Integrating Hepatitis C Care for Opioid Substitution Treatment Patients Attending General Practice: Feasibility, Clinical, and Cost-Effectiveness Analysis

Background Hepatitis C virus (HCV) infection is common among people who inject drugs, yet well-described barriers mean that only a minority have accessed HCV treatment. Recent developments in HCV diagnosis and treatment facilitate innovative approaches to HCV care that improve access to, and uptake of, care by people who inject drugs. Objective This study aims to examine feasibility, acceptability, likely clinical effectiveness, and cost-effectiveness of an integrated model of HCV care for patients receiving opioid substitution treatment in general practice. Methods A pre- and postintervention design with an embedded economic analysis was used to establish the feasibility, acceptability, and clinical and cost-effectiveness of a complex intervention to optimize HCV identification and linkage to HCV treatment among patients prescribed methadone in primary care. The “complex intervention” comprised general practitioner (GP)/practice staff education, nurse-led clinical support, and enhanced community-based HCV assessment of patients. General practices in North Dublin were recruited from the professional networks of the research team and from GPs who attended educational sessions. Results A total of 135 patients from 14 practices participated. Follow-up data were collected 6 months after intervention from 131 (97.0%) patients. With regard to likely clinical effectiveness, among patients with HCV antibody positivity, there was a significant increase in the proportions of patients who had a liver FibroScan (17/101, 16.8% vs 52/100, 52.0%; P<.001), had attended hepatology/infectious diseases services (51/101, 50.5% vs 61/100 61.0%; P=.002), and initiated treatment (20/101, 19.8% vs 30/100, 30.0%; P=.004). The mean incremental cost-effectiveness ratio of the intervention was €13,255 (US $13,965.14) per quality-adjusted life-year gained at current full drug list price (€39,729 [US $41,857.48] per course), which would be cost saving if these costs are reduced by 88%. Conclusions The complex intervention involving clinical support, access to assessment, and practitioner education has the potential to enhance patient care, improving access to assessment and treatment in a cost-effective manner.


HepLink Cost-effectiveness Analysis Supplementary Material Background
In Ireland opiate substitution therapy can be prescribed by doctors based either at drug treatment centres or in general practice. There are two levels of GPs for OST prescribing. Level 1 GPs can prescribe OST to patients who are already on OST and are continuing therapy and xx patients are allowed per GP at any one time. Level 2 GPs can initiate OST and can prescribe up to xx patients. The aim of the HepLink intervention was to identify and link HCV Ab positive patients to tertiary care for treatment of HCV. 14 GPs were involved in the study and 135 OST patients were enrolled in the study. A nurse liaison was tasked with meeting with patients, determining HCV Ab status and arranging for follow up tests (RNA or Antigen) and conducting a fibroscan if appropriate (Ab+ and either chronic infection status positive or unknown).
Patients who were either chronically infected or Ab+ and awaiting chronic testing were referred to tertiary care. Demographic data and history of bloodborne virus testing and treatment was collected from patient notes at baseline before the nurse met with patients and at least 6 months afterwards to determine if they had been treated for HCV.

Methods
A Markov model of HCV disease progression was developed to simulate the disease progression of a cohort of individuals that are chronically infected with HCV. The model included Metavir disease stages for liver disease: F0 to F4, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), liver transplant, post-liver transplant and disease related death ( Figure 1). The model was further stratified by whether individuals were infected, on treatment or achieved SVR. Transition probabilities for disease progression and movement between infection, treatment and SVR are given in Table 1. We assume no disease progression or disease related death whilst on treatment, with treatment either leading to SVR (effective cure) or failing and returning back into the infected compartment at the end of 1 year. If SVR is achieved, there is no disease progression from disease stages F0 to F4, reduced disease progression from F4 to HCC and DC, and the same rate of disease progression from DC and HCC onwards. Background mortality is applied to all disease states assuming a male population with mean age of 43 years. We used mortality rates for 5-year age intervals from WHO and converted them to yearly transition probabilities in order to use yearly timesteps. The study population was modelled as a cohort of chronically infected individuals. As the number of chronically infected individuals in the study population was not fully determined an estimate was used based on the data collected from the HepLink study. There were 100 /135antibody positive patients enrolled in the HepLink intervention (data from baseline collection). Of those who had previously been tested for chronic disease, 81% had a previous RNA+ status (14 attained SVR prior to the start of HepLink). Therefore the initial chronic population size was sampled between 59 and 76 (69-88% chronically infected) and these were then split between Metavir stages F0 to F4 according to the distribution found amongst patients who had a fibroscan score on record. The population of those chronically infected at baseline is used as the initial condition for the Markov model in the comparator. The initial condition for the intervention has the same number of patients altogether, but those who initiated treatment during HepLink were placed in the associated treatment categories rather than chronically infected categories so that all treatment related to HepLink happened in the first year of the modelled time horizon.

