PRISMA 2009 Flow Diagram

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Appendix Table 1. Electronic Database Searching Strategy...... 4 Table 2. Pooled Prevalence of Antibiotic Resistance Rates of H. pylori by Country ...... 5 Table 3. Narration of Enrolled Trials ...... 6-9 Table 4A, 4B Characteristics of Enrolled Trials ...... 10-14 Table 5. Risk of Bias for Randomised Trials of Second-line H. pylori Eradication Therapies ...... 15 Table 6. Design Inconsistency of Second-line H. pylori Eradication Therapies ...... 16 Table 7. Loop Inconsistency of Second-line H. pylori Eradication Therapies ...... 17 Table 8. Side-splitting Inconsistency of Second-line H. pylori Eradication Therapies ...... 18-20 Figure 1A. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%) ...... 21 Figure 1B. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%) ...... 22 Figure 1C. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy) ...... 23 Figure 1D. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Dropout Rate) ...... 24 Figure 2A. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Overall) ...... 25 Figure 2B. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%) ...... 26 Figure 2C. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%) ...... 27 Figure 2D. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy) ...... 28

Chang Y-L, et al. BMJ Open Gastro 2020; 7:e000472. doi: 10.1136/bmjgast-2020-000472 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Gastro

Figure 2E. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Dropout Rate) ...... 29 Figure 3A. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second- line H. pylori Eradication Therapies (Overall) ...... 30 Figure 3B. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second- line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%) .... 31 Figure 3C. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second- line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%) ...... 32 Figure 3D. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second- line H. pylori Eradication Therapies (Failure of First-line Triple Therapy) ... 33 Figure 3E. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second- line H. pylori Eradication Therapies (Dropout Rate) ...... 34 Figure 4A. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Overall) ...... 35 Figure 4B. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%) ...... 36 Figure 4C. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%) ...... 38 Figure 4D. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy) ...... 38 Figure 4E. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Dropout Rate) ...... 39 Figure 5A. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Overall) ...... 40 Figure 5B. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%) ...... 41 Figure 5C. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%) ...... 42 Figure 5D. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy) ...... 43

Figure 5E. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Dropout Rate) ...... 44 Figure 6A. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)...... 45 Figure 6B. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)...... 46 Figure 6C. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy) ...... 47 Figure 6D. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Dropout Rate) ...... 48 Reference ...... 49-53

Supplementary Table 1. Electronic Database Searching Strategy Electronic search strategy PubMed search Population / #1 ("Helicobacter"[Mesh] OR Helicobacter) Helicobacter infection Intervention/ #2 (Retreatment [Mesh] OR "Salvage Therapy"[Mesh] Second-line OR "second line" OR "second-line" OR rescue OR therapy salvage OR retreat* OR re-treat* OR fail*) Filters #3 Publication date from 2000/01/01 to 2018/12/31 Search algorithm #4 #1 AND #2 AND #3 Embase search Population / #1 ('helicobacter pylori'/exp OR 'campylobacter pylori' Helicobacter OR 'campylobacter pyloridis' OR 'campylobacter infection pyloris' OR 'helicobacter nemestrinae' OR 'helicobacter pylori') OR ('helicobacter'/exp OR helicobacter OR 'gastrospirillum' OR 'helicobacter') OR ('helicobacter infection'/exp OR 'helicobacter gastritis' OR 'helicobacter infection' OR 'helicobacter infections' OR 'helicobacter pylori gastritis' OR 'helicobacter pylori infection') Intervention/ #2 ('salvage therapy'/exp OR 'salvage procedure' OR Second-line 'salvage therapy') OR ('retreatment'/exp OR therapy retreatment OR 'retreatment') OR ('second line therapy'/exp OR 'second line therapy') OR ('second line':ti,ab,kw) OR (rescue:ti,ab,kw) OR (failure:ti,ab,kw) OR (failed:ti,ab,kw) OR (failing:ti,ab,kw) OR (retreated:ti,ab,kw OR 're treated':ti,ab,kw OR retreating:ti,ab,kw OR 're treating':ti,ab,kw OR retreatments:ti,ab,kw OR 're treatments':ti,ab,kw)) Filters #3 [2000-2018]/py Search algorithm #4 #1 AND #2 AND #3 Cochrane clinical trial search Population/ #1 MeSH descriptor Helicobacter explode all trees OR Helicobacter Helicobacter infection Intervention/ #2 MeSH descriptor Retreatment explode all trees OR Second-line MeSH descriptor Salvage Therapy explode all trees therapy OR "second line" OR "second-line" OR rescue OR salvage OR retreat* OR re-treat* OR fail* Search algorithm #3 #1 AND #2

Supplementary Table 2. Pooled Prevalence of Antibiotic Resistance Rates of H. pylori by Country a

Clarithromycin Levofloxacin Country Resistance rate of H. pylori (%)

Brazil 16 10 China 37 33 Croatia 14 2 France 43 15 Germany 13 18 Greece 36 10 Iran 21 25 Israel 47 5 Italy 15 5 Japan 28 15b Korea 18 28 Spain 19 16 Taiwan 26 15 Turkey 28 30 USA 22 37 Vietnam 63 32 The references are from aGastroenterology. 2018;155:1372-1382. bHelicobacter. 2006;11:243-9.

Supplementary Table 3. Narration of Enrolled Trials

Outcome Author Year Country Study type Sample size Comparison intervention Inclusion criteria measures Non-blinded RCT BQT-14 vs P + BQT-14 vs BQT-14 Chronic non-atrophic gastritis +/- erosions; Jin L, et al.1 2018 China 280 UBT (multi-center) (P) non-bismuth eradication therapy Non-blinded RCT Liou JM, et al.2 2018 Taiwan 379 BQT-10 vs QST-14 NA NA (multi-center) Non-blinded RCT Wu TS, et al.3 2017 Taiwan 73 QTT-10 vs QBQT-10 RUT, H, C PUD (multi-center) Non-blinded RCT Lu JH, et al.4 2017 China 400 QTT-14 vs QTT-14 (P) UBT Chronic gastritis (multi-center) Non-blinded RCT Munteanu D, et al.5 2017 Israel 101 ST-10 vs BQT-14 UBT, SAT NA (single center) Non-blinded RCT Hsu PI, et al.6 2017 Taiwan 102 QTT-10 vs QBQT-10 UBT PUD (multi-center) Non-blinded RCT Chuah SK, et al.7 2016 Taiwan 164 QTT-10 vs QST-10 UBT, RUT, H Gastritis; PUD (single center) Non-blinded, non- Kwon YH, et al.8 2016 Korea randomized trial 178 QTT-14 vs BQT-14 UBT NA (single center) Non-blinded RCT QTT-14 vs QBQT-14 vs P + QTT-14 Peng W, et al.9 2016 China 192 UBT Chronic gastritis; PUD (single center) vs QTT-14 (P) Non-blinded RCT Liou JM, et al.10 2016 Taiwan 600 QTT-10 vs QST-10 UBT NA (multi-center) Non-blinded RCT Yu H, et al.11 2016 China 220 TT-14 vs TT-14 (P) UBT Functional dyspepsia (multi-center) Non-blinded RCT Chronic gastritis with atrophy or erosions; Wang JX, et al. 12 2015 China 167 ST-10 vs QBQT-12 UBT (single center) PUD Non-blinded RCT Zeng LN, et al.13 2015 China 195 QBQT-14 vs QST-10 + QST-14 UBT Chronic gastritis; PUD (single center) Non-blinded RCT Jheng GH, et al.14 2015 Taiwan 124 CT-10 vs BQT-10 UBT Chronic gastritis; PUD (multi-center) Hung IF, et al.15 2015 China Non-blinded RCT 151 RTT-7 vs QCT-7 UBT NA Non-blinded RCT Huang H, et al.16 2014 China 80 TT-10 vs BQT-10 UBT Chronic gastritis (single center) Non-blinded RCT Wang F, et al.17 2014 China 180 BQT-10 vs P + BQT-10 UBT PUD (single center) Kuo CH, et al.18 2013 Taiwan Non-blinded RCT 150 BQT-10 vs QBQT-10 UBT, RUT, H, C NA

