Disease burden of chronic hepatitis B and complications in China from 2006 to 2050: an individual-based modeling study

Chronic hepatitis B has become a major public health problem in China. An accurate depiction of the disease burden has not yet been thoroughly conducted. We aimed to project the disease burden of chronic hepatitis B virus (HBV) infection and related complications by modeling various scenarios. An individual-based Markov model was used to predict disease burden from 2006 through 2050. We simulated 5 scenarios with different annual incidences, diagnoses and nucleotide analog (NA) treatment rates as well as treatment eligibility, which included a natural history without diagnosis or NA therapy, a base case, a World Health Organization (WHO)-proposed target case and two ideal cases. The natural history scenario is projected to have the fewest HBsAg losses (27.59 million) and highest number of HBV-related deaths (27.19 million). With improved diagnosis and treatment rates of NA therapy, ideal cases have fewer HBV-related deaths (14.46–14.77 million) than do WHO-proposed cases (15.13 million) and base cases (16.89 million), but the proportion of HBsAg loss is similar among them. With a reduction in new infections, the prevalence of chronic HBV in 2050 is expected to be a minimum of 27.03–27.49 million under WHO and ideal cases. Ideal scenarios 1 and 2 contribute to the lowest disease burden of HBV and its complications in the future, in which new infection control is more effective than increasing diagnosis, treatment rate and treatment eligibility. However, considering the large existing chronic HBV infected population and the low HBsAg loss rate of NA therapy, it is still difficult to avert the increasing trend of cumulative cirrhosis, DC, HCC, LT, and HBV-related death in all scenarios. If new high-potency drugs are not developed, the disease burden of chronic HBV will remain high in the future.


Background
Chronic hepatitis B virus (HBV) infection has always been a major public health issue in China. In the latest nationwide seroepidemiologic survey conducted in 2006, the prevalence rate of HBsAg positivity in the general population was 7.18% [1]. Although an updated survey was reconducted in 2014, it only covered a population aged 1-29 years [2]. Based on these data, approximately 93 million people were chronically infected with HBV. People living with chronic HBV infection can be classified into several categories according to serum markers and liver function [3,4], including immune-tolerant carriers, inactive carriers, HBeAg-positive hepatitis, and HBeAg-negative hepatitis. In 2006, an estimated 63-73 million inactive carriers made up the largest group [4][5][6].
A main concern about chronic HBV infection is its long-term complications. Chronic HBV infection carries a risk of developing into primary liver cancer, which ranks as the sixth-most common cancer worldwide [7]. It also leads to 786,000 HBV-related deaths per year, making it the tenth-leading cause of death worldwide [8]. Over their lifetimes, 15-40% of people with chronic HBV infection can develop complications ranging from hepatocellular carcinoma (HCC) to HBV-related death [9].
Considering these potential progressions and adverse outcomes, the World Health Organization (WHO) endorsed its first global health sector strategy on viral hepatitis in 2016 with the goal of eliminating hepatitis B and C by 2030 [10]. There are various ways to achieve this goal, including preventing new infections and treating current cases. For those already infected, a 'functional cure' (HBsAg loss) is the only method available. The international guidelines also suggested treatment for those who are eligible as well as continued monitoring of all currently infected individuals [11]. Nucleotide analog (NA) therapy was first introduced in approximately 2000. Since 2005, high-potency NAs with minimal risk and side effects, such as entecavir (ETV), have been widely applied in China as the first-line recommendation [12,13]. However, there are still several problems with diagnosis and treatment in China and worldwide. The rates of diagnosis and treatment are only 18.6 and 10.8%, respectively, in China and 10 and 5% worldwide. In addition, as few as 3-7% of chronic HBV patients could undergo HBsAg loss with NA therapy [14]. To improve these problems, both the WHO and China have mentioned increasing the diagnosis and treatment rate and reducing new infections in strategies to eliminate viral hepatitis [15]. Additionally, China updated its guidelines for chronic HBV treatment in 2019, advocating the expansion of NA treatment eligibility to treat more patients [16].
Several previous HBV modeling studies have evaluated the epidemiology of chronic HBV infection in China [17][18][19]. Those studies found that increased screening and treatment were effective in reducing chronic HBV infection, and enhanced vaccination was beneficial in eliminating transmission. However, previous studies have rarely clearly projected diseases complicated by HBV, including cirrhosis, DC, HCC, and liver transplantation. Meanwhile, there is no cohort study in China thus far that could accurately follow up on the long-term outcomes of all HBV-infected populations, which is quite important for the systematic assessment of health consequences and decision-making. Therefore, our study developed an individual-level Markov model aiming to project the disease burden of total chronic HBV infections, cirrhosis, DC, HCC, LT, and HBV-related death from 2006 to 2050 under various scenarios representing different levels of diagnosis, treatment rates, treatment eligibility, and annual new infections.

