Table 1:

Strengths and limitations of methods to monitor hepatitis C virus (HCV) incidence

METHOD	STRENGTHS	LIMITATIONS
Measurement based on prospective HCV re-testing of people at risk	• Can be used to estimate primary HCV infection or HCV reinfection • Systematic data collection procedures can be implemented to maximise data quality and participant retention in follow-up • Offers scope for adopting different sampling methods to recruit a nationally representative sample	• Not an efficient study design for rare outcomes: sample size requirements could be very high if incidence is low • May not well represent true HCV incidence due to losses to follow-up and changes in behaviour due to risk reduction counselling • Expensive if HCV RNA testing is performed to capture reinfections • Resource intensive given the need to track individuals over time
Measurement based on retrospectively-collected HCV re-testing data	• Can be used to estimate primary HCV infection or HCV reinfection • Is an efficient study design for rare outcomes like HCV acquisition because it is relatively easy and inexpensive to obtain large sample sizes by capitalising on existing data	• Limited application, since few population groups receive routine HCV testing • May not well represent true HCV incidence because there is no standardised data collection protocol (e.g., HCV testing interval may be too wide and variable) and participants receive risk reduction counselling • May not be generalizable to target population since method is based on convenience sample of individuals in contact with healthcare services and re-attending for care
Measurement based on a linked repeated cross-sectional study	• Can be used to estimate primary HCV infection or HCV reinfection • Can capitalise on cross-sectional surveys, which may be already ongoing or are generally easier to implement relative to cohort studies • Offers scope for adopting different sampling methods to recruit a nationally representative sample	• May not well represent true incidence if participants captured in multiple survey rounds are systematically different to those who are not • Not an efficient study design for rare outcomes like HCV acquisition: sample size requirements could be very high if incidence is low • May lead to statistically imprecise estimates if too few participants are linked over time • Can be difficult to implement if survey participation is kept anonymous although methods can be used to link participants even with anonymised data • Expensive if HCV RNA testing is performed to capture reinfections
Estimation based on tests for recent HCV infection*	• Faster because a single sample derived from one survey is needed • Limitations typically related to longitudinal follow-up (i.e., bias resulting from participant attrition and changes in behaviour due to risk reduction counselling) are circumvented • Can capitalise on cross-sectional surveys, which may be already ongoing or are generally easier to implement • Offers scope for adopting different sampling methods to have a nationally representative sample	• Only been used to estimate primary HCV incidence; unclear whether the antibody-avidity assay can be adapted to capture HCV reinfection • Unless assay is adequately calibrated to target population, it may over-estimate true primary HCV incidence due to potential for misclassification of non-recent infection as recent • Requires large sample sizes because the average duration of the recent infection state is short—not feasible if incidence is low and, for the viraemic pre-seroconversion assay, if the antibody prevalence is too high • Expensive because it requires HCV RNA testing • Requires elaborate laboratory infrastructure (at least for the antibody-avidity assay)
Estimation based on HCV antibody prevalence and duration of risk behaviour	• Lower cost and faster because a one-time measurement and a single test (HCV antibody) is needed • Limitations relating to longitudinal follow-up (i.e., losses to follow-up, changes in behaviour due to risk reduction counselling) are circumvented • Offers scope for adopting different sampling methods to have a nationally representative sample • Can capitalise on cross-sectional surveys, which may be already ongoing or are generally easier to implement	• Cannot be used to estimate overall incidence, as these methods typically focus on people with recent onset of risk behaviour (e.g., people who have recently started injecting), who often have a higher risk of HCV infection than everyone else • Multiple simplifying assumptions are made, which could lead to biased estimates if they do not hold (e.g., HCV acquisition should not have occurred prior to initiation of injecting, HCV acquisition occurred at the midpoint between the date of initiation of injecting and date of the survey, HCV incidence has remained stable over time) • Use of self-reported data to define duration of risk behaviour could introduce errors, leading to a mis-estimation of incidence • Restricting the sample to individuals with a recent onset of risk behaviour can considerably reduce the statistical precision of estimates
Estimation based on serial measurements of HCV antibody prevalence	• Limitations relating to longitudinal follow-up (i.e., losses to follow-up, changes in behaviour due to risk reduction counselling) are circumvented • Offers scope for adopting different sampling methods to have a nationally representative sample • Can capitalise on cross-sectional surveys, which may be already ongoing (e.g., for HIV surveillance) or are generally easier to implement	• Requires two consecutive survey measurements of HCV antibody prevalence to estimate HCV incidence and ≥three time points to monitor trends, thus could be expensive • Other relevant data (e.g., HCV-related mortality, level of in- and out-migration by HCV status) may not be available or be of poor quality which could introduce bias and/or uncertainty in the estimation • Large-scale studies can only be conducted once every couple of years, therefore, this method may not capture current trends in HCV incidence • Assumes a similar recruitment scheme and participant response by age groups between survey rounds • Requires large sample sizes • Requires additional data to capture HCV reinfection (e.g., HCV RNA, number of people who were treated and cured for different age groups)
Estimation of relative HCV incidence trends based on surveillance of acute HCV infection	• Relatively easy and inexpensive to implement on a large scale by capitalising on existing data	• Applicability of this method is limited since not many countries perform serological testing to distinguish between acute HCV and other types of viral hepatitis • It does not provide an estimate of HCV incidence because few participants with acute HCV seek testing, case ascertainment is prone to misclassification, and clinician reporting and data capture may be incomplete • Trends over time could mis-estimate trends in HCV incidence if the case definition of acute HCV, testing patterns or the reporting system have changed over time

^*Strengths and limitations apply to both assays classified as tests of recent infection (i.e., viraemic pre-seroconversion assay and antibody avidity assay), unless indicated otherwise