Research paperReaching hepatitis C virus elimination targets requires health system interventions to enhance the care cascade
Introduction
The advent of highly effective direct-acting antiviral (DAA) therapies for the treatment of hepatitis C virus (HCV) is a game-changer for the disease. With cure rates >90% (Lawitz et al., 2014, Poordad et al., 2011), DAAs are highly tolerable, require only short-duration (8–12 weeks) therapy, have simple dosing (once-daily) and are effective even in advanced liver disease. This advancement from interferon-based therapies, which had only moderate (40–70%) success rates, required prolonged therapy (6–12 months), and had considerable side-effects (Gane et al., 2011; Manns, Wedemeyer, & Cornberg, 2006; Poordad et al., 2011), means that elimination is now firmly on the agenda (Burki, 2014). In response, the World Health Organization (WHO) have released elimination targets aiming for a 65% reduction in HCV-related mortality and a 90% reduction in combined HCV and hepatitis B virus (HBV) incidence by the year 2030—further specified as a 95% reduction in HBV incidence and an 80% reduction in HCV incidence (World Health Organisation, 2016). However, for many countries a significant barrier to achieving these goals will be the high cost of DAA treatments. In the USA, a single DAA course can be as much as US$80,000 (Hepatitis C Online, 2015), and even in countries like Egypt where a DAA treatment course costs approximately US$1000 (Hill & Cooke, 2014), the high prevalence (∼10%) of HCV in the general population (Egypt Ministry of Health, El-Zanaty and Associates, & Macro International, 2009; Sievert et al., 2011) means that restrictions on treatment access are required to limit government expenditure.
Overcoming cost barriers to DAA access is a necessary first step to achieving elimination but there are many others that need to follow. Health system limitations in the HCV cascade of care means many people will remain chronically infected. Currently between infection and cure individuals must undergo: (1) a blood test to detect HCV antibodies (which could be present due to either acute, chronic or resolved infection); (2) a polymerase chain reaction (PCR) test to detect HCV RNA (to distinguish current infections from previous infections); (3) a genotype and viral load test to determine the correct treatment protocol; (4) an assessment of liver fibrosis through either an aspartate aminotransferase-to-platelet ratio index (APRI), other serum fibrosis biomarker, or transient elastography (e.g. FibroScan (Echosens), HepaScore); and in most settings (5) a further consultation with a specialist to commence treatment. There is a need to consolidate or remove some of these steps as each one represents a point of loss to follow-up (Yehia, Schranz, Umscheid, & Re, 2014).
Australia provides an important case study because it represents a situation with unrestricted treatment access but similar health system barriers to other developed settings. Since March 2016, DAA treatments for HCV have been listed on the Australian Pharmaceutical Benefits Scheme (PBS) (Commonwealth of Australia Department of Health, 2015, Pharmaceutical Benefits Advisory Committee (PBAC), 2015) as a result of the Australian government committing AU$1 billion over 5 years for an unlimited number of treatment courses, with no restrictions on access according to disease stage, treatment history or drug use status (Australian Government Department of Health, 2015, Hepatitis C Virus Infection Consensus Statement Working Group, 2016, Thompson, 2016). This listing on the PBS means that patient co-payments for treatment are under US$30 per month (or under US$5 for concession holders), minimizing cost barriers. Treatments in Australia now can also be prescribed by primary care doctors in the community (Australian Pharmaceutical Benefits Scheme, 2016), further improving access. However, at the end of 2012 (before DAAs were seen on the horizon) more than 58% of people who tested HCV antibody positive had not completed a PCR and genotype test, let alone progressed to treatment (Snow, Scott, Clothier, MacLachlan, & Cowie, 2017). This sub-optimal care cascade is compounded by limited access to FibroScan machines, which are expensive and normally based at hospital clinics, not in community settings.
Modelling has shown that the elimination targets can be achieved in Australia if treatments are targeted to people who inject drugs (PWID) (Scott, McBryde, Thompson, Doyle, & Hellard, 2017)—the group at greatest risk of infection and transmission. Since the listing of DAAs on the PBS, approximately 30,000 people (13% of all people living with HCV) were successfully treated in 2016 (the first ten months) (The Kirby Institute, 2016). However, this reflects a large backlog of people with advanced liver disease who have already been engaged in care, waiting for DAA treatment, and treatment numbers among PWID are likely to be significantly lower. Maintaining high treatment rates will be a challenge, and increasing testing rates is likely to be necessary to meet global HCV elimination targets. As the number of cured individuals with HCV antibodies increases, standard antibody tests will also become less useful and biomedical advances such as point-of-care (POC) RNA tests, which have already been successfully trialled (Grebely et al., 2017; Gupta, Agarwala, Kumar, Maiwall, & Sarin, 2017; McHugh et al., 2017; Rahamat-Langendoen, Kuijpers, & Melchers, 2015), may be required.
Previous models of HCV transmission have been used to project the HCV epidemic and associated disease burden in many countries (Razavi et al., 2014), as well as to consider the cost-effectiveness of DAAs (Martin et al., 2012; Scott, Iser, Thompson, Doyle, & Hellard, 2016; Visconti, Doyle, Weir, Shiell, & Hellard, 2013), the potential impact of DAA treatment scale-up (Cousien et al., 2015, Cousien et al., 2017, Hellard et al., 2012, Martin et al., 2013) and to estimate the treatment numbers required to achieve global targets (Scott et al., 2017); however it remains unclear how enough treatment demand can be generated among PWID to enable this to occur. In this paper we expand an existing mathematical model of HCV transmission, liver disease progression and treatment to include the complete cascade of care. The model is calibrated to epidemic and clinical conditions in Australia and used to estimate the cost and impact of: scaling up primary care treatment services; using APRI < 1 to triage for risk of cirrhosis and bypass the need for further hepatic fibrosis assessment; introducing POC RNA testing; and recommending annual testing of PWID through drug treatment services. We therefore determine the total cost and combination of additional policy interventions that will be required to achieve the WHO elimination targets in Australia.
Section snippets
Model description
We extended the dynamic compartmental model from Scott et al. (2017) to include the complete cascade of care (Fig. 1). In brief, METAVIR scores (Bedossa & Poynard, 1996) were used to classify stages of liver disease, and individuals were distinguished as either: susceptible (S—infection naïve or previously achieving spontaneous clearance or SVR through treatment); acutely infected (A); chronically infected with liver fibrosis (in stage F0–F4); chronically infected with decompensated cirrhosis
Impact on cascade of care and incidence
Unlimited and unrestricted treatment access is projected to lead to a dramatic decline in the number of people living with HCV (Fig. 2). Even in the base scenario (Fig. 2, top-left), the number of people with living with HCV in the model was reduced to approximately 24,000 by 2030. However, the majority (74%) of remaining infections were undiagnosed PWID, who could continue to transmit HCV to others. The base scenario reduced incidence in 2030 by 45% compared to 2015 levels.
Scenario 1 and
Discussion
By modelling the complete HCV epidemic in Australia, including transmission, liver disease progression and the cascade of care from infection to cure, we have shown that even in a setting with unlimited and unrestricted treatment access, achieving global HCV elimination targets will require policy and health system interventions to ensure that priority populations have access to testing, care and DAA therapy. In particular, to achieve the target of an 80% reduction in incidence by 2030, HCV RNA
Conclusions
Treatment scale-up in Australia could reduce the number of people living with HCV from 230,000 in 2015 to 24,000 by 2030 and reduce incidence by 45%, but without improvements to the cascade of care Australia is unlikely to reach the WHO elimination target for new infections. Delivering services through primary care settings and using APRI to bypass hepatic fibrosis assessment produced only modest impacts but saved AU$32 million by 2030, with no decrease in health outcomes, and are therefore
Conflict of interest
JD, MH, AT, AW and the Burnet Institute receive investigator-initiated research funding from Gilead Sciences, AbbVie and BMS. JD’s institution has received honoraria from Merck, Gilead and BMS. No pharmaceutical grants were received in the development of this study.
Acknowledgements
MH, JD, AT, JH, AP, AW and DW are the recipients of National Health and Medical Research Council fellowships. The authors gratefully acknowledge the support provided to the Burnet Institute by the Victorian Government Operational Infrastructure Support Program.
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