Patient demographics
Our study constructed a simulated chronic HBVinfected population representing a nationwide baseline in 2006 using the results of the national survey of chronic HBV infection epidemiologic study [20,21] (Supplementary Tables 1, 2). New HBV infections after 2006 were added to the simulated population annually based on reports by the Chinese Centers for Disease Control and Prevention, and the age distribution was derived from published data. Since there are no data regarding age structure after 2017, we adopted the same distribution as that adopted in 2017 [22][23][24] (Supplementary Table 3).

Model schematics
In the natural history scenario, we simplified and organized chronic HBV infection status into the following: three 'CHB states', including HBsAg-positive inactive carriers, HBeAg-negative hepatitis, HBeAg-positive hepatitis; four 'complication states', including cirrhosis, DC, HCC, and LT; and three absorbing states, including HBsAg losses, background deaths, and HBV-related deaths (Supplementary Figure 2). Each 'CHB state', at predefined probability rates, could either progress into cirrhosis and HCC states or undergo HBsAg loss or background death as absorbing states. All of the 'complication states' could transfer to each other or undergo HBV-related death (Supplementary Table 4). We also modeled the annual probability of background death caused by non-liver disease, and the background mortality of the agestandardized rate (ASR) was estimated from the National Bureau of Statistics of China [25].
We did not consider immune tolerance as one of the states here, which was common among infants and children, due to less epidemiologic data being available and the largest population comprising chronic HBV infection in adults who were inactive carriers in China [5,[26][27][28].
We also assumed that those who met the treatment criteria in the Chinese Medical Association and Asian Pacific Association for the Study of the Liver (APASL) guidelines for HBeAg-negative hepatitis, HBeAg-positive hepatitis and cirrhosis states could receive NA therapy and achieve a virological response (defined as undetectable serum HBV DNA during therapy), thereafter progressing at different probability rates (see Supplementary  Table 5) [4,29]. For those who did not achieve a virological response, we assumed that they had the same progression as that observed in the natural history scenario. For DC, HCC, or LT patients, we assumed that the progression rate was relatively constant regardless of NA therapy.
We did not use different strategies for HBV vaccination in our model because it has already been covered universally, with more than 95% coverage at present, and the blocking of vertical transmission is also highly effective, with an incidence of less than 10/100,000 new HBV infections [30,31]. Meanwhile, the vaccine's effect has already been shown as the new infection number every year in our model. We simulated only NA therapy, electing not to include interferon therapy due to its finite coverage, numerous side effects and contraindications [13].

HBV diagnosis, awareness, and treatment
During the simulation, we assumed that newly enrolled individuals were neither diagnosed nor aware at first, and they could become diagnosed with a certain probability. Once diagnosed, patients were assumed to accept their condition and awareness of HBV infection. A certain proportion of diagnosed patients could receive therapy. Newly treated individuals were divided into virological response or non-virological response states, which were permanent until simulation ended.

Simulation scenarios
Considering the current problems and improvement plans of diagnosis and therapy, we designed five scenarios to simulate different diagnosis rates, treatment rates, treatment eligibility, and new infection numbers. The clinical characteristics of the simulated scenarios are summarized in Table 1, and the simulation parameters are shown in Table 2.
The five scenarios were as follows: 1) Natural history scenario: No interventions (diagnosis or treatment) were applied; 2) Base case scenario: The current diagnosis and  Tables 3 and 6). In brief, among all the scenarios, the base case scenario represented the current problems of diagnosis and therapy. The WHO targeted scenario and ideal scenario 1 represented a gradually and rapidly increased diagnosis and treatment rate, respectively. Ideal scenario 2 mainly represented expanded treatment eligibility.

