Cost effectiveness of direct acting antivirals in the treatment of hepatitis C in vulnerable populations

1. Introduction

Hepatitis C Virus (HCV) is recognized as a prominent medical concern, being a common cause of cirrhosis, a risk factor for hepatocellular carcinoma, and a leading indication for liver transplantation. This bloodborne infection affects 71 million people worldwide [1]. Unlike other infectious diseases tracked by the World Health Organization (WHO) the prevalence of HCV is increasing across the globe [2]. This increase is being at least partially fueled by the changing demographics of HCV [3]. Whereas blood transfusion has been a major risk factor among baby boomers, large increases in HCV infection rates today are a result of illicit drug use among young adults.

Given the prevalence of HCV and its associated mortality rates, the WHO has set in its goal the elimination of HCV by the year 2030 [1]. Conceptually, elimination of HCV will be achieved not through immunization as in other infectious conditions but largely by the administration of oral Direct-Acting Antivirals (DAA), that are safe, effective, and tolerable [4]. There are a number of barriers that delay the goal of HCV elimination in the next decade. One of the most important ones is the identification and linkage to care infected individuals. Two cohorts in particular have seroprevalences several fold higher than the general population: incarcerated individuals and persons who inject drugs (PWIDs). Whereas the prevalence of HCV in the general population is reported to be 1.2–6%, it is estimated to be 10–40% among incarcerated individuals and 70–77% in PWIDs [5–7]. In addition, injectable drug use is the most common risk factor for acquiring HCV amongst incarcerated individuals [8]. For these reasons, HCV treatment of vulnerable populations such as incarcerated individuals and PWIDs is paramount.

Cost-effectiveness analysis (CEA) considers the effectiveness of treatment, cost of treatment, and value of treatment. Studies on CEA compare different treatment options to address whether to invest in one treatment option vs. another that would provide better outcomes. Overall goal of CEA is not only cost saving but health benefit and provides guidance in prioritizing treatment options by objectively comparing cost and health benefit. Cost-effectiveness (CE) is typically expressed as incremental cost-effective ratio (ICER) which is (cost of new treatment – cost of current treatment)/(benefit new treatment – benefit current treatment). A CEA compares the ICER to a willingness to pay threshold. For a treatment to be considered cost-effective the ICER must be lower than a predetermined threshold value. CEA have been utilized to assess the pharmacoeconomic basis of treating HCV using DAAs. CEA studies have consistently found the use of DAAs to be cost-effective in the general population. However, there is limited data in its use in vulnerable populations.

These vulnerable populations have access limitations, possible reinfection, and reduced adherence that may impact the CE of antiviral therapy. Given the prevalence of HCV and unique challenges in individuals who are incarcerated and PWIDs, we sought to review and comment on the cost-effectiveness of DAAs in the treatment of HCV in these populations.

2. Cost-effectiveness of DAAs in incarcerated population

Individuals in correctional facilities are believed to be disproportionally affected by HCV. Even in the correctional facilities, injectable drug use is the most common risk factor for HCV transmission. Majority of incarcerated persons are released back into society with the risk of potentially infecting other individuals and thus perpetuating the disease [9]

One of the earliest studies assessing the CE of DAA therapy in correctional facilities was performed by Martin et al. [10]. The study was an effort to argue for increased HCV testing among those incarcerated in the United Kingdom. The authors assessed CE of voluntary risk-based opt out testing among patients treated with interferon versus an all DAA regimen. The authors argued that increasing testing and treatment with oral DAA therapy would be CE. An important limitation of the CE model is that it does not incorporate individuals’ transition to communities. A separate study by Dalgic et al. assessed the CE of HCV therapy in Spain’s prisons [11]. The model considered a number of important variables such as viral transmission and prison-community dynamics. Not only did their model find treating HCV reduced health-related outcomes in prison, it also resulted in less community transmission when incarcerated individuals were released. The model was robust to a number of variables in the sensitivity analysis, including the prison sentence length. Compared to the status quo, the ICER was €9,600 per Quality-Adjusted Life Years (QALY) and thus considered cost-effective. The status quo was defined by limited access to HCV treatment. A separate study assessing treating prisoners in Spain by Marco et al. also found DAA to be CE [12]. They found that comparing DAA treatment with no treatment was cost-effective (€690 per QALY). Although their model allowed treatment regardless of liver disease severity, it did not account for the possibility of reinfection. These two Spanish studies, Dalgic et al. and Marco et al., assessed cost-effectiveness in similar populations however had different incremental cost ratios as their respective study models compared varying treatment strategies: cost of treatment versus cost of status quo and cost of treatment versus no treatment. Furthermore, these studies differed in that the Marco et al. model did not consider variables such as prison length of stay and viral transmission among prisoners. Given these contrasts the two studies demonstrated varying cost-effective ratios.

The results from the United States demonstrated that the ‘test all, treat all’ with linkage to care after release resulted in an ICER of 24,000 USD/QALY and thus considered cost-effective compared to a willingness to pay threshold of 100,000 USD/QALY [13]. The model was no longer CE when the prevalence of HCV was below 0.1%. The author also noted an interaction between fibrosis severity and DAA drug costs, as patients with advanced fibrosis were treated with a different and prolonged regimen.

3. Cost-effectiveness of DAAs in PWID

PWIDs pose special challenges toward the goal of HCV elimination. The prevalence and transmission rate of HCV is substantially higher among PWIDS. Furthermore, PWIDS are less likely to be screened for HCV, linked to care, and undergo antiviral treatment if infected. Moreover, since treatment does not confer immunity, PWIDs who are cured of HCV are at risk of being re-infected.

Studies have consistently shown the use of DAAs against HCV to be cost-effective [10–18]. These studies differ in the country of origin, base populations, comparative treatment groups, and a variety of assumptions such as reinfection rates (See Table 1). In addition, some CE models include ancillary services like needle and syringe programs (NSP). For instance, Scott et al. calculated the ICER to be $A25,121 per QALY gained [18]. Their model, applying data from Australia, included the possibility of reinfection and utilization of NSP. A separate study by Scott et al. compared the timing of antiviral therapy [16]. They compared the costs and quality-adjusted life years of no treatment to starting therapy at different severities of liver disease. Although treating HCV was CE for disease severities among PWIDs, the ICER was lowest for patients with greatest severity of liver disease. A separate CE model by Stevens et al. utilized two perspectives: health care and societal perspectives [17]. Although the study found the use of DAA to be at CE, only the societal perspective showed the combination of DAAs and medication-assisted therapy (MAT) to be cost-effective. Utilizing the health care perspective, the ICER was 27, USD 251 per quality of life year saved with DAA but without MAT. In contrast, the combination of DAA and MAT was CE with an ICER of 23,932 USD with the societal perspective. A study by van Santen et al. compared different antiviral regimens in stable and declining HCV rates among PWIDs extrapolating input assumptions from the Netherlands [15]. The authors noted dual DAA therapy to be the most cost-effective strategy irrespective of the type of epidemic. However, the comparative group was defined as the use of pegylated interferon and ribavirin which is now considered obsolete.

Table 1. Summary of select cost-effective studies in vulnerable populations*

4. Limitations

Our paper has several limitations. First, the CE studies in our review did not provide data about specific DAA regimens. There are two first line treatments that are pan-genomic that differ in duration of therapy, drug class, drug–drug interaction, safety in patients with liver failure, and pill burden [19,20]. Because these regimens are similar in costs, safety, and efficacy we do not believe this limitation introduces bias in the review. Secondly, reinfection was considered in only one study [18]. However, we do not believe this omission necessarily introduces a significant bias in the models because reinfection rates among PWIDs appear low [21]. Another limitation of the CE studies in our review is the lack of consideration of societal benefits. Variables affecting society such as reduced productivity and economic burden associated with the management of HCV-related extrahepatic manifestations have not been formally evaluated. Our study did not include data on the effect of DAAs on HCV incidence and risk of infection. Given the higher rates of transmission among PWIDs, it is difficult to demonstrate a decrease in the incidence of HCV through antiviral therapy. Recently Chen et al. presented a modeling-based study to simulate the clinical landscape of HCV treatment in European countries and projected that by 2020 the number of individuals alive with HCV cure will supersede the number of actively infected individuals [22].

5. Conclusion

Given their high efficacy and favorable safety profile DAAs are first line treatment therapy for HCV. WHO has set a goal of HCV elimination by the year 2030. To achieve this goal treatment protocols must be implemented targeting high-risk individuals such as PWIDs and incarcerated individuals as these cohorts have high prevalence of seropositivity. In our paper we reviewed six international studies and 3 domestic studies assessing the cost-effectiveness of treatment of HCV with DAAs amongst these vulnerable populations. All studies, although differing in methodology, found that DAAs were cost-effective. Treating high risk individuals results in overall reduction in health care costs [23].

6. Expert Opinion

Targeting chronic HCV infection in prisons and amongst PWIDs represents a public health opportunity. Now with the advent of DAAs, which are highly efficacious with little side effect profile, treatment of high-risk individuals must be implemented not only for individual benefit to prevent cirrhosis and hepatocellular carcinoma but also for the societal benefit to prevent future transmission and overall reduction in health service usage and overall reduction in health service usage and costs. HCV elimination will not be achieved unless we actively extend therapy to vulnerable populations. The results of CE studies demonstrate the pharmacoeconomic basis of treating PWIDs and incarcerated individuals. The ICER is likely to be even lower if current DAA costs are considered. However, one of the biggest challenges is not necessarily the costs of DAAs but understanding who is infected and subsequent linkage to care.

Declaration of interest

SS in a consultant and member of the speaker bureau for Gilead and AbbVie. There has been no financial support for this study. This includes royalties, grants or patents received or pending, stock ownership or options, or employments. We declare that this manuscript is original and has not been published before and has not been submitted for publication elsewhere. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Author contributions

Role in the Study: Study concept and design (SS); acquisition of data (DV, CB); analysis and interpretation of data (all); drafting of the manuscript (DV, SS); critical revision of the manuscript for important intellectual content (All); obtained funding (not applicable); administrative, technical, or material support (SS); study supervision (SS).

Additional information

Funding

This paper was not funded.