under treatment.
Calculated cumulative costs for the general population and targeted groups in the case of regular care and active scenario are given in Table 4 for 1, 5, and 20 years.The active scenario resulted in higher spending for the general population and all targeted groups compared with regular care in the first year.The highest cost saving was seen in the refugees group.For refugees, cumulative costs were equalized in the twelfth year, followed by cost savings of 1.1 billion TL by 2040.For the PWID group, cumulative costs were equalized in the thirteenth year, and a cost saving of 288.6 million TL was achieved by 2040.
Similarly, cumulative costs were equalized in the eighth year and a cost saving of 49.7 million TL was achieved for prisoners with HCV by 2040.No significant cost saving was observed in MSM, blood transfusion, and general population groups (Table 4).When all people with HCV were considered, the costs were equalized from the 16th year onward, and 883.4 million TL were saved at 20 years.
Cost savings over the years in PWID, prisoners, refugees, and the total population are given in Figure 1.
Estimated cumulative mortality for regular care and the active scenario are given in Table 5.In all groups, the mortality was found to be lower with the active scenario.The highest reduction (73.4%) in mortality rate in 5 years was observed in refugees, followed by PWID (68.1%), while the lowest reduction was in the MSM group (20.7%).In total, 62.8% and 50.6% of expected deaths with regular care in 5 and 20 years, respectively, were prevented with the active scenario.

DISCUSSION
In our study, we found that an active screening and treatment program for HCV infection in Turkey would be cost-effective for the total population as well as the higher-risk groups of PWID, prisoners, and refugees in 8 to 16 years.However, no significant cost saving was observed in the MSM group.A reduction in mortality rates in patients with HCV was anticipated: half of all deaths in these patients over 20 years could be prevented with the active scenario.
One of the most at-risk groups for HCV infection is PWID.This group had the highest incidence rate of all groups in   this study and the lowest rate of treatment access after refugees.It has been estimated that there are 15.6 million PWID globally and that 52.3% are HCV-antibody positive. 63Controlling HCV infection in PWID is a focal point for WHO in combating HCV. 4 Although sterile syringe/ needle programs are an important step for harm reduction, active screening and treatment are also crucial for the prevention of HCV in this group.In Iceland, a program was launched in January 2016 aiming to provide treatment to all patients infected with HCV. 64The program, which was primarily focused on PWID, includes screening and DAA treatment as well as harm reduction and education.With these efforts, Iceland is anticipated to achieve HCV elimination goals well before the WHO goal of 2030.
In our study, it was cost-effective after 13 years to launch an active scenario approach for PWID.Despite spending being almost 9 times higher than with regular care in the first year, the cumulative cost was favorable with the active scenario after 12 years.However, cultural and social differences among countries should be taken into consideration, and HCV screening and treatment programs should be tailored for PWID groups.The PWID status is also related to incarceration history, meaning that these 2 targeted groups, PWID and prisoners, could overlap.Degenhardt et al 63 showed that 57.9% of PWID had a history of incarceration.Stone et al 65 stated that recent and past incarcerations were associated with a 62% and 21% increase in HCV acquisition risk, respectively.Therefore, active screening and treatment efforts for one group could be of benefit to the other.
Prisoners have an increased risk of HCV transmission because of the continued use of drugs and shared syringes, getting new tattoos, and other incidents that involve contact with blood. 41There are several studies in the literature about the economic burden and the level of cost-effectiveness of scaling-up HCV screening and treatment among prisoners.In a study by He et al, 66 it is shown that risk-or time-based screening scenarios could prevent 5500 to 12 700 new HCV infections and 4200 to 11 700 deaths related to liver diseases compared with no screening.Prisons, however, would require an additional 12.4% of their current health budget to implement such interventions. 668][69] In our study, the active scenario was beneficial at cumulative cost levels in the medium term (starting from the eighth year) in prisoners.However, because prisoners are a more isolated and controllable group, it may be preferable to prioritize other targeted groups for active scenario from an economic point of view.
Turkey hosts over 3.6 million refugees, the largest number for any country. 14Refugees could be a difficult group to engage because of issues such as limited available HCV data, their reluctance to volunteer for testing, and the difficulties inherent in accessing treatment in a foreign country. 70Data regarding the cost-effectiveness of HCV treatment in refugees varied in the literature, depending on the treatment. 71In our study, the cost of care in the active scenario was almost 10 times the expenditure of regular care in the first year, but, beginning with the twelfth year, the costs equalized, resulting in a 1.1 billion TL benefit in 20 years.Special issues for refugees are also within the focus of national health authorities, and further studies are needed.
In previous studies, hepatitis C screening in the MSM group has been shown to be cost-effective. 72,73dditionally, treatment with DAAs was found to be also effective to reduce HCV infection among human immunodeficiency virus (HIV)-positive MSM. 74,75espite being one of the targeted groups, the active scenario was not cost-effective in 5 and 20 years of expenditures for MSM in our study.However, in a metaanalysis, HCV was found to be highly associated with HIV and drug injection in the MSM group. 76Therefore, overlap between targeted groups should be considered for economic evaluation.
The most prominent reduction in mortality at 5 and 20 years was found among refugees, followed by PWID.Almost two-thirds of deaths for patients in regular care could have been prevented in 5 years' time with the active scenario, reaching the WHO goal of a 65% reduction in mortality by 2030. 4 There are a few limitations.Panel discussions were used to provide model input estimates for which real-world data were not available.Economic losses due to loss of workforce, indirect expenses, new cases of HCV infection in the community caused by the presence of infected individuals, and a quality-of-life analysis of chronic HCV infection periods were not included.
In conclusion, an active screening and treatment approach for HCV infection could be cost-effective in the medium term for PWID, prisoners, and refugees.For the total HCV-infected population, it could mean an 883.4 million TL saving in 20 years.Because prisoners are more isolated, it might be preferable to focus on PWID and refugees first to ease the short-term economic burden of the active program.Combating HCV in the general and targeted populations requires the attention of medical professionals as well as socioeconomic experts and policymakers.

Figure 1 .
Figure 1.Cumulative total costs of HCV management with regular care and active scenario for (A) people who inject drugs, (B) prisoners, (C) refugees, and (D) total population.HCV, hepatitis C virus; TL, Turkish liras.

Table 1 .
Population Estimates Used as Model Input

Table 2 .
Estimates for Natural History of HCV Infection Across Disease States

Table 3 .
Total and HCV populations in Turkey according to the treatment status

Table 4 .
Cumulative Costs of Regular Care and Active Scenario in the General and Targeted Groups MSM, men who have sex with men; PWID, people who inject drugs; TL, Turkish liras.

Table 5 .
Mortality with Regular Care and Active Scenario Approach of the Groups at 5 and 20 Years MSM, men who have sex with men; PWID, people who inject drugs.