Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis

The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and ident...

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Veröffentlicht in:Journal of hepatology 2023-03, Vol.78 (3), p.534-542
Hauptverfasser: Choi, Won-Mook, Yip, Terry Cheuk-Fung, Wong, Grace Lai-Hung, Kim, W. Ray, Yee, Leland J., Brooks-Rooney, Craig, Curteis, Tristan, Cant, Harriet, Chen, Chien-Hung, Chen, Chi-Yi, Huang, Yi-Hsiang, Jin, Young-Joo, Jun, Dae Won, Kim, Jin-Wook, Park, Neung Hwa, Peng, Cheng-Yuan, Shin, Hyun Phil, Shin, Jung Woo, Yang, Yao-Hsu, Lim, Young-Suk
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container_end_page 542
container_issue 3
container_start_page 534
container_title Journal of hepatology
container_volume 78
creator Choi, Won-Mook
Yip, Terry Cheuk-Fung
Wong, Grace Lai-Hung
Kim, W. Ray
Yee, Leland J.
Brooks-Rooney, Craig
Curteis, Tristan
Cant, Harriet
Chen, Chien-Hung
Chen, Chi-Yi
Huang, Yi-Hsiang
Jin, Young-Joo
Jun, Dae Won
Kim, Jin-Wook
Park, Neung Hwa
Peng, Cheng-Yuan
Shin, Hyun Phil
Shin, Jung Woo
Yang, Yao-Hsu
Lim, Young-Suk
description The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status. We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61–0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59–0.88; p
doi_str_mv 10.1016/j.jhep.2022.12.007
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Ray ; Yee, Leland J. ; Brooks-Rooney, Craig ; Curteis, Tristan ; Cant, Harriet ; Chen, Chien-Hung ; Chen, Chi-Yi ; Huang, Yi-Hsiang ; Jin, Young-Joo ; Jun, Dae Won ; Kim, Jin-Wook ; Park, Neung Hwa ; Peng, Cheng-Yuan ; Shin, Hyun Phil ; Shin, Jung Woo ; Yang, Yao-Hsu ; Lim, Young-Suk</creator><creatorcontrib>Choi, Won-Mook ; Yip, Terry Cheuk-Fung ; Wong, Grace Lai-Hung ; Kim, W. Ray ; Yee, Leland J. ; Brooks-Rooney, Craig ; Curteis, Tristan ; Cant, Harriet ; Chen, Chien-Hung ; Chen, Chi-Yi ; Huang, Yi-Hsiang ; Jin, Young-Joo ; Jun, Dae Won ; Kim, Jin-Wook ; Park, Neung Hwa ; Peng, Cheng-Yuan ; Shin, Hyun Phil ; Shin, Jung Woo ; Yang, Yao-Hsu ; Lim, Young-Suk</creatorcontrib><description>The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status. We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61–0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59–0.88; p &lt;0.01) and PSW (HR 0.83; 95% CI 0.67–1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58–1.00; p &lt;0.05), male (HR 0.74; 95% CI 0.58–0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49–0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63–1.00; p &lt;0.05) subgroups. TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups. Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent. [Display omitted] •Relative HCC risk for TDF vs. ETV treatment is undetermined in patients with CHB.•Prior meta-analyses are limited by heterogeneity of observational studies.•Using individual patient data enables a consistent analytic approach across studies.•TDF was consistently associated with lower HCC risk than ETV.</description><identifier>ISSN: 0168-8278</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2022.12.007</identifier><identifier>PMID: 36572349</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Antiviral Agents - therapeutic use ; Carcinoma, Hepatocellular - etiology ; Chronic hepatitis B ; entecavir ; Female ; Hepatitis B e Antigens ; Hepatitis B, Chronic - drug therapy ; hepatocellular carcinoma ; Humans ; individual patient data ; Liver Neoplasms - etiology ; Male ; meta-analysis ; Middle Aged ; Retrospective Studies ; Tenofovir - therapeutic use ; tenofovir disoproxil fumarate ; Treatment Outcome</subject><ispartof>Journal of hepatology, 2023-03, Vol.78 (3), p.534-542</ispartof><rights>2022 The Author(s)</rights><rights>Copyright © 2022 The Author(s). 