(multi-center) Non-blinded RCT Lu Q, et al.19 2013 China 93 QBQT-14 vs DT-14 UBT NA (single center) Non-blinded RCT Chronic gastritis with atrophy or intestinal Calhan T, et al. 20 2013 Turkey 148 QST-12 vs QBQT-10 SAT, H (single center) metaplasia; duodenitis; PUD Non-blinded RCT Chronic gastritis with atrophy or erosions; Liu X, et al.21 2013 China 584 BQT-7 vs BQT-7 + P UBT (single center) PUD Non-blinded RCT Moon JY, et al. 22 2013 Korea 113 QTT-7 vs BQT-7 UBT NA (multi-center) Non-blinded RCT Bago J, et al.23 2013 Croatia 56 QTT-10 vs QST-10 UBT NA (single center) Non-blinded RCT Yoon JH, et al.24 2012 Korea 169 BQT-7 vs BQT-14 UBT, RUT, H NA (multi-center) Non-blinded RCT He Y, et al.25 2012 China 98 BQT-7 vs QST-10 UBT Chronic atrophic gastritis; PUD (single center) Non-blinded RCT Ojetti V, et al.26 2012 Italy 90 QTT-7 vs QTT-7 + P UBT NA (single center) Non-blinded RCT Chuah SK, et al.27 2012 Taiwan 128 TT-14 vs QTT-7 UBT, RUT, H NA (multi-center) Non-blinded RCT Chuah SK, et al.28 2012 Taiwan 101 QTT-14 vs BQT-14 UBT, RUT, H NA (multi-center) Non-blinded RCT Yoon H, et al.29 2011 Korea 337 QTT-14 vs QTT-14 + P UBT, RUT, H NA (single center) Non-blinded RCT Chronic atrophic gastritis; PUD; Hu TH, et al.30 2011 Taiwan 90 QTT-7 vs TT-14 UBT, RUT, H (multi-center) asymptomatic H. pylori infection Non-blinded RCT Chung JW, et al.31 2011 Korea 199 BQT-7 vs BQT-14 UBT NA (multi-center) Non-blinded RCT Chronic gastritis with atrophy or erosions; Zhang CH, et al.32 2011 China 98 QST-10 vs BQT-7 UBT (single center) PUD Non-blinded RCT Zheng XL, et al.33 2010 China 109 QTT-7 vs BQT-7 UBT NA (single center) Non-blinded RCT Minakari M, et al.34 2010 Iran 220 QBQT-14 vs BQT-14 UBT NA (single center) Non-blinded RCT Lee BH, et al.35 2010 Korea 227 BQT-7 vs BQT-14 UBT, RUT, H, C NA (single center) Non-blinded RCT Kuo CH, et al.36 2009 Taiwan 166 BQT-7 vs QTT-7 UBT, RUT, H, C NA (multi-center) Karatapanis S, et 2009 Greece Non-blinded RCT 77 QTT-10 vs BQT-10 UBT NA al.37 Di Caro S, et al.38 2009 Italy Non-blinded RCT 160 QTT-7 vs QTT-10 UBT, RUT, H NA

(single center) Non-blinded RCT Bago J, et al.39 2009 Croatia 160 QTT-7 vs BQT-7 UBT NA (excluding PUD) (single center) Non-blinded RCT Tran TT, et al.40 2009 Vietnam 58 QTT-10 vs BQT-14 UBT, RUT NA (single center) Non-blinded RCT Jung HS, et al.41 2008 Korea 76 QTT-7 vs BQT-7 UBT, RUT Chronic gastritis with/without atrophy; PUD (single center) Non-blinded RCT Sanches B, et al.42 2008 Brazil 60 BQT-10 vs QTT-10 UBT, RUT, H NA (single center) Navarro-Jarabo JM, Non-blinded RCT 2007 Spain 99 RTT-7 vs BQT-7 UBT NA et al.43 (multi-center) Non-blinded RCT Gisbert JP, et al.44 2007 Spain 100 BQT-7 vs QTT-7 UBT Functional dyspepsia; P (single center) Non-blinded RCT Kang JM, et al.45 2007 Korea 192 QTT-10 vs BQT-14 UBT NA (single center) Non-blinded RCT Kang MS, et al.46 2006 Korea 59 QTT-7 vs BQT-7 UBT, RUT, H NA (single center) Non-blinded RCT Cheon JH, et al.47 2006 Korea 85 QTT-7 vs BQT-7 UBT NA (single center) Non-blinded RCT Sheu BS, et al.48 2006 Taiwan 138 BQT-7 vs P + BQT-7 UBT Gastritis; DU (single center) Non-blinded RCT Wu DC, et al.49 2006 Taiwan 93 BQT-7 vs CT-7 UBT, RUT, H, C NA (multi-center) Mantzaris GJ, et Non-blinded RCT 2005 Greece 115 BQT-7 vs BQT-14 UBT DU al.50 (single center) Chronic gastritis with atrophy, intestinal Non-blinded RCT Tursi A, et al.51 2004 Italy 70 BQT-10 vs BQT-10 (P) UBT, RUT, H metaplasia, or dysplasia; PUD; Family (multi-center) history of gastric cancer Non-blinded RCT Nista EC, et al.52 2003 Italy 280 QTT-10 vs BQT-7 vs BQT-14 UBT, H Functional dyspepsia (single center) Non-blinded RCT Perri F, et al.53 2003 Italy 120 BQT-7 vs QTT-7 UBT NA (single center) Non-blinded RCT Magaret N, et al.54 2001 USA 48 TT-14 vs BQT-14 UBT NA (single center) RCT, randomized controlled trial; RUT, rapid urease test; UBT, 13C or 14C urea breath test; H, histology; C, culture; SAT, stool antigen test; PUD, peptic ulcer disease; DU, duodenal ulcer; NA, not available; RTT-7, rifabutin-based triple therapy for 7 days; TT-10/14, triple therapy for 10-14 days; BQT-7, bismuth-containing quadruple therapy for 7 days; BQT-10/14, bismuth-containing quadruple therapy for 10-14 days; ST-10, sequential therapy for 10 days; CT-7, concomitant therapy for 7 days; CT-10, concomitant therapy for 10 days; DT-14, high-dose dual therapy for 14 days; QTT-7, quinolone-based triple therapy for 7 days; QTT-10/14, quinolone-based triple therapy for 10-14 days; QBQT-10/12/14, quinolone-based bismuth-