Validation
We validated our model's results using authoritative public health data sources, which included the following: the annual cirrhosis and DC incidence from the Institute for Health Metrics and Evaluation (IHME) Global Health Data Exchange (GHDx) online database; the annual HCC incidence from WHO CI5plus/IARC 2010-2012, WHO Globocan 2018, Polaris online database; the annual HBV-related death with WHO Globocan 2018 online database; the annual LT incidence from the China Liver Transplant Registry (CLTR) online database [32][33][34][35][36]; the annual number of cirrhosis deaths from published global disease burden studies [37,38]; and the total chronic HBV infection prevalence from studies published by Chinese hepatology experts for the base case scenario [22]. In addition, in the natural history scenario, we compared our predicted cumulative 10-year probabilities of HBsAg loss and chronic hepatitis with those in published studies on inactive carriers [39] (Supplementary S 1.5).

Sensitivity analysis
We performed a 1-way sensitivity analysis on the model in base-case parameters by considering uncertainty in all probability rates. We defined each annual transition probability using the upper range and lower range values and then compared the upper or lower values of cirrhosis, DC, HCC, and LT cumulative incidence and cumulative death with base-case values (Supplementary S 1.6).

Validation and sensitivity analysis
Our model projected that the total number of chronic HCV infections in 2016 was 86.06 million, which is equal to the number reported in the epidemiologic data. The projected annual incidence of cirrhosis, DC, HCC, LT from 2010 to 2018, and HBV-related deaths in 2018 closely matched the reported values [32][33][34]40] (Supplementary Table 7). Finally, our model's 10-year cumulative incidence rates of HBsAg loss and hepatitis in inactive carriers closely matched those of a published real-world study [39] (Supplementary Table 8). Sensitivity analysis revealed that 81.75% (327/400) of all predicted upper or lower values of cirrhosis, DC, HCC, LT cumulative incidence and cumulative death fluctuated within 10, and 96% (384/400) fluctuated within 20% (Supplementary Table 9, 10).   3-5. Similarly, the proportions of HBV-related deaths in the base case scenario (19.35%), the WHO target scenario (18.53%), ideal scenario 1 (17.99%) and ideal scenario 2 (17.62%) were far lower than that of the natural history scenario (31.00%) ( Table 3).

Incidence of chronic HBV complications and death
The cumulative and annual incidence of HBV-related complications and deaths are presented in Fig. 2 Table 11). Compared to the natural history scenario, the cumulative incidence of HBV-related complications was predicted to decrease significantly to 38.10 million, 33.25 million, 32.02 million, and 31.54 million under scenarios 2-5. Among the four complications, the cumulative incidence of cirrhosis was found to have the largest decline,

Annual incidence of HBeAg negative and positive hepatitis B
Our model also predicted a decreasing trend in the annual incidence of HBeAg-negative and HBeAg-positive hepatitis in Fig. 4. We estimated that the annual incidence of HBeAg-negative hepatitis was the lowest among all the scenarios under the natural history scenario from 2006 (1.69 million) to 2023 (1.13 million). Thereafter, the annual incidences in the natural history    and base case scenarios became close and higher than those in the other three scenarios (Fig. 4a). The estimated annual incidence of HBeAg-positive hepatitis under the natural history scenario was consistently the highest among all the scenarios; the incidence in 2050 yielded 294,430, which was more than five times that of ideal scenario 2 (54,255) (Fig. 4b).

Prevalence of total chronic HBV infection
The trend of total chronic HBV infection prevalence over time is presented in Supplementary Figure 5 Table 3).

Discussion
Our model used the most updated domestic data on Chinese hepatitis B epidemiologic studies, national notifiable disease surveillance, published cohort data, and other similar models to systematically and prospectively project chronic HBV infection disease burden in China through 2050. We estimated that the cumulative incidence of cirrhosis, DC, HCC, LT, and HBV-related death would still increase, and the total chronic HBV-infected prevalence would decrease over time under all scenarios. Among them, ideal scenarios 1 and 2 were predicted to have the lowest disease burden of complications and chronic infections. In addition, reducing new infections is projected to be the most effective method now available. The 100% diagnostic modalities and treatment rates simulated in ideal scenario 1 projected more HBsAg losses, fewer HBV-related deaths and lower total chronic HBV infection prevalence than did gradually increased diagnosis and treatment rates under the WHO-targeted scenario. A simple test-and-treat modality was proven effective in reducing chronic HBV infection and complications. Current HBV screening in China only include childbirth screening and vaccinations, blood product screening, and screening for safe injection practices [41]. More than 80% of HBV infections are unaware of their HBV status [22]. In the United States, screening is recommended for those who are at high risk, including immigrants from places with > 2% prevalence, HIVinfected people, and pregnant women at their first prenatal visits [42,43]. According to that standard, implementing a 100% HBV screen and achieving full diagnosis in all Chinese individuals is clinically significant due to the medium-high prevalence nationwide. However, given the potentially tremendous economic expense generated by screening and treatment, a further cost-effectiveness analysis is warranted in the future.
Similarly, ideal scenario 2 led to fewer HBV-related deaths and more HBsAg losses than did the WHOtargeted scenario, which proved that increased treatment eligibility was beneficial in reducing the chronic HBV disease burden. In the past, only hepatitis patients with a twofold higher upper limit of normal ALT met the treatment eligibility criteria in China, but recently, the newest Chinese guidelines suggested full treatment for all hepatitis patients with elevated ALT [16]. Our model result provided theoretical evidence and clearly endorsed the recommendation of increasing treatment eligibility by the newest Chinese guidelines.
We also observed a large disparity in the total prevalence between the base case and WHO-targeted scenarios, which were mostly derived from the different settings of annual new infections. Diagnosis and treatment rate only contributed to a minor difference compared with a reduction in new infections. Therefore, controlling new infections is the most effective method available of lowering the chronic HBV disease burden. Although the Chinese government has administered immunization after birth since 1992 and has achieved a significant reduction in total HBV prevalence, there are still 50,000 vertical transmissions and 800,000 new infections every year [1,22,44,45]. New infections were found to be more common in the undeveloped region and among those who were born before 1992 without vaccine protection [46]. Thus, more efforts are still needed, especially on birth immunization in remote regions and catch-up vaccines for susceptible adults.
In addition, the cumulative incidences of cirrhosis, DC, HCC, LT, and HBV-related deaths were predicted to increase over time under all scenarios, implying that NA therapy could only decelerate but not reverse the growing trend. The potential attribution was based on the assumption that only a small group of patients receiving NA therapy would reach a 'functional cure' status [47]. Even with the help of Peg-IFN therapy, 3-7% of patients would lose HBsAg, far less than 97% of HCV elimination using DAAs [3,48,49]. Additionally, the large baseline of the infected population would generate a large disease burden of hepatitis and complications every year, greatly exceeding the number of individual HBsAg losses. These two reasons explain why DAAs could convert the increasing trend of HCV complications, as shown in our previous modeling study, but not NA therapy in HBV [50]. Hence, we suggest that without new high-potency drugs, it will be difficult to avert the increasing trend of cumulative cirrhosis, DC, HCC, LT and HBV-related deaths.
Our study has several limitations, as a modeling study can never exactly simulate an actual situation, particularly with such complicated disease progression. First, the parameters chosen in the model were selected from different published articles. We selected updated and large-scale population studies of Asians published in high impact factor journals. Probabilities that could not be determined were assumed based on Chinese public data and studies. Second, we paid less attention to the economic points of chronic HBV diagnosis and treatment in the current study; thus, further costeffectiveness analysis is still warranted given the expense of diagnosis and treatment. Third, data from a national open public health database might be underreported. However, we tried to find unpublished data from expert reviews. Finally, HBV pathogenesis and clinical progression are complicated. Our model simplified and focused on the most important components of these issues.

Conclusions
In conclusion, this study comprehensively predicts the future HBV burden in China and offers several policy implications. We find that ideal scenario 1 (reduced new infection, rapidly increased diagnosis/treatment rate) and ideal scenario 2 (reduced new infection, rapidly expanded treatment eligibility) contribute to the lowest disease burden of HBV and its complications in the future, in which new infection control is more effective than diagnosis and therapeutic advancements and treatment eligibility expansion. However, considering the high existing chronic HBV infection rate and the low HBsAg loss rate of NA therapy, it is still difficult to avert the increasing trend of cumulative cirrhosis, DC, HCC, LT, and HBV-related death in all simulated scenarios. Hence, if new high-potency drugs are not developed, the disease burden of chronic HBV will remain high in the future.