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Ray</creatorcontrib><creatorcontrib>Yee, Leland J.</creatorcontrib><creatorcontrib>Brooks-Rooney, Craig</creatorcontrib><creatorcontrib>Curteis, Tristan</creatorcontrib><creatorcontrib>Cant, Harriet</creatorcontrib><creatorcontrib>Chen, Chien-Hung</creatorcontrib><creatorcontrib>Chen, Chi-Yi</creatorcontrib><creatorcontrib>Huang, Yi-Hsiang</creatorcontrib><creatorcontrib>Jin, Young-Joo</creatorcontrib><creatorcontrib>Jun, Dae Won</creatorcontrib><creatorcontrib>Kim, Jin-Wook</creatorcontrib><creatorcontrib>Park, Neung Hwa</creatorcontrib><creatorcontrib>Peng, Cheng-Yuan</creatorcontrib><creatorcontrib>Shin, Hyun Phil</creatorcontrib><creatorcontrib>Shin, Jung Woo</creatorcontrib><creatorcontrib>Yang, Yao-Hsu</creatorcontrib><creatorcontrib>Lim, Young-Suk</creatorcontrib><title>Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status. We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61–0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59–0.88; p &lt;0.01) and PSW (HR 0.83; 95% CI 0.67–1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58–1.00; p &lt;0.05), male (HR 0.74; 95% CI 0.58–0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49–0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63–1.00; p &lt;0.05) subgroups. TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups. Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent. [Display omitted] •Relative HCC risk for TDF vs. ETV treatment is undetermined in patients with CHB.•Prior meta-analyses are limited by heterogeneity of observational studies.•Using individual patient data enables a consistent analytic approach across studies.•TDF was consistently associated with lower HCC risk than ETV.</description><subject>Antiviral Agents - therapeutic use</subject><subject>Carcinoma, Hepatocellular - etiology</subject><subject>Chronic hepatitis B</subject><subject>entecavir</subject><subject>Female</subject><subject>Hepatitis B e Antigens</subject><subject>Hepatitis B, Chronic - drug therapy</subject><subject>hepatocellular carcinoma</subject><subject>Humans</subject><subject>individual patient data</subject><subject>Liver Neoplasms - etiology</subject><subject>Male</subject><subject>meta-analysis</subject><subject>Middle Aged</subject><subject>Retrospective Studies</subject><subject>Tenofovir - therapeutic use</subject><subject>tenofovir disoproxil fumarate</subject><subject>Treatment Outcome</subject><issn>0168-8278</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFv1DAQhS1ERZfCH-CAfOSSMLaziY24QNXSSpW4wNlynEnXS2IvtrOov4U_i6NtOfY0Gs33njTvEfKOQc2AtR_39X6Hh5oD5zXjNUD3gmxYC1BB27CXZFMgWUneyXPyOqU9AAhQzStyLtptx0WjNuTvDR5MDhanaZlMpNZE63yYDY0u_aLO03J26HOif1zeUbuLwTtLd6vMZZfoVxrRojs6f08z-jCGo4sVPaaaFhlas669STgU8N7N6NMneuuHohgWMz3508FkQ2fMpjLeTA_JpTfkbDRTwreP84L8vL76cXlT3X3_dnv55a6yDUCuUMhewdgrK2zXomw5WiXLg2BAbTlYMciRmU50fSuUEgMaqXhvcdu0Y9MIcUE-nHwPMfxeMGU9u7QmYjyGJWnebYudYkoWlJ9QG0NKEUd9iG428UEz0Gspeq_XUvRaimZcl1KK6P2j_9LPOPyXPLVQgM8nAMuXR4dRJ1sysTi4km3WQ3DP-f8D9RyhCg</recordid><startdate>202303</startdate><enddate>202303</enddate><creator>Choi, Won-Mook</creator><creator>Yip, Terry Cheuk-Fung</creator><creator>Wong, Grace Lai-Hung</creator><creator>Kim, W. 