Cost and Health Utilities
Costs for treatment of HCV related disease were taken from a recent study (Supplementary Table 2). HepLink intervention costs (in primary care) and HCV treatment costs (in secondary care) were collected as part of the cost-effectiveness study.

Estimation of HepLink intervention costs
Costs for the liaison nurse-led intervention were estimated directly from intervention data using a micro-costing approach from the healthcare system's (the health and social care system in Ireland) perspective in 2018 Euros. The total costs of the nurse liaison service included intervention set-up and implementation costs. Set up and implementation costs included 4 staff over a 15-month time period and were allocated using a top down approach. Research related costs were identified and excluded from the analysis. A detailed review of the intervention protocol and interviews with key technical staff involved in the planning, implementation and coordination of the intervention were performed to identify all the activities and resources utilized in the integrated model of HCV care that enhances liaison between primary and secondary care in Dublin. The main activities in the intervention included liaison with the general practitioners, patient assessments for HCV status, patient counselling/education, arranging for HCV tests with staff at the GP centre, patient assessment for addiction, fibroscanning patients and referral. Information on the types and quantities of all the resources utilized for each activity were measured from primary data for each activity, including staff time (liaison nurse, general practitioner, phlebotomist/nurse), and laboratory tests (HCV antibody, HCV antigen, HCV RNA, HCV genotype, fibroscan). Information on the number of patients accessing each service (laboratory investigations and diagnostic tests) and resources used in the pathway was obtained from the study records. The amount of time spent by the liaison nurse, general practitioner, phlebotomist and any other staff involved in the intervention was estimated for each activity using staff time sheets and interviews with the relevant staff.
Information on the acquisition costs and replacement values for capital items were gathered from the project's intervention records. to 2018 price levels. Equivalent annual costs for capital items (equipment, set-up costs) were estimated based on the expected service lives using differential rates recommended in the economic evaluation of health technologies guideline for Ireland [37]. The per patient unit cost for fibroscan was estimated from intervention data. where patients are assessed for their medical history and medication use, and a liver ultrasound is done (not necessary in non-cirrhotic patients with fibroscan score <12 kPa,). Patients diagnosed with decompensated liver disease and hepatocellular carcinoma are referred to the hepatology department where they are treated for these complications and, in most cases, for HCV too. We assumed that treatment monitoring costs the same regardless of which department the patient is treated at.

Supplementary
Using the detailed description of the treatment protocol, we identified and quantified the Health utilities for HCV disease progression stages were taken from the literature and a decrement for DAA treatment was applied to 12/52 portion of the base health utility during the treatment year. Once a patient attains SVR the health utility depends on the disease progression stage reached before treatment. For those F0 to F4, the health utility is assumed to increase, whereas for other more severe disease stages the health utility remains the same.

Cost-effectiveness analysis
Using the Markov model, the cohort of patients was followed for 50 years and costs and health utilities attached to each state in the model for each parameter set. The cost-effectiveness analysis is undertaken using a 50 year time horizon and a 5% discount rate for costs and QALYs [37]. The mean incremental cost-effectiveness ratio was calculated (ratio of the mean difference in costs and the mean difference in QALYs between the intervention and the comparator arms) and cost-effectiveness determined using the Irish willingness to pay threshold of €30,000 per QALY [37].

Sensitivity analyses
A probabilistic sensitivity analysis was carried out using 1000 parameter sets sampled from appropriate distributions. The impact of parameter uncertainty on the incremental costs and QALYs was ascertained by an ANCOVA analysis [44]. A cost-effectiveness acceptability curve was obtained to determine the probability of cost-effectiveness at different willingness to pay thresholds.  Table 3 shows the total costs and QALYs for the two comparators and the results of the cost-effectiveness analysis.