Cost-effectiveness analysis of oral antiviral therapy in patients with indeterminate chronic hepatitis B infection

Introduction

According to the World Health Organization (WHO), there were 296 million chronic hepatitis B virus (HBV) infections worldwide in 2019 (1), with 80.65 million new cases reported annually (2). An estimated 3.31 million deaths can be attributed to HBV-related cirrhosis and chronic liver disease (1,3). China has the most considerable burden of HBV infection globally, with an HBV prevalence of 5.6% in 2022 (4), translating to 79.75 million hepatitis B surface antigen (HBsAg)-positive individuals (4). In China, only 24% (19.13 million) of chronic HBV patients were diagnosed (4), and although 33.87 million were eligible for treatment, only 5.08 million (15%) received antiviral therapy (AVT) (4). The WHO has set a goal of “eliminating viral hepatitis as a public health hazard by 2030”, aiming to reduce new infections by 90% and the case fatality rate by 65% (5). In China, according to the 2016 national cancer statistics, liver cancer ranked fourth in incidence and second in mortality among malignant tumors (6). An estimated 367,700 new cases of liver cancer are reported annually (7).

According to the Guideline for Chronic Hepatitis B (CHB) (2022 edition) (8), the natural history of chronic HBV infection can be divided into four stages: hepatitis B e antigen (HBeAg)-positive chronic HBV infection, HBeAg-positive CHB, HBeAg-negative chronic HBV infection, and HBeAg-negative CHB. However, the condition of CHB patients can be complex, and a significant proportion cannot be classified into these four categories, leading to what is known as the indeterminate phase (IP). Patients in this phase have a history of infection lasting more than six months, but their HBV deoxyribonucleic acid (DNA) and alanine transaminase (ALT) patterns differ from those in the traditional stages of chronic HBV infection (9). This is why the IP is also referred to as the grey zone (10-13). It has been reported that individuals in the IP represent up to 27.8% to 59.5% of patients with chronic HBV infection (9-16). Liver biopsy studies have shown that significant necrotic inflammation is present in 29.2% to 84.4% of patients in the IP, while significant liver fibrosis is observed in 34.0% to 73.3% of these patients (11,12,16-18). Notably, significant necrotic inflammation and/or significant liver fibrosis were previously identified in 49.7% to 91.1% of patients in the IP (11,12,16,17). Nevertheless, there are no established recommendations regarding whether patients in the IP should receive AVT (19).

Oral AVT can reduce the burden of liver cirrhosis by approximately 74% (20). Several studies have indicated that patients in the IP have a higher risk of developing hepatocellular carcinoma (HCC) (9,21-23). However, a study by Huang et al. has indicated that AVT for patients in the IP can reduce the risk of liver cancer by 70% (24). Whether oral AVT is cost-effective for patients in the IP remains unclear. Therefore, in the present study, we conducted a cost-effectiveness analysis (CEA) of AVT for CHB patients in the IP. We present this article in accordance with the CHEERS reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-163/rc).

Methods

Overview of the cost-effectiveness model

Herein, we conducted a CEA using a Markov model to compare two scenarios for patients with IP-CHB who do not meet the criteria for oral AVT: patients who received oral AVT (scenario I) vs. those who did not receive oral AVT, reflecting the current clinical practice (scenario II) (Figure 1).

Figure 1 The Markov model used for the cost-effectiveness analysis of antiviral therapy in patients with CHB in the IP. AVT, antiviral therapy; CC, compensated cirrhosis; CHB, chronic hepatitis B; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; IP, indeterminate phase; OLT, orthotopic liver transplantation; PLT, post-orthotopic liver transplantation.