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Ray ; Yee, Leland J. ; Brooks-Rooney, Craig ; Curteis, Tristan ; Cant, Harriet ; Chen, Chien-Hung ; Chen, Chi-Yi ; Huang, Yi-Hsiang ; Jin, Young-Joo ; Jun, Dae Won ; Kim, Jin-Wook ; Park, Neung Hwa ; Peng, Cheng-Yuan ; Shin, Hyun Phil ; Shin, Jung Woo ; Yang, Yao-Hsu ; Lim, Young-Suk</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-e38b90fb9c3c76e862ec985720a09520c3d8f1a737b63993dea892bce546f4433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antiviral Agents - therapeutic use</topic><topic>Carcinoma, Hepatocellular - etiology</topic><topic>Chronic hepatitis B</topic><topic>entecavir</topic><topic>Female</topic><topic>Hepatitis B e Antigens</topic><topic>Hepatitis B, Chronic - drug therapy</topic><topic>hepatocellular carcinoma</topic><topic>Humans</topic><topic>individual patient data</topic><topic>Liver Neoplasms - etiology</topic><topic>Male</topic><topic>meta-analysis</topic><topic>Middle Aged</topic><topic>Retrospective Studies</topic><topic>Tenofovir - therapeutic use</topic><topic>tenofovir disoproxil fumarate</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choi, Won-Mook</creatorcontrib><creatorcontrib>Yip, Terry Cheuk-Fung</creatorcontrib><creatorcontrib>Wong, Grace Lai-Hung</creatorcontrib><creatorcontrib>Kim, W. 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Ray</au><au>Yee, Leland J.</au><au>Brooks-Rooney, Craig</au><au>Curteis, Tristan</au><au>Cant, Harriet</au><au>Chen, Chien-Hung</au><au>Chen, Chi-Yi</au><au>Huang, Yi-Hsiang</au><au>Jin, Young-Joo</au><au>Jun, Dae Won</au><au>Kim, Jin-Wook</au><au>Park, Neung Hwa</au><au>Peng, Cheng-Yuan</au><au>Shin, Hyun Phil</au><au>Shin, Jung Woo</au><au>Yang, Yao-Hsu</au><au>Lim, Young-Suk</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2023-03</date><risdate>2023</risdate><volume>78</volume><issue>3</issue><spage>534</spage><epage>542</epage><pages>534-542</pages><issn>0168-8278</issn><eissn>1600-0641</eissn><abstract>The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other. Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status. We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61–0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59–0.88; p &lt;0.01) and PSW (HR 0.83; 95% CI 0.67–1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58–1.00; p &lt;0.05), male (HR 0.74; 95% CI 0.58–0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49–0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63–1.00; p &lt;0.05) subgroups. TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups. Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent. [Display omitted] •Relative HCC risk for TDF vs. ETV treatment is undetermined in patients with CHB.•Prior meta-analyses are limited by heterogeneity of observational studies.•Using individual patient data enables a consistent analytic approach across studies.•TDF was consistently associated with lower HCC risk than ETV.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>36572349</pmid><doi>10.1016/j.jhep.2022.12.007</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects Antiviral Agents - therapeutic use
Carcinoma, Hepatocellular - etiology
Chronic hepatitis B
entecavir
Female
Hepatitis B e Antigens
Hepatitis B, Chronic - drug therapy
hepatocellular carcinoma
Humans
individual patient data
Liver Neoplasms - etiology
Male
meta-analysis
Middle Aged
Retrospective Studies
Tenofovir - therapeutic use
tenofovir disoproxil fumarate
Treatment Outcome
title Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis
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