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Economic evaluation of hepatocellular carcinoma surveillance in chronic hepatitis B patients with virological remission
BMC Public Health volume 24, Article number: 2202 (2024)
Abstract
Background
Subsequent risk of hepatocellular carcinoma (HCC) persists in chronic hepatitis B (CHB) patients with virological remission. We aimed to assess the cost-effectiveness of HCC surveillance in those patients and determine appropriate age to commence or discontinue surveillance.
Methods
We developed an individual-based state transition model, simulating the advancement of HCC in CHB patients with virological remission. We used this model to compare the incremental cost-effectiveness ratio (ICER) and long-term health outcomes of biannual or annual HCC surveillance for varying durations with no surveillance.
Results
For compensated cirrhosis patients with CHB, biannual surveillance was not cost-effective for all age groups, while annual surveillance was cost-effective for patients aged 55 to 70 (ICER USD 28,076 / quality-adjusted life years [QALY] gained), which detected 176 additional early HCC cases in a 100,000-person cohort compared to no surveillance. In CHB patients with advanced fibrosis, annual surveillance for patients aged 40 to 75 was the most cost-effective strategy (ICER USD 4,984/QALY gained), which detected 289 additional early HCC per 100,000 patients.
Conclusions
Annual surveillance for patients with compensated cirrhosis or advanced fibrosis was a more cost-effective option that demonstrated substantial economic benefits, being slightly less effective than biannual surveillance at a significantly lower cost, providing insights for professionals in evaluating HCC surveillance among high-risk patients in China.
Lay summary
The most cost-effective age group for surveillance of hepatocellular carcinoma (HCC) varied depending on the stage of the disease. Regular annual surveillance for patients with compensated cirrhosis or advanced fibrosis was more cost-effective option, showing great economic and clinical benefits with slightly less effective than biannual surveillance but significantly lower cost.
Background
China bears the largest burden of liver cancer worldwide, with 410,000 cases and 391,200 deaths in 2020, accounting for almost half of the new cases and deaths attributed to liver cancer across the globe [1]. The primary cause of hepatocellular carcinoma (HCC) in China is predominantly chronic hepatitis B (CHB), with over 80% of individuals diagnosed with HCC testing positive for hepatitis B virus (HBV) [2]. China has established a relatively comprehensive surveillance system for HBV epidemiology, known as the National Notifiable Disease Reporting System (NNDRS) [3]. In 1992, HBV vaccination was incorporated into the routine immunization schedule for infants, and since 2005, the cost of HBV vaccination has been covered by public health insurance [4]. These national efforts have significantly reduced the prevalence of HBsAg seroprevalence from 9.6% during 1984 to 3.0% in 2021 [5]. However, current medical surveillance systems are unable to capture asymptomatic infections and also do not pay attention to those patients with virological remission.
The approved nucleos(t)ide analogues (NAs) used in the treatment of CHB have demonstrated strong antiviral effectiveness, leading to a notable decrease in the risk of HBV-related diseases and HCC [6]. Despite their ability to suppress HBV replication in the long term, many studies have indicated that the risk of HCC still exists in CHB patients remaining in virological remission after treatment with NAs [7, 8]. Pieces of evidence have shown that HCC can occur in CHB patients even after hepatitis B surface antigen (HBsAg) loss, and the annual incidence of HCC was 3.68% in a cohort study [7, 9]. HCC has a dismal prognosis with an extremely low 5-year survival rate of 18% unless diagnosed at stages with no symptoms [10]. If detected early, improved chances of survival through curative treatments, including radiofrequency ablation (RFA), surgical removal, and liver transplantation, are available [10, 11].
Regular surveillance can identify early-stage HCC that is still amenable to curative treatment, thereby improving long-term survival outcomes [12]. Currently, most studies are focused on expanding screening and treatment for HBV-positive patients [13, 14]. Given the residual HCC risk after successful NA treatment, CHB patients with virological remission were recommended to continue regular HCC surveillance [15, 16]. However, there is a paucity of studies exploring the necessity of HCC surveillance in these patients, as well as the cost-effectiveness of regular surveillance, particularly in the Chinese context where the burden of HBV is particularly heavy. This study assesses the cost-effectiveness of implementing biannual or annual HCC surveillance among CHB patients with virological remission after NA treatment and provides information on when to start HCC surveillance.
