Long-term monitoring, and hepatocellular carcinoma surveillance in patients with chronic hepatitis B infection

Abstract

Background: Guidelines reported that the patients infected with hepatitis B (HBV) need monitoring of disease progression and hepatocellular carcinoma (HCC) screening to reduce the risk of decompensated cirrhosis and HCC. The present study aimed to examine the rates and risk factors of adherence to guideline-recommended long-term monitoring and HCC surveillance in patients with chronic hepatitis B Virus (CHB) infection.

Methods: We performed a retrospective study of outpatients with CHB infection who from the outpatient database of a Chinese hospital in 2018 by using the International Classification of Diseases revision 10 code and computer queries. The guideline-recommended long-term monitoring and HCC surveillance require to monitor ≥2 times during the2-year follow-up period.

Results: We analyzed 402 eligible outpatients with CHB infection. The number and rates of guideline-recommended long-term monitoring and HCC surveillance annually were as follows: 171 (42.54%) for alanine aminotransferase (ALT) and hepatitis B virus DNA (HBV-DNA), 107 (26.62%) for HCC surveillance, and 103 (25.62%) for all examinations which including ALT, HBV-DNA, and HCC surveillance. Age (P=0.018), gender (P=0.010), outpatient visit times (P=0.036), and antiviral treatment (P=0.044) were associated with the guideline-recommended long-term monitoring of ALT and HBV-DNA. Antiviral treatment (P=0.003, P=0.002) and initial liver imaging (P<0.001, P<0.001) were associated with the guideline-recommended HCC surveillance and also the monitoring of all examination.

Conclusions: The present study observed poor adherence to the guideline-recommended long-term monitoring and HCC surveillance in patients with CHB infection. Additional measures are needed to promote disease monitoring and achieve optimal HBV management.

Background

According to the World Health Organization (WHO) report in 2015, an estimated 325 million people were infected with hepatitis B virus (HBV) and 257 million patients with chronic hepatitis B (CHB), while 7.8 million patients die of hepatitis B complications (including cirrhosis and liver cancer) every year [1]. CHB infection is a clinically complex disease with a long period of few or no symptoms, and hence, it is often undiagnosed. When patients develop clinical discomfort, the disease is in an advanced stage, and treatment options are limited. Due to the failure to capture disease progression, the risk of decompensated cirrhosis and hepatocellular carcinoma (HCC) significantly increases. Therefore, long-term monitoring is required and recommended by the clinical practice guidelines because it allows diagnosis at an early stage when effective therapies are feasible. Guidelines including WHO, American Association for the Study of Liver Diseases (AASLD) 2018, and Chinese 2019 CHB reported that the patients infected with HBV need to be managed systematically, emphasizing the importance of long-term monitoring for disease progression and HCC surveillance through laboratory tests combined with liver imaging [2–4]. Several studies have demonstrated that periodic monitoring is cost-effective in the long term [5, 6]. Additionally, early diagnosis and access to first-line curative treatment, such as antiviral therapy, liver resection, transplantation, or local ablation, to curb the deterioration of hepatitis B-related diseases are attributed to high benefits and survival probability [6–8]. Hosaka et al. demonstrated found that long-term use of entecavir reduces the 5-year cumulative incidence of HCC in HBV-infected patients by 10% compared to the nontreated group [9], while a retrospective national cohort study from Taiwan found a 20% reduction in the 7-year HCC incidence in the nucleoside antiviral treatment group compared to the untreated group. HCC may be developed without cirrhosis or liver enzyme abnormalities and is asymptomatic until presented clinically at an advanced stage [10]. The guidelines emphasized that patients with chronic HBV infection should be screened for HCC, especially those with cirrhosis, family history of HCC, age > 40-years-old, and HBV DNA level > 2000 IU/mL, and monitored with abdominal ultrasound and AFP [3, 4]. HCC surveillance every 6 months resulted in a 37% decrease in HCC-related deaths [11]. Also, if patients are diagnosed early and treated with liver resection, transplantation, or local ablation, the 5-year survival rate is increased to 40–70% [10]. The optimal monitoring for HCC is the key for early detection, curative treatment, and increased survival.

However, in practice, adherence to long-term monitoring and HCC surveillance is not optimistic. The present study aimed to examine the rates and risk factors of adherence to guideline-recommended long-term monitoring and HCC surveillance in patients with chronic hepatitis B Virus (CHB) infection in a Chinese hospital.