containing quadruple therapy for 10-14 days; QST-10/12/14, quinolone-based sequential therapy for 10-14 days; QCT-7, quinolone-based concomitant therapy for 7 days; P + Regimen, add-on therapy of probiotics before second-line antibiotic regimens; Regimen (P), add-on therapy of probiotics during second-line antibiotic regimens; Regimen + P, add-on therapy of probiotics after second-line antibiotic regimens.

Supplementary Table 4A. Characteristics of Enrolled Trials

Intervention group Mean Intervention group 2 Intervention group 3 Male Diagnostic First-line Intervention 1 Author age (%) methods regimen group Eradication Eradication Eradication rate (years) Event/Total rate by ITT Event/Total rate by Event/Total by (%) ITT (%) ITT (%) BQT-14 vs P + BQT-14 Jin L, et al.1 39 57.1 UBT NA 44/70 62.9 107/140 76.4 50/70 71.4 vs BQT-14 (P) Liou JM, et al.2 NA NA NA NA BQT-10 vs QST-14 172/189 91.0 169/190 88.9 NA NA Wu TS, et al.3 54 32.8 RUT, UBT, H TT QTT-10 vs QBQT-10 23/38 60.5 28/35 80.0 NA NA Lu JH, et al.4 47 55.5 UBT BQT QTT-14 vs QTT-14 (P) 121/200 60.5 142/200 71.0 NA NA Munteanu D, et al.5 44 37.6 RUT, UBT, H, SAT TT ST-10 vs BQT-14 23/50 46.0 20/51 39.2 NA NA Hsu PI, et al.6 56 41.2 RUT, UBT, H, C TT, BQT, CT QTT-10 vs QBQT-10 36/52 69.2 49/50 98.0 NA NA Chuah SK, et al.7 56 43.9 RUT, UBT, H, C TT QTT-10 vs QST-10 66/82 80.5 74/82 90.2 NA NA Kwon YH, et al.8 57 59.0 RUT, UBT, H, C TT-7 QTT-14 vs BQT-14 63/89 70.8 67/89 75.3 NA NA QTT-14 vs QBQT-14 vs Peng W, et al.9 45 60.4 RUT, UBT TT P + QTT-14 vs QTT-14 29/48 60.4 33/48 68.8 39/48 81.3 (P) (40/48, 83.3%) Liou JM, et al.10 55 50.5 RUT, UBT, H, C NA QTT-10 vs QST-10 226/300 75.3 253/300 84.3 NA NA Yu H, et al.11 NA NA UBT TT-7 TT-14 vs TT-14 (P) 78/110 70.9 94/110 85.5 NA NA Wang JX, et al. 12 39 56.3 UBT NA ST-10 vs QBQT-12 60/85 70.6 61/82 74.4 NA NA QBQT-14 vs QST-10 + Zeng LN, et al.13 NA NA RUT, UBT, H BQT-14 49/65 75.4 120/130 92.3 NA NA QST-14 Jheng GH, et al.14 55 46.0 RUT, UBT, H, C TT-7 CT-10 vs BQT-10 55/61 90.2 58/63 92.1 NA NA Hung IF, et al.15 NA NA NA TT RTT-7 vs QCT-7 67/76 88.2 68/75 90.7 NA NA Huang H, et al.16 42 53.8 RUT, UBT TT TT-10 vs BQT-10 28/40 70.0 36/40 90.0 NA NA Wang F, et al.17 41 74.4 UBT, H TT-7 BQT-10 vs P + BQT-10 68/90 75.6 69/90 76.7 NA NA Kuo CH, et al.18 54 33.3 RUT, UBT, H TT BQT-10 vs QBQT-10 59/74 79.7 60/76 78.9 NA NA Lu Q, et al.19 51 37.6 RUT, UBT NA QBQT-14 vs DT-14 40/48 83.3 36/45 80.0 NA NA Calhan T, et al. 20 43 48.0 RUT, UBT, H, SAT TT QST-12 vs QBQT-10 60/73 82.2 68/75 90.7 NA NA Liu X, et al.21 56 64.9 NA TT-7 BQT-7 vs BQT-7 + P 189/308 61.4 234/276 84.8 NA NA Moon JY, et al. 22 54 45.1 UBT TT-7 QTT-7 vs BQT-7 38/56 67.9 48/57 84.2 NA NA Bago J, et al.23 NA NA NA TT QTT-10 vs QST-10 20/28 71.4 21/28 75.0 NA NA Yoon JH, et al.24 52 52.7 RUT, UBT, H TT BQT-7 vs BQT-14 71/85 83.5 72/84 85.7 NA NA He Y, et al.25 44 53.1 RUT, UBT, H NA BQT-7 vs QST-10 35/49 71.4 44/49 89.8 NA NA Ojetti V, et al.26 42 66.7 UBT NA QTT-7 vs QTT-7 + P 27/45 60.0 36/45 80.0 NA NA

Chuah SK, et al.27 57 47.7 RUT, H TT-7 TT-14 vs QTT-7 48/64 75.0 50/64 78.1 NA NA Chuah SK, et al.28 55 52.5 RUT, H TT-7 QTT-14 vs BQT-14 43/51 84.3 43/50 86.0 NA NA Yoon H, et al.29 54 44.8 RUY, UBT, H TT-7 QTT-14 vs QTT-14 + P 124/186 66.7 104/151 68.9 NA NA Hu TH, et al.30 56 55.6 RUT, H TT QTT-7 vs TT-14 31/45 68.9 38/45 84.4 NA NA Chung JW, et al.31 55 55.3 RUT, UBT, H TT BQT-7 vs BQT-14 80/98 81.6 86/101 85.1 NA NA Zhang CH, et al.32 NA 54.1 UBT TT-7 QST-10 vs BQT-7 39/50 78.0 30/48 62.5 NA NA Zheng XL, et al.33 44 56.9 UBT TT-7 QTT-7 vs BQT-7 40/53 75.5 35/56 62.5 NA NA Minakari M, et al.34 33 54.1 RUT, UBT, H BQT QBQT-14 vs BQT-14 85/110 77.3 71/110 64.5 NA NA Lee BH, et al.35 55 47.6 RUT, UBT, H TT BQT-7 vs BQT-14 72/112 64.3 95/115 82.6 NA NA Kuo CH, et al.36 50 50.6 RUT, UBT, H, C TT BQT-7 vs QTT-7 53/83 63.9 58/83 69.9 NA NA Karatapanis S, et al.37 44 49.4 UBT TT-7/10 QTT-10 vs BQT-10 37/39 94.9 30/38 78.9 NA NA Di Caro S, et al.38 NA 45.0 RUT, UBT, H TT QTT-7 vs QTT-10 54/80 67.5 70/80 87.5 NA NA Bago J, et al.39 49 51.9 UBT TT QTT-7 vs BQT-7 60/82 73.2 42/78 53.8 NA NA Tran TT, et al.40 NA NA NA TT QTT-10 vs BQT-14 14/23 60.9 33/35 94.3 NA NA Jung HS, et al.41 49 57.9 RUT, UBT TT QTT-7 vs BQT-7 16/31 51.6 22/45 48.9 NA NA Sanches B, et al.42 46 43.3 UBT TT BQT-10 vs QTT-10 24/29 82.8 24/31 77.4 NA NA Navarro-Jarabo JM, et 48 48.5 RUT, UBT, H, C NA RTT-7 vs BQT-7 20/45 44.4 38/54 70.4 NA NA al.43 Gisbert JP, et al.44 47 33.5 UBT TT BQT-7 vs QTT-7 34/50 68.0 34/50 68.0 NA NA Kang JM, et al.45 54 54.7 RUT, UBT, H TT QTT-10 vs BQT-14 100/139 71.9 38/53 71.7 NA NA Kang MS, et al.46 49 71.2 NA TT QTT-7 vs BQT-7 19/29 65.5 27/30 90.0 NA NA Cheon JH, et al.47 53 55.3 RUT, UBT, H TT QTT-7 vs BQT-7 31/41 75.6 24/44 54.5 NA NA Sheu BS, et al.48 48 55.8 UBT TT-7 BQT-7 vs P + BQT-7 49/69 71.0 59/69 85.5 NA NA Wu DC, et al.49 51 49.5 RUT, UBT, H, C TT BQT-7 vs CT-7 36/47 76.6 34/46 73.9 NA NA Mantzaris GJ, et al.50 40 54.8 RUT, UBT, H, S TT-10 BQT-7 vs BQT-14 36/54 66.7 48/61 78.7 NA NA Tursi A, et al.51 56 57.1 RUT, H TT BQT-10 vs BQT-10 (P) 30/35 85.7 33/35 94.3 NA NA QTT-10 vs BQT-7 vs Nista EC, et al.52 48 47.9 UBT, H TT 129/140 92.1 44/70 62.9 48/70 68.6 BQT-14 Perri F, et al.53 46 47.8 UBT TT-7 BQT-7 vs QTT-7 50/60 83.3 38/60 63.3 NA NA Magaret N, et al.54 52 33.3 UBT NA TT-14 vs BQT-14 15/20 75.0 20/28 71.4 NA NA RUT, rapid urease test; UBT, 13C or 14C urea breath test; H, histology; C, culture; SAT, stool antigen test; S, serum IgG of H. pylori; TT, triple therapy; BQT, bismuth-containing quadruple therapy; CT, concomitant therapy; NA, not available.

Supplementary Table 4B. Characteristics of Enrolled Trials

Author Intervention groups Intervention group 1 Intervention group 2 Intervention group 3

[Bifidobacterium x 28] + [PPI (bid) + Colloidal bismuth [PPI (bid) + Colloidal bismuth pectin 200mg (bid) + Amo BQT-14 vs P + BQT-14 [PPI (bid) + Colloidal bismuth pectin 200mg (bid) + Amo Jin L, et al.1 pectin 200mg (bid) + Amo 1g (bid) + Furazolidone 100mg 1g (bid) + Furazolidone 100mg (bid) + Bifidobacterium] x vs BQT-14 (P) 1g (bid) + Furazolidone 100mg (bid)] x 14 (bid) +/- Bifidobacterium] x 14 14 [PPI (bid) + Bismuth tripotassium dicitrate 300mg (qid) + [PPI (bid) + Amo 1g (bid)] x 7 + [PPI (bid) + Lev 250mg 2 BQT-10 vs QST-14 NA Liou JM, et al. Met 500mg (tid) + Tet 500mg (qid)] x 10 (bid) + Met 500mg (bid)] x 7 [PPI (bid) + Bismuth subcitrate 120mg (qid) + Lev 500mg Wu TS, et al.3 QTT-10 vs QBQT-10 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 10 NA (qd) + Amo 1g (bid)] x 10 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid) + Lu JH, et al.4 QTT-14 vs QTT-14 (P) [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 14 NA Saccharomyces boulardii] x 14 [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Cla 500mg [PPI (bid) + Bismuth 525mg (qid) + Met 500mg (tid) + Tet Munteanu D, et al.5 ST-10 vs BQT-14 NA (bid) + Tinidazole 500mg (bid)] x 5 500mg (qid)/Doxy 100mg (bid)] x 14 [PPI (bid) + Tripotassium dicitrate bismuth 120mg (qid) + Hsu PI, et al.6 QTT-10 vs QBQT-10 [PPI (bid) + Lev 500mg (qd) + Amo 500mg (qid)] x 10 NA Lev 500mg (qd) + Tet 500mg (qid)] x 10 [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Lev 500mg Chuah SK, et al.7 QTT-10 vs QST-10 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 10 NA (qd) + Met 500mg (tid)] x 5 [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) Kwon YH, et al.8 QTT-14 vs BQT-14 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 14 NA + Met 500mg (tid) +Tet 500mg (qid)] x 14 QTT-14 vs QBQT-14 vs Intervention 3: [Bifidobacterium + Lactobacillus] x 14 + [PPI (bid) + Bismuth potassium citrate 600mg (bid) + Lev [PPI (bid) + Lev 200mg (bid) + Amo 1g (bid)] x 14 Peng W, et al.9 P + QTT-14 vs QTT-14 [PPI (bid) + Lev 200mg (bid) + Amo 1g (bid)] x 14 200mg (bid) + Amo 1g (bid)] x 14 Intervention 4: [PPI (bid) + Lev 200mg (bid) + Amo 1g (P) (bid) + Bifidobacterium/Lactobacillus] x 14 [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Lev 250mg Liou JM, et al.10 QTT-10 vs QST-10 [PPI (bid) + Lev 250mg (bid) + Amo 1g (bid)] x 10 NA (bid) + Met 500mg (bid)] x 5 [PPI (bid) + Amo 1g (bid) + Furazolidone 100mg (bid)] x [PPI (bid) + Amo 1g (bid) + Furazolidone 100mg (bid) + Yu H, et al.11 TT-14 vs TT-14 (P) NA 14 Bifidobacterium] x 14 [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Cla 500mg [PPI (bid) + Bismuth potassium citrate 300mg (bid) + Lev Wang JX, et al. 12 ST-10 vs QBQT-12 NA (bid) + Ornidazole 500mg (bid)] x 5 200mg (bid) + Amo 1g (bid)] x 12 QBQT-14 vs QST-10 + [PPI (bid) + Colloidal bismuth pectin 200mg (bid) + Lev [PPI (bid) + Amo 1g (bid)] x 5-7 + [PPI (bid) + Lev 200mg Zeng LN, et al.13 NA QST-14 200mg (bid) + Amo 1g (bid)] x 14 (bid) + Furazolidone 100mg (bid)] x 5-7 [PPI (bid) + Amo 1g (bid) + Met 250mg (qid) + Tet 500mg [PPI (bid) + Bismuth subcitrate 120mg (qid) + Met 250mg Jheng GH, et al.14 CT-10 vs BQT-10 NA (qid)] x 10 (qid) + Tet 500mg (qid)] x 10 Hung IF, et al.15 RTT-7 vs QCT-7 [PPI (NA) + Amo + Rifabutin] x 7 [PPI (NA) + Lev + Met + Tet] x 7 NA [PPI (bid) + Amo 1g (bid) + Furazolidone 100mg (bid)] x [PPI (bid) + Colloidal bismuth subcitrate 220mg (bid) + Huang H, et al.16 TT-10 vs BQT-10 NA 10 Amo 1g (bid) + Furazolidone 100mg (bid)] x 10 [Lactobacillus acidophilus] x 14 + [PPI (bid) + Bismuth [PPI (bid) + Bismuth 300mg (qid) + Amo 1g (bid) + 17 BQT-10 vs P + BQT-10 300mg (qid) + Amo 1g (bid) + Furazolidone 100mg (bid)] NA Wang F, et al. Furazolidone 100mg (bid)] x 10 x 10 Kuo CH, et al.18 BQT-10 vs QBQT-10 [PPI (bid)+ Bismuth subcitrate 300mg (qid) + Met 500mg [PPI (bid)+ Bismuth subcitrate 300mg (qid) + Lev 500mg NA