Methods
Baseline population
The baseline population consisted of a cohort of 100,000 CHB patients aged 40 to 70 years (with a greater risk of developing HCC) [17]. These patients have achieved virological remission following NA treatment, which is defined as the loss of HBsAg accompanied by undetectable levels of HBV DNA in the serum [18], and without any previous known diagnosis of HCC.
Model overview
We have developed an individual-based state transition model, referred to as a microsimulation model. The model mainly includes a natural history component and a surveillance component, which is designed to simulate the progression of HCC in HBV patients achieving virological remission after NA treatment. We utilized this model to assess the cost-effectiveness of implementing biannual or annual surveillance for HCC at different initiation ages, spanning from 40 to 65, as well as considering different cessation ages, ranging from 50 to 75 (average life expectancy 77 years of the Chinese population in 2021) [19]. The model employed a monthly timeframe and evaluated the effectiveness of various surveillance strategies by measuring quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs) and costs. The model was constructed using TreeAge Pro 2022 suite software (Williamstown, MA, USA), and the analyses were executed with R Studio (version 4.2.2) using the R packages tidyverse (version 1.3.2) and ggplot2 (version 3.4.0). The results of this study were presented in line with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) [20].
Nature history
We conducted simulations of the clinical course of HBV, including the progression of liver diseases and HCC (Fig. 1). Details of the model’s parameters are provided in Supplementary Table 1. Briefly, the parameters were derived primarily from published literature or previous modeling studies. The disease progression parameters were mainly obtained from long-term cohort study results. To reduce parameter variability, we used a weighted average approach to estimate average rates. For instance, for patients with compensated cirrhosis (F4 stage), we calculated the hepatocellular carcinoma incidence rate by averaging the findings of three studies [8, 21, 22], yielding a weighted average of 2.37 cases per 100 person-years. For non-cirrhotic patients with advanced fibrosis (F3 stage), we used a weighted average from four studies [21, 23,24,25], resulting in an incidence rate of 0.46 per 100 person-years. Treatment effectiveness and patient survival parameters were prioritized based on results from randomized controlled trials. Parameters for screening and diagnostic accuracy were selected from two systematic reviews and meta-analyses. Finally, cost parameters were determined within the context of China.
Patients face the risk of developing HCC at an “early” stage, which may subsequently progress to “intermediate/advanced” stages, with the definition of HCC stage based on the Milan Criteria [26] and China’s liver cancer staging system and tumor size [17]. Patients with a diameter under 5 cm or a maximum of 3 tumors, each measuring under 3 cm, were categorized as having “early HCC”. On the other hand, the remaining stages were classified as “intermediate/advanced HCC”. The annual progression rate from “early stage” to “intermediate/advanced stage” is estimated to be 0.4581 based on the tumor doubling times (Supplementary Sect. 1). In the univariate sensitivity analysis, we varied the HCC risk and progression rate by setting values above and below the base case values.
HCC surveillance
We conducted simulations for every virtual patient to compare the outcomes of “no surveillance” versus biannual/annual HCC surveillance, monitoring the progression of HCC and the stage at which it was detected for each patient. The surveillance involved the use of both ultrasound and AFP, which is in accordance with clinical guidelines [17]. By altering the duration of surveillance in increments of 5 years from 10 years to lifetime, we simulated various HCC surveillance strategies. For example, we conducted simulations for a 40-year-old patient with biannual or annual HCC surveillance from age 40 to 50, 55, 60, and so on. If the surveillance tests showed normal results, the patient proceeded with their regular course until the next examination. Nevertheless, if the results were abnormal, the patient had to undergo contrast-enhanced abdominal magnetic resonance imaging (MRI) to possibly verify the diagnosis of HCC. Our assumption was that a solitary MRI would be sufficient to confirm the diagnosis [27]. For patients in the no surveillance group, HCC could also be identified incidentally.