The model consisted of seven health states that patients with IP-CHB may progress through until the end of life. These health states, depicted in Figure 1, represent the entire clinical course of disease progression: (I) IP-CHB; (II) compensated cirrhosis (CC); (III) decompensated cirrhosis (DC); (IV) HCC; (V) orthotopic liver transplantation (OLT); (VI) post-orthotopic liver transplantation (PLT); and (VII) HBV-related death. A hypothetical cohort of patients aged 34 years (n=100,000) was created. Each cycle period was one year, and patients were distributed across each state according to transition probabilities at the end of each cycle. The base case analysis used a 50-year analytic period and was conducted from the healthcare system’s perspective. A discount rate of 5% was applied, following the Chinese guidelines for CEA, along with half-cycle corrections for costs and quality-adjusted life years (QALYs). In 2023, the gross domestic product (GDP) per capita of China was approximately $12,690.1 (25), which served as the threshold for the willingness to pay (WTP).

Effects in this study are expressed in QALYs, and the CEA also assessed the incremental cost-effectiveness ratio (ICER). The Markov model was calculated and implemented using TreeAge Pro 2019 (TreeAge Software, Williamstown, MA, USA) and Microsoft Excel 2019.

Transition probabilities

The transition probabilities for each cycle were crucial in determining the distribution of patients across the seven specified health states. These probabilities were derived from previously published studies involving patient populations comparable to those in the current research. The transition probabilities are illustrated by arrows in Figure 1.

The probability of IP-CHB progressing to liver cirrhosis without oral AVT was 0.96% (9). Since cirrhosis includes both CC and DC, we hypothesized that each type accounted for half of the cases, resulting in a probability of 0.48% for either CC or DC. Oral antiviral treatment can reduce the burden of liver cirrhosis by 74% (20). Therefore, the probability of IP-CHB patients receiving oral AVT developing either CC or DC was only 0.12%. The probability of IP-CHB progressing to HCC without AVT was 0.43%, while the probability for those undergoing oral AVT was 0.13% (9,20,24). However, the study has indicated that AVT for patients in the IP can reduce the risk of liver cancer by 70% (24). The other transition probabilities were obtained from published medical literature and public databases, along with parameterized treatment costs and other model parameters (Table 1).

Cost and utility estimates

From the perspective of the Chinese health system, this study estimates only the direct medical costs, which include the cost of oral antiviral drugs, the direct costs of biannual tests and examinations, and the direct medical costs associated with hepatitis B-related diseases. Three antiviral therapies, namely entecavir (ETV) (0.5 mg tablet taken once daily), tenofovir disoproxil fumarate (TDF) (300 mg tablet taken once daily), and tenofovir alafenamide fumarate (TAF) (25 mg tablet taken once daily), are recommended by the Guideline for Chronic Hepatitis B (2022 edition) (8). Currently, generic versions of ETV, TDF, and TAF are much cheaper and widely prescribed. The median cost of these generic versions is 202.39 CNY per year. The cost of AVT-related serum measurements and examinations, such as liver biochemistry, HBV DNA, HBV markers, α-fetoprotein, and ultrasound, amounts to 1,394.40 CNY per year. Therefore, the total cost related to AVT for patients in the IP is estimated to be around 202.39+1,394.40=1,596.79 CNY per year. We used the average exchange rate of 6.7659 RMB to 1 USD ($), according to the rates offered by the Bank of China in 2023, which amounted to 236.01 USD.

Next, we hypothesized that the utility of indeterminate CHB was 0.79, which is equivalent to that of CHB. The other costs and utilities were obtained from recent CEA of Chinese individuals with CHB (45) and were used to estimate health state utility (Table 1).

Statistical analysis

Statistical analyses were conducted using TreeAge Pro 2019 and Microsoft Excel 2019, including probabilistic modeling of transition probabilities (Table 1), one-way deterministic sensitivity analysis (parameter ranges derived from literature extrema), and probabilistic sensitivity analysis (PSA) (1,000 Monte Carlo simulations). All parameters were estimated via literature synthesis or expert consensus, following China’s Pharmacoeconomic Guidelines (44) for discounting (5%) and half-cycle correction.