Methods

Results

A total of 1200 outpatients with chronic HBV infection were retrieved according to the inclusion criteria. Then, 67 and 731 outpatients were excluded according to the exclusion criteria and the definition of long-term outpatients, respectively. Finally, 402 outpatients were analyzed. The schematic of the study is illustrated in Fig. 1. The demographic and clinical characteristics of the patients are presented in Table 1. The overall mean age at baseline was 42 ± 12 years and comprised 242 (60.2%) males. Moreover, 367 (91.3%) had health insurance, and 225 (56.0%) had received antiviral treatment. The median outpatient visit was 13 times. Among them, the initial ALT was measured in 181 (45.0%) patients and was normal in 125 (69.1%) patients. In addition, 128 (31.8%) patients underwent initial AFP examination, initial HBV-DNA was detected in 185 (46.0%) patients, and 113 (28.1%) underwent initial liver imaging. A higher proportion of patients in the analyzed population had health insurance and antiviral treatment than in the included population. However, a lower proportion of patients in the analyzed population were assessed for the initial ALT, AFP, HBV-DNA, and liver imaging than in the included population.

The number and rates of long-term monitoring at least annually within the following 2 years were as follows: 197(49.0%) for ALT, 151 (37.6%) for HBV-DNA, 186 (46.3%) for AFP, and 127 (31.6%) for liver imaging. Furthermore, the number and rates of guideline-recommended long-term monitoring and HCC surveillance were as follows: 171 (42.5%) for ALT and HBV-DNA, 107 (26.6%) for HCC surveillance, and 103 (25.6%) for all examinations which including ALT, HBV-DNA, and HCC surveillance (Table 2). The univariate and multivariate analysis results are shown in Tables 2 and 3, respectively. Age (odds ratio (OR) = 0.95 (0.91–0.99), P = 0.018), gender (OR = 0.33 (0.14–0.77), P = 0.010), outpatient visit times (OR = 1.08 (1.01–1.15), P = 0.036), and antiviral treatment (OR = 3.51 (1.04–11.90), P = 0.044) were associated with the guideline-recommended monitoring of ALT and HBV-DNA. The antiviral treatment (OR = 3.30 (1.50–7.25), P = 0.003) and initial liver imaging (OR = 4.00 (1.83–8.50), P < 0.001) was associated with the guideline-recommended HCC surveillance and also the monitoring of all examination (OR = 3.54 (1.59–7.86), P = 0.002; OR = 4.78(2.04–9.83), P < 0.001, respectively).

Discussion

In the current study, the monitoring rate of chronic HBV infection was low, and patients had poor adherence to long-term monitoring and HCC surveillance. A series of retrospective studies demonstrated that the monitored rate every year was 50–70% for ALT and 15–40% for HBV-DNA [12–15]; One meta-analysis reported that the overall adherence rate to HCC surveillance was suboptimal at 52% [16]. It could be attributed to the lack of disease knowledge, no follow-up management rules, fragmented services, health care costs, social discrimination, transportation, and scheduling process difficulties [16–18]. Moreover, many patients might underestimate the seriousness of the disease and the importance of disease monitoring. CHB infection takes a long time to develop into severe liver disease, and patients’ awareness of the seriousness of HBV infection decreases over time. Therefore, significant disease educational efforts are needed. Interventional studies conducted programs, such as mailed outreach, clinical reminder, and education to improve adherence to disease monitoring [19–22]. In the present internet age, the medical institution can develop clinical tools, such as electronic medical reminders, order sets, and progress note templates to improve patient adherence; nonetheless, additional studies are needed. The department of infectious disease,3rd affiliated hospital, SUN Yat-sen University from Guangzhou of China has set up a special follow-up clinic for chronic HBV infection and adopted various methods (including SMS, WeChat, website, and phone to book a return visit in advance) to remind and urge patients to regular monitoring [23]. Beste et al. implemented a clinical reminder program to increase the HCC surveillance rate from 18.2–51% [20]. In recent years, clinical management of hepatitis B advocates transition from specialist to primary care. The Third National Hepatitis B Strategy 2018–2022 identifies general practice as a ‘priority setting’ for delivering education, prevention, treatment and care services [24]. However, general practitioners have some challenges to overcome in the management of hepatitis B.

