Online supplement to: Chan HLY, Chan CK, Hui AJ, et al. Tenofovir Disoproxil Fumarate in Chronic HBV Infected Patients with Normal ALT and High HBV DNA Levels Supplementary Figure 1. CONSORT disposition of study patients. Supplementary Figure 2. Per-protocol proportion of patients with HBV DNA <69 IU/mL throughout the study. Supplementary Figure 3. Week 192 viral loads of those subjects with detectable HBV DNA at the end of the study. Supplementary Figure 4. Proportion of patients receiving TDF alone (solid circle) or TDF/FTC (open circle) who achieve a >0.5 log10 HBsAg decline from baseline. Proportion is based on subjects with values at each time point (on-treatment). Supplementary Figure 5. Mean values of HBsAg over time among patients receiving TDF alone (solid circle) or TDF/FTC (open circle). Supplementary Table 1. ITT analysis of achieving the primary efficacy endpoint for patients who achieve and don t achieve the primary endpoint at Week 48. Supplementary Table 2. Per-protocol analysis of achieving the primary efficacy endpoint for patients who achieve and don t achieve the primary endpoint at Week 48. Supplementary Table 3. HBV DNA levels of patients with HBV DNA >69 IU/mL at Week 192 over the final year of treatment. Supplementary Table 4. Bivariate analysis of associations of baseline characteristics with having HBV DNA <29 IU/mL among those subjects with Week 192 values. Supplementary Table 5. Odds ratio of baseline characteristics from logistic regression analysis of those subjects with Week 192 values. Supplementary Table 6. Cox proportional hazard analysis evaluating predictors of achieving either HBV DNA <69 IU/mL or HBV DNA <29 IU/mL. Supplementary Table 7. Intention to treat and per protocol proportion of patients with HBV DNA <69 IU/mL at Week 192 by baseline HBV DNA level. Supplementary Table 8. Resistance Surveillance of HBV isolates. Supplementary Table 9. Phosphate, egfr (calculated using Cockcroft-Gault) over time.
Supplementary Figure 1: CONSORT disposition of study patients. 309 Assessed for eligibility 180 Excluded (Screening Failures) 129 Randomized 64 Allocation to TDF/FTC 62 Received TDF/FTC 2 Did not receive TDF/FTC 65 Allocation to TDF 64 Received TDF 1 Did not receive TDF 1 Lost to follow-up 9 (15%) Discontinued TDF/FTC 1 Investigator s decision 1 Protocol violation 5 Withdrawal of consent 2 Adverse events * 0 Lost to follow-up 12 (18%) Discontinued TDF 2 Investigator s decision 1 Protocol violation 8 Withdrawal of consent 1 Adverse events ** 54 (87%) remaining in study at Week 192 53 (83%) remaining in study at Week 192 * depression, spontaneous abortion ** death (homicide)
Supplemental Figure 2: Per-protocol proportion of patients with HBV DNA <69 IU/mL throughout the study.
Supplemental Figure 3: Week 192 viral loads of those subjects with detectable HBV DNA at the end of the study.
M e a n H B s A g (lo g 1 0 IU /m L ) Supplemental Figure 4: Proportion of patients receiving TDF alone (solid circle) or TDF/FTC (open circle) who achieve a >0.5 log 10 HBsAg decline from baseline. Proportion is based on subjects with values at each time point (on-treatment). Supplemental Figure 5: Mean values of HBsAg over time among patients receiving TDF alone (solid circle) or TDF/FTC (open circle). 5.0 4.5 T D F T D F /F T C 4.0 3.5 3.0 0 2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 W e e k o f S tu d y
Supplemental Table 1: ITT analysis of achieving the primary efficacy endpoint for patients who achieve and don t achieve the primary endpoint at Week 48. TDF FTC+TDF HBV DNA >69 IU/mL at Week 48, N 36 21 HBV DNA <69 IU/mL at Week 96, n/n (%) 12/36 (33.3%) 14/21 (66.7%) HBV DNA <69 IU/mL at Week 144, n/n (%) 20/36 (55.6%) 17/21 (81.0%) HBV DNA <69 IU/mL at Week 192, n/n (%) 16/36 (44.4%) 14/21 (66.7%) HBV DNA 69 IU/mL at Week 48, N 26 37 DNA<400 copies/ml at Week 96, n/n (%) 22/26 (84.6%) 33/37 (89.2%) DNA<400 copies/ml at Week 144, n/n (%) 20/26 (76.9%) 33/37 (89.2%) DNA<400 copies/ml at Week 192, n/n (%) 19/26 (73.1%) 33/37 (89.2%) Supplemental Table 2: Per-protocol analysis of achieving the primary efficacy endpoint for patients who achieve and don t achieve the primary endpoint at Week 48. TDF FTC+TDF HBV DNA >69 IU/mL at Week 48 HBV DNA <69 IU/mL at Week 96, n/n (%) 12/36 (33.3%) 14/21 (66.7%) HBV DNA <69 IU/mL at Week 144, n/n (%) 20/33 (60.6%) 17/21 (81.0%) HBV DNA <69 IU/mL at Week 192, n/n (%) 16/33 (48.5%) 14/20 (70.0%) HBV DNA 69 IU/mL at Week 48 DNA<400 copies/ml at Week 96, n/n (%) 22/23 (95.7%) 33/35 (94.3%) DNA<400 copies/ml at Week 144, n/n (%) 20/22 (90.9%) 33/35 (94.3%) DNA<400 copies/ml at Week 192, n/n (%) 19/20 (95.0%) 33/34 (97.1%)
