Direct-Acting Antivirals Remain Cost-Effective Treatments for Chronic Hepatitis C in Australia Despite Changes to the Treated Population and the Availability of Retreatment: The Glecaprevir/Pibrentasvir (Maviret®) Example
verfasst von:
Emma Warren, Belinda J. C. Castles, Gillian C. Sharratt, Aitor Arteaga
The first direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection were reimbursed via Australia’s Pharmaceutical Benefits Scheme (PBS) in March 2016. This was based on the recommendation from the Pharmaceutical Benefits Advisory Committee (PBAC) that the regimens would be acceptably cost-effective at an incremental cost-effectiveness ratio (ICER) no greater than $15,000/quality-adjusted life-year (QALY). Since the initial PBS listings for DAA therapies and subsequent listings of newer DAA treatments such as glecaprevir/pibrentasvir (Maviret®), the demographics and some of the disease characteristics of currently treated patients have markedly changed. This analysis aims to reassess the cost-effectiveness of glecaprevir/pibrentasvir, accounting for the changes to the HCV population currently seeking treatment and incorporating retreatment in first-line failures and the treatment of new infections in previously treated individuals.
Methods
To assess the cost-effectiveness 7 years after initial listing of DAAs, an update was made to the Markov model used to achieve PBS reimbursement for Viekira-Pak® in May 2016. Amendments to the Viekira-Pak® model include: changes to baseline age and fibrosis distribution of treated patients, and inclusion of retreatment of first-line failures [those not achieving a sustained virologic response (SVR12)] and reinfected individuals. Treatment-related inputs including SVR12 response rates, adverse events, treatment-related disutility, and discontinuations were sourced from pivotal glecaprevir/pibrentasvir clinical trials.
Results
Using the published price of glecaprevir/pibrentasvir, the ICER is below $15,000/QALY.
Conclusions
Despite changes in demographics and disease characteristics of treated patients, and changes to the model structure to reflect retreatment in clinical practice in Australia, DAAs remain cost-effective in 2023.
Hinweise
Prior Presentation: The economic analysis was presented as a poster at the Health Technology Assessment International (HTAi) conference in Adelaide, Australia, 24–28 June, 2023.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Key Summary Points
Direct-acting antivirals (DAAs) for the treatment of hepatitis C virus have been reimbursed in Australia since 2016.
The demographics and disease characteristics of currently treated patients have changed markedly since 2016.
This analysis demonstrates that DAAs remain cost-effective despite changes in the treated patient population, in addition to incorporating changes to the model structure to reflect clinical practice in Australia, which includes the retreatment of first-line treatment failures and retreatment of reinfected individuals.
Introduction
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and has been identified as a significant public health issue in Australia for several decades [1]. In 2016, the Australian government endorsed the World Health Organization Global Health Sector Strategy on viral hepatitis, which aims to reach elimination of viral hepatitis as a major public health threat by 2030 [2] and updated its fifth National Hepatitis C Strategy (2018–2022) to include goals, targets, and priority areas to guide the national response to hepatitis C [1].
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Chronic hepatitis C virus infection, when left untreated, may result in fibrosis and cirrhosis, which can further progress to liver disease, resulting in considerable morbidity, mortality, and cost burden [3, 4]. The availability of direct-acting antiviral (DAA) therapies has transformed clinical management for HCV, providing potentially curative, well-tolerated, short-term treatments [5].
In Australia in 2015, the Pharmaceutical Benefits Advisory Committee (PBAC) supported a recommendation to the Minister for Health for the reimbursement of the first DAA regimens (sofosbuvir, daclatasvir, ribavirin, and ledipasvir/sofosbuvir) for the treatment of patients with chronic hepatitis C virus [6]. Nine DAAs were reimbursed via the Pharmaceutical Benefits Scheme (PBS), with the first reimbursed treatments listed in March of 2016. Following the introduction of two first-line pangenotypic agents (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) and one second-line agent (sofosbuvir/velpatasvir/voxilaprevir) in 2017–2019, five products that targeted specific genotypes of HCV have been delisted from the PBS (Table 1).
