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

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 [4‐6].

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 [17‐19]. 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.

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, HIV-infected 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 WHO-targeted 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 cost-effectiveness 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.

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.