This study suggested that many patients did not undergo all the examinations recommended by the guidelines at each follow-up visit. ALT assessment is carried out frequently, followed by HBV-DNA, HCC surveillance for the least, consistent with the previous studies [13, 16]. This survey showed that only about 26% of patients underwent HCC surveillance annually, which is crucial for managing CHB infection but easy to overlook in practice. Some surveys demonstrated that HCC surveillance for patients with CHB infection is not satisfactory in many countries [10, 12, 16, 23, 25]. A cohort study of 2338 patients with CHB in the United States showed that 46% of patients with cirrhosis never underwent liver imaging [15]. Thus, HCC surveillance should gain increasing attention in clinical follow-up.

This survey also showed that younger, male patient, more outpatient visit times and antiviral treatment with better adherence to the monitoring of ALT and HBV-DNA. Previous studies demonstrated significant differences in age, gender, and outpatient visit times among patients monitored for ALT and HBV-DNA [12, 15, 23]. Juday et al. demonstrated that the male gender was a risk factor of monitoring HBV DNA and ALT [13]. Previous studies indicated that age is related to adherence. Two studies of clinical follow-up in hepatitis B treatment found a high adherence rate among older patients [26, 27]. However, a retrospective study of the medical records of 1727 patients with HBV infection demonstrated that older age was negatively associated with recommended HBV monitoring [28]. These differences need to be explored further. The current result suggested that patients receiving antiviral treatment and initial liver imaging had better adherence to the monitoring of HCC surveillance and all examinations. Supposedly, most patients who need antiviral treatment have a long course of the disease and a high risk of liver-related morbidity. They may also have a deeper understanding of the disease and adverse consequences of HBV infection, requiring additional attention to their health status for high follow-up compliance [23]. On the other hand, patients with antiviral treatment need frequent patient-specialist visits for prescription, and Goldberg et al. demonstrated that the patients who have more specialist visits have better adherence to HCC surveillance [29]. Wong et al. found that regular routine clinic visits might improve adherence to HCC surveillance [30]. This might be because frequent clinic visits indicate that patients are likely to be reminded by physicians to undergo regular HCC surveillance. Patients who detected initial liver imaging had improved compliance. Typically, when the patient is first diagnosed with HBV infection, the initial disease education plays a significant role in the compliance of subsequent disease monitoring. Therefore, patients should be made aware of the importance of disease monitoring, especially at the first diagnosis, to comply with the recommendation.

Nevertheless, the present study has several limitations. First, this was a retrospective study, and only one hospital was included. HBV-related examination performed outside other medical settings could have been missed, and selection bias could not be excluded. To counteract these disadvantages, we utilized the long-term and consecutive outpatient population in January–December 2018 as participants. Thus, a prospective study with a larger sample size and scope is required. Second, the disease-related and socioeconomic background data, such as education, income, and occupation, were not included in the medical records, and the associating factors were not analyzed. These findings suggested that additional supplementary qualitative studies are required to explore the associating factors.

Conclusions

In conclusion, despite the recommendation in the guidelines, the monitoring rate of CHB infection was low, and patients have poor adherence to long-term monitoring and HCC surveillance. Many patients did not undergo all the examinations at each follow-up visit. The patients of the male gender, younger age, more outpatient visits, and antiviral treatment have better adherence to the monitoring of ALT and HBV-DNA, and patients with antiviral therapy and initial liver imaging have better adherence to HCC surveillance and monitoring of all examinations. Further efforts and measures are needed to promote long-term monitoring and achieve optimal HBV management, such as disease education, especially initial disease education. Medical institutions are trying to develop various clinical tools to remind and urge patients to monitor regularly.

Abbreviations

Declarations

Ethics approval and consent to participate

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Institutional Review Board of Zhongshan Hospital (Xiamen), Fudan University (Number: No. B2020-009). Since only medical data without identifiable patient information has been used for the study, we applied the informed consent waiver and it was approved by the Institutional Review Board of Zhongshan Hospital (Xiamen), Fudan University.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this article. 

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the Xiamen Branch of Zhongshan Hospital, Fudan University (Grant no. 2019ZSXMYS09).

