Table 1.
Summary of baseline characteristics and outcomes of studies comparing entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment on risk of HCC development (Modified from Choi et al. [57] and Dave et al. [56]
| Study (Year) | Data source, country (study period) |
Study type | No. of patients (% Male) |
Age, yearsa | No. (%) of HBeAg positivity | No. (%) of NA treatment-naïve (%) | No. (%) of liver cirrhosis | Follow-up time, months | No. (%) of HCC and HR of TDF vs. ETV on HCC with 95% CI | PSM variablesd |
|---|---|---|---|---|---|---|---|---|---|---|
| Liaw YF et al. (2011) [71] | 39 sites in Europe (17 sites), Canada (4), Singapore (4), Taiwan (5) and the USA (9) (Apr 2006–Dec 2008) | Phase 2, double‐blind, RCT | TDF: 45 (82.2) | 52 (48–57) | 14 (31.1) | 17 (37.8) | 45 (100)b | 48 weeks |
TDF = 3 (6.7%) vs ETV = 1 (4.5%); HR, N.A |
N.A |
| ETV: 22 (77.3) | 54 (47–58) | 7 (31.8) | 9 (40.9) | 22 (100)b | 48 weeks | |||||
| Koklu S et al. (2013) [72] | 18 centers, Turkey | Observational | TDF: 72 (75.0) | 54.2 ± 10.5 | 9 (12.5) | N.A | 72 (100) | 21.4 ± 9.7 |
TDF = 2 (2.8%) vs ETV = 4 (5.2%); HR, 0.60; 95% CI, 0.11–3.28 |
N.A |
| ETV: 77 (77.9) | 52.4 ± 11.2 | 17 (22.1) | N.A | 77 (100) | 24.0 ± 13.3 | |||||
|
Batirel et al (2014) [73] |
4 centers (two universities, one tertiary education and research center, and one state hospital), Turkey (January 2008–October 2013) |
Observational | TDF: 90 (65.6) | 43.3 ± 12.9 | 29 (32.2) | 90 (100) | 0 (0) | 27.2 ± 15.4 | TDF = 0 vs. ETV = 0 | N.A |
| ETV: 105 (78.1) | 42.0 ± 11.2 | 36 (34.3) | 105 (100) | 0 (0) | 33.0 ± 15.4 | HR, N.A | ||||
|
Goyal SK et al (2015) [74] |
Banaras Hindu University Hospital, India (January 2007–January 2014) |
Observational | TDF: 220 | 47.3 (24–65) | 85 (38.6) | 173 (78.6) | 220 (100) | 45 (12–68) |
TDF = 6 (2.7%) vs ETV = 4 (2.2%); HR, 0.49; 95% CI, 0.14–1.72 |
N.A |
| ETV: 180 | 48.1 (26–65) | 70 (38.8) | 137 (76.1) | 180 (100) | 36 (11–60) | |||||
| Wu et al. (2007) [75] |
Chang Gung Memorial Hospital, Taiwan (TDF: October 2011 to January 2014) (ETV: January 2007 to January 2012) |
Observational |
(Entire) TDF: 106 (69.8) |
(Entire) 47.1 ± 12.1 |
(Entire) 50 (47.2) |
(Entire) 106 (100) |
(Entire) 29 (27.4) |
(Entire) 37.9 ± 7.2 |
(Entire) TDF = 7.7% at 48 months vs ETV = 6.7% at 48 months HR, 0.73; 95% CI, 0.26–2.05 Cirrhosis subgroup, TDF = 17.1% at 48 months vs ETV = 16.2% at 48 months HR, N.A |
1, 3–5 |
| ETV: 313(73.5) | 47.0 ± 12.3 | 172 (55.0) | 313 (100) | 94 (30.0) | 49 ± 19.1 | |||||
|
(PSM) TDF: 106 (69.8) |
(PSM) 47.1 ± 12.1 |
(PSM) 50 (47.1) |
(PSM) 106 (100) |
(PSM) 29 (27.4) |
(PSM) 37.9 ± 7.2 |
(PSM) TDF = 7.7% at 48 months vs ETV = 5.1% at 48 months HR, N.A |
||||
| ETV: 212 (76.4) | 46.3 ± 13.2 | 100 (47.2) | 212 (100) | 57 (26.9) | 47.8 ± 19.1 | |||||
