Cost‐effectiveness of screening and treatment using direct‐acting antivirals for chronic Hepatitis C virus in a primary care setting in Karachi, Pakistan

Abstract Despite the availability of effective direct‐acting antiviral (DAA) treatments for Hepatitis C virus (HCV) infection, many people remain undiagnosed and untreated. We assessed the cost‐effectiveness of a Médecins Sans Frontières (MSF) HCV screening and treatment programme within a primary health clinic in Karachi, Pakistan. A health state transition Markov model was developed to estimate the cost‐effectiveness of the MSF programme. Programme cost and outcome data were analysed retrospectively. The incremental cost‐effectiveness ratio (ICER) was calculated in terms of incremental cost (2016 US$) per disability‐adjusted life year (DALY) averted from the provider's perspective over a lifetime horizon. The robustness of the model was evaluated using deterministic and probabilistic sensitivity analyses (PSA). The ICER for implementing testing and treatment compared to no programme was US$450/DALY averted, with 100% of PSA runs falling below the per capita Gross Domestic Product threshold for cost‐effective interventions for Pakistan (US$1,422). The ICER increased to US$532/DALY averted assuming national HCV seroprevalence (5.5% versus 33% observed in the intervention). If the cost of liver disease care was included (adapted from resource use data from Cambodia which has similar GDP to Pakistan), the ICER dropped to US$148/DALY, while it became cost‐saving if a recently negotiated reduced drug cost of $75/treatment course was assumed (versus $282 in base‐case) in addition to cost of liver disease care. In conclusion, screening and DAA treatment for HCV infection are expected to be highly cost‐effective in Pakistan, supporting the expansion of similar screening and treatment programmes across Pakistan.


| INTRODUC TI ON
An estimated 71 million people world-wide are chronically infected with Hepatitis C virus (HCV), leading to 400 000 annual HCV-related deaths. 1 Eighty per cent of HCV infections are in low-and middle-income countries (LMIC), 2 with Pakistan harbouring the second-largest HCV-burden in the world (7.5 million infected persons in 2015). 3 Without treatment scale-up, the number of infected persons in Pakistan is projected to rise to 12.6 million by 2030. 4 Furthermore, in Pakistan the HCV epidemic is generalized, with most HCV transmission attributable to community and medical practices. 5,6 Direct-acting antivirals (DAAs), available globally since 2014, offer high cure rates (sustained virologic response (SVR) over 90%) with few side effects for all HCV-infected patients. 7,8 However, access in most LMICs has been limited by their high cost, 9,10 the lack of infrastructure required for scaling up treatment, and the need for complex diagnostics and monitoring during treatment. 11 Pakistan has had national hepatitis prevention and control programmes in place since 2005. 12 Despite this, most HCV treatment programmes in Pakistan have been offered through specialized private or government hospitals with limited access and high out-ofpocket expenses for most patients. 13,14 As of 2015, approximately 150,000 patients were treated annually. However, to reach global HCV elimination targets in Pakistan, the number of treatments needs to be scaled up to at least 500 000/year, 4 which will require an expansion of testing and treatment beyond specialized hospitals.
Médecins Sans Frontières (MSF), in collaboration with local organization SINA Health Education and Welfare Trust, operated a primary health clinic in Machar Colony, an informal settlement in Karachi with a high prevalence of risk factors for Hepatitis C (6%). 14,15 MSF is an international, independent medical humanitarian organization that provides medical assistance or care to people affected by conflict, epidemics, disasters or exclusion from healthcare.
Patients who come to the MSF clinic are treated with no charge to the patients. In 2015, the MSF clinic in Machar colony started offering screening for HCV and all-oral (interferon-free) DAA treatment free of charge to their patients.
Although numerous studies in Pakistan have documented favourable clinical outcomes for DAA-based treatment, [15][16][17][18] there is a paucity of information on their costs and cost-effectiveness. This information would help inform decision-making related to programme planning and resource allocation for expanding HCV treatment access. 13 Previous economic evaluations of DAA-based HCV treatment programmes in LMICs have generally not used locally derived cost or programme outcome data [19][20][21] and have not considered the provision of screening and treatment in a primary health clinic. 22,23 In this study, we aimed to provide information to decision makers on the cost-effectiveness of HCV screening and treatment in a setting where access to healthcare is limited. To do this, we used 'real-world' cost and outcome data collected from the MSF Machar colony clinic to estimate the costs and cost-effectiveness of testing and treating individuals with chronic HCV in a low-income, urban primary health care setting in comparison to no screening and treatment.