Table 1
Summary of PBS reimbursed direct-acting antivirals in Australia
Drug name
Genotype reimbursed at time of initial reimbursement
Source: Schedule of Pharmaceutical benefits (Summary of Changes) Archive [7]
The Minister of Health endorsed PBS access to PBAC recommended oral DAA therapies, enabling treatment for the broadest possible indication; patients aged 18 years and over with chronic hepatitis C infection, irrespective of liver disease stage, or drug and alcohol use.
At the end of 2015, an estimated 188,690 people had chronic HCV infection in Australia [8]. During 2016 to 2021, a total of 99,735 individuals initiated DAA treatments for chronic HCV infection, including 95,395 individuals via the PBS and an estimated 4340 individuals through early DAA access avenues in 2014–15, equating to 53% of the 2015 estimated HCV prevalent population. Amongst the patients who initiated PBS DAA treatment, 68% were men with a median (quartiles 1–3) age of 48 years (39–57) [9]. The annual number of patients initiating DAA treatment has steadily declined year on year, from 33,201 patients treated in 2016, to 6474 in 2021 [9].
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Since the initial availability of DAAs, the demographic and disease characteristics of treated patients were substantially different to those undergoing antiviral treatment in Australia in 2022 (Table 2). This evolution of patient demographics is consistent with changes amongst HCV populations prescribed DAAs globally, demonstrating the relevance of this research in other countries [10‐12]. Many patients with a primary diagnosis of HCV-related cirrhosis have now been treated [13], and thus most patients being presently treated have mild/moderate fibrosis at treatment initiation. Subsequently, the number of patients with a primary diagnosis of HCV-related cirrhosis who received a liver transplant has also declined over the past 8 years [8, 13].
At the time of PBS listing, retreatment with DAAs was not a major consideration. As such, the costs and outcomes associated with reinfection and/or second-line treatment were not captured in the original cost-effectiveness analyses of DAAs. However, retreatment is now occurring in patients who become reinfected following successful treatment with DAAs (referred to a treatment of a new infection) along with those who never achieved a sustained virological response (SVR12) with first-line DAA treatment (referred to as second-line treatment of the same infection). Of the 95,395 patients who have received DAA therapies via the PBS, 7% received at least one further treatment course, of which an estimated 52% of these received retreatment due to HCV reinfection (which equates to 3.6% of the initially treated population; 7% × 52%) and 48% due to first-line treatment failure [9]. Furthermore, one percent of the total treated population has received multiple courses of DAAs [9].
Due to the considerable evolution of patients being managed with chronic HCV infection in Australia, it is of interest to understand if DAAs remain cost-effective. The aim of our analysis was to re-assess the cost-effectiveness of DAAs given the changes to the characteristics of the treated population and the availability of second-line treatments for first-line failures and the treatment of new infections in reinfected individuals, using glecaprevir/pibrentasvir (Maviret®) as an example. Therefore, we assessed the cost-effectiveness of DAA treatment (incorporating potential retreatment) in 2023 versus ‘no treatment’ to determine whether this drug class remains value for money in the remaining prevalent pool.
Methods
Description of the Economic Model
The 2017 PBAC recommendation to list glecaprevir/pibrentasvir on the PBS was not achieved on cost-effectiveness grounds versus ‘no treatment’. The PBAC recommended glecaprevir/pibrentasvir under the condition that the cost per course be identical (cost-minimized) to sofosbuvir/velpatasvir [14]. The model structure used to retrospectively assess the cost-effectiveness of DAAs in 2016 and to determine whether DAAs remain cost-effective in 2023, is similar to the model presented as part of the reimbursement submission to achieve a PBAC recommendation for Viekira PAK® in 2015 [15]. However, where appropriate, amendments have been made to the Viekira PAK® model to better reflect newly available evidence (e.g., the model now incorporates transition from cirrhosis to liver-related death, and retreatment).
Only direct medical care costs incurred using an Australian government perspective were included. In accordance with Australian PBAC guidelines, 5% discount rates and half-cycle corrections were applied. The model was developed in Microsoft Excel (Microsoft Corporation, Redmond, WA, USA).
