Optimization of hepatitis C virus screening strategies by birth cohort in Italy

Abstract Background and Aims Cost‐effective screening strategies are needed to make hepatitis C virus (HCV) elimination a reality. We determined if birth cohort screening is cost‐effective in Italy. Methods A model was developed to quantify screening and healthcare costs associated with HCV. The model‐estimated prevalence of undiagnosed HCV was used to calculate the antibody screens needed annually, with a €25 000 cost‐effectiveness threshold. Outcomes were assessed under the status quo and a scenario that met the World Health Organization's targets for elimination of HCV. The elimination scenario was assessed under five screening strategies. Results A graduated birth cohort screening strategy (graduated screening 1: 1968‐1987 birth cohorts, then expanding to 1948‐1967 cohorts) was the least costly. This strategy would gain approximately 144 000 quality‐adjusted life years (QALYs) by 2031 and result in an 89.3% reduction in HCV cases, compared to an 89.6%, 89.0%, 89.7% and 88.7% reduction for inversed graduated screening, 1948‐77 birth cohort, 1958‐77 birth cohort and universal screening, respectively. Graduated screening 1 yielded the lowest incremental cost‐effectiveness ratio (ICER) of €3552 per QALY gained. Conclusions In Italy, a graduated screening scenario is the most cost‐effective strategy. Other countries could consider a similar birth cohort approach when developing HCV screening strategies.


| INTRODUC TI ON
Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality, causing an estimated 71 million infections globally. 1 The size of the infected population and the risk of severe complications make HCV a serious public health problem. 2 However, the use of direct-acting antiviral (DAA) therapy regardless of fibrosis stage is the current standard of care in many high-income countries.
Thus, the limitation of HCV therapy is no longer treatment efficacy or adherence, but the identification of available patients to treat. Italy has been considered the European country with one of the largest burdens of HCV in the general population, with the highest prevalence in the older population and decreasing risk in younger populations. 6,7 The HCV prevalence in the country is approximately 1%, though previous studies have estimated rates as high as 7% in those born between 1935 and 1944, while those aged 30 years and younger are at less risk of acquiring HCV. 7 A large number of infections occurred from the 1950s to the 1960s via iatrogenic transmission due to the use of unsterilized materials. 6,7 More so, there are geographical differences in prevalence distribution. The highest rates of HCV have been reported in Southern Italy, where the HCV prevalence in younger cohorts is quite limited. [6][7][8] Considering the natural history of chronic HCV infection and the wide use of antiviral therapy in Italy, total HCV cases still remain higher than in other European countries, such as Spain and France. 9 With more than 56 000 patients treated in 2018, Italy has taken substantial strides in managing its HCV disease burden. However, the number of HCV-infected individuals available to treat is estimated to run out by 2025 given the current treatment rates, leaving a large proportion of individuals with the potential to progress to later stage liver disease. 8 Thus, cost-effective screening strategies are needed to make elimination a reality in Italy. We aimed to determine the cost-effectiveness of expanded HCV screening strategies among different population cohorts in Italy.

| Study design
An Excel-based Markov disease burden model 1 was populated with Italian data to quantify the annual HCV-infected population by liver disease stage, sex and age. 8 The model simulates the natural history of the disease and forecasts disease burden, medical costs and health effects of HCV, assessed under the status quo and a scenario to achieve the WHO's GHSS targets (80% reduction in incidence of interpretation of the data, in the writing of the report and in the decision to submit the paper for publication.

| Input parameters
The Italian HCV-infected population, with or without a prior HCV diagnosis, 7 disease burden, 8 cost (in euros) 10 infections not yet linked to care was used to calculate the number of HCV antibody screens needed annually to diagnose one case, as described in Appendix S1.

| Sensitivity analysis
Deterministic and probabilistic sensitivity analyses were conducted for each scenario to identify the drivers in the model that accounted for the greatest variation in the incremental cost-effectiveness ratio (ICER) and to generate 95% uncertainty intervals (UIs) around the ICER, given uncertainties in model parameters, using Crystal Ball, a Microsoft Excel (Microsoft Corporation) add-in by Oracle (Oracle Corporation). In accordance with the International Society of Pharmacoeconomics and Outcomes Research, 14 costs were assumed to be gamma-distributed and quality-adjusted life year (QALY) utilities were assumed to be beta-distributed (Table 1). Uncertainty in starting prevalence was not considered, since the ICER was calculated relative to the status quo, and the starting prevalence under the status quo would be the same as the prevalence under a screening scenario.
Finally, to determine the impact of uncertainty in the cost of screening on the variation in ICER, deterministic and probabilistic sensitivity analyses were conducted for the scenario found to be the most costeffective, assuming a beta-PERT-distributed cost of screening among both low-and high-risk groups, with a minimum of half the base-case price and a maximum of double the base-case price (Table 1).

| RE SULTS
Under the status quo, 290 400 persons would be diagnosed and linked to care, corresponding to 11.3 million screening tests ( Figure 1; Table 2). Additionally, 309 200 patients would be initiated on treatment between 2018 and 2031. Total viraemic infections and liver-related deaths (LRDs) would decline 65% by 2031 ( Figure 1).
Although this meets the WHO target for a reduction in LRDs, Italy would not achieve the incidence and diagnosis targets.
A WHO target scenario ( Table 2)  The results of the cost-effectiveness analysis are presented in Table 3 and shown in Figure 2. Under the status quo, annual screening costs would increase 55%, from €3. 4  costs of cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, the QALY utility for cirrhosis and the cost of liver transplantation ( Figure 3). Since the choice of scenario does not make a difference in the ranking of uncertain parameters by explained variation in the ICER, only results for the graduated screening scenario 1 were reported. The probabilistic sensitivity analysis revealed that, at a willingness to pay (WTP) threshold of €25 000 per QALY gained, all scenarios were cost-effective 100% of the time (Figure 4).
Allowing for uncertainty (ie varying the price from half to up to double the assumed base price of screening) in the cost of screening among both low-and high-risk groups, graduated screening 1, which was the most cost-effective scenario relative to the status quo, had an ICER of €3552/QALY (95% UI 1570-6359). One-way sensitivity analysis revealed that more than 90% of variation in the ICER was mainly due to the annual follow-up costs of cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, followed by the cost of screening among low-risk groups, the QALY utility for cirrhosis and the cost of liver transplantation ( Figure 5A). The probabilistic sensitivity analysis showed that at a WTP of €25 000, graduated screening 1 remained cost-effective 100% of the time ( Figure 5B).