| Study design
We assessed the cost-effectiveness of the MSF HCV screening and DAA-based treatment programme offered at a free of charge primary health clinic in comparison to no screening and treatment from the provider's perspective. Due to generally limited access to any healthcare in this setting, 14 we assumed there was no access to screening and treatment for HCV in this population before the introduction of the programme.

| Setting and model of treatment
Patient characteristics and resource utilization data were collected from the on-going HCV screening and treatment programme, integrated into the MSF primary health clinic in Machar Colony, Karachi, Pakistan. The programme, procedures and preliminary outcomes have been described previously. 14,15 In short, the HCV programme was included as a new component to the MSF clinic in February 2015, with dedicated budget, space and personnel, although some resources were shared with existing services. All patients 18 years of age or above presenting with HCV risk factors 14 (Supplementary Figure S1) were referred from the outpatient department by the consulting medical officer to the in-house MSF laboratory, where they were screened for HCV antibodies, initially using an OraQuick® rapid diagnostic test (RDT) (OraSure Technologies) and later (starting 2018) using SD Bioline RDT (Standard Diagnostic Inc, Korea). All HCV antibody positive patients were tested for HCV RNA (to confirm chronic infection) using qualitative polymerase chain reaction (PCR) testing; initially done externally, but later using quantitative PCR performed in-house on the GeneXpert® platform (GeneXpert 1V system, Cepheid, USA). Patients confirmed to have chronic HCV infection, as well as those previously diagnosed by another provider, were evaluated and prioritized for treatment based on liver disease stage, assessed using the AST/Platelet Ratio index (APRI) score. 24 An APRI score ≥ 1.0 (~Metavir stage F3 25 ) was used as the prioritization threshold for treatment until October 2016 when it was reduced to >0.5. The medical team (two HCV K E Y W O R D S chronic hepatitis C, cost-effectiveness, low-income population, Pakistan, treatment costs doctors and one nurse) performed eligibility, baseline, on-treatment and post-treatment clinical evaluations for all diagnosed patients.
Individual counselling sessions were given at each step of the care cascade (Supplementary Figure S1). The main regimen used was sofosbuvir with daclatasvir for 12 or 24 weeks, with or without ribavirin; sofosbuvir and daclatasvir were procured by MSF outside of Pakistan. 14 Genotyping was performed in patients with evidence of cirrhosis to determine the length of treatment; genotype 3 patients with cirrhosis were treated for 24 weeks. Supplementary Table S3 shows the distribution of patients by treatment regimen. Sustained virological response (SVR12) was determined by PCR test 12 weeks after treatment completion.

| Model framework for economic evaluation
The costs and outcomes of the screening and treatment programme

| Disease progression rates
Health state transition probabilities were sourced from literature [31][32][33] ( Table 1). These transition probabilities were adjusted to reflect the higher proportion of genotype 3 in Pakistan, which has faster disease progression (see Appendix S1). 4 progression is assumed to cease for pre-cirrhotic patients, while for cirrhotic patients, progression continues at a slower rate compared to infected patients. 31,33 We assumed no reinfection risk in the basecase analysis and therefore estimate impact excluding any benefits of preventing new infections due to treatment.

| Treatment costs
HCV screening and treatment costs were estimated directly from programme data using a retrospective, cohort-based, micro-costing approach capturing all the provider costs. A detailed review of the treatment protocol and interviews with key staff identified all activities performed and resources utilized in the programme (see Appendix S1).
Information on the types and quantities of resources used for each activity was collected from screening to 12 weeks following treatment completion. The costs borne by the programme included staff time (doctors, nurses, counsellors, laboratory technicians), clinic visits (eligibility assessment, baseline assessments, treatment initiation, on-treatment monitoring, and SVR12 assessment), diagnostic and laboratory tests, medicines and overheads (buildings, support staff, utilities and consumables).
Primary data were collected on the type and quantity of resources consumed for each activity in the pathway of care for patients. Data on the time spent by staff in providing services were measured using staff time sheets (for patient support nurses and HCV doctors), by interview, or according to total number of patients  Supplementary Tables S6, S7 and S8. Costs of screening included the test for HCV antibodies (anti-HCV), and when positive, the HCV-RNA test to confirm chronic infection. The costs also included overheads and staff time for phlebotomy, doing the tests and counselling. The average cost per diagnosis was calculated for the observed anti-HCV and chronic prevalence at the clinic including costs for patients who received an anti-HCV and/or HCV-RNA test but were not reactive.
Information on the healthcare costs for different HCV disease states was not available for Pakistan, and so was not included in the base-case analysis.