| Kayaaslan et al. (2018) [76] | 6 Different centers (3 university hospitals and 3 education and research hospitals), Turkey (June 2008–June 2014) | Observational | TDF: 86 (55.8) | 42 (range 18–71) | 41 (47.7) | 86 (100) | 0 (0) | 18 (range 12–72) | TDF = 0 vs. ETV = 0 | N.A |
| ETV: 166 (71.0) | 43 (range 18–81) | 56 (33.7) | 166 (100) | 0 (0) | 48 (range 12–72) | HR, N.A | ||||
| Kim YM et al. (2018) [77] | Kyung Hee University Hospital, Korea (July 2007–January 2017) | Observational | TDF: 112 (62.5) | 49.3 ± 10.9 | 62 (55.4) | 70 (62.5) | 30 (26.8) | 38.5 ± 9.2 |
TDF = 3 (2.7%) vs ETV = 13 (6.8%); HR, 0.67; 95% CI, 0.19–2.35 |
N.A |
| ETV: 191 (60.7) | 47.7 ± 12.3 | 116 (60.7) | 165 (86.4) | 53 (27.8) | 66.6 ± 26.8 | |||||
|
Yu JH et al (2018) [78] |
Inha University Hospital, Korea (January 2007–December 2015) | Observational | TDF: 176 (59.1) |
49 (range 20–84) |
104 (59.1) | 176 (100.0) | 77 (43.8) |
33.6 (range 6.3–60.5) |
TDF = 7 (4.0%) vs ETV = 31 (7.6%); HR, 1.39; 95% CI, 0.56–3.45 |
N.A |
| ETV: 406 (67.0) |
53 (range 18–84) |
212 (52.2) | 406 (100.0) | 148 (36.5) |
69.9 (range 6–119.4) |
|||||
|
Kim BG et al (2018) [79] |
Ulsan University Hospital, Korea (January 2007–April 2017) | Observational |
(Entire) TDF: 604 (60.1) |
(Entire) 50 ± 11 |
(Entire) 376 (62.3) |
(Entire) 604 (100.0) |
(Entire) 267 (44.2) |
(Entire) 33 (21–46) |
(Entire) TDF = 14 (2.3%) vs. ETV = 40 (5.5%); HR, 0.74; 95% CI, 0.39–1.39 aHR, 0.60; 95% CI, 0.28–1.30 Cirrhosis subgroup, TDF = 14 (5.2%) vs. ETV = 36 (10.4%); aHR, 0.67; 95% CI, 0.30–1.49 (PSM cohort) TDF = 7 (2.0%) vs. ETV = 24 (6.8%); HR, 0.53; 95% CI, 0.22–1.25 |
1–15 |
| ETV: 721 (65.3) | 52 ± 11 | 430 (59.7) | 721 (100.0) | 346 (48.0) | 66 (36–88) | |||||
|
(PSM) TDF: 354 (62.7) |
(PSM) 51 ± 11 |
(PSM) 223 (63.0) |
(PSM) 354 (100) |
(PSM) 156 (44.1) |
(PSM) N.A |
|||||
| ETV: 354 (62.1) | 51 ± 11 | 232 (65.5) | 354 (100) | 169 (47.7) | N.A | |||||
|
Choi J et al (2019) [15] |
Asan Medical Center, Korea (January 2010–December 2016) National registry of patients with CHB (NHIS), Korea (January 2010–December 2016) |
Observational |
(Entire) TDF: 1141(60.6) |
(Entire) 48.1 ± 10.5 |
(Entire) 641 (56.2) |
(Entire) 1141 (100) |
(Entire) 653 (57.2) |
(Entire) 32.0 (23–40) |
(Entire cohort) TDF = 39 (3.4%) vs. ETV = 115 (7.4%); HR, 0.64; 95% CI, 0.45–0.93; aHR, 0.66; 95% CI, 0.46–0.96 Cirrhosis subgroup TDF = 35 (5.4%) vs. ETV = 107(11.4%); aHR, 0.64; 95% CI, 0.43–0.95 (PSM cohort) TDF = 31 (3.6%) vs. ETV = 61 (7.0%); HR, 0.68; 95% CI, 0.46–0.99 (Entire cohort) TDF = 394 (3.1%) vs. ETV = 590 (5.1%); aHR, 0.68; 95% CI, 0.59–0.77 (PSM cohort) TDF = 350 (3.2%) vs. ETV = 567 (5.2%); HR, 0.68; 95% CI, 0.60–0.78 Cirrhosis subgroup TDF = 206 (7.1%) vs. ETV = 338 (11.6%); HR, 0.67; 95% CI, 0.56–0.80 |
1–6, 8–10, 12–21 1–2, 5, 14–15, 22–24 |