Sensitivity analysis

To avoid uncertainty in the analytical results and mitigate the risk of potential bias, this study employed one-way deterministic sensitivity analyses and PSA to assess the robustness of the model. The minimum and maximum values were determined by obtaining the lower and upper limits in the one-way deterministic sensitivity analyses. The findings were presented using a tornado diagram. PSA characterized the combined uncertainty of all model parameters based on 1,000 Monte Carlo simulations, generating a cost-effectiveness acceptability curve and an incremental cost-effectiveness scatter plot. These indicated the probability that each alternative would be the most cost-effective treatment as a dominant strategy at various WTP thresholds. Herein, we set the WTP threshold at one time the GDP per capita.

Results

Base-case analysis

From the healthcare system’s perspective, oral AVT for patients with IP-CHB provided greater health benefits at a higher cost than no treatment (see Table 2). Over a 50-year period, the estimated total cost per patient was $5,777.57 for the AVT group (scenario I) and $5,408.95 for the no-treatment group (scenario II), resulting in a cost difference of $368.6225. The simulation indicated that patients receiving oral AVT gained an additional 1.4541 QALYs (14.1520 vs. 12.6979) compared to those who did not receive treatment. As a result, the ICER for AVT was calculated to be $253.51 per QALY.

In a cohort of 100,000 patients with IP-CHB receiving oral AVT, a significant reduction in the incidence of cirrhosis-related complications and liver disease-related mortality could be achieved. Over a 50-year period of continued AVT, it is estimated that 11,581 cases of CC, 15,436 cases of DC, and 718 cases of OLT could be prevented. These findings underscore the long-term benefits of sustained antiviral treatment in alleviating the burden of advanced liver disease among patients with IP-CHB.

In a cohort of 100,000 patients with IP-CHB, the incidence of HCC over a 50-year period was significantly lower in those receiving oral AVT compared to those who did not receive treatment. In the no-treatment group, there were 23,470 new cases of HCC, whereas only 8,358 cases were observed in the AVT group. This indicates that oral AVT could prevent approximately 15,112 new cases of HCC over 50 years. Furthermore, oral AVT was associated with a substantial reduction in mortality, potentially saving over 30% of patients’ lives. Specifically, the AVT group averted 28,923 deaths, with 14,652 deaths recorded compared to 43,575 deaths in the no-treatment group. These findings underscore the critical role of AVT in reducing both the incidence of HCC and liver disease-related mortality in patients with IP-CHB. In addition, the cumulative cases of new HBV-related diseases would be significantly reduced year by year following the initiation of antiviral treatment (Figure 2). As shown in Figure 2, AVT (black dotted line) significantly reduced the cumulative cases of CC, DC, HCC, and OLT compared to no treatment (red dotted line) over the 50-year period (Figure 2).

Figure 2 The four figures illustrate the cumulative cases of various liver-related complications in patients with indeterminate chronic hepatitis B undergoing antiviral therapy (black dotted line) compared to those receiving no treatment (red dotted line) over a specified period. (A) CC; (B) DC; (C) HCC; (D) OLT. CC, compensated cirrhosis; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; OLT, orthotopic liver transplantation.

One-way sensitivity analysis

The results of the one-way sensitivity analysis, illustrated by the incremental net monetary benefit (INMB) tornado plot, revealed that the most influential variable affecting the INMB was the probability of IP-CHB progressing to DC. As this probability increased from 0.38% to 0.58%, the INMB ranged from $15,956.13 to $20,163.15. The other two significant factors influencing the economic outcomes were the probability of IP-CHB progressing to liver cancer and the utility value associated with IP-CHB. Notably, across all variations in parameter values within their respective upper and lower limits, the economic efficiency of AVT for IP-CHB remained superior to no treatment, with an INMB consistently greater than zero (INMB >0) (Figure 3).

Figure 3 The tornado diagram of the one-way deterministic sensitivity analysis. AVT, antiviral therapy; c, cost; CC, compensated cirrhosis; CHB, chronic hepatitis B; DC, decompensated cirrhosis; EV, expected value; HCC, hepatocellular carcinoma; INMB, incremental net monetary benefit; IP-CHB, indeterminate phase-chronic hepatitis B; OLT, orthotopic liver transplantation; p, probability; PLT, post post-orthotopic liver transplantation; u, utility.