(qid) + Tet 500mg (qid)] x 10 (qd) + Tet 500mg (qid)] x 10 [PPI (bid) + Ranitidine bismuth citrate 220mg (bid) + Lu Q, et al.19 QBQT-14 vs DT-14 [high-dose PPI (bid) + Amo 1g (tid)] x 14 NA Rufloxacin 200mg (qd) + Furazolidone 100mg (bid)] x 14 [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Lev 500mg [PPI (bid) + Bismuth subcitrate 300mg (qid) + Lev 500mg Calhan T, et al. 20 QST-12 vs QBQT-10 NA (qd) + Met 500mg (tid)] x 7 (qd) + Tet 500mg (qid)] x 10 [PPI (bid) + Bismuth aluminum 1.3g (tid) + Cla 250mg [PPI (bid) + Bismuth aluminum 1.3g (tid) + Cla 250mg Liu X, et al.21 BQT-7 vs BQT-7 + P (bid) + Tinidazole 1g (bid) + Vitamin C] x 7 + [Vitamin C] x (bid) + Tinidazole 1g (bid) + Lactobacillus acidopilus] x 7 NA 84 + [Lactobacillus acidopilus] x 84 [PPI (bid) + Bismuth subcitrate 120mg (qid) + Met 500mg Moon JY, et al. 22 QTT-7 vs BQT-7 [PPI (bid) + Lev 500mg (qd) + Met 500mg (tid)] x 7 NA (tid)+ Tet 500mg (qid)] x 7 [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Moxi 400mg Bago J, et al.23 QTT-10 vs QST-10 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 10 NA (qd) + Met 400mg (bid)] x 5 [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) Yoon JH, et al.24 BQT-7 vs BQT-14 NA + Met 500mg (tid) + Tet 500mg (qid)] x 7 + Met 500mg (tid) + Tet 500mg (qid)] x 14 [PPI (bid) + Bismuth subcitrate 220 mg (bid)+ Amo 1g [PPI (bid) + Amo 1g (bid)] x 5 + [PPI (bid) + Lev 200mg He Y, et al.25 BQT-7 vs QST-10 NA (bid) + Cla 500mg (bid)] x 7 (bid) + Cla 500mg (bid)] x 5 [PPI (bid) + Lev 500mg (bid) + Amo 1g (bid) + Ojetti V, et al.26 QTT-7 vs QTT-7 + P [PPI (bid) + Lev 500mg (bid) + Amo 1g (bid)] x 7 NA Lactobacillus reuteri] x 7 + [Lactobacillus reuteri] x 7 Chuah SK, et al.27 TT-14 vs QTT-7 [PPI (bid) + Amo 1g (bid) + Tet 500mg (qid)] x 14 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 7 NA [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) Chuah SK, et al.28 QTT-14 vs BQT-14 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 14 NA + Met 250mg (qid) + Tet 500mg (qid)] x 14 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid) + Will yogurt] x 14 + [Will yogurt] x 14 Yoon H, et al.29 QTT-14 vs QTT-14 + P [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 14 (Will yogurt: L. acidophilus HY 2177, L. casei HY 2743, NA Biﬁdobacterium longum HY 8001, Streptococcus thermophilus B-1) Hu TH, et al.30 QTT-7 vs TT-14 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 7 [PPI (bid) + Amo 1g (bid) + Met 250mg (qid)] x 14 NA [PPI (bid) + Bismuth subcitrate 300mg (qid) + Met 500mg [PPI (bid) + Bismuth subcitrate 300mg (qid) + Met 500mg 31 BQT-7 vs BQT-14 NA Chung JW, et al. (tid) + Tet 500mg (qid)] x 7 (tid) + Tet 500mg (qid)] x 14 [PPI (bid) + Lev 200mg (bid)] x 5 + [PPI (bid) + [PPI (bid) + Bismuth 1.3g (tid) + Met 400mg (bid) + Amo Zhang CH, et al.32 QST-10 vs BQT-7 NA Furazolidone 100mg (bid) + Cla 500mg (bid)] x 5 1g (bid)] x 7 [PPI (bid) + Bismuth 150mg (tid) + Met 400mg (bid) + Cla Zheng XL, et al.33 QTT-7 vs BQT-7 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 7 NA 500mg (bid)] x 7 [PPI (bid) + Bismuth subcitrate 240mg (bid) + Ofloxacin [PPI (bid) + Bismuth subcitrate 240mg (bid) + Amo 1g Minakari M, et al.34 QBQT-14 vs BQT-14 NA 200mg (bid) + Azithromycin 250mg (bid)] x 14 (bid) + Cla 500mg (bid)] x 14 [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) Lee BH, et al.35 BQT-7 vs BQT-14 NA + Met 500mg (tid) + Tet 500mg (qid)] x 7 + Met 500mg (tid) + Tet 500mg (qid)] x 14 [PPI (bid) + Bismuth subcitrate 120mg (qid) + Met 250mg Kuo CH, et al.36 BQT-7 vs QTT-7 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 7 NA (qid) + Tet 500mg (qid)] x 7 Karatapanis S, et [PPI (bid) + Bismuth 120mg (qid) + Met 500mg (tid) + Tet QTT-10 vs BQT-10 [PPI (bid) + Lev 500mg (bid) + Amo 1g (bid)] x 10 NA al.37 500mg (tid)] x 10 Di Caro S, et al.38 QTT-7 vs QTT-10 [PPI (bid) + Lev 500-1000mg (qd) + Amo 1g (bid)] x 7 [PPI (bid) + Lev 500-1000mg (qd) + Amo 1g (bid)] x 10 NA Bago J, et al.39 QTT-7 vs BQT-7 [PPI (bid) + Moxi 400mg (qd) + Met 500mg (tid)] x 7 [PPI (bid) + Colloidal bismuth subcitrate 120mg (qid) + NA