After confirmation of HCC, the patient was started on treatment for HCC. We evaluated 4 treatments for HCC, including resection, ablation, liver transplantation and transarterial chemoembolization, as well as other palliative treatments, such as systemic chemotherapy, external radiotherapy and selective internal radiotherapy. The choice of treatment is based on the stage of HCC and the severity of liver disease at the time of diagnosis (Supplementary Table 2). According to the guidelines, liver transplantation was considered suitable exclusively for patients aged 75 years or younger who presented either with decompensated cirrhosis or HCC at early stages, meeting the Milan criteria. It is noted that patients with decompensated cirrhosis were deemed ineligible for resection (Supplementary Sect. 2) [17]. Details of treatment allocation based on HCC stage and fibrosis stage are detailed in Supplementary Sect. 3.
Costs and utility
Published sources were used to obtain the expenses associated with HCC surveillance and treatment, liver transplantation, and management of liver diseases in general [28]. The costs were converted to US dollars using the exchange rates applicable in 2021. We assigned utility weights to both health states and treatments, taking into account their impact on quality of life. These weights were adjusted based on the patient’s age and the stage of their liver disease [23]. We applied a 3% yearly discount rate to all future costs and QALYs [14] (Supplementary Table 1).
Model outcomes
We evaluated the cases of HCC identified by tumor stage, total QALYs, and expenses for every simulated monitoring approach and patient profile. We evaluated the cost-effectiveness of diverse surveillance strategies at various initial screening ages using two approaches. First, we estimated the incremental cost-effectiveness ratio (ICER) for each surveillance approach compared to no surveillance. The ICER represents the additional costs per QALY gained. Second, we determined the ICER for each surveillance strategy compared to the next strategy at the same age to commence surveillance. There is a lack of information on the willingness to pay (WTP) of the Chinese population, and we have used the definition of cost-effectiveness developed by the World Health Organization [29]. According to this definition, we consider an ICER of less than one times the gross domestic product (GDP) per capita in China to be highly cost-effective. We classified ICERs between one and three times GDP per capita as cost-effective, and ICERs above three times GDP per capita were not cost-effective. As of 2020, the GDP per capita in China was US $10,756 [30].
Sensitivity analysis
To better understand the effect of uncertainty in each input of the models, we utilized a univariate sensitivity analysis on each input variable, as shown in Supplementary Table 1. Additionally, our study employed a comprehensive multivariate probabilistic sensitivity analysis where 1,000 sets of parameter values were sampled from their respective distributions. Each parameter set was evaluated using a population size of 10,000. The outcomes of this analysis were then represented using cost-effectiveness acceptability curves.
Results
Table 1 presents the costs, QALYs and ICERs of biannual HCC surveillance strategies. Compared with no surveillance, for patients with compensated cirrhosis, biannual surveillance was not cost-effective at the WTP threshold (USD 32,268/QALY gained). The study revealed that conducting biannual surveillance for advanced fibrosis in individuals aged 40 had the most favorable incremental cost-effectiveness ratio (ICER) when discontinuing surveillance at the age of 65. This approach was associated with an ICER of USD 4,760/QALY gained. Conversely, the highest ICER was identified when surveillance was discontinued at 50 years of age, leading to a cost of USD 18,900 per QALY gained. Surveillance up to age 75 (USD 12,970/QALY gained) provided most QALY gains of 0.67 at an additional cost of USD 6,446 and was the most cost-effective strategy, with an ICER below the WTP threshold. Surveillance starting from compensated cirrhosis was less effective and more costly than surveillance starting from advanced fibrosis.
The costs, QALYs and ICERs of annual HCC surveillance strategies are shown in Table 2. Regarding patients with compensated cirrhosis, annual surveillance was found to be more cost-effective than biannual surveillance. At the willingness-to-pay (WTP) threshold, targeting surveillance toward patients aged 40–50 yielded an ICER of USD 25,511/QALY gained. Similarly, targeting patients aged 55–70 resulted in an ICER of USD 28,076/QALY gained, while targeting those aged 55–65 led to an ICER of USD 32,072/QALY gained. Therefore, annual surveillance in these age groups proved to be a more economically viable option. In the case of 40-year-old patients with advanced fibrosis, the ICER of annual surveillance was found to be the lowest when the surveillance was discontinued at the age of 60, with an ICER of USD 2,759 per QALY gained, and was highest when the stopping age was 55 (USD 34,363/QALY gained), which was not cost-effective with the ICERs exceeding the WTP threshold (USD 32,268/QALY gained). The effectiveness of biannual surveillance is marginally superior to that of annual surveillance, but costs are also higher.