Supplemental Table 3: HBV DNA levels of patients with HBV DNA >69 IU/mL at Week 192 over the final year of treatment. Subject Number Treatment Arm HBV DNA (IU/mL) Week 144 Week 160 Week 176 Week 192 1113 TDF 39 60 134 471000000 1102 TDF <29 46 <29 20900 1048 TDF 41 <29 49 70 1006 TDF 434 1220 976 1740 1050 TDF 688 648 281 613 1015 TDF 42 63 217 76 1074 TDF 1190 760 719 403 1080 TDF 134 391 436 131 1085 TDF <29 <29 <29 427 1111 TDF 31 59 59 107 1042 TDF 54100 5590000 3400000 27100 1072 TDF 107 55 69 73 1093 TDF 115 228 598 1260 1027 TDF 36 161 <29 224 1031 TDF 70 40 34 90 1059 TDF 64 118 471 139000000 1124 TDF 45 100 138 162 1052 TDF 331 111 98 37 1047 TDF+FTC 37 <29 139 91 1129 TDF+FTC <29 <29 69 39 1040 TDF+FTC 1070 506 420 110 1070 TDF+FTC <29 <29 <29 303 1034 TDF+FTC <29 <29 <29 605 1065 TDF+FTC 111 43 299 182 1032 TDF+FTC <29 <29 <29 37200000
Supplemental Table 4: Bivariate analysis of associations of baseline characteristics with having HBV DNA <29 IU/mL among those subjects with Week 192 values. HBV DNA 29 IU/mL N=35 HBV DNA <29 IU/mL N=72 p- value Female gender, n/n (%) 11/35 (31.4) 40/72 (55.6) 0.024 Baseline HBsAg, log 10, mean 4.88 4.67 0.004 TDF/FTC treatment, n/n (%) 11/35 (31.4) 43/72 (59.7) 0.008 Baseline HBV DNA, log 10, mean 9.26 9.11 0.021 Age >30, n/n (%) 18/35 (51.4) 41/72 (56.9) 0.68 Genotype B, n/n (%) 19/35 (54.3) 32/72 (44.4) 0.411 Asian race, n/n (%) 29/35 (82.9) 66/72 (91.7) 0.201 Baseline BMI, n/n (%) 24.18 22.90 0.132 Baseline ALT, n/n (%) 27.23 26.92 0.414 Years of HBV Positive, n/n (%) Age, n/n (%) 9.21 31.63 9.46 34.72 0.939 0.25 Supplemental Table 5: Odds ratio of baseline characteristics from logistic regression analysis of those subjects with Week 192 values. Odds Ratio Confidence Interval Female gender 2.88 1.14-7.25 TDF/FTC treatment 3.19 1.29-7.91 Supplemental Table 6: Cox proportional hazard analysis evaluating predictors of achieving either HBV DNA <69 IU/mL or HBV DNA <29 IU/mL. Hazard Ratio Confidence Interval HBV DNA <69 IU/mL at Wk 192 Female gender 1.997 1.253-3.181 TDF/FTC treatment Baseline HBsAg HBV DNA <29 IU/mL at Wk 192 1.648 0.451 1.034-2.625 0.256-0.793 Female gender 1.670 1.022-2.729 TDF/FTC treatment Baseline HBsAg 1.763 0.390 1.070-2.903 0.225-0.677
Supplemental Table 7: Intention to treat and per protocol proportion of patients with HBV DNA <69 IU/mL at Week 192 by baseline HBV DNA level. TDF 300mg + placebo TDF 300mg + FTC 200mg Intention To Treat, % (CI) HBV DNA <9 log10 copies/ml 57.1 (34-78.2) 84.2 (60.4-96.6) HBV DNA 9 log10 copies /ml 53.5 (37.3-68.8) 72.1 (56.3-84.7) Per Protocol, n/n (%) HBV DNA <9 log10 copies /ml 75 (47.6-92.7) 88.9 (65.3-98.6) HBV DNA 9 log10 copies /ml 62.2 (44.8-77.5) 86.1 (70.5-95.3) Supplemental Table 8: Resistance Surveillance of HBV isolates. TDF 300mg + placebo (n=64) TDF 300mg + FTC 200mg (n=62) HBV Genotype performed Baseline, n (%) 63 (98) 62 (100) Week 48, n (%) 36 (56) 24 (39) Week 96, n (%) 26 (41) 10 (16) Week 144, n (%) 16 (25) 7 (11) Week 192, n (%) 18 (28) 8 (13) HBV genotype samples, total samples/unique subjects 96/40 49/29 Unable to PCR 12 11 No changes from baseline pol/rt 62 24 Conserved-site changes 6 5 rtl29f/l 2 0 rtp170p/s 0 2 Unique polymorphic-site changes 16 9
Supplemental Table 9: Phosphate, egfr (calculated using Cockcroft-Gault) over time. TDF 300mg + placebo (n=64) TDF 300mg + FTC 200mg (n=62) Phosphate mg/dl (median) Baseline 3.6 3.5 Wk 48 3.6 3.7 Wk 96 3.5 3.5 Wk 144 3.5 3.45 Wk 192 3.5 3.5 egfr ml/min (median) Baseline 109 107 Wk 48 108.5 101.5 Wk 96 106 103 Wk 144 101 103 Wk 192 98 94.5 GFR <70 ml/min, n (%) 0 5 (8.1) GFR <60 ml/min, n (%) 0 2 (3.2) GFR decline by 20%, n (%) 10 (15.6) 14 (22.6)