FINAL CENSORED REPORT: Treatment for Chronic Hepatitis B. Systematic Review and Network Meta-Analysis. September 28 th, 2015

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1 FINAL CENSORED REPORT: Treatment for Chronic Hepatitis B Systematic Review and Network Meta-Analysis William W. L. Wong, Petros Pechlivanoglou, Aysegul Erman, Yasmin Saeed, Mona Younis, Noha Zaki Rayad, Joanna Bielecki, Valeria Rac, Murray D. Krahn September 28 th, Bond Street, Toronto ON, M5B 1W8 info@odprn.ca

2 Table of Contents Executive Summary... 3 Results... 9 Efficacy Virologic response ALT normalization HBeAg Loss HBeAg Seroconversion HBsAg Loss Histological improvement Comparisons among the CHB therapies Safety Serious adverse events Any adverse events Withdrawal due to adverse events Observational Studies Discussion Key Messages Reference List Appendix A: Study selection Diagrams and Search terms Appendix B: Cochrane risk of bias tool results Appendix C: Included Randomized Controlled Trial List Appendix D: Characteristics of included RCTs Appendix E: Observational Study List Appendix F: Full NMA RESULTS (EFFICACY): ODDS RATIOS FOR RANDOM EFFECTS MODEL (SIGNIFICANT IN RED FONTS) Appendix G: Full NMA RESULTS (SAFETY): ODDS RATIOS FOR RANDOM EFFECTS MODEL (SIGNIFICANT IN RED FONTS)... 84

3 3 Executive Summary Objective The objective of this review is to identify the available evidence on Randomized Controlled Trial (RCT) and observational studies investigating the comparative effectiveness and safety between the available chronic hepatitis B (CHB) treatments (standard interferon (IFN), pegylated interferon-alfa (PEG), adefovir (ADV), lamivudine (LAM), entecavir (ETV), telbivudine (LDT), and tenofovir (TDF), and their combinations) through a systematic review and synthesize this evidence using network meta-analysis. Systematic Reviews Randomized Control trial (RCT) studies A total of 5,021 studies were identified from the published literature. Upon screening the titles and abstracts, 884 potentially relevant publications were retrieved for further screening. Of the 884 potentially relevant articles, a total of 62 studies were selected for inclusion. These 62 studies were focused on mono-infected patients (40 in HBeAg positive, 22 in HBeAg negative). The total number of participants in each study ranged from 10 to 657. The overall number of included participants was 13,697. Observational Studies A total of 4,530 studies were identified from the published literature and, upon screening the titles and abstracts, 452 potentially relevant publications were retrieved for further screening. Of the 452 potentially relevant reports, a total of 52 studies were selected for inclusion. Network Meta Analyses Network meta-analyses (NMA) were conducted to estimate pooled effectiveness and safety data from the RCT studies on the following outcomes: Efficacy for HBeAg positive patients: virologic response; alanine aminotransferase (ALT) normalization; HBeAg loss; HBeAg seroconversion; and HBsAg loss; Efficacy for HBeAg negative patients: virologic response and ALT normalization. Safety: Serious adverse events, any adverse events, and withdrawal due to adverse events Results In terms of efficacy for HBeAg positive patients: LDT, TDF and ETV were found to be significantly better than LAM, PEG or IFN in terms of virologic response; TDF was also found to be significantly better than ADV, LDT, ETV, PEG and IFN in terms of virologic response. In terms of normalization of ALT, LDT was also significantly better than LAM, PEG or IFN for the HBeAg positive patients. ETV was significantly better than LAM, PEG or IFN in terms of normalization of ALT. In addition, LDT and PEG were significantly better than LAM in terms of HBeAg loss and HBeAg seroconversion. PEG was also significantly better than ETV in terms of HBeAg loss and HBeAg seroconversion.