PSA

The economic evaluation of AVT for patients with IP-CHB yielded highly favorable results. Compared to no treatment, AVT was deemed cost-effective with a 100% probability at a WTP threshold of one time the GDP per capita. This threshold, set at $12,690.1 (China’s per capita GDP in 2023), showed that AVT emerged as the preferred option in all simulations for patients with IP-CHB.

As shown in Figure 4A, the incremental cost-effectiveness scatter plot illustrates that 100% of the incremental cost-effectiveness points are positioned below the line, representing one time the GDP per capita, indicating that antiviral treatment is consistently more cost-effective than no treatment. Moreover, the cost-effectiveness acceptability curve reveals that AVT becomes more cost-effective at WTP values above $340 (Figure 4B). These findings confirm that antiviral treatment strategies for patients with IP-CHB provide a significant economic advantage compared to no treatment across various WTP thresholds.

Figure 4 Cost-effectiveness analysis of antiviral treatment vs. no treatment in patients with IP-CHB. (A) Incremental cost-effectiveness scatter plot displaying the distribution of incremental costs (y-axis, in dollars) and incremental effectiveness (x-axis, in QALYs) when comparing patients receiving antiviral treatment (scenario I) to those without treatment (scenario II). Each point represents one iteration from probabilistic sensitivity analysis. (B) Cost-effectiveness acceptability curve showing the probability of each strategy being cost-effective across different willingness-to-pay thresholds. Scenario I (blue line) represents patients receiving antiviral treatment, while scenario II (orange line) represents patients without antiviral treatment. CE, cost-effectiveness; IP-CHB, indeterminate phase-chronic hepatitis B; QALY, quality-adjusted life year.

Discussion

Herein, we used a Markov model to perform a CEA of AVT in patients with IP-CHB. This approach allowed for a systematic evaluation of the economic impact and health outcomes of antiviral treatment, offering valuable insights into its efficacy and potential benefits for this patient population. Our findings showed that AVT significantly increases QALYs gained, with the ICER well below one time the GDP per capita. The ICER was calculated at 253.51 USD per QALY, substantially lower than the GDP per capita ($12,690.1), indicating apparent cost-effectiveness. The simulation involving 100,000 IP-CHB cases showed that AVT significantly reduces the incidence of end-stage liver disease and hepatitis B-related mortality compared to no treatment. Our findings suggest that AVT could potentially prevent 27,017 cases of liver cirrhosis and 15,112 cases of liver cancer, thereby easing the economic burden associated with these conditions. Both the one-way and PSA confirmed the robustness of the model’s results. These findings suggest that AVT for patients with indeterminate HBV infection provides substantial cost-effectiveness.

Previous studies have underscored the importance of antiviral treatment for patients with IP-CHB. A significant proportion of these patients, regardless of age, show considerable liver tissue damage, ranging from 55.6% to 64.3% (13,14,17,46). Additionally, the risk of developing HCC in this population is 14 times higher than in patients with inactive HBV infection (1). AVT for individuals with indeterminate HBV infection has been shown to significantly reduce the incidence of both liver cirrhosis (20) and HCC (22,47).