| Treatment impact
The studies. 38 We assumed that patients with METAVIR score F0 had no disability, and that compensated cirrhosis (F4) is equivalent to a moderate abdominopelvic problem, with a linear increase in disability from F0 to F4 modelled for F1-F3. The GBD estimate for DC was used, and the value for metastatic cancer was assumed for HCC (Table 1).

| Cost-effectiveness analysis
In the base-case analysis, we modelled the costs and DALYs for

| Sensitivity Analysis
To quantify the impact of parameter uncertainty on our model results, a probabilistic sensitivity analysis was conducted on all key parameters by simultaneously sampling each parameter 1,000 times from their predefined probability distributions (Table 1) and running the model with each sampled parameter set.
We also examined the effect of changing specific model assumptions through scenario analyses (Supplementary Table S9). These included the following: increasing treatment coverage to 80% (from

| Cost of treatment
The average cost of treatment for the 2453 patients that initiated treatment with DAA-based regimens was $717 (SD $336), with an additional $123 to diagnose each of 4764 patients, and an average of $112 (SD $43) for pre-treatment assessment for 2,311 patients not treated ( Table 2). The major cost driver was the cost of DAAs, contributing 52% of the total cost per initiated treatment from screening through to SVR12 (Table S10), followed by the costs of clinic visits (19%), diagnosis (15%) and laboratory investigations (14%).  Figure 3). Overall, the treatment programme prevents 1.04 DALYs per diagnosed patient.

| Base-case cost-effectiveness
Under the base-case projections, the ICER of the treatment programme was $450 per DALY averted (Table 3) Other sensitivity analyses (Figure 4) on DAA costs, discount rate, time horizon and reinfection rate suggested the cost-effectiveness projections were robust to these parameter changes (ICER<$1000/ DALY averted).

| DISCUSS ION
This study demonstrates that the MSF testing and DAA-based treat- This study draws major strength from the use of 'real-world' data on patients screened, diagnosed, and treated as part of an on-going programme in Pakistan. This enabled collection of patient-level data on resource use to estimate the full costs associated with DAA-based testing and treatment of HCV. We also used outcome (testing and linkage data) and effectiveness data (SVR12 rates) from  19,20,23 In India, an analysis found DAA-based HCV testing and treatment to be cost-saving, 19 but India-derived costs or treatment outcome data were not used. In addition, savings in health care costs, derived from the USA, may have been too high for low-income settings. In Egypt, screening and treatment were found to be cost-effective but the intervention used a combination of DAA and interferon-based treatment which are no longer widely used. 20,49 Our study provides important new data from a 'real-world' economic evaluation of HCV testing and treatment in a resource-limited setting-providing the first real evidence that testing and DAA-based treatment can be highly cost-effective in LMICs. This is the first study to evaluate a primary health clinic-based intervention in LMIC.

TA B L E 2 Component costs of HCV treatment intervention. Costs are mean (SD) in 2016 USD
The favourable cost-effectiveness of the HCV testing and treatment programme has important implications for Pakistan.
It provides important data that supports the scale-up of testing and treatment, which recent modelling suggests is urgently needed for containing the current increasing HCV epidemic. 4,56 The generalized nature of the HCV epidemic in Pakistan requires decentralization of services in order to reach all the affected populations, particularly among marginalized groups that may not have regular access to healthcare facilities, such as individuals living in informal settlement areas. Our results support the countrywide expansion of decentralized screening and treatment strategies among these populations across Pakistan, with our cost estimates being useful for determining the likely costs of such a strategy. 56 Further simplification of the pathway of care, reductions in cost of screening, diagnosis and DAA prices will further improve access and cost-effectiveness.