| ETV: 1560(61.9) | 49.2 ± 10.5 | 853 (54.7) | 1560 (100) | 935 (59.9) | 48.0 (36–48) | |||||
|
(PSM) TDF: 869 (62.1) |
(PSM) 48.8 ± 10.4 |
(PSM) 481 (55.4) |
(PSM) 869 (100) |
(PSM) 505 (58.1) |
(PSM) 32.0 (22–40) |
|||||
| ETV: 869 (59.7) | 48.8 ± 10.4 | 479 (55.1) | 869 (100) | 511 (58.8) | 48.0 (35–48) | |||||
|
(Entire) TDF: 12,692(62.6) |
(Entire) 48.6 ± 9.8 |
(Entire) N.A |
(Entire) 12,692 (100) |
(Entire) 3488 (27.5) |
(Entire) 37 (30.1–43.5) |
|||||
| ETV: 11,464(62.6) | 49.3 ± 9.8 | N.A | 11,464 (100) | 2991 (26.1) | 51 (37.3–57.0) | |||||
|
(PSM) TDF: 10,923 (62.6) |
(PSM) 49.0 ± 9.8 |
(PSM) N.A |
(PSM) 10,923 (100) |
(PSM) 2919 (26.7) |
(PSM) 37 (30.0–43.4) |
|||||
| ETV: 10,923 (62.3) | 49.1 ± 9.8 | N.A | 10,923 (100) | 2891 (26.5) | 51 (37.7–57.3) | |||||
| Cai et al. (2019) [80] | 14 Tertiary hospitals or university hospitals, China (January 2012–December 2015) | Double‐blind for 48 weeks, then an open trial for 96 weeks, RCT | TDF: 157 (75.8) | 30.8 ± 8.8 | 157 (100) | 157 (100) | 0 (0) | 36 | TDF = 0 vs. ETV = 0 | |
| ETV: 158 (76.6) | 31.0 ± 8.4 | 158 (100) | 158 (100) | 0 (0) | 36 | HR, N.A | ||||
|
Kim SU et al (2019) [16] |
Yonsei University Severance Hospital, Kyungpook National University Hospital, Korea University Anam Hospital, and CHABundang Medical Center, Korea (January 2012–December 2014) |
Observational |
(Entire) TDF: 1413(64.6) |
(Entire) 48.8 ± 12.0 |
(Entire) 694 (49.1) |
(Entire) 1413 (100) |
(Entire) 411 (29.1) |
(Entire) N.A |
(Entire cohort) TDF = 102 (7.2%) vs. ETV = 138(9.3%); aHR, 0.98; 95% CI, 0.75–1.27 Cirrhosis subgroup TDF = 66 (16.1%) vs. ETV = 108(21.6%); aHR, 0.83; 95% CI, 0.61–1.14 (PSM cohort) HR, 1.02; 95% CI, 0.77–1.35 |
1–3, 5, 8–9, 13–15 |
| ETV: 1484(59.9) | 48.2 ± 11.5 | 758 (51.1) | 1484 (100) | 499 (33.6) | N.A | |||||
|
(PSM) TDF: 1278(62.1) |
(PSM) 48.2 ± 12.0 |
(PSM) 640 (50.1) |
(PSM) 1278 (100) |
(PSM) 400 (31.3) |
(PSM) N.A |
|||||
| ETV: 1278(62.1) | 48.6 ± 114 | 640 (50.1) | 1278 (100) | 394 (30.8) | N.A | |||||
| Gordon et al. 2019 [81]e | Longitudinal Chronic Hepatitis Cohort Study (CHeCS), USA | Observational | TDF: 407 | 48 | N.A | 164 (20.0) of all 822 patients | 151 (18.4) of all 822 patients | 48 |
TDF = 13 (3.2%) vs. ETV = 18 (4.3%); aHR for Asian, 0.70; 95% CI, 0.29–1.68 aHR for non-Asian, 1.87; 95% CI, 0.60–5.87 |
N.A |
| ETV: 415 | 51 | N.A | 66 | |||||||
|
Yip TC et al (2019) [58] |
Territory-wide registry of patients with CHB (CDARS), Hong Kong, (January 2008–June 2018) |
Observational |
(Entire) TDF: 1309 (45.1) |
(Entire) 43.2 ± 13.1 |
(Entire) 721 (55.1) |
(Entire) 1309 (100) |
(Entire) 38 (2.9) |
(Entire) 33.6 (16.8–54) |
(Entire cohort) TDF = 13 (1.9%) vs. ETV = 285(5.9%); aHR, 0.36; 95% CI, 0.16–0.80 (PSM cohort) aHR, 0.39; 95% CI, 0.18–0.84 |
1–6, 8–10, 12–16, 25–27 |
| ETV: 28,041(64.5) | 53.4 ± 13.0 | 8317 (29.7) | 28,041(100) | 3822 (13.6) | 44.4 (20.4–60) | |||||
