|
1
|
Cui H, Li S, Lv W, Xiang J. Association of hepatitis B virus DNA levels with efficacy and safety and the impact of antiviral therapy on prognosis in liver cancer patients receiving immune checkpoint inhibitors therapy: a systematic review and meta-analysis. Front Microbiol 2025; 16:1501139. [PMID: 39911258 PMCID: PMC11794511 DOI: 10.3389/fmicb.2025.1501139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 01/08/2025] [Indexed: 02/07/2025] Open
Abstract
Background The current evidence regarding the relationship between baseline hepatitis B virus (HBV) DNA levels and survival outcomes in liver cancer patients receiving immune checkpoint inhibitors (ICIs) remains inconsistent. Therefore, this review was intended to explore the impact of the baseline HBV-DNA level on the efficacy and safety of ICIs in patients with liver cancer. Methods Relevant studies were identified through a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science up to August 1, 2024. The outcomes were hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as odds ratios (ORs) for objective response rate (ORR), disease control rate (DCR) and HBV reactivation (HBVr). Subgroup analysis, publication bias, and sensitivity analysis were conducted with STATA 14.0. Results This meta-analysis comprised 17 articles involving a total of 2,130 patients. The pooled results demonstrated that high HBV DNA was associated with a worse OS (HR = 1.48 95% CI 1.11-1.96). Further subgroup analysis showed that there was no difference in OS between the high HBV DNA group and low HBV DNA group when all patients received antiviral treatment. No associations between baseline HBV DNA and PFS (HR = 1.08, 95% CI 0.90-1.29), ORR (OR = 0.91, 95% CI 0.65-1.28), or DCR (OR = 0.83, 95% CI 0.58-1.20) were observed. The risk of HBVr in the high HBV DNA group was lower than that in the low HBV DNA group (OR = 0.30, 95% CI 0.15-0.58), especially among patients who received antiviral therapy (OR = 0.42, 95% CI 0.18-0.98). Conclusion High HBV DNA was associated with worse OS, but not with PFS, ORR, or DCR in liver cancer patients receiving ICIs. When patients were simultaneously treated with antiviral treatment, elevated HBV DNA level had no unfavorable impact on the efficacy of ICIs. Furthermore, the risk of HBVr in the high HBV-DNA group was lower than that in the low HBV DNA group. More prospective studies with larger sample sizes are essential to confirm the results.
Collapse
Affiliation(s)
- Hongxia Cui
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Su Li
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Wu Lv
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Jing Xiang
- Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| |
Collapse
|
|
2
|
Xia Z, Zhang J, Chen W, Zhou H, Du D, Zhu K, Chen H, Meng J, Yang J. Hepatitis B reactivation in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis. Infect Dis Poverty 2023; 12:87. [PMID: 37736699 PMCID: PMC10515058 DOI: 10.1186/s40249-023-01128-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 08/10/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Immunotherapy shows promise as a treatment option for various cancers. However, there is growing concern over potential complications from hepatitis B virus (HBV) reactivation after checkpoint blockade immunotherapy. Although most of the previous clinical trials on immune checkpoint inhibitors (ICIs) excluded patients with HBV, a few case reports and retrospective studies of HBV reactivation have been published. The aim of this study is to assess the risk of hepatitis B virus reactivation (HBVr) in patients receiving ICIs for advanced cancer. METHODS English and Chinese language literature published prior to April 30, 2023, was searched in PubMed, EMBASE, Web of Science, Cochrane, SinoMed, CNKI and Wanfang Data for studies reporting HBVr rates in cancer patients treated with ICIs. A pooled risk estimate was calculated for HBVr rates with 95% confidence intervals (CI). RESULTS Data from 34 studies including 7126 patients were retrieved and analyzed. The pooled HBVr rate in cancer patients treated with ICIs was 1.3% (I2 = 90.44%, 95% CI: 0.2-2.9%, P < 0.001). Subgroup analysis revealed that patients diagnosed with hepatocellular carcinoma (HCC), HBV carriers, and patients from Asian regions or in developing countries have a higher rate of HBVr. CONCLUSIONS Our meta-analysis demonstrated a low risk of HBVr in patients treated with ICIs for advanced cancer. ICI treatment may be safely used in patients with existing HBV infection or chronic hepatitis B, accompanied by regular monitoring and appropriate antiviral prophylaxis if necessary.
