This systematic review was conducted according to the preferred reporting items for systematic review and meta-analysis recommendations (Prism) .
On August 31, 2019, we conducted a literature search to identify COI studies related to HCV infection using Embase, Scopus, and PubMed. The phrase “cost of illness” was found in the medical subject headings (mesh) for pubmed and emtree headings for embase and was combined with “hepatitis c” for these databases. the “explode” function has been enabled within embase to allow a broader search of emtree headers. for scopus, a combination of ‘cost of illness’ and ‘hepatitis c’ was used to search for abstract/title/keywords. searches of the three databases were limited to the period 2010-present. the term “cost of illness” was used over the more generic heading “cost” to narrow the search within health economics. see the “online supplement” in the electronic supplementary material for more information on review search strategies.
Studies were included if they were full-text original investigations or systematic reviews using real-world observations to estimate HCV-related costs. therefore, modeling studies that simulated cost estimates or burden of disease studies focused solely on epidemiology without cost reporting were excluded. studies were also excluded if hcv costs were aggregated with other liver diseases (hepatitis a or b) where hcv-specific costs were unknown.
All three authors completed the abstract selection and two votes were required for all abstracts. any disagreement was discussed by the entire research team until full consensus was reached. full-text articles were retrieved and reviewed by one author (tjm), and all exclusions at the full-text step required agreement from the entire research team.
data extraction included article citation details (year, authors, title), country of HCV patients observed, population characteristics, sample size (if applicable), study description, study years included , presence of social costs (yes/no), description of the costing method, category of the costing method, type of analysis, results (detail), source of financing, cost adjustments for currency and inflation, and specific costs of the disease reported. Costing method categories were previously defined in a systematic review of COI studies for all diseases by Onukwugha et al. . For the extraction of HCV costs, all costs were extracted from the social and health sector perspective as reported by the study authors. Health sector costs and social perspective were identified based on definitions of formal, informal, and non-health impact provided by the second panel on profitability in health and medicine  (table 1).
To compare costs reported in the studies, all costs were converted to United States dollars (USD) and inflated as of December 31, 2019 using the Bureau of Labor Statistics’ Consumer Price Index (CPI) for services health care . the extracted costs were stratified by health states commonly used in the economic evaluation for ills in hcv (fig. 1). Due to the expected heterogeneity of costing methods, the authors determined current reported costs a priori without combining multiple studies. exploratory bivariate analyzes were performed to determine any associations between key variables. costing methods were further classified as simple (sum of all physicians, sum of specific diagnoses) and complex (regression, matching, multiple) for comparison . in addition, the types of analysis were classified as simple (descriptive statistics) and complex (regression, matching, multiple) for comparison.
assessment of risk of bias
In accordance with prism recommendations, we assessed risk of bias within the included studies at the outcome level, which required consensus from the entire research team. Specifically, the authors considered how study methods may have influenced HCV-attributable costs for the purposes of this review. qualitatively, we described potential sources of bias and rated studies as low, moderate, or high risk of bias. categorization of the costing method helped in the assessment of risk of bias, as more complex costing methods (eg, comparison, regression, and other incremental) may reduce certain types of bias in the resulting cost appropriate for the disease [13, 14]. the authors agreed that studies reporting descriptively with little or no statistical adjustment for cost estimates, no reported method to incorporate price inflation, or unadjusted sources of costs (e.g. high risk of bias. meanwhile, studies that attempted to control for some, but not all, of these factors would be classified as moderate risk.funding source was discussed as a potential source of bias, however, the authors agreed that it was difficult to assess bias in function of funding source and felt that more weight should be given to established methods therefore funding source was not included in the final risk of bias assessment based on this categorization one reviewer (tjm ) proposed a risk of bias rating and rationale described before group discussion Proposed ratings and rationale were reviewed and dis considered by all three authors for final risk of bias ratings requiring unanimous consent. exploratory bivariate analyzes were performed to assess risk of bias and other key variables (eg, inclusion of social costs, presence of industry funding, us/other). all statistical analyzes were performed in r version 3.5.3 .