4 4 For HBeAg negative patients: LDT, ADV, TDF and ETV were found significantly better than LAM in terms of virologic response; TDF was also found to be significantly better than ADV, LDT, PEG and IFN in terms of virologic response. In terms of normalization of ALT, only ETV was significantly better than LAM. PEG was not significantly better than IFN in terms of efficacy for both HBeAg positive and HBeAg negative patients. In terms of safety, PEG was associated with a significantly higher number of serious adverse events than LAM, LDT, and ETV. The likelihood of any adverse event was also significantly higher in studies involving PEG than LAM, PLA, ADV, LDT, TDF and ETV. Withdrawal due to adverse events was significantly less frequent in ETV compared to LAM and PEG.Other than these, there was no significant difference was found between oral agents in terms of safety. Conclusion Our systematic review of RCT studies and network meta-analysis show that for HBeAg positive patients, tenofovir is the most effective treatment followed by entecavir, in terms of virologic response and ALT normalization. In terms of HBeAg loss and HBeAg seroconversion, pegylated interferon is the most effective treatment. In terms of HBsAg loss, pegylated interferon is the most effective treatment followed by tenofovir. For HBeAg negative patients, tenofovir is also the most effective treatment, followed by adefovir and entecavir, in terms of virologic response and ALT normalization. Findings of the observational studies show that the probability of achieving virologic response and ALT normalization in a real-world setting is high among the oral agents assessed, while the probability of achieving HBeAg loss, HBeAg seroconversion, and HBsAg loss was generally low. However, direct comparisons between the treatments with respect to their relative effectiveness could not be achieved through the observational studies. More research on the comparative effectiveness of the treatments in a real-world setting is needed.

5 5 Efficacy and Safety Systematic Review Literature Search Strategy The literature search was performed by an information specialist using a peer-reviewed search strategy (Appendix A). Published literature was identified by searching the following bibliographic databases: Ovid MEDLINE (1946 ), Ovid MEDLINE In-Process; Ovid Embase (1974 ); the Cochrane Central Register of Controlled Trials; and Web of Science: Science Citation Index Expanded (1900-) and Conference Proceedings Citation Index- Science (1990-). Our search started from the date of inception of each database until October 29, Search terms included controlled vocabulary (MeSH) and text-words in the following three concept areas: chronic hepatitis B (CHB), antiviral agents (standard interferon, pegylated interferon, lamivudine, adefovir, entecavir, telbivudine, tenofovir) and the following published and validated filters were applied consecutively: Randomized Control Trials (RCTs) 1 or Prognosis studies 2 or Causation (Etiology) studies 3 or Cohort and case-control studies 4. Selection Criteria and Methods The systematic review included RCTs and observational studies (i.e. case-control and cohort studies) that compared at least two CHB treatments or placebo/no treatment in adults patients diagnosed with HBeAg-positive and/or HBeAg-negative CHB. Studies were selected for inclusion in the systematic review based on the selection criteria presented in Table 1 and 2. The review included treatment options of standard and pegylated interferon-alfa, lamivudine, adefovir, entecavir, telbivudine, and tenofovir as monotherapy or combination therapy. Table 1: Inclusion and Exclusion Criteria for Randomized Controlled Trials Inclusion Criteria Population Adult patients diagnosed with HBeAg-positive and/or HBeAg-negative CHB Treatment of interest (TO) standard interferon (IFN) pegylated interferon (PEG) lamivudine (LAM) adefovir (ADV) entecavir (ETV) telbivudine (LDT) tenofovir (TDF) Comparators Treatment of interest (TO) can be monotherapy or combination therapy TO v. placebo TO v. TO (different TO)

6 6 Inclusion Criteria Outcomes (Efficacy) virologic response alanine aminotransferase (ALT) normalization HBeAg loss HBeAg seroconversion HBsAg loss histologic improvement Outcomes (Safety) serious adverse events any adverse events withdrawals due to adverse events Study design Published, randomized, controlled interventional studies Exclusion Criteria Studies that did not meet the aforementioned selection criteria; provided results of a qualitative study; or were follow-up, extension, or observational studies. Duplicate publications, narrative reviews, and editorials were also excluded. Additional criteria include: Studies not conducted in English Uncontrolled non-randomized studies Studies breaking randomization treatment duration shorter than 48 weeks treatment experienced population > 50% Table 2: Inclusion and Exclusion Criteria for Observational studies Inclusion Criteria Population Adults patients diagnosed with HBeAg-positive and/or HBeAg-negative CHB Interventions standard interferon (IFN) pegylated interferon (PEG) lamivudine (LAM) adefovir (ADV) entecavir (ETV) telbivudine (LDT) tenofovir (TDF)