We plotted the cost-effectiveness frontiers of HCC surveillance at different surveillance intervals for CHB patients with compensated cirrhosis or advanced fibrosis (Fig. 2). For patients with compensated cirrhosis, compared with no surveillance, biannual surveillance was not cost-effective at any age group, as it exceeded the WTP threshold (Fig. 2A), while annual surveillance for some age groups was cost-effective, and surveillance targeting patients aged 55–70 (USD 28,076/QALY gained) was the most cost-effective (Fig. 2B). For patients with advanced fibrosis, compared with no surveillance, biannual (Fig. 2C) and annual (Fig. 2D) surveillance for any age group were nondominated. Surveillance targeting those aged 40–75 was the most cost-effective strategy, either biannual (USD 12,970/QALY gained) or annual (USD 4,984/QALY gained) surveillance intervals.
For 40-year-old patients with compensated cirrhosis, after 35 years in the “no surveillance” arm, there were 5,331 HCC cases per 100,000 patients, of which 358 were detected either incidentally or through symptoms. Among these, 58 cases were discovered at an early stage, while 300 cases were detected at intermediate or advanced stages. In contrast, after 15 years of annual surveillance (from 55 to 70), there were 3,178 HCC cases, of which 408 were detected as regular surveillance or incidental findings. Among them, 234 were detected at an early stage, and 174 were detected at intermediate/advanced stages (Fig. 3A). As a result, this approach successfully identified an additional 176 cases of HCC at an early stage, leading to a decrease of 126 cases in the number of HCC cases detected at intermediate or advanced stages.
Comparable patterns were noticed among patients with advanced fibrosis (Fig. 3B). Among 40-year-old noncirrhotic patients with no HCC surveillance, 52 HCC cases were incidentally diagnosed at an early stage and 257 at an intermediate/advanced stage. On the other hand, the biannual surveillance conducted over a span of 35 years (from 40 to 75) identified 329 cases at an early stage and 52 cases at the intermediate/advanced stages. In comparison, the annual surveillance conducted over the same 35-year period detected 341 cases at an early stage and 53 cases at the intermediate/advanced stage. Therefore, the 35-year biannual surveillance detected 277 additional HCC cases in the early stage and avoided 205 cases of intermediate/advanced HCC. The 35-year annual surveillance detected 12 additional HCC cases in the early stage and 1 additional HCC case in intermediate/advanced HCC compared with biannual surveillance, which may be caused by the longer surveillance interval. The number of HCC cases with different surveillance strategies on the cost-effectiveness frontier is shown in Supplementary Fig. 1.
Sensitivity analysis
In the univariate probability sensitivity analysis, we assessed a total of 50 parameters. The ten most important parameters of the three cost-effective strategies affecting HCC surveillance in patients with compensated cirrhosis or advanced fibrosis are shown in the tornado diagram (Supplementary Fig. 2). For patients with compensated cirrhosis, the cost-effective strategy (annual surveillance from 55 to 70) was most sensitive to the probability from compensated cirrhosis to hepatocellular carcinoma. For patients with advanced fibrosis, the cost-effective strategies (biannual or annual surveillance from 40 to 75) were most sensitive to the probability from hepatitis B with advanced fibrosis to hepatocellular carcinoma.
The results of the multivariate probabilistic sensitivity analysis are presented in Fig. 4, which shows the cost-effectiveness acceptability curve. It depicts the probability of age-specific HCC surveillance being cost-effective, taking into account the uncertainty in all model parameters. At a threshold of USD 32,268 (3 times GDP), the annual surveillance for compensated cirrhosis patients aged 55–70 years had a 25% probability of being cost-effective. At one-time GDP per capita, biannual surveillance for advanced fibrosis patients aged 40–75 years was the leading cost-effective strategy (33%). For annual surveillance among patients with advanced fibrosis, targeting patients aged 55–65 years and patients aged 40–75 years was the most cost-effective strategy at one-time GDP per capita (33%).