Collapse
Affiliation(s)
- Zhengzheng Xia
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jianyu Zhang
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Wenjun Chen
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Haiyan Zhou
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Di Du
- Department of Pharmacy, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kongcai Zhu
- Department of Pharmacy, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Hui Chen
- Department of Pharmacy, Tangshan Central Hospital, Tangshan, China
| | - Jun Meng
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
| | - Jun Yang
- Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
3
|
Zou H, Lei Q, Yan X, Lai Y, Ung COL, Hu H. Clinical Outcomes Associated with Monotherapy and Combination Therapy of Immune Checkpoint Inhibitors as First-Line Treatment for Advanced Hepatocellular Carcinoma in Real-World Practice: A Systematic Literature Review and Meta-Analysis. Cancers (Basel) 2022; 15:260. [PMID: 36612256 PMCID: PMC9818755 DOI: 10.3390/cancers15010260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs)-based therapy has recently been demonstrated to greatly ameliorate survival outcomes in advanced hepatocellular carcinoma (HCC). We aimed to evaluate clinical outcomes of ICIs-based monotherapy and combination therapy as first-line treatment of adults with advanced HCC in real-world practice by conducting a systematic literature review and meta-analysis. METHODS PubMed, Web of Science, and Embase were searched up to 25 April 2022. Retrospective or prospective real-world studies evaluating progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) of patients with advanced HCC receiving first-line ICIs-based therapy were included. RESULTS Of 7805 studies retrieved, 38 were deemed eligible for inclusion. For patients receiving first-line ICIs-based therapy in real-world practice, the pooled median PFS and OS were 7.03 (95% CI: 5.55-8.51) and 14.39 (95% CI: 10.91-17.86) months. The ORR and DCR were 0.432 (95% CI: 0.327-0.538) and 0.756 (95% CI: 0.677-0.836), according to mRECIST 1.1, 0.317 (95% CI: 0.218-0.416) and 0.740 (95% CI: 0.644-0.835), judged by RECIST 1.1. The best outcomes of survival and response rate were observed in ICIs-based combination therapy of ICIs, TKIs, plus LRTs. Furthermore, ORR, DCR judged by mRECIST 1.1, and PFS could be potential prognostic factors for OS. CONCLUSIONS This research revealed diversified first-line ICIs-based therapies for advanced HCC in real-world practice. Future studies are needed to adopt prospective, multicentric and comparative designs to test the ICIs-based combination therapies, especially triple therapies of ICIs, TKIs, plus LRTs.
Collapse
Affiliation(s)
- Huimin Zou
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Qing Lei
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Xin Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Yunfeng Lai
- School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao, China
| |
Collapse
|
|
4
|
Pan S, Yu Y, Wang S, Tu B, Shen Y, Qiu Q, Liu X, Su N, Zuo Y, Luan J, Zhang JY, Shi M, Meng F, Wang FS. Correlation of HBV DNA and Hepatitis B Surface Antigen Levels With Tumor Response, Liver Function and Immunological Indicators in Liver Cancer Patients With HBV Infection Undergoing PD-1 Inhibition Combinational Therapy. Front Immunol 2022; 13:892618. [PMID: 35711409 PMCID: PMC9195870 DOI: 10.3389/fimmu.2022.892618] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Background Thus far, few studies have investigated the safety and efficacy of programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) antibodies in patients with hepatitis B virus (HBV)-related liver cancer. Objective To investigate the effect of combination therapy with programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) on HBV-related liver cancer. Methods Until January 31, 2022, liver cancer patients with hepatitis B surface antigen (HBsAg) or HBV DNA positivity, treated with PD-1 ICIs and TKIs combined with nucleoside analogs (NAs), were retrospectively reviewed. The correlation between the change in HBV DNA and HBsAg levels and tumor response was analyzed using the χ2 test. Cox univariate and multivariate survival analyses and Kaplan–Meier curves were used to identify and compare risk factors and overall survival (OS). Results A total of 48 patients were enrolled in the study, with an objective response rate (ORR) of 31.3%, a disease control rate (DCR) of 66.7%; the incidence of adverse events was mostly mild. A significant decrease in HBV DNA and HBsAg levels was observed at 12 and 24 weeks compared with the baseline (p < 0.05). Compared to patients with progressive disease (PD), patients with disease control showed a more significant decrease in HBV DNA and HBsAg levels at 12 and 24 weeks (p < 0.001). Eleven patients showed elevations in HBV DNA level and one of them showed HBV reactivation; however, the reactivation was not associated hepatitis. Moreover, eight patients showed elevation in HBsAg. Elevation in HBV DNA level was associated with poor tumor response (P=0.001, OR=18.643 [95% CI: 3.271–106.253]). Cox survival analysis suggested that HBV DNA increase (P=0.011, HR=4.816, 95% CI: 1.439–16.117) and HBsAg increase (P=0.022, HR=4.161, 95% CI: 1.224–16.144) were independent risk factors associated with survival time. Kaplan–Meier curves suggested that patients who exhibited an increase in HBV DNA (6.87 months vs undefined, log-rank test: p= 0.004) and HBsAg (8.07 months vs undefined, log-rank test: p= 0.004) levels had a shorter median survival time (MST). Patients without increased HBsAg showed better baseline liver function and routine blood tests (p<0.05) than patients with increased HBsAg. An increase in C-reactive protein (CRP) and interleukin-6 (IL-6), and a decrease in T lymphocytes, CD4+ T lymphocytes, and B lymphocytes at 1-week post-treatment associated with HBsAg well-controlled. Conclusion HBV-related liver cancer patients treated with combination therapy showed improved efficacy and safety profiles. Combination therapy has some effect on HBV infection, and a correlation between tumor response and antiviral efficacy was found. Elevation of HBV DNA and HBsAg levels may indicate poorer tumor response and survival time. Better baseline liver function and early immune activation may be associated with decline in HBsAg levels.
Collapse
Affiliation(s)
- Shida Pan
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China.,Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yingying Yu
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.,Peking University 302 Clinical Medical School, Beijing, China
| | - Siyu Wang
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China.,Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Bo Tu
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yingjuan Shen
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Qin Qiu
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xiaomeng Liu
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Nan Su
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yanmei Zuo
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China.,Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Junqing Luan
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Ji Yuan Zhang
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Ming Shi
- Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.,Peking University 302 Clinical Medical School, Beijing, China
| | - Fanping Meng
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China.,Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Fu-Sheng Wang
- Chinese People's Liberation Army (PLA) Medical School, Beijing, China.,Department of Infectious Diseases, The Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| |
Collapse
|