7 7 Inclusion Criteria Comparators Treatment of interest (TO) can be monotherapy or combination therapy Outcomes (Efficacy) virologic response alanine aminotransferase (ALT) normalization HBeAg loss HBeAg seroconversion HBsAg loss histologic improvement Outcomes (Safety) serious adverse events withdrawals due to adverse events any adverse events Study design Published, randomize but not included in NMA, non-randomized, controlled or uncontrolled, prospective, retrospective interventional studies. Exclusion Criteria Studies that did not meet the aforementioned selection criteria; provided results of a qualitative study; Duplicate publications, narrative reviews, and editorials were also excluded. Additional criteria include: Studies not conducted in English Uncontrolled non-randomized studies Less than 50 patients in the study scientific abstract treatment duration shorter than 48 weeks treatment experienced population > 50% Study selection and screening process Two reviewers independently screened the titles and abstracts of the studies identified by the search strategy to determine if they met the inclusion criteria, using a hierarchical screening method adapted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 5. Subsequently, the full text of the eligible studies was assessed by the same reviewers independently to determine if they met the inclusion criteria. Disagreements between the two reviewers at any stage of the study selection process were resolved with discussion. Clinical experts were consulted and existing systematic reviews and meta-analysis were reviewed to identify any relevant studies that were not identified through the screening process.

8 8 Data Analysis Methods The characteristics of randomized identified studies were presented narratively while the patient characteristics of the identified studies were pooled separately for RCTs and observational studies to create descriptive summary estimates for the synthesized population. For patient characteristics that could not be pooled, the estimates from each study were narratively described. Risk of bias for each study and bias domain were accessed. Network meta-analysis (NMA) methods were used to synthesize the evidence from the RCTs identified on relative effectiveness and safety across the treatment options. Binomial NMA models were applied for all the outcomes. The NMA was conducted within a Bayesian framework using WinBUGS v (MRC Biostatistics Unit, Cambridge, England) 6. Under this framework the distribution of each parameter of interest (posterior distribution) was estimated through a Markov Chain Monte Carlo simulation method. Both fixed and random effect models were considered based on the data availability in the included studies. Mean or median estimates for the parameters of interest together with their 95% credible intervals were constructed from the posterior distributions of the MCMC simulations. An important assumption underlying network meta-analysis is that of consistency between the direct and indirect evidence of relative efficacy, safety and tolerability. Any presence of inconsistency in closed loops was visually assessed using coherence plots 7, which statistically compares the similarity of the pooled estimates from the direct evidence to those from indirect evidence. Sensitivity analyses were performed to assess the impact of assumptions related to the type of model (fixed vs random) and the prior distributions of the model (e.g. informative vs vague, type of distribution assumed etc.) on the estimates of relative efficacy and safety.

9 9 Results Selection of Randomized Control trials A total of 5,021 studies were identified from the original literature. Upon screening the titles and abstracts, 884 potentially relevant publications were retrieved for further screening. Of the 884 potentially relevant articles, a total of 62 studies, were selected for inclusion (See Appendix B for Risk of bias for each study, and Appendix C for the included study characteristics). These 62 studies were for mono-infected patients (40 in HBeAg positive 8-47, 22 in HBeAg negative 22,25,27,29,32,34,37,43,44, Table 3 summarizes the included studies by interventions according to the HBeAg status. Table 3: Summary of Interventions Evaluated Interventions Publications (n) DB RCT (n) Patients (n) Publication Years Included in the NMA HBeAg Positive Patients Lamivudine (LAM) Adefovir (ADV) Telbivudine (LDT) Tenofovir (TDF) Entecavir (ETV) pegylated interferon (PEG) Conventional interferon (IFN) Combination therapies TOTAL 40* 18* 10,071 HBeAg Negative Patients Lamivudine (LAM) Adefovir (ADV) Telbivudine (LDT) Tenofovir (TDF)

10 10 Interventions Publications (n) DB RCT (n) Patients (n) Publication Years Entecavir (ETV) pegylated interferon (PEG) Conventional interferon (IFN) Combination therapies TOTAL 22* 12* 3,616 *unique publication/study Abbreviations: DB RCT: Double Blind Randomized Controlled Trial The total number of participants in each study ranged from 10 to 657. The overall number of included participants was 13,697. See Appendix D for participant baseline characteristics.

11 11 Efficacy Network meta-analyses (NMA) were conducted for 5 efficacy outcomes in HBeAg positive patients: virologic response; alanine aminotransferase (ALT) normalization; HBeAg loss; HBeAg seroconversion; and HBsAg loss; and NMA were conducted for 2 efficacy outcomes in HBeAg negative patients: virologic response and ALT normalization. The choice of these outcomes for NMA was based on their importance and the sufficiency of the data available to derive robust and consistent network models. To illustrate, the evidence networks for virologic response (Figure 1a: HBeAg positive patients; Figure 1b: HBeAg negative patients) and ALT normalization (Figure 2a: