Received: 22 December 2021 | Revised: 25 March 2022 | Accepted: 1 April 2022 DOI: 10.1111/jvh.13686 S H O R T C O M M U N I C AT I O N Cost-­effectiveness analysis of an active search to retrieve HCV patients lost to follow-­up (RELINK-­C strategy) and the impact of COVID-­19 Elena Vargas-­Accarino1,2 | Joan Martínez-­Campreciós1,2 | 3 4,5 Raquel Domínguez-­Hernández | Ariadna Rando-­Segura | Mar Riveiro-­Barciela1,2,6 | Francisco Rodríguez-­Frías6,7,8 | Ana Barreira1,2 | Adriana Palom1,2 | Miguel Ángel Casado3 | Rafael Esteban1,6 | María Buti1,2,6 1 Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain 2 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Pharmacoeconomics & Outcomes Research Iberia (PORIB), Madrid, Spain 4 Department of Microbiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain 5 Department of Microbiology, Universitat Autònoma de Barcelona, Bellaterra, Spain 6 CIBERehd, Instituto Carlos III, Barcelona, Spain 7 Biochemistry and Microbiology Department, Clinical Laboratories Hospital Universitari Vall d'Hebron, Barcelona, Spain 8 Liver Pathology Unit, Biochemistry and Microbiology Departments, Hospital Universitari Vall d'Hebron, Barcelona, Spain Correspondence Maria Buti, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Passeig de la Vall d'Hebron 119-­129, Barcelona 08035, Spain. Email: mbuti@vhebron.net Funding information: This study has an unrestricted grant by Gilead Sciences. Keywords: cost-­effectiveness analysis, COVID-­19 pandemic, hepatitis C elimination, linkage to care, lost to follow-­up patients 1 | I NTRO D U C TI O N The ReLink-­C strategy was based on a retrospective search for HCV-­RNA-­positive cases from the central laboratory of Barcelona Hepatitis C virus (HCV) infection affects 71 million people world- area between 2019 and 2021 and included the COVID-­19 pandemic. wide. The World Health Organization (WHO) has set a goal of HCV The impact of the COVID-­19 pandemic on global efforts for HCV elimination by 2030, and this implies that 90% of HCV cases must elimination has been evaluated in several studies,3 which show that 1 be diagnosed and 80% treated. To improve the diagnosis of HCV, a one-­year delay in HCV elimination programs is associated with an a one-­s tep approach (HCV-­R NA reflex testing) was introduced in increase in the number of hepatocellular carcinoma (HCC) cases and the Spanish National Health System in 2018. A high proportion of liver-­related mortality in the next years.4 patients with diagnosed HCV infection (mainly psychiatric or de- The aims of this study were as follows: (1) identify and retrieve pendency individuals) are lost to follow-­up (LTFU), likely because individuals previously diagnosed with HCV infection who were lost of asymptomatic and silent progression of the disease. Retrieval to medical follow-­up, and linked them to care; (2) assess the impact of these patients for treatment could stop further progression of of the COVID-­19 pandemic on the rates of HCV-­positive patient re- liver disease, reduce the number of infected individuals, and serve trieval and linkage to care; and (3) evaluate the cost-­effectiveness of as secondary prevention, by averting ongoing transmission. 2 this strategy. Abbreviations: ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; DAA, direct-­acting antivirals; HCV, Hepatitis C virus; LTFU, Lost to follow-­up; RNA, Ribonucleic acid. Elena Vargas-­Accarino and Joan Martínez-­C ampreciós authors are contributed equally to the study. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2022 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd. J Viral Hepat. 2022;29:579–583.  wileyonlinelibrary.com/journal/jvh | 579 580 | VARGAS-­ACCARINO et al. 2 | PATI E NT S A N D M E TH O DS practice guidelines. All data were processed confidentially in an anonymous database accessible only to the researchers, in keeping ReLink-­C study has a first retrospective phase, focused in identi- with Spanish legislation. fying HCV-­R NA-­p ositive cases and a medical records review. The following individuals were excluded as follows: those deceased, those already treated, those with life-­t hreatening comorbidities 3 | R E S U LT S or those lacking contact information. The interventional second phase was focused on individuals who had been LTFU. They were In total, 1591 HCV-­RNA-­positive patients were identified. Among called a maximum of five times and sent appointment reminders them, 599 (37.6%) had already been treated or linked to care, 78 by post when telephone contact failed. Successfully contacted (5%) had died, and 914 (57.4%) had been LTFU and were selected for individuals were informed about our retrieval project and HCV retrieval. Within the latter, 166 were candidates for contact. Those therapy. who were not eligible to be contacted included 379 (41%) with a In a one-­step visit, a hepatologist recorded the medical history, limited life expectancy, life-­threatening disease, or HCV treatment HCV-­RNA and HCV genotype were performed as well as transient contraindication, and 369 (40%) lacking contact details. After a max- elastography (TE). Severe liver fibrosis was defined by TE between imum of 5 telephone calls, 104 of the 166 candidates (63%) were lo- 9.5 and 12.4 kPa and cirrhosis if ≥12.5 kPa. Patients with advanced cated, and 51 (50%) agreed to an appointment (29 refused a medical fibrosis underwent abdominal ultrasound. DAAs therapy was of- visit, 23 were already treated, and 1 had died). Finally, 43 patients fered to all patients with active infection. attended the appointment (84%) and 41 were treated (95%) (2.5% of the 1591 HCV-­RNA-­positive individuals identified). A flowchart of the results during the two periods (pre-­COVID-­19 and COVID-­19) is 2.1 | Cost-­effectiveness analysis shown in Figure 1A. During the COVID-­19 period, a lower percentage of patients had An economic evaluation was performed to estimate the cost-­ been linked to care (27% vs 43%; p < 0.0001), and therefore, a higher effectiveness of ReLink-­C compared with no intervention. ReLink-­C percentage were selected for retrieval (70% vs 51%; p < 0.0001). cost was calculated as the sum of the cost of healthcare resources In contrast, in the pre-­COVID-­19 period, a lower percentage were for the HCV diagnosis and linkage to care. candidates for contact (5% vs 13%; p < 0.0001) due to a limited life The impact on healthcare and economic outcomes of ReLink-­C expectancy or comorbidities, and a lower percentage were located vs no intervention were estimated using a previously reported (3.3% vs 8%; p < 0.005). At the end of the analysis, however, a similar Markov model5 to simulate the evolution of chronic HCV through percentage of cases started treatment in the two groups (2.4% vs different health states over the patient's lifetime. The mean age of 2.7%; p < 0.7239). patients entering the model was 57 years according to our study Patients treated with DAAs were mainly men (58.5%), mean age data, and the distribution between the different health states and 54 years, 10 (25%) had advanced fibrosis and 15 were infected by sustained virological response (92–­97%) was obtained from official genotype 1 (37%). data. 3.1 | Cost-­effectiveness analysis 2.2 | Statistical analysis The cost of diagnosing all patients who attended the medical visit Relink strategies and linkage to care were compared for the two was €19,924. Therefore, the total investment of the ReLink-­C strat- 14-­m onth time periods before and after emergency response egy was €26,075. In the Markov model lifetime simulation, 141 policies were implemented on 13 March 2020. Descriptive sta- HCV-­RNA-­positive patients were included (166 candidates to con- tistics were used to show the differences between the num- tact excluding 23 already treated, 1 death, and 1 spontaneous cure). ber of patients LTFU who were retrieved and tested in the Based on our results, treating 41 patients with DAAs vs no patients pre-­C OVID and the COVID-­19 period. Statistical analyses were treated (no intervention) reduced decompensated cirrhosis cases by made with EPIDAT 3.1 software. Qualitative data were com- 30%, HCC by 27%, and liver transplantation requirement by 20%. pared using the chi-­s quared test or the Fisher exact test when HCV-­related deaths decreased by 26%. The reduction in liver com- frequencies were <5. plications generated a cost-­saving of €456,796 (Figure 1B). 