The current analysis demonstrates significant health and economic benefits, offering strong justification for timely antiviral treatment in patients with IP-CHB. Our findings show that treating 100,000 patients over a 50-year period could prevent 42,000 new cases of HBV-related complications and avoid 29,000 HBV-related deaths. The low cost of domestically produced generic antiviral drugs, at just $236.01 USD per year for both medication and monitoring, further enhances the cost-effectiveness of treatment. Furthermore, the ICER in this study is notably lower than that for treating all HBsAg-positive patients (48), allowing for more targeted and efficient use of AVT. This approach avoids unnecessary resource expenditure and reduces the potential risks of adverse drug reactions, reinforcing that the antiviral treatment strategy evaluated in this study is indeed cost-effective. Jeng et al. (49) proposed that regular monitoring without AVT might be sufficient to prevent adverse outcomes in patients with IP-CHB. This recommendation likely stems from the relatively low probability of HCC development in this population (0.08%) (50) and the fact that progression to HCC generally requires transition to the immune-active phase of CHB. However, the median follow-up period in these studies was only 4.7 years, which may not have been long enough to fully capture the risk of HCC development (31). However, the median follow-up period in the study by Lo et al. was only 4.7 years (31), which may not have been long enough to fully capture the risk of HCC development, as demonstrated in studies with longer observation periods (22). In contrast, another study with a median follow-up of 10 years for patients with indeterminate CHB estimated an HCC progression rate of 0.43%, providing a more reliable assessment of the long-term risk (9). Besides, two studies from Korea (47,51) analyzed disease progression and cost-effectiveness of AVT in patients who did not meet treatment criteria with HBV DNA levels above 2,000 IU/mL (32), including some IP-CHB patients. Our study, however, specifically focused on a cohort entirely comprised of indeterminate CHB patients. Based on these findings, antiviral treatment for indeterminate CHB is strongly recommended and cost-effective.

Nonetheless, this study has several limitations. First, our analysis was conducted from the perspective of the Chinese healthcare system, utilizing cost and effectiveness data specific to China. Healthcare infrastructure, drug pricing, and willingness-to-pay thresholds vary significantly across different countries, which may affect the generalizability of our findings. Future studies could incorporate international comparisons to assess the cost-effectiveness of AVT in diverse healthcare settings. Second, our model may have underestimated the economic burden of the disease, as it did not include the costs associated with originally developed antiviral drugs, travel expenses for appointments, direct non-medical costs, or indirect costs. Moreover, if productivity losses were factored into the calculation of disability-adjusted life years, the cost-effectiveness would likely improve significantly. Furthermore, the analysis did not account for the impact of natural mortality from non-hepatitis B-related diseases. Lastly, the economic burden associated with adverse drug reactions was not considered in this study.

The heterogeneity of IP-CHB underscores the importance of subgroup stratification, particularly between patients with high viral load and normal ALT levels (GZ-C category) and those with low viral load and elevated ALT levels (GZ-D category), as defined by existing classifications (10). However, critical gaps in subgroup-specific data hinder such analyses. For example, while 70% of the indeterminate-phase population may fall into the GZ-C subgroup (9), longitudinal progression data for GZ-D and other subgroups remain limited. This is compounded by a lack of robust transition probabilities (e.g., progression to cirrhosis or HCC) specific to each subgroup, which are essential for stratified cost-effectiveness modeling. Future studies should prioritize real-world data collection on disease trajectories, healthcare utilization, and clinical outcomes across IP-CHB subgroups. Such data would enable the development of dynamic models that account for subgroup-specific risks and treatment responses, thereby refining cost-effectiveness estimates and guiding personalized management.

Conclusions

In conclusion, our study shows that oral AVT for patients with IP-CHB reduces HBV-related disease progression and mortality, alleviating the global burden of HBV in a cost-effective manner.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CHEERS reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-163/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-163/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-163/prf

Funding: The study was funded by the Natural Science Foundation of China (No. 82372318, to J.S.P.), the Natural Science Foundation of Fujian Province of China (No. 2022J02030 to J.S.P.), and Major Research Project for Young and Middle-aged People of the Health Commission of Fujian Province (No. 2022ZQNZD004, to J.S.P.), and Integrated Chinese and Western Medicine “Flagship” Department (Construction Project) of National Health Commission of the People’s Republic of China and National Administration of Traditional Chinese Medicine to M.Z.H.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-163/coif). M.Z.H. reports the funding from Integrated Chinese and Western Medicine “Flagship” Department (Construction Project) of National Health Commission of the People’s Republic of China and National Administration of Traditional Chinese Medicine. J.S.P. reports the funding from the Natural Science Foundation of China (No. 82372318), the Natural Science Foundation of Fujian Province of China (No. 2022J02030), and the Major Research Project for Young and Middle-aged People of the Health Commission of Fujian Province (No. 2022ZQNZD004). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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