Met 500mg (tid) + Tet 500mg (qid)] x 7 [PPI (bid) + Bismuth 120mg (tid) + Met 500mg (tid) + Tet Tran TT, et al.40 QTT-10 vs BQT-14 [PPI (bid) + Lev 250mg (bid) + Amo 1g (bid)] x 10 NA 500mg (tid)] x 14 [PPI (bid) + Bismuth subcitrate 600mg (bid) + Met 500mg Jung HS, et al.41 QTT-7 vs BQT-7 [PPI (bid) + Lev 300mg (bid) + Amo 1g (bid)] x 7 NA (bid) + Tet 500mg (qid)] x 7 [PPI (bid) + Bismuth subcitrate 240mg (bid) + Doxycycline [PPI (qd) + Lev 500mg (qd) + Furazolidone 400mg (qd)] x Sanches B, et al.42 BQT-10 vs QTT-10 NA 100mg (bid) + Furazolidone 200mg (bid)] x 10 10 Navarro-Jarabo JM, [PPI (bid) + Bismuth citrate 120mg (qid) + Met 500mg (tid) RTT-7 vs BQT-7 [PPI (bid) + Amo 1g (bid) + Rifabutin 150mg (bid)] x 7 NA et al.43 + Tet 500mg (tid)] x 7 [Ranitidine bismuth citrate 400mg (bid) + Met 250mg (qid) Gisbert JP, et al.44 BQT-7 vs QTT-7 [PPI (bid) + Lev 500mg (bid) + Amo 1g (bid)] x 7 NA + Tet 500mg (qid)] x 7 [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) Kang JM, et al.45 QTT-10 vs BQT-14 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 10 NA + Met 500mg (tid) + Tet 500mg (qid)] x 14 [PPI (bid) + Lev 500mg (qd) + Azithromycin 500mg (qd)] x [PPI (bid) + Bismuth 120mg (qid) + Met 500mg (tid) + Tet 46 QTT-7 vs BQT-7 NA Kang MS, et al. 7 500mg (qid)] x 7 [PPI (bid) + Tripotassium dicitrate bismuthate 300mg (qid) Cheon JH, et al.47 QTT-7 vs BQT-7 [PPI (bid) + Moxi 400mg (qd) + Amo 1g (bid)] x 7 NA + Met 500mg (tid) + Tet 500mg (qid)] x 7 [AB-yogurt] x 28 + [PPI (bid) + Bismuth subcitrate 120mg [PPI (bid) + Bismuth subcitrate 120mg (tid) + Amo 1g (tid) + Amo 1g (bid) + Met 500mg (bid)] x 7 Sheu BS, et al.48 BQT-7 vs P + BQT-7 NA (bid) + Met 500mg (bid)] x 7 (AB-yogurt: L. acidophilus La5, Bifidobacterium lactis Bb12, L. bulgaricus, Streptococcus thermophilus) [PPI (bid) + Bismuth subcitrate 120mg (qid) + Met 250mg [PPI (bid) + Cla 500mg (bid) + Met 250mg (qid)+ Tet Wu DC, et al.49 BQT-7 vs CT-7 NA (qid) + Tet 500mg (qid)] x 7 500mg (qid)] x 7 [PPI (bid) + Bismuth subcitrate 120mg (qid) + Met 500mg [PPI (bid) + Bismuth subcitrate 120mg (qid) + Met 500mg Mantzaris GJ, et al.50 BQT-7 vs BQT-14 NA (tid) + Tet 500mg (qid)] x 7 (tid) + Tet 500mg (qid)] x 14 [PPI (qd) + Ranitidine bismuth citrate 400mg (bid) + Amo [PPI (qd) + Ranitidine bismuth citrate 400mg (bid) + Amo Tursi A, et al.51 BQT-10 vs BQT-10 (P) 1g (tid) + Tinidazole 500mg (bid) + Lactobacillus casei NA 1g (tid) + Tinidazole 500mg (bid)] x 10 DG] x 10 QTT-10 vs BQT-7 vs [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)/Tinidazole [PPI (bid) + Bismuth 120mg (qid) + Met 500mg (tid) + Tet [PPI (bid) + Bismuth 120mg (qid) + Met 500mg (tid) + Tet Nista EC, et al.52 BQT-14 500mg (bid)] x 10 500mg (qid)] x 7 500mg (qid)] x 14 [PPI (bid) + Bismuth citrate 240mg (bid) + Met 500mg Perri F, et al.53 BQT-7 vs QTT-7 [PPI (bid) + Lev 500mg (qd) + Amo 1g (bid)] x 7 NA (bid) + Tet 500mg (qid)] x 7 [PPI (qid) + Bismuth subsalicylate (qid) + Met 250mg (qid) Magaret N, et al.54 TT-14 vs BQT-14 [PPI (bid) + Amo 1g (bid) + Cla 500mg (bid)] x 14 NA + Tet 250mg (qid)] x 14 PPI, proton pump inhibitor; Amo, amoxicillin; Met, Metronidazole; Cla, Clarithromycin; Tet, Tetracycline; Lev., Levofloxacin; Moxi, Moxifloxacin; qd, quaque die; bid, bis in die; tid, ter in die; qid, quater in die; NA, not available.