2.3 | Ethical considerations 4 | DISCUSSION This study was approved by the Research Ethics Committee of The Relink-­C strategy enabled identification of a substantial per- Vall d'Hebron Hospital and was conducted following good clinical centage of HCV patients LTFU and provided linkage to care. With VARGAS-­ACCARINO et al. | 581 F I G U R E 1 (A) Flowchart of ReLink-­C strategy for the total period and comparison of pre-­COVID and COVID periods. (All percentages are calculated from the total number of HCV-­positive patients identified). Abbreviations: HCV: Hepatitis C virus; RNA: Ribonucleic acid; DAA: Direct acting antivirals. (B) Number of cases of liver complications, mortality and costs projected over the patients' lifetime 582 | VARGAS-­ACCARINO et al. this case-­finding approach, we can prevent potentially severe com- and proved to be a cost-­effective approach in a publically funded uni- plications, and reduce further transmission, thereby contributing to versal health system. HCV elimination. In total, 1591 HCV-­RNA-­positive tests were re- viewed, 166 patients were candidates for retrieval, and 25% of these AU T H O R C O N T R I B U T I O N S individuals could be relinked to care and cure. Elena Vargas-­Accarino, Joan Martínez-­Campreciós, Ariadna Rando-­ 6 In a similar study in Utrech, among 1913 individuals with HCV Segura and Maria Buti performed the research. Raquel Domínguez-­ infection, 269 were LTFU and eligible for retrieval. After contacting Hernández and Miguel Ángel Casado analysed the data. Elena them by letter, 15.5% of candidates were treated, a lower percentage Vargas-­Accarino, Joan Martínez-­Campreciós, Raquel Domínguez-­ than in our strategy (25%); suggesting that a phone call may be more Hernández and Maria Buti designed the research study and wrote the 7 effective than a letter for this purpose. In another study, 499 HCV manuscrit. Mar Riveiro-­Barciela, Francisco Rodríguez-­Frías, Ana Barreira, cases were identified and 3 started DAA (12.5%). In this study, pa- Adriana Palom and Rafael Esteban contributed to the design of the tients were contacted by primary care physicians, a possible reason study. All authors reviewed and approved the final version of the paper. for the lower rate of linkage to care. Finally, in a study performed in 2 centers in France,8 more than 95% of candidates were contacted, C O N FL I C T O F I N T E R E S T due to an active search strategy in which the primary care physicians Raquel Domínguez-­Hernández and Miguel Ángel Casado are em- were involved. ployees of Pharmacoeconomics & Outcomes Research Iberia, a The approach used in our study has several strengths. First, the consultancy firm specializing in the economic evaluation of health- use of universal reflex HCV-­RNA testing. Second, the simplified care care interventions, which has received unconditional funding from circuit model to assess liver disease. In a single medical visit, HCV-­ Gilead Sciences for the development of the analysis. Dr Mar Riveiro-­ RNA testing and TE were performed, allowing initiation of DAAs. Of Barciela has served as a speaker of Gilead Sciencies and Abbvie. the 43 individuals who attended the appointment, 41 started treat- Prof. Rafael Esteban has served as a speaker and advisory board of ment (>95%). Gilead Sciencies and Abbvie. Prof. Maria Buti has served as a speaker A novel finding of this study is the observation that during the and advisory board of Gilead Sciencies and Abbvie. COVID-­19 period, a lower percentage of patients were linked to care (27 vs 43%), and consequently, more patients were selected DATA AVA I L A B I L I T Y S TAT E M E N T for retrieval (70 vs 51%). Nevertheless, the percentage of can- The data that support the findings of this study are available from didates to contact was lower in the COVID-­19 period, as there the corresponding author upon reasonable request. was a higher percentage of patients with comorbidities or with a limited life expectancy (33% vs 54%). A higher percentage of ORCID patients was located (65% vs 62%) among candidates to contact Elena Vargas-­Accarino https://orcid.org/0000-0002-2521-0368 during the COVID-­19 pandemic, and a larger number of patients Joan Martínez-­Campreciós https://orcid. located attended the physician's appointment (88% vs 41%) than org/0000-0002-8899-8447 during pre-­COVID-­19. Raquel Domínguez-­Hernández https://orcid. Another significant finding to point out is the result of the cost-­ org/0000-0003-1083-7288 effectiveness analysis, which showed a cost-­saving of €456,796 for Mar Riveiro-­Barciela https://orcid.org/0000-0001-9309-2052 the public health system because of the estimated reductions in liver María Buti https://orcid.org/0000-0002-0732-3078 disease complications and mortality. Our study has the limitations of a retrospective design. After REFERENCES the records search, a large percentage of patients could not be 1. World Health Organization. Global Hepatitis Report. 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