A ten-state Markov model captures disease progression and death over a 30-year time horizon (Fig. 1). In the first year (in which treatment occurs) a four-weekly cycle length is used to capture the different treatment durations for glecaprevir/pibrentasvir. From the second year, annual Markov cycles are used.
Fig. 1
Schematic of Markov model. CHC chronic hepatitis C, SVR sustained virological response. Background (all-cause) mortality not shown in figure; however, background mortality is applied to all health states in the model, including health states relating to retreatment
×
Consistent with PBS reimbursement of antivirals in Australia, chronic HCV patients with either mild fibrosis, moderate fibrosis, or compensated cirrhosis are eligible for DAA treatment. Baseline patient demographics and disease characteristics are reported in Table 2. Initially, for this study, we assumed a dramatic change over time of the fibrosis distribution of HCV-infected individuals in Australia. However, data presented in Table 2 suggest that patients living with HCV in 2020 (latest available data) have a similar fibrosis distribution to those living with HCV prior to the introduction of DAAs. At the time of initial DAA reimbursement consideration (2015–2016), there were limited data on the fibrosis distribution of individuals who might be likely to seek treatment. Therefore, cost-effectiveness models were informed by clinical trial participants or published Australian prevalence estimates. The fibrosis distribution of treated patients in the last 2–3 years is not yet known. Therefore, for consistency, the model uses the fibrosis distribution for those living with HCV. A sensitivity analysis has been conducted in which the fibrosis distribution of treated patients in 2020 (latest available data) has been used. A further sensitivity analysis assumes a substantially less severe patient population (in which all patients have mild/moderate fibrosis at the time of treatment initiation) to reflect the potentially lesser severity of treated patients in future years.
Changes to the Model Regarding Reinfection and Retreatment
In the earlier PBAC assessments, reinfection following SVR12 could occur (based on an annual probability of 0.9% taken from a meta-analysis of three trials [16]). However, in these earlier models, reinfected patients returned to the fibrosis health state that they occupied prior to achieving their SVR12 and were not subsequently retreated. Similarly, first-line patients who do not achieve SVR12 (first-line failures) were not retreated in the 2015/2016 analyses. Given second-line treatment is permitted on the PBS, the 2023 analysis incorporates additional Markov tunnel states to allow reinfected individuals to be retreated infinitely over the 30-year time horizon. As such, the model allows for multiple reinfections (and subsequent treatment each time). In the model, first-line virologic failures (2.6%; equivalent to 100% minus the SVR12 rate of 97.4% described below) only receive one subsequent course of treatment (unless they achieve SVR12 during their second treatment course, and subsequently become reinfected, and then they are permitted treatment for this second infection). While the first-line failure rate is higher than the annual reinfection rate (2.60 vs. 2.23%), first-line failures only enter the second-line treatment model once at the time at which they do not achieve SVR12, whereas the annual reinfection rate of 2.23% is applied over the entirety of the modeled time horizon to those who achieve SVR12. Thus, over the entire modeled time horizon, more reinfected individuals are retreated than first-line failures.
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As reported previously, 7% of the patients who have received PBS-subsidized DAA therapies have received more than one line of therapy [9]. Thus, the current annual rate of re-infection is likely to be higher than that originally modeled (0.9%). The 2023 analysis uses an annual probability of reinfection in those who previously achieved SVR12 of 2.23%, taken from high-risk individuals in Simmons 2016 [17]. The reinfection rate reported by Simmons 2016 was comparable to that reported by the Australian Kirby Institute (2.5%) [18].
Not all first-line failures and reinfected individuals actively seek additional lines of treatment. An Australian observational study of 10,843 individuals reported that 52% of first-line virologic failures were retreated [19]. Thus, in the 2023 analysis in which retreatment is permitted, 52% of first-line failures and reinfected individuals are retreated. This percentage is assessed in sensitivity analyses. Patients in the first-line setting are treated with either glecaprevir/pibrentasvir or sofosbuvir/velpatasvir, and PBS script data were used to determine the proportional use of these two brands. Given that publicly available PBS script data do not distinguish between first- and subsequent-line use, the model assumes that reinfected individuals (i.e., patients who achieved an SVR12 but subsequently acquired a new infection) are retreated with their first-line regimen (i.e., weighted average of PBS script data for glecaprevir/pibrentasvir and sofosbuvir/velpatasvir). However, consistent with Australian clinical practice, first-line failures (i.e., patients that did not achieve an SVR12) will switch to a different DAA in the second-line treatment setting (sofosbuvir/velpatasvir/voxilaprevir as this is the only regimen recommended for retreatment in first-line treatment failures [20]).
Efficacy of DAAs in Chronic HCV Infection (Using Glecaprevir/Pibrentasvir as an Example)
Given that PBS reimbursement is restricted to chronic HCV (rather than acute HCV), the model does not incorporate spontaneous remission, as this usually occurs within 6 months of diagnosis [21]. Treated individuals either achieve a SVR12 or remain infected and potentially develop progressive liver disease. Efficacy and safety data in the model are taken from the glecaprevir/pibrentasvir trials, and are considered broadly representative of the efficacy of all DAAs used in the first-line treatment setting. A pooling of seven glecaprevir/pibrentasvir trials (covering 1262 treatment-naive and treatment-experienced individuals from all six genotypes) results in an SVR12 rate of 97.4% [22‐24]. With regard to reinfected individuals, as each re-infection behaves as a new infection [25], it is assumed that SVR12 rates in these patients are also comparable to the pooled estimate of 97.4%. With regard to first-line DAA failures, it is assumed that patients will switch to a different DAA in the second-line treatment setting. Evidence suggests that SVR12 rates in first-line failures (when second-line treatment occurs with a different DAA) remain high [26]. This is confirmed by several of the glecaprevir/pibrentasvir trials, which permitted enrolment of DAA-experienced individuals [22] and yielded SVR12 rates > 90%. Therefore, the model assumes that the SVR12 rate in first-line DAA failures is also comparable to the first-line setting. Thus, in the 2023 analysis, which incorporates the costs and outcomes associated with retreatment, an SVR12 rate of 97.4% has been assigned to any retreated individual (irrespective of whether their second-line treatment is due to first-line failure or reinfection). This assumption is tested in sensitivity analyses.
Markov Transition Probabilities
Markov transition probabilities (Table 3) were primarily obtained from Australian-specific sources, and where possible, meta-analyses were preferred over results from single studies. Rates of background, all-cause mortality are sourced from Australian life tables [27] and have been increased by 40% to account for the potentially higher risk profile of this patient group [28, 29].
DCC decompensated cirrhosis, HCC hepatocellular carcinoma, HCV hepatitis C virus, SVR12 sustained virological response 12 weeks post cessation of therapy
aAssumed to be the same as CC to HCC
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Costs and Utilities
In Australia, published prices for pharmaceutical therapies are presented in the Schedule of Pharmaceutical Benefits [30]. However, many pharmaceuticals have confidential rebates implying that the effective price (paid by the Australian government) is below the published price. Given that effective prices are confidential, this analysis uses the published General Schedule prices (DPMQ) of glecaprevir/pibrentasvir and sofosbuvir/velpatasvir to inform the cost per course of first-line treatment. It should be noted that while the published per-pack prices for glecaprevir/pibrentasvir and sofosbuvir/velpatasvir differ on the PBS schedule due to differences in treatment duration and the public prices agreed between Commonwealth and the sponsor, these DAA therapies are cost-minimized to each other, and therefore, the confidential, post-rebate, effective cost per course are identical across both brands [14]. It should further be noted that use of the published prices overestimates the incremental cost-effectiveness ratio (ICER) as the true cost per course paid by the Australian government is based on the lower post-rebate, effective prices.
The cost per course in the first-line setting is based on a weighted average of the (published) cost per courses for glecaprevir/pibrentasvir and sofosbuvir/velpatasvir. PBS script data were used to determine the proportional use of glecaprevir/pibrentasvir versus sofosbuvir/velpatasvir. Based on the Australian prescribing rules and the rates of discontinuation observed in the clinical trials, the average duration of first-line therapy is estimated to be 7.95 weeks for glecaprevir/pibrentasvir (where the approved duration of therapy is 8 weeks [31]) and 11.98 for sofosbuvir/velpatasvir (where the approved duration of therapy is 12 weeks [32]). After the incorporation of trial-based discontinuation rates and weighting between the two brands, the (published) cost per course of first-line treatment in DAA-naïve individuals, as of July 2023, is calculated to be $35,897. As reinfections in patients who achieved an SVR12 behave as a new infection [25], it is assumed that the treatment duration for reinfected individuals is comparable to the DAA-naïve setting (weighted average of 7.95 weeks of glecaprevir/pibrentasvir and 11.98 weeks of sofosbuvir/velpatasvir).
While first-line DAA failures (those that did not achieve an SVR12 during first-line treatment) would switch to a different agent in the second-line setting (namely sofosbuvir/velpatasvir/voxilaprevir), DAA therapies are all cost-minimized to each other, and therefore, the confidential, effective cost per course would be identical across brands. However, this analysis uses published prices, and therefore, the cost per course varies between the first-line and second-line settings. For this analysis, the cost of second-line treatment in first-line failures is based on 12 weeks of sofosbuvir/velpatasvir/voxilaprevir. The cost of second-line treatment in first-line DAA failures is based on sofosbuvir/velpatasvir/voxilaprevir at $36,111 per 12-week course.
The model incorporated the cost of treatment-induced adverse events (headache, rash, and nausea). The incidences of these adverse events were taken from a pooled analysis of the glecaprevir/pibrentasvir trials [22].
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Resource use for the Markov health states was collected from medical records for a stratified random sample of 276 GT1 patients first attending two Australian liver clinics between January 2011 and December 2013, and supplemented by 112 GT1 patients attending one liver transplant clinic in the same period; patients were followed to June 30, 2014 [4]. The sample included in the medical resource utilization (MRU) audit was restricted to patients attending treatment centers. Given that the majority of patients who achieve SVR12 may no longer require management at a treatment center (and can be managed by their GP), it was not possible to use the audit to inform the long-term MRU used by patients who achieve SVR12. Expert opinion has been used to inform the medical resource items used by patients who have achieved SVR12. Patients without cirrhosis (i.e., patients with F0–F3 prior to achieving their SVR12) who achieved SVR12 following treatment are assumed to visit their GP every 2 years. As per current Australian guidelines in HCV management [20], patients with cirrhosis who achieved SVR12 following treatment are assumed to visit their specialist every year, and undergo an ultrasound to detect HCC. Furthermore, the 5.3% of patients who have returned to injecting drug use [33] are assumed to undergo a confirmatory HCV RNA qualitative assay every year. Many of the published models assumed that SVR12 is equivalent to a cure (and thus SVR12 patients incur no further costs). However, this model conservatively assumes that SVR12 patients incur the costs shown in Table 4 every year of the 30-year model.
Table 4
Utility values and costs for each Markov state
Health state
Utility
Annual cost (AUD)
2016
2023
SVR12 after treatment at mild (F0–F1) stage
0.941 (= 0.900 + 0.041)
$23.41a
$24.76a
SVR12 after treatment at moderate (F2–F3) stage
0.851 (= 0.810 + 0.041)
$23.41a
$24.76a
SVR12 after treatment at cirrhotic stage
0.811 (= 0.770 + 0.041)
$85.74a
$90.39a
Mild HCV (F0–F1)
0.900
$403.00
$579.57b
Moderate HCV (F2–F3)
0.810
$756.00
$1087.22b
Compensated cirrhosis
0.770
$1049.00
$1508.60b
Decompensated cirrhosis
0.463c
$19,560.75d
$28,130.86b
HCC
0.650
$32,407.00
$46,605.41b
Liver transplante
0.560
$155,137.00
$221,455.09
Post liver transplant
0.770
$7358.00
$10,581.75b
HCC hepatocellular carcinoma, HCV hepatitis C virus, SVR12 sustained virological response 12 weeks post cessation of therapy
aMRU informed by expert opinion, unit costs taken from Medicare Benefits Schedule [58]
bInflated to 2023 dollars using the medical and hospital services component of the Consumer Price Index [59]
cSimilar to other Australian analyses, decompensated disease (DCC) was kept as a single health state rather than subdividing into its different clinical manifestations (such as ascites, variceal hemorrhage, hepatic encephalopathy). Therefore, the utility scores for ascites, variceal hemorrhage, hepatic encephalopathy presented in Szabo 2015 [34] were weighted based on demographic data collected in the audit [4] to generate a single utility score for DCC
dMcElroy 2015 [4] found that the resource use for DCC patients attending a liver transplant clinic is higher ($31,221) than the resource use for DCC patients managed at a liver clinic ($15,674). The analysis arbitrarily assumes that 75% of DCC patients undergo their treatment at a liver clinic and the remaining 25% undergo their treatment at a transplant clinic
eUnit cost of liver transplant based on AR-DRG inpatient cost in that year [60]
Health state utility values were taken from a time-trade-off (TTO) utility study conducted on 100 members of the Australian general public (Table 4) [34]. The PBAC has previously accepted a utility gain of 0.041 for patients achieving SVR12 [35]. To adjust for treatment-induced adverse events, an annualized disutility of 0.0037 was applied while on DAA treatment (average of glecaprevir/pibrentasvir trials [36]).
Ethical Approval
Given the economic analysis was based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors, ethics approval was not required.
Results
Due to the high SVR12 rate, patients treated with DAAs will avoid a greater number of future hepatic events versus no treatment. Table 5 shows ICERs from a stepped analysis, tracking the impact on the ICER from 2016 to 2023. In 2015, when the PBAC supported the reimbursement of DAAs, it did so with the advice that the new interferon-free regimens would be acceptably cost-effective at an incremental cost-effectiveness ratio (ICER) of no greater than $15,000/quality-adjusted life year (QALY) [35]. The results suggest that not only does the weighted published cost per course of glecaprevir/pibrentasvir and sofosbuvir/velpatasvir generate an ICER that sits around the $15,000/QALY threshold set by PBAC for HCV drugs, the ICER is also well below the commonly used ICER threshold in other chronic diseases ($45,000/QALY) [37]. When the confidential, effective prices of glecaprevir/pibrentasvir and sofosbuvir/velpatasvir are used, the ICERs sit well below the $15,000/QALY threshold used by PBAC for these therapies. Thus, despite substantial changes to the patient population currently seeking DAA treatment in Australia, these therapies remain cost-effective.
Table 5
Stepped ICER from 2016 to 2023 analysis
Stepped analysis
Assumptions used in analysis
Discounted incremental costsa
Discounted incremental QALYs
Incremental cost/QALY
2016 analysis
2016 unit prices
Baseline age 49 years
Fibrosis distribution at baseline as per 2016
0.9% annual reinfection rate;
Retreatment not permitted
$16,552
1.44
$11,475
Increasing the reinfection rate
As above, but increasing reinfection rate from 0.9% to 2.23% (but retreatment not permitted)
$18,928
1.29
$14,711
Permitting retreatment in first-line failures and reinfected individuals
As above, but 52% of first-line failures and re-infected individuals are retreated
$25,942
1.51
$17,143
Updating baseline fibrosis distribution
As above, but fibrosis distribution at baseline as per most recently available data from 2020
$24,468
1.58
$15,514
As above, with reduction in baseline age
As above, but baseline age reduced from 49 to 44 years
aPublished rather than confidential, effective price of glecaprevir/pibrentasvir used
Univariate sensitivity analyses were performed on parameter values to determine the impact on the ICER (Table 6). As described above, when the DAAs were originally assessed for cost-effectiveness, the fibrosis distribution was based on the entire prevalent pool (rather than restricted to treated patients only). For consistency, the base-case model continues to use a fibrosis distribution based on the prevalent pool [38]. The fibrosis distribution of patients treated in most recent years is now available [38] and has been used in a sensitivity analysis. The PBAC Guidelines mandate a discount rate of 5% to be applied to costs and outcomes, however, the discount rate in many other jurisdictions is 1.5%. Similarly, other jurisdictions permit a lifetime horizon whereas a 30-year time horizon was mandated in Australia for DAAs. Thus, we have examined the impact of discounting and time horizon on the ICER. Based on observational study of 10,843 individuals, the base-case assumes that 52% of first-line failures and reinfected individuals are retreated [19]. Sensitivity analyses determine the impact of subsequent treatment uptake on the ICER. The base-case model assumes SVR12 rates in retreated individuals (reinfected and first-line failures) are identical to that observed for first-line DAA treatment (97.4%). A sensitivity analysis assumes that the SVR12 rate for second-line treatment is 95% [25]. In the sensitivity analysis in which retreatment is costed based on glecaprevir/pibrentasvir, PBS script data were used to determine the proportional use of 12 vs. 16 weeks of treatment with glecaprevir/pibrentasvir. The results from the sensitivity analyses demonstrate the robustness of the ICER, always sitting below the PBAC’s ICER threshold of $45,000/QALY.
Table 6
Sensitivity analyses versus no treatment (discounted cost/QALY)
Variable
ICER using 2016 unit prices
ICER using 2023 unit prices
Base case
$14,540
$8357
Discount rate 1.5%
$6368
$706
Time horizon of 60 years
$9913
$4507
Fibrosis distribution based on treated patients in 2020
$11,272
$4920
Less severe fibrosis distribution to reflect future treated population (F0–F1: 80%, F2–F3: 20%, F4: 0%)
$21,344
$15,701
Subsequent treatment uptake increased from 52 to 75%
$14,587
$8409
SVR12 rate in retreated patients is 95%
$14,705
$8521
Duration of retreatment in all DAA-experienced patients (reinfections and first-line failures) is 12–16 weeks with G/P
$18,556
$12,372
Cost of retreatment of first-line failures based on 12–16 weeks of G/P (depending on genotype)
$15,021
$8838
Removal of the SMR applied to Australian lifetables
$14,167
$8021
DAA direct-acting antiviral, F fibrosis score, G/P glecaprevir/pibrentasvir, ICER incremental cost-effectiveness ratio, QALY quality-adjusted life year, SMR standardized mortality ratio, SVR12 sustained virological response 12 weeks post cessation of therapy
Probabilistic sensitivity analysis was not performed, as it is not necessary for reimbursement in Australia [39], thus the full extent of the uncertainty remains unknown.
Discussion
In 2015, the PBAC supported the recommendation of the first DAAs for the treatment of HCV, with the advice that the new interferon-free regimens would be acceptably cost-effective at a conservative ICER threshold of $15,000/QALY. Since 2015, numerous DAAs have been considered cost-effective and subsequently listed on the PBS. This analysis demonstrates that despite changes in demographics and disease characteristics of treated patients, and changes to the economic model to reflect clinical practice, which includes the second-line treatment of first-line treatment failures and retreatment in patients with new infections, DAAs remain cost-effective in 2023. It is evident from Table 6 that due to the inflation of health state costs over time, the current ICERs are lower than were approved by PBAC in 2015/2016 despite changes to the treated population characteristics and the incorporation of retreatment.
These results are significant in their alignment with the Australian government’s Fifth National Hepatitis C Strategy (2018–2022), which aims to ensure equitable access to treatment for all HCV patients with the aim of eliminating HCV by 2030 [1]. The results demonstrate that the continued investment in DAA treatment in the broad HCV population remains a cost-effective approach to reaching this goal.
The therapeutic purpose of the DAA class of medicine is treatment rather than prevention and thus, harm reduction measures and patient education schemes are crucially important in reducing the risk of a new infection and the subsequent need for retreatment in those that have previously achieved an SVR12. This analysis demonstrates that costs and reimbursement of DAA regimens for the treatment of HCV infections including the treatment of reinfections and prior treatment failures remain cost-effective.
The many changes in the disease characteristics of treated patients since 2016 are a direct result of the evolution of HCV management in Australia since DAAs have been reimbursed; patients with chronic HCV infection now have access to treatments much earlier in the disease course, with fewer patients having advanced disease [38]. Internationally, the cost-effectiveness of DAAs in early stage versus advanced stage disease has been widely evaluated [40‐44]. Similarly, other countries have also evaluated the impact retreatment has on DAA cost-effectiveness [45]. Overall, international results are consistent with our Australian analysis, demonstrating that DAAs are still cost-effective when early-stage disease factors and retreatment rates are included.