| D ISCUSS I ON
This study aimed to evaluate the cost-effectiveness of five potential HCV screening strategies in Italy. The universal screening and birth cohort screening scenarios, which achieve all targets of the HCV elimination goals, were found to be cost-effective when compared to the status quo scenario, suggesting a coordinated screening program may be beneficial in moving Italy towards elimination of HCV.

| Birth cohort screening
We evaluated the cost-effectiveness of screening in the birth cohorts 1948-1988, as they were previously identified as having the highest prevalence of undiagnosed HCV infection. 8  sub-populations with high HCV prevalence is cost-effective. 15,16 In a previous meta-analysis of all available cost-effectiveness studies before the availability of DAAs, the cost per QALY gained of screening programs among asymptomatic cohorts at general risk for HCV ranged between US $4200 and $50 000. This was much lower than focusing on specific risk groups, which had an estimated ICER F I G U R E 5 A, One-way sensitivity analysis for the 2018-2031 incremental cost-effectiveness ratio, including uncertainty in cost of screening, graduated screening 1 scenario. B, Cost-effectiveness acceptability curve, including uncertainty in cost of screening, graduated screening 1 scenario. DCC, decompensated cirrhosis; HCC, hepatocellular carcinoma; QALY, quality-adjusted life year of between $848 and $128 424 per QALY gained. In the study, age of the target population to be screened and prevalence were the main drivers of cost-effectiveness. 17 These are also important drivers for developing screening strategies in Italy. 18 Despite the lower rates of drug use across Italy compared to other countries, this risk group represents the most recent wave of new infections, 19 which in addition to other high risk populations as imnates and migrants are mainly distributed among the 1968-1988 birth cohorts, 20-22 who are asymptomatic. Without including these groups in specific screening policies, continued disease burden is expected. Additionally, results of the sensitivity analysis, which examined the cost-effectiveness of each strategy using a €25 000/QALY WTP threshold, remained high (P > 99%) once the uncertainty in parameters was considered.
Parameters relating to the disease state costs and health outcome utilities were found to have the highest impact on the cost-effectiveness results.

| Graduated screening
Consequently, the graduated screening strategies aim to capture individuals who may be at a higher risk for HCV but are currently asymptomatic. The graduated screening 1 scenario, which identifies young populations at risk for transmitting HCV before expanding to identify older populations before their disease advances, was the least costly screening strategy, with €6.0 billion in direct medical costs by 2031.
Relative to the status quo, graduated screening 1 would gain approximately 144 000 QALYs by 2031, which was more than the other birth cohort strategies and also produced a lower ICER. The graduated screening 2 scenario, which first identifies older populations before their disease advances and then screens younger cohorts at risk for transmitting HCV, was also less costly (€6.0 billion), but had fewer QALYs gained (125 000) compared to graduated screening 1 scenario.
From a disease burden perspective, both graduated screening strategies have significant impact on overall reduction in total viraemic infections and liver-related mortality by 2031 (Figure 1), though graduated screening scenario 1 results in more QALYs gained because it is more likely to identify asymptomatic individuals early and prevent the progression of liver disease. Additionally, both graduated scenarios were found to be highly cost-effective (as seen in Table 3). Even upon allowing for a wide variation in the cost of screening among both low-and high-risk groups, the graduated screening 1 scenario remained highly likely (P > 99%) to be cost-effective at the €25 000/QALY WTP threshold ( Figure 5B).
Screening in this younger cohort would likely detect individuals at higher risk of infectiousness, decreasing the potential to transmit new infections compared to screening older patients who are more likely already identified and less likely to contribute to further disease burden.

| Programmatic considerations
It is important for policymakers to consider not only the cost-effectiveness of such strategies, but also their implementation and sustainability. Though the universal screening strategy is recently recommended, 23,24   sectional study in Spain found that a stepwise screening strategy, similar to the graduated screening 1 scenario described here, was cost saving, 28 supporting that this type of strategy may be feasible.

| Limitations
Though graduated or birth cohort screening is less costly than universal screening, further examinations of each scenario's associated programmatic costs should be evaluated in terms of their impact on the Italian Health Sanitary budget and their sustainability.

| CON CLUS IONS
Holistic screening strategies for hepatitis C should be implemented, considering the prevalence, the reliability of diagnostic assays, the natural history of infection, the benefits and risks of therapeutic intervention and the potential benefits to society.
Universal screening and birth cohort screening scenarios, which achieve all targets of the HCV elimination goals, were found to be cost-effective when compared to the status quo scenario in Italy, suggesting a coordinated screening program may be beneficial in moving Italy towards elimination of HCV. A graduated screening strategy has both clinical and economic benefits to the population and could sustain Italy's momentum towards achieving the HCV elimination goals. Other countries, particularly those which may not have the economic or structural means to implement universal screening but are interested in developing screening strategies based on specific HCV epidemiology, could consider a birth cohort approach based on specific epidemiological data and real-life treatment rates.