Supplementary Table 5. Risk of Bias for Randomised Trials of Second- line H. pylori Eradication Therapies

Deviations from Randomization Missing outcome Measurement of Selection of the Author Year intended Overall Bias process data the outcome reported result interventions Jin L, et al.1 2018 Some concerns Some concerns Low risk Low risk Low risk Some concerns Liou JM, et al.2 2018 Some concerns Low risk Low risk Low risk Low risk Some concerns Wu TS, et al.3 2017 Some concerns Some concerns Low risk Low risk Low risk Some concerns Lu JH, et al.4 2017 Some concerns Some concerns Some concerns Low risk Low risk Some concerns Munteanu D, et al.5 2017 Some concerns Some concerns High risk Low risk Low risk High risk Hsu PI, et al.6 2017 Low risk Low risk Low risk Low risk Low risk Low risk Chuah SK, et al.7 2016 Low risk Low risk Low risk Low risk Low risk Low risk Kwon YH, et al.8 2016 High risk Low risk Low risk Low risk Low risk High risk Peng W, et al.9 2016 Some concerns Low risk Low risk Low risk Low risk Some concerns Liou JM, et al.10 2016 Low risk Low risk Low risk Low risk Low risk Low risk Yu H, et al.11 2016 Some concerns Low risk Low risk Low risk Low risk Some concerns Wang JX, et al. 12 2015 Some concerns Low risk Low risk Low risk Low risk Some concerns Zeng LN, et al.13 2015 Some concerns High risk High risk Low risk Some concerns High risk Jheng GH, et al.14 2015 Some concerns Low risk Low risk Low risk Low risk Some concerns Hung IF, et al.15 2015 Some concerns Some concerns Low risk Low risk Some concerns Some concerns Huang H, et al.16 2014 Some concerns Low risk Low risk Low risk Low risk Some concerns Wang F, et al.17 2014 Some concerns Low risk Low risk Low risk Low risk Some concerns Kuo CH, et al.18 2013 Low risk Low risk Low risk Low risk Low risk Low risk Lu Q, et al.19 2013 Some concerns Low risk Low risk Low risk Low risk Some concerns Calhan T, et al. 20 2013 Some concerns Low risk Low risk Low risk Low risk Some concerns Liu X, et al.21 2013 Some concerns Low risk Low risk Low risk Low risk Some concerns Moon JY, et al. 22 2013 Some concerns High risk Low risk Low risk Low risk High risk Bago J, et al.23 2013 Some concerns Low risk Low risk Low risk Low risk Some concerns Yoon JH, et al.24 2012 Some concerns Some concerns Low risk Low risk Some concerns Some concerns He Y, et al.25 2012 Some concerns Low risk Low risk Low risk Low risk Some concerns Ojetti V, et al.26 2012 Some concerns Low risk Low risk Low risk Low risk Some concerns Chuah SK, et al.27 2012 Low risk Low risk Low risk Low risk Low risk Low risk Chuah SK, et al.28 2012 Low risk Low risk Low risk Low risk Some concerns Some concerns Yoon H, et al.29 2011 Some concerns Some concerns Low risk Low risk Low risk Some concerns Hu TH, et al.30 2011 Low risk Low risk Low risk Low risk Low risk Low risk Chung JW, et al.31 2011 Low risk Some concerns Low risk Low risk Low risk Some concerns Zhang CH, et al.32 2011 Some concerns Low risk Low risk Low risk Low risk Some concerns Zheng XL, et al.33 2010 High risk Some concerns Low risk Low risk Low risk High risk Minakari M, et al.34 2010 Low risk Low risk Low risk Low risk Low risk Low risk Lee BH, et al.35 2010 Some concerns Some concerns Low risk Low risk Low risk Some concerns Kuo CH, et al.36 2009 Low risk Some concerns Low risk Low risk Low risk Some concerns Karatapanis S, et al.37 2009 Some concerns Low risk Low risk Low risk Low risk Some concerns Di Caro S, et al.38 2009 High risk Low risk Low risk Low risk Low risk High risk Bago J, et al.39 2009 Some concerns Some concerns Low risk Low risk Low risk Some concerns Tran TT, et al.40 2009 High risk Low risk Low risk Low risk Low risk High risk Jung HS, et al.41 2008 Some concerns Some concerns Low risk Low risk Low risk Some concerns Sanches B, et al.42 2008 Some concerns Low risk Low risk Low risk Low risk Some concerns Navarro-Jarabo JM, et al.43 2007 Some concerns Low risk Low risk Low risk Low risk Some concerns Gisbert JP, et al.44 2007 Some concerns Some concerns Low risk Low risk Low risk Some concerns Kang JM, et al.45 2007 Some concerns Some concerns Low risk Low risk Low risk Some concerns Kang MS, et al.46 2006 Some concerns Low risk Low risk Low risk Low risk Some concerns Cheon JH, et al.47 2006 Some concerns Some concerns Low risk Low risk Low risk Some concerns Sheu BS, et al.48 2006 Some concerns Low risk Low risk Low risk Low risk Some concerns Wu DC, et al.49 2006 Some concerns Low risk Low risk Low risk Low risk Some concerns Mantzaris GJ, et al.50 2005 Low risk Some concerns Low risk Low risk Low risk Some concerns Tursi A, et al.51 2004 Some concerns Low risk Low risk Low risk Low risk Some concerns Nista EC, et al.52 2003 Some concerns Low risk Low risk Low risk Low risk Some concerns Perri F, et al.53 2003 Some concerns Low risk Low risk Low risk Low risk Some concerns Magaret N, et al.54 2001 Some concerns High risk Low risk Low risk Low risk High risk NI, no information.