Authors’ contributions

Concept or design: Cui-Ling Huang, Hua Yang, Jian Gao, Ying Yu; Acquisition of data: Cui-Ling Huang, Cheng-Dian Lan; Analysis or interpretation of data: Cui-Ling Huang, Jian Gao, Cheng-Dian Lan; Drafting of the article: Cui-Ling Huang; Critical revision for important intellectual content: Hua Yang, Jian Gao. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Acknowledgements

The authors thank Chen-Wei Huang and Rui Huang for their contributions to date collection.

References

1. Smith S, Harmanci H, Hutin Y, Hess S, Bulterys M, Peck R, et al. Global progress on the elimination of viral hepatitis as a major public health threat: An analysis of WHO Member State responses 2017. JHEP reports: innovation in hepatology. 2019;1:81–9. doi:10.1016/j.jhepr.2019.04.002.
2. Chinese Society of Infectious Diseases of Chinese Medical Association, Chinese Society of Hepatology of Chinese Medical Association. The guidelines of prevention and treatment for chronic hepatitis B (2019 version). Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese. J Hepatol. 2019;27:938–61. doi:10.3760/cma.j.issn.1007-3418.2019.12.007.
3. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology (Baltimore, Md). 2018;67:1560–99. doi:10.1002/hep.29800.
4. WHO. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015. http://www.ncbi.nlm.nih.gov/books/NBK305553/.
5. Cadier B, Bulsei J, Nahon P, Seror O, Laurent A, Rosa I, et al. Early detection and curative treatment of hepatocellular carcinoma: A cost-effectiveness analysis in France and in the United States. Hepatology (Baltimore MD). 2017;65:1237–48. doi:10.1002/hep.28961.
6. Post SE, Sodhi NK, Peng CH, Wan K, Pollack HJ. A simulation shows that early treatment of chronic hepatitis B infection can cut deaths and be cost-effective. Health Aff. 2011;30:340–8. doi:10.1377/hlthaff.2008.0905.
7. Singal AG, Mittal S, Yerokun OA, Ahn C, Marrero JA, Yopp AC, et al. Hepatocellular Carcinoma Screening Associated with Early Tumor Detection and Improved Survival Among Patients with Cirrhosis in the US. Am J Med. 2017;130:1099 – 106.e1. doi:10.1016/j.amjmed.2017.01.021.
8. Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 2014;11:e1001624. doi:10.1371/journal.pmed.1001624.
9. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology (Baltimore MD). 2013;58:98–107. doi:10.1002/hep.26180.
10. Li ZL, Wu H, Wei YP, Zhong Q, Song JC, Yu JJ, et al. Impact of Surveillance in Chronic Hepatitis B Patients on Long-Term Outcomes After Curative Liver Resection for Hepatocellular Carcinoma. J Gastrointest surgery: official J Soc Surg Aliment Tract. 2020;24:1987–95. doi:10.1007/s11605-019-04295-w.
11. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417–22. doi:10.1007/s00432-004-0552-0.
12. Wu Y, Johnson KB, Roccaro G, Lopez J, Zheng H, Muiru A, et al. Poor adherence to AASLD guidelines for chronic hepatitis B Management and treatment in a large academic medical center. Am J Gastroenterol. 2014;109:867–75. doi:10.1038/ajg.2014.72.
13. Juday T, Tang H, Harris M, Powers AZ, Kim E, Hanna GJ. Adherence to chronic hepatitis B treatment guideline recommendations for laboratory monitoring of patients who are not receiving antiviral treatment. J Gen Intern Med. 2011;26:239–44. doi:10.1007/s11606-010-1549-9.
14. Kushner T, Lam R, Gray DL, Kaplan DE, Serper M. Identifying Patient and Provider-specific Gaps in Care Among Patients With Hepatitis B. J Clin Gastroenterol. 2017;51:900–6. doi:10.1097/mcg.0000000000000806.
15. Spradling PR, Xing J, Rupp LB, Moorman AC, Gordon SC, Teshale ET, et al. Infrequent Clinical Assessment of Chronic Hepatitis B Patients in United States General Healthcare Settings. Clin Infect diseases: official publication Infect Dis Soc Am. 2016;63:1205–8. doi:10.1093/cid/ciw516.
16. Zhao C, Jin M, Le RH, Le MH, Chen VL, Jin M, et al. Poor adherence to hepatocellular carcinoma surveillance: A systematic review and meta-analysis of a complex issue. Liver international: official journal of the International Association for the Study of the Liver. 2018;38:503–14. doi:10.1111/liv.13555.
17. Fang Q, Hao YH, Li L, Zhang ZH, Wang JZ, Chen MF, et al. Chronic HBV carrier's acceptance of regular surveilling program in China. Journal of Huazhong University of Science and Technology Medical sciences = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban. 2013;33:288–92. doi:10.1007/s11596-013-1113-z.
18. Ispas S, So S, Toy M. Barriers to Disease Monitoring and Liver Cancer Surveillance Among Patients with Chronic Hepatitis B in the United States. J Community Health. 2019;44:610–25. doi:10.1007/s10900-018-00604-7.
19. Singal AG, Tiro JA, Marrero JA, McCallister K, Mejias C, Adamson B, et al. Mailed Outreach Program Increases Ultrasound Screening of Patients With Cirrhosis for Hepatocellular Carcinoma. Gastroenterology. 2017;152:608 – 15.e4. doi:10.1053/j.gastro.2016.10.042.
20. Beste LA, Ioannou GN, Yang Y, Chang MF, Ross D, Dominitz JA. Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder. Clin Gastroenterol hepatology: official Clin Pract J Am Gastroenterological Association. 2015;13:172–9. doi:10.1016/j.cgh.2014.04.033.
21. Dalton-Fitzgerald E, Tiro J, Kandunoori P, Halm EA, Yopp A, Singal AG. Practice patterns and attitudes of primary care providers and barriers to surveillance of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol hepatology: official Clin Pract J Am Gastroenterological Association. 2015;13:791–8.  e1
    . doi:10.1016/j.cgh.2014.06.031.
22. Harris PS, Hansen RM, Gray ME, Massoud OI, McGuire BM, Shoreibah MG. Hepatocellular carcinoma surveillance: An evidence-based approach. World J Gastroenterol. 2019;25:1550–9. doi:10.3748/wjg.v25.i13.1550.
23. Zhu CH, Wu YK, Li XY, Lin GL, Jie YS, Yang FJ, et al. The compliance and its affecting factors with treatment guideline recommendations of chronic HBV infection: A long-term follow-up cohort study. Guangdong Med J. 2016;37:3578–82. doi:10.3969/j.issn.1001-9448.2016.23.030.
24. Wallace J, Richmond J, Allard N, Howell J, Adamson E, Xiao Y, et al. Facilitating hepatitis B clinical management in general practice: A qualitative investigation. Australian J Gen Pract. 2020;49:599–604. doi:10.31128/ajgp-02-20-5225.
25. Sarkar M, Stewart S, Yu A, Chen MS, Nguyen TT, Khalili M. Hepatocellular carcinoma screening practices and impact on survival among hepatitis B-infected Asian Americans. J Viral Hepatitis. 2012;19:594–600. doi:10.1111/j.1365-2893.2011.01577.x.
26. Chi H, Japhary A, de Man RA, de Knegt RJ, Janssen HLA, Hansen BE. Younger age and language barriers are associated with nonadherence to clinical follow-up in hepatitis B treatment. J Viral Hepatitis. 2018;25:1216–9. doi:10.1111/jvh.12920.
27. Tütüncü EE, Güner R, Gürbüz Y, Kaya Kalem A, Öztürk B, Hasanoğlu İ, et al. Adherence to Nucleoside/Nucleotide Analogue Treatment in Patients with Chronic Hepatitis B. Balkan Med J. 2017;34:540–5. doi:10.4274/balkanmedj.2016.1461.
28. Burman BE, Mukhtar NA, Toy BC, Nguyen TT, Chen AH, Yu A, et al. Hepatitis B management in vulnerable populations: gaps in disease monitoring and opportunities for improved care. Dig Dis Sci. 2014;59:46–56. doi:10.1007/s10620-013-2870-z.
29. Goldberg DS, Taddei TH, Serper M, Mehta R, Dieperink E, Aytaman A, et al. Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis. Hepatology (Baltimore MD). 2017;65:864–74. doi:10.1002/hep.28765.
30. Wong CR, Garcia RT, Trinh HN, Lam KD, Ha NB, Nguyen HA, et al. Adherence to screening for hepatocellular carcinoma among patients with cirrhosis or chronic hepatitis B in a community setting. Dig Dis Sci. 2009;54:2712–21. doi:10.1007/s10620-009-1015-x.