|
(PSM) TDF: 1200(48.9) |
(PSM) 44.4 ± 13.1 |
(PSM) 625 (52.1) |
(PSM) 1200 (100) |
(PSM) 37 (3.1) |
(PSM) 33.6 (18–54) |
|||||
| ETV: 4636(48.9) | 42.9 ± 12.7 | (53.5) | 4636 (100) | (3.6) | 34.8 (18–55.2) | |||||
|
Hsu YC et al (2019) [66] |
19 Centers from 6 countries or Regions (USA, China, HK, Japan, Korea, and Taiwan) based on the REAL-B consortium database | Observational |
(Entire) TDF: 700(65.1) |
(Entire)c 45.7 ± 0.5 |
(Entire) 208 (33.7) |
(Entire) 700 (100) |
(Entire) 131 (18.7) |
(Entire) 38.7 (23.8–56.2) |
(Entire cohort) TDF = 13 (1.9%) vs. ETV = 285(5.9%); aHR, 0.81; 95% CI, 0.42–1.56 Cirrhosis subgroup aHR, 0.68; 95% CI, 0.27–1.68 PSM cohort) TDF = 11 (2.1%) vs. ETV = 19(3.7%); HR, 0.77; 95% CI, 0.37–1.60; aHR, 0.89; 95% CI, 0.41–1.92 |
1–6, 13–14, 28–29 |
| ETV: 4837(68.8) | 50.2 ± 0.2 | 1537 (33.0) | 4837 (100) | 1344 (27.8) | 60 (39.6–60) | |||||
|
(PSM) TDF: 520(65.0) |
(PSM)c 44.9 ± 0.6 |
(PSM) 338 (65.0) |
(PSM) 520 (100) |
(PSM) 105 (20.2) |
(PSM) 38.9 (23.9–57.7) |
|||||
| ETV: 520(68.1) | 44.1 ± 0.5 | 354 (68.1) | 520 (100) | 107 (20.6) | 60 (36.5–60) | |||||
|
Lee SW et al (2019) [62] |
Catholic University, Korea (February 2007–January 2018) | Observational |
(Entire) TDF: 1439(58.4) |
(Entire) 47.3 ± 11.2 |
(Entire) 823 (57.2) |
(Entire) 1439 (100) |
(Entire) 483 (33.6) |
(Entire) 36.4 (N.A.-N.A.) |
(Entire cohort) TDF = 50 (3.5%) vs. ETV = 84(5.3%); aHR, 0.97; 95% CI, 0.68–1.40 Cirrhosis subgroup aHR, 0.99; 95% CI, 0.66–1.48 (PSM cohort) TDF = 47 (3.4%) vs. ETV = 64(4.7%); HR, 1.03; 95% CI, 0.70–1.51; aHR, 1.08; 95% CI, 0.52–2.24 |
1–15, 17, 30–35 |
| ETV: 1583(58.5) | 46.7 ± 11.8 | 974 (61.5) | 1583 (100) | 567 (35.8) | 60 (N.A.-N.A.) | |||||
|
(PSM) TDF: 1370(58.2) |
(PSM) 46.9 ± 11.1 |
(PSM) 807 (58.9) |
(PSM) 1370 (100) |
(PSM) 464 (33.9) |
(PSM) N.A |
|||||
| ETV: 1370(58.8) | 47.0 ± 11.8 | 814 (59.4) | 1370 (100) | 465 (33.9) | N.A | |||||
|
Kim WR et al (2019) [65]e |
IQVIA Pharmetrics PlusTM Claims dataset, USA (January 2006–September 2018) | Observational | TDF: 5903(56.0) | N.A | N.A | 5903 (100) | 463 (7.8) | 17.9 (7.9–34.7) |
TDF = 39 (0.7%) vs. ETV = 46(1.2%); aHR, 0.61; 95% CI, 0.39–0.94 |
N.A |
| ETV: 3819(63.1) | N.A | N.A | 3819 (100) | 370 (9.7) | 17.0 (8.0–32.2) | |||||
|
Lee CJ et al (2019) [61]e |
Taipei Veterans General Hospital, Taiwan (March 2007–April 2018) | Observational | TDF: 288(61.8) | 54.1 (24.0–94.1) | 75 (33.5) | N.A | 39 (13.5) | 33.6 (8.4–124.8) |
TDF = 8 (2.8%) vs. ETV = 31(6.9%); aHR, 0.86; 95% CI, 0.39–1.91 Cirrhosis subgroup TDF = 2 (5.1%) vs. ETV = 28(19.7%); aHR, 0.29; 95% CI, 0.07–1.24 |
N.A |
| ETV: 452(65.7) | 53.0 (23.4–89.7) | 122 (33.7) | N.A | 142 (31.4) | 37.2 (6–145.2) | |||||
|
Chang KC et al (2019) [82]e |
Kaohsiung Chang Gung Memorial Hospital & Linko Chang Gung Memorial Hospital, Taiwan (January 2008—March 2018) | Observational |
