This large, retrospective study of urban Chinese patients with CHB leveraged the only nationally representative database for urban workers and residents, and is the first study to characterize the demographics, comorbidity burden, and recent trends in NA treatment patterns in this population. The data revealed that the Chinese urban population with CHB is aging and that the comorbidity burden is increasing, even over the relatively short time span assessed in this analysis.
These results are consistent with data from multiple studies conducted across Asia that together show that the CHB population is rapidly aging and accumulating comorbidities.10−13 A recent evaluation of CHB comorbidities in Hong Kong over an 18-year period spanning 2000 to 2017. In this study, the prevalence of hypertension (25.5–28.6%), diabetes (10.6–20.1%), cardiovascular disease (12.5–22.2%), and malignancies (7–23.6%) increased between the initial study period (2000 to 2004) and the latest data collection period (2014 to 2017). There was also a dramatic and statistically significant shift in the age of the HBV population, from 41 ± 15 in 2000–2004 to 55 ± 15 years in 2014–2017. A second study, conducted in a Korean population, identified a significant increase in age from 47 years in 2007 to 52 years in 2016. As in other studies, the comorbidity burden increased in parallel with age, with significant increases in the percentage of patients with hyperlipidemia, hypertension, diabetes, osteoporosis/bone fracture, and chronic kidney disease.11 In Taiwan, a retrospective claims review of data from the National Health Insurance Research Database found that the Taiwanese CHB population had aged substantially between 2001 and 2011, at which point nearly 42% of patients were aged ≥ 55 years. Increases in the percentage of patients with clinically significant comorbidities, including chronic kidney disease, osteoporotic fractures, and metabolic syndrome, were also apparent, with the latter increasing almost 4-fold over the time period assessed in the analysis.12 In Japan, an analysis of 13,639 patients that compared the demographics of the CHB population in 2011 and 2016 found that the average age of patients with CHB increased from 62 to 66 years across this brief time period and that the rates of key comorbidities and complications, including diabetes (from 8–14%), kidney disease (from 4–5%), bone fracture (from 5–9%), and NAFLD (from 14–16%), all increased significantly.13
Globally, a similar pattern appears. An analysis conducted in the United States compared demographics and comorbidities between 2000 to 2015 and found a similar shift in demographics.9 Mean age in this US-based study increased from 43.3 years during the 2000–2005 assessment period to 49.1 during the 2011–2015 period. Also consistent with this analysis, the percentage of patients with non-liver comorbidities increased substantially: diabetes by almost 5-fold, hypertension by 3-fold, and chronic kidney disease by 4.5-fold. The prevalence of osteopenia and osteoporosis likewise increased by 3-fold and 2.5-fold, respectively, in the US analysis.
Although the time periods assessed in this study were separated by only 3 years, there was a small but significant increase in the percentage of renal disease that may be concerning, particularly in light of the fact that renal function decline may be associated with aging and antiviral treatments.14 Further, some data suggest that patients with CHB may be fundamentally at greater risk for kidney and bone disease compared with non-CHB controls.15 For these reasons, the most recent European Association for the Study of the Liver (EASL) guidelines indicate that all patients at risk for renal disease who are on antiviral therapy, as well as all patients treated with tenofovir disoproxil fumarate regardless of renal risk, should undergo baseline and periodic renal monitoring, including at least estimated glomerular filtration rate and serum phosphate levels.14
There was a larger and statistically significant increase in the percentage of patients with bone disease, which may also potentially be exacerbated by NA treatment and has also been raised as a concern in updated guidelines.14 Given that aging is associated with reduced renal function and an increasing prevalence of bone disease, the superimposition of age- and treatment-related changes in renal function and bone health may represent a significant emerging clinical issue as CHB patients continue to age and the proportion of treated patients increases.
Another interesting finding was a striking increase in the percentage of patients with NAFLD over the time period of the study, consistent with recent analyses indicating that the prevalence of NAFLD is increasing globally.16,17 This finding is concerning, as NAFLD associated with CHB may be associated with an increased risk for end-stage liver disease and death.17 It is noteworthy that the prevalence of diabetes only increased from 3.2–3.6% in this study, yet this may be an underestimate as many physicians may not code comorbidities, such as diabetes, if the primary reason for the visit is CHB.
The percentage of patients with CHB-related liver complications, including cirrhosis and decompensated cirrhosis, increased significantly between 2013 and 2016. There was a small but significant decline in the rate of HCC in this population; however, it is important to note that this estimate may not by accurate due to the fact that cancer patients are not well captured in the CHIRA dataset.
An analysis of treatment trends found that the percentage of patients receiving any NA therapy increased by nearly 40% even over the relatively short span assessed in this study, from 39.5–55.2%. While promising, these data also show that more than half of Chinese patients with CHB remain untreated. Further, while much of this increase was driven by increased prescription of entecavir, an NA with a high genetic barrier to resistance,18 at least half of the treated patients included in this analysis were still receiving therapy with agents that have a low genetic barrier to resistance (eg, adefovir, lamivudine, telbivudine) as of 2016. Tenofovir alafenamide, along with entecavir, has particular utility in patients with or at risk for renal or bone disease and is recommended in these patients by the most recent iteration of the EASL guidelines.14
The trends observed in this study have several important implications for the future management of CHB in Chinese patients. Current Chinese clinical practice guidelines do not recommend routine screening of comorbidities in CHB patients.8 Increasing age, a greater likelihood of comorbidities, and a consequent increase in the need for comedications raise potential safety risks. Additionally, the observed trends of rapid increases in the percentage of CHB patients with comorbid cardiovascular diseases, chronic renal diseases, NAFLD, and osteoporosis in this study clearly demonstrate the need to assess and manage these comorbidities to improve overall patient health outcomes. Routine screening for comorbidities is thus increasingly important to guide the selection of appropriate NA treatment and manage comorbidities in CHB patients. These data also point to the ongoing need for new CHB therapies with improved safety profiles and high genetic barriers to resistance.
The design of this study is accompanied by a number of inherent limitations. The study periods assessed in this study, 2013 and 2016, were separated by only 3 years. Thus, they provide only a limited snapshot of changes in demographics and comorbidities over a short period of time. Nevertheless, the changes observed for age and for many comorbidities were striking and significant and point toward the potential for major shifts in the clinical profile of CHB patients in China over longer assessment periods. Estimates of comorbidity burden may be low because clinicians may not code comorbidities if the primary reason for the visit was for CHB. This study also provides no information on the impact of treatment on renal function or bone disease, as it included a mixed population of treated and untreated patients. The use of the CHIRA annual claims database, which included only patients from the 2 major urban health insurance plans in China, as a data source may result in some degree of selection bias. Further, the data sources used do not track previous treatment history or accurately estimate the duration of CHB treatment. The design and available data sources precluded following patients longitudinally, pointing to the need for future studies to follow a real-world cohort of Chinese CHB patients with detailed clinical information to address the needs of screening and monitoring comorbidities in the current clinical management of CHB in China.