Supplementary Table 6. Design Inconsistency of Second-line H. pylori Eradication Therapies

Outcomes of second-line H. pylori eradication therapies Chi-square P value for test of global inconsistency

Efficacy (Overall) 14.19 0.77

Efficacy (Clarithromycin Resistance ≥ 15%) 14.15 0.78

Efficacy (Levofloxacin Resistance ≥ 15%) 6.01 0.95

Efficacy (Failure of First-line Triple Therapy) 12.91 0.46

Dropout Rate (Overall) 21.61 0.30

Supplementary Table 7. Loop Inconsistency of Second-line H. pylori Eradication Therapies

Outcomes of second-line H. pylori eradication therapies Chi-square P value for test of global inconsistency

Efficacy (Overall) 11.78 0.62

Efficacy (Clarithromycin Resistance ≥ 15%) 11.89 0.62

Efficacy (Levofloxacin Resistance ≥ 15%) 3.00 0.98

Efficacy (Failure of First-line Triple Therapy) 14.00 0.23

Dropout Rate (Overall) 16.83 0.27

Supplementary Table 8. Side-splitting Inconsistency of Second-line H. pylori Eradication Therapies

Comparison p-value Comparison p-value Efficacy (Overall) Efficacy (CLA ≥ 15%) A B 0.19 A B 0.23 A E - A E - A H 0.58 A H 0.76 A I 0.04 A I 0.03 A K 0.73 A K 0.72 A M 0.99 A M 0.99 A N 0.55 A N 0.47 A O 0.56 A O 0.58 B C 0.73 B C 0.80 B D 0.93 B D 0.93 B F 1.00 B F 1.00 B I 0.39 B I 0.34 B J 0.84 B J 0.83 B K 0.22 B K 0.19 B O 0.63 B O 0.63 B P 0.98 B P 1.00 C H 0.96 C H 0.93 C P 0.75 C P 0.71 D J 0.93 D J 0.93 G J 0.99 G J 0.99 H I 0.40 H I 0.47 H N 0.91 H N 0.82 I J 0.09 I J 0.10 I K 0.66 I K 0.56 I N 0.60 I N 0.60 I O 0.39 I O 0.39 I P 0.63 I P 0.63 J K 0.35 J K 0.38 J O 0.34 J O 0.33 J P 0.29 J P 0.28 L M 0.99 L M 0.99 O P 0.55 O P 0.57

Supplementary Table 8. Side-splitting Inconsistency of Second-line H. pylori Eradication Therapies

Comparison p-value Comparison p-value Efficacy (LEV ≥ 15%) Efficacy (Failure TT) A B 0.39 A B 0.13 A E - A E - A H 0.71 A G 0.49 A K 0.99 A H 0.06 A M 0.99 A J 0.79 A N 0.14 A K 0.61 A O 0.65 A L 0.65 B C 0.77 B C 0.25 B F 1.00 B D 0.99 B I 0.97 B F 1.00 B J 0.69 B H 0.48 B K 0.26 B I 0.44 B O 0.86 B L 0.49 B P 0.94 B M 0.78 C H 0.71 C G 0.84 C P 0.93 C M 0.36 D J 0.99 G H 0.50 G J 0.99 H I 0.45 I J 0.25 H J 0.31 I K 1.00 H K 0.61 I N 0.14 H L 0.28 I O 0.65 H M 0.41 I P 0.90 I J 0.36 J K 0.30 I L 0.23 J O 0.34 I M 0.37 J P 0.20 L M 0.71 L M 0.99 O P 0.80

Supplementary Table 8. Side-splitting Inconsistency of Second-line H. pylori Eradication Therapies

Comparison p-value Dropout rate (Overall) A B 0.08 A E - A H 0.35 A I 0.78 A K 0.54 A M 1.00 A N 0.08 A O 0.78 B C 0.27 B D 0.57 B F 1.00 B I 0.98 B J 0.83 B K 0.31 B O 0.11 B P 0.43 C H 0.32 C P 0.88 D J 0.57 G J 1.00 H I 0.93 H N 0.92 I J 0.97 I K 0.63 I N 0.07 I O 0.15 I P 0.36 J K 0.27 J O 0.09 J P 0.13 L M 1.00 O P 0.26

For comparison groups of efficacy (overall), efficacy (CLA ≥ 15%), efficacy (LEV ≥ 15%), dropout rate (Overall): A: BQT-7; B: BQT-10/14; C: TT-10/14; D: ST-10; E: CT-7; F: CT-10; G: DT-14; H: QTT-7; I: QTT-10/14; J: QBQT-10/12/14; K: QST-10/12/14; L: QCT-7; M: RTT-7; N: Probiotics (After); O: Probiotics (Before); P: Probiotics (During). For comparison group of efficacy (Failure TT): A: BQT-7; B: BQT-10/14; C: TT-10/14; D: ST-10; E: CT-7; F: CT-10; G: QTT-7; H: QTT-10/14; I: QBQT- 10/12/14; J: QST-10/12/14; K: Probiotics (After); L: Probiotics (Before); M: Probiotics (During).

Supplementary Figure 1A. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)

Supplementary Figure 1B. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)

Supplementary Figure 1C. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy)

Supplementary Figure 1D. Network Comparisons Geometry of Second-line H. pylori Eradication Therapies (Dropout Rate)

Supplementary Figure 2A. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Overall)

Supplementary Figure 2B. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)

Supplementary Figure 2C. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)

Supplementary Figure 2D. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy)

Supplementary Figure 2E. Forest Plot of Direct Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Dropout Rate)

Supplementary Figure 3A. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second-line H. pylori Eradication Therapies (Overall)

Supplementary Figure 3B. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)

Supplementary Figure 3C. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)

Supplementary Figure 3D. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy)

Supplementary Figure 3E. Cumulative SUCRA Ranking Curves for Overall Efficacy of Second-line H. pylori Eradication Therapies (Dropout Rate)

Supplementary Figure 4A. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Overall)

A: BQT-7; B: BQT-10/14; C: TT-10/14; D: ST-10; E: CT-7; F: CT-10; G: DT-14; H: QTT-7; I: QTT-10/14; J: QBQT-10/12/14; K: QST-10/12/14; L: QCT-7; M: RTT-7; N: Probiotics (After); O: Probiotics (Before); P: Probiotics (During). 35

Supplementary Figure 4B. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)

Supplementary Figure 4C. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)

Supplementary Figure 4D. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy)

A: BQT-7; B: BQT-10/14; C: TT-10/14; D: ST-10; E: CT-7; F: CT-10; G: QTT-7; H: QTT-10/14; I: QBQT-10/12/14; J: QST-10/12/14; K: Probiotics (After); L: Probiotics (Before); M: Probiotics (During). 38

Supplementary Figure 4E. Comparison-adjusted Network Funnel Plot of Second-line H. pylori Eradication Therapies (Dropout Rate)

Supplementary Figure 5A. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Overall)

Supplementary Figure 5B. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)

Supplementary Figure 5C. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)

Supplementary Figure 5D. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy)

Supplementary Figure 5E. Egger's Test for Publication Bias of Second-line H. pylori Eradication Therapies (Dropout Rate)

Supplementary Figure 6A. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Clarithromycin Resistance ≥ 15%)

Supplementary Figure 6B. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Levofloxacin Resistance ≥ 15%)

Supplementary Figure 6C. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Failure of First-line Triple Therapy)

Supplementary Figure 6D. Network Forest Plot of Indirect Comparisons (ORs) of Second-line H. pylori Eradication Therapies (Dropout Rate)

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Chang Y-L, et al. BMJ Open Gastro 2020; 7:e000472. doi: 10.1136/bmjgast-2020-000472