(Entire) TDF: 216(75.0) |
(Entire) 56.1 ± 11.6 |
(Entire) 41 (19.0) |
(Entire) 216 (100) |
(Entire) 216 (100) |
(Entire) N.A |
(Entire cohort) TDF = 19 (8.8%) vs. ETV = 138(20.4%); aHR, 0.59; 95% CI, 0.36–0.95 (PSM cohort) aHR, 0.56; 95% CI, 0.31–0.98 |
1,6,8,11 |
| ETV: 678(72.4) | 59.4 ± 11.1 | 125 (18.4) | 678 (100) | 678 (100) | N.A | |||||
|
(PSM) TDF: 159(74.2) |
(PSM) 58.6 ± 11.2 |
(PSM) 28 (17.6) |
(PSM) 159 (100) |
(PSM) 159 (100) |
(PSM) N.A |
|||||
| ETV: 610(73.6) | 58.7 ± 10.6 | 114 (18.7) | 610 (100) | 610 (100) | N.A | |||||
|
Papatheodoridis GV et al. (2020) [63] |
10 Centers from 6 countries (Greece, Germany, Italy, Turkey, Spain, and the Netherlands) | Observational | TDF: 1163(71.1) | 53 ± 13 | 233 (20.0) | 521 (44.8) | (31.6) | 90 (N.A.-N.A.) | TDF = 93 (8.0%) vs. ETV = 51(6.6%); aHR, 1.00; 95% CI, 0.70–1.42 | N.A |
| ETV: 772(69.7) | 52 ± 14 | 110 (14.2) | 607 (78.6) | (22.0) | 91.2 (N.A.-N.A.) | |||||
| Pol S et al. (2019) [64]e |
ANRS CO22 HEPATHER cohort, France |
Observational | TDF: 1075(68.5) | 46.7 ± 14.4 | N.A | 520 (48.4) | N.A | N.A | aHR, 1.07; 95% CI, 0.45–2.54 | N.A |
| ETV: 885(73.2) | 50.0 ± 13.7 | N.A | 567 (64.1) | N.A | N.A |
aHR adjusted hazard ratio, CI confidence interval, ETV entecavir, HCC hepatocellular carcinoma, NA nucleos(t)ide analogues, N.A. not applicable, No. numbers, PSM propensity score matching, RCT randomized controlled trial, SEM standard error or the mean, TDF tenofovir disoproxil fumarate
aParentheses indicate interquartile ranges; otherwise, data are expressed as mean ± standard deviation
bAll patients had decompensated cirrhosis
cData are expressed as mean ± SEM
dPropensity score-matched variables; 1. age; 2. sex; 3. hepatitis B e-antigen; 4. hepatitis B virus (HBV) DNA; 5. cirrhosis; 6. alanine aminotransferase; 7. aspartate aminotransferase (AST); 8. albumin; 9. bilirubin; 10. creatinine; 11. Alpha fetoprotein; 12. international normalized ratio or prothrombin time; 13. platelet count; 14. diabetes mellitus; 15. hypertension; 16. ascites; 17. Child–Pugh score; 18. Chinese University HCC score; 19. guide with age, gender, HBV DNA, core promoter mutations and cirrhosis-HCC score; 20. platelet age gender B score; 21. risk estimation for HCC in chronic hepatitis B score; 22. socioeconomic status; 23. level of health care; 24. smoking; 25. renal replacement therapy; 26. hepatic encephalopathy; 27. calendar year of treatment initiation; 28. country of study centers; 29. hepatic decompensation; 30. AST-to-platelet ratio index; 31. fibrosis-4 index; 32. body mass index; 33. alcohol; 34. esophageal varix; 35. gamma glutamyl transferase
eConference abstracts presented in the Liver Meeting 2019, American Association for the Study of Liver Diseases (AASLD), Boston, the USA