In accordance with Australian PBAC guidelines [39], the perspective of this study was that of the Australian health care system whereby indirect costs, such as absenteeism from work or the loss of productivity to employers are excluded. Given the average age of patients diagnosed with HCV in Australia is 40–50 years, most patients will be in their prime years of productivity. Increases in production as a consequence of access to effective DAA treatments will benefit Australian society and has the potential to increase government taxation revenues and reduce government expenditure on disability and unemployment support. Furthermore, the model did not capture the costs of other diseases, which may arise from no treatment such as chronic kidney disease and diabetes mellitus. However, the omission of these costs underestimates the economic benefits of treatment [46].
Limitations to the analysis included relying on data from 2020 for the fibrosis distribution, which may have overestimated the severity of fibrosis in patients treated with DAAs in 2023. In 2015, the PBAC’s recommendation to the Minister for Health was that the new interferon-free regimens would be acceptably cost-effective at an ICER of no greater than $15,000/QALY [35]. However, the ICER threshold for other therapies that extend survival (e.g., oncology treatments) are typically deemed cost-effective at an ICER of $45,000/QALY [37]. In comparison, the PBAC assessment of DAAs was conservative. A sensitivity analysis was conducted with more conservative inputs (80% mild HCV, 20% moderate HCV, and 0% with cirrhosis at baseline) and still produced an ICER below $45,000/QALY.
Given that the sequelae for HCV (e.g., decompensating events, HCC, death) can take many years to develop and that the sequelae persist for a long time and have an impact on survival, a lifetime horizon would generally be considered appropriate in assessing the cost-effectiveness of such treatments. However, the PBAC has requested a 30-year time horizon be used. Despite the shortened time horizon, DAAs continue to offer cost-effective treatment for patients with chronic HCV in Australia. Another potential limitation is that the model allows reinfected individuals to be retreated infinitely over the 30-year time horizon. As such, the model allows for unlimited reinfections (and subsequent treatment is permitted each time). Until longer-term data are available on the uptake of multiple courses of treatment, it is unknown whether patients would continue to seek treatment for third, fourth, or later reinfections.
An additional limitation relates to the application of background, all-cause mortality in the model. For all modeled patients, Australian life tables (increased by 40% to account for the higher risk profile of this patient group) have been used to inform age-related all-cause mortality rates. However, it is possible that current drug users and re-infected individuals experience higher all-cause mortality rates than the general HCV population. The model structure (in which re-infected and re-treated individuals reenter the mild, moderate, and compensated cirrhosis health states in Fig. 1) does not permit certain patients to experience different all-cause mortality rates.
Further, it should be noted that the model used in this analysis is not a dynamic model, and as such does not capture the benefits associated with herd immunity (i.e., the reduction in future infections due to a smaller prevalent pool). Further, this study focuses on the cost-effectiveness of DAA treatment versus no treatment in individuals with a diagnosis of chronic HCV and does not report the cost-effectiveness of the HCV screening program, which has previously been demonstrated [47]. A population-based model would be required to assess the costs and value (i.e., increase in diagnosis rates) of HCV screening strategies.
Conclusions
In conclusion, DAAs remain cost-effective despite changes in demographics and disease characteristics of treated patients and when incorporating retreatment in first-line failures and the treatment of new infections in previously treated individuals.
Acknowledgements
The authors gratefully acknowledge Associate Professor Behzad Hajarizadeh from The Kirby Institute, University of New South Wales, for the provision of Australian epidemiological data.
Declarations
Conflict of Interest
No honoraria or payments were made for authorship. Financial arrangements of the authors with companies whose products may be related to the present report are listed as declared by the authors: Belinda Castles, Gillian Sharratt, and Aitor Arteaga are full-time employees of AbbVie. Emma Warren has served as a consultant for AbbVie.
Ethical Approval
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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Direct-Acting Antivirals Remain Cost-Effective Treatments for Chronic Hepatitis C in Australia Despite Changes to the Treated Population and the Availability of Retreatment: The Glecaprevir/Pibrentasvir (Maviret®) Example
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