Discussion
Currently, there is a research gap in the HCC surveillance among CHB patients with virological remission. This is an economic evaluation study to assess the regular surveillance for HCC of Chinese patients, which may provide important information on the necessity of HCC surveillance, the appropriate age to initiate or stop surveillance, as well as the surveillance intervals. Our analysis revealed several key findings. First, we determined that the cost-effective age group for HCC surveillance varied depending on the stage of the disease. Our analysis determined that individuals aged between 55 and 70 years with compensated cirrhosis are the appropriate demographic for surveillance. Conversely, for advanced fibrosis, the most cost-effective strategy involved annual surveillance for individuals aged 40 to 75. Second, surveillance starting from compensated cirrhosis was less effective and more costly than surveillance starting from advanced fibrosis, and in addition, regardless of the stage at which surveillance began, biannual surveillance was more costly but also more effective than annual surveillance. Finally, our study demonstrated that routine surveillance had the potential to facilitate a significant stage shift in HCC diagnosis. Specifically, a greater proportion of HCC cases could be detected at an early stage, while the number of intermediate/advanced stage cases was substantially reduced.
Our findings support the current recommendations of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver (EASL) for the surveillance of HCC among compensated cirrhosis patients who achieved virological remission [16, 31]. Furthermore, our study may provide important insights into cost-effective surveillance and the appropriate age threshold to discontinue surveillance for compensated cirrhosis in China. Specifically, our modeling study may support annual surveillance for patients with compensated cirrhosis aged 55 to 70. It is interesting to note that the Asian Pacific Association for the Study of the Liver (APASL) guidelines suggest monitoring for liver cancer in specific high-risk groups, such as those with advanced fibrosis, even if they do not have cirrhosis [32], whereas the AASLD guidelines do not recommend liver cancer surveillance for patients without cirrhosis [31]. Our results revealed that surveillance for hepatitis B patients aged 40 to 75 who achieved virological remission with advanced fibrosis was also cost-effective, whether biannual or annual surveillance. For patients at different stages of chronic hepatitis, different age groups are recommended for regular HCC surveillance. This will provide evidence for healthcare professionals to carry out regular follow-up of such patients in clinical practice.
Annual surveillance was the most cost-effective choice regardless of fibrosis stage, mainly due to the comparatively low HCC incidence in patients with viral remission. Similar findings have been illustrated in an early study in which annual surveillance for HCV-infected patients who have obtained sustained virologic response (SVR) was the cost-effective strategy under different surveillance intervals [33]. In addition, it would be more cost-effective to start surveillance at an earlier stage of the disease, with HCC surveillance for patients with advanced fibrosis being relatively less expensive than in compensated cirrhosis patients but with better outcomes, partly due to a higher HCC incidence as well as a higher competing risk of liver-associated deaths in the advanced stages [34].
Ensuring regular HCC surveillance plays a crucial role in enhancing survival rates, as it facilitates early detection of HCC and improves accessibility to curative first-line treatment. Patients with HCC diagnosed at advanced stages have a median survival of approximately one year and are treated with systemic therapies. However, curative options for early-stage HCC may result in a 5-year survival rate surpassing 70% [10]. According to our model, surveillance may produce a significant shift in the stage of HCC diagnosis, resulting in the early detection of most cases. The stage at the time of diagnosis is the paramount factor influencing the overall survival of patients with HCC. Individuals harboring small, localized tumors possess the opportunity to undergo curative treatments, including resection, ablation, or liver transplantation, which can yield significantly better long-term survival outcomes [35]. Therefore, the objective of implementing a surveillance program for HCC is to detect tumors during the early stages in individuals at high risk. This enables them to undergo curative treatments, leading to enhanced long-term survival rates and ultimately reducing liver cancer mortality. Additionally, the public health insurance provided by the state can also assist in the HCC surveillance. By 2015, the population coverage of public health insurance in China had exceeded 95%, and at least 70% of insurance-listed healthcare expenditures are publicly funded [36]. This included a portion of the tests and medical care for HBV and HCC, as well as a portion of the first-line antiviral agents for HBV [37, 38].
The benefits of routine HCC surveillance have been shown in several observational studies [12]. However, there is a scarcity of randomized controlled trials to evaluate the long-term benefits of HCC surveillance among CHB patients, which would be a costly and lengthy process [10, 39]. Incorporating a control group would present ethical challenges in the clinical trials, as nearly 99% of patients are unwilling to accept the possibility of being randomly assigned to the group that does not receive surveillance [40]. In this case, a decision analysis model can simulate a virtual trial showing the long-term health outcomes among a specific population to generate data on the relative effectiveness of different approaches and is frequently used to assist policymakers in developing strategies [41]. This study could provide valuable information for professionals to assess the surveillance of HCC among high-risk people in China.
This study has limitations. First, the cost and willingness-to-pay thresholds associated with the model are specific to China. A degree of caution is required when extrapolating the results to distinct settings. Second, we assumed a high adherence rate for surveillance in that 90% of patients completed the follow-up processes for each surveillance test. Third, we decided to model surveillance at 5-year intervals instead of shorter intervals because this age grouping is more practical to apply in real-world scenarios. Fourth, in our study, there were no restrictions on other treatments except for liver transplantation, which was restricted to patients under 75 years old. Fifth, this study was focused on age factors, while there are other risk factors, such as comorbidities, body mass index and sex, and future research is warranted in subgroups with other risk factors.
Conclusions
In summary, our research indicated that conducting HCC surveillance every six months in compensated cirrhosis patients who have achieved viral remission of HBV was not economically viable in China, whereas annual surveillance in those with compensated cirrhosis was cost-effective, especially for patients aged 55 to 70 years. Additionally, for advanced fibrosis patients, annual surveillance of HCC was the most cost-effective for patients aged 40 to 75 years. Regular HCC surveillance detected earlier HCC cases and reduced the intermediate or advanced cases, demonstrating substantial economic and clinical benefits and improving survival. This study may provide some insights for professional societies to evaluate HCC surveillance among high-risk patients in China.
Data availability
All data and materials relevant to the study are included in the article or uploaded as supplementary information.
Abbreviations
- HCC:
-
hepatocellular carcinoma
- CHB:
-
chronic hepatitis B
- HBV:
-
Hepatitis B virus
- NA:
-
nucleos(t)ide analogues
- ICER:
-
incremental cost-effectiveness ratio
- QALY:
-
quality-adjusted life years
- HBsAg:
-
Hepatitis B surface antigen
- RFA:
-
radiofrequency ablation
- EASL:
-
the European Association for the Study of Liver
- AASLD:
-
the American Association for the Study of Liver Diseases
- AFP:
-
alpha-fetoprotein
- MRI:
-
magnetic resonance imaging
- WTP:
-
willingness to pay
- GDP:
-
gross domestic product
- APASL:
-
Asian Pacific Association for the Study of the Liver
- SVR:
-
sustained virologic response
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Acknowledgements
We highly appreciate the financial support from National Natural Science Foundation of China, Zhejiang University K. P. Chao’s High Technology Development Foundation, Mega-Project of National Science and Technology for the 13th Five-Year Plan of China, the Fundamental Research Funds for the Central Universities, and Zhejiang Province Healthcare Innovation Talent Program.
Funding
This study was funded by National Natural Science Foundation of China (72374179,71904170), Zhejiang University K. P. Chao’s High Technology Development Foundation(2022RC017), Mega-Project of National Science and Technology for the 13th Five-Year Plan of China (2018ZX10721102-003-006, 2018ZX10715013-003-003), the Fundamental Research Funds for the Central Universities (K20210205, 2022ZFJH003), and Zhejiang Province Healthcare Innovation Talent Program.
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Conception and design: Jie Wu, Kailu Fang; Financial support: Jie Wu; Administrative support: Yushi Lin, Shuwen Li, Yu Zhang; Acquisition of data: Kailu Fang; Data analysis and interpretation: Kailu Fang, Yushi Lin, Shuwen Li, Yu Zhang; Manuscript writing: Kailu Fang; Critical revision of the manuscript for important intellectual content: Jie Wu. Jie Wu and Kailu Fang were the guarantors of this article and all authors read and approved the final manuscript.
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Fang, K., Li, S., Lin, Y. et al. Economic evaluation of hepatocellular carcinoma surveillance in chronic hepatitis B patients with virological remission. BMC Public Health 24, 2202 (2024). https://doi.org/10.1186/s12889-024-19670-9
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DOI: https://doi.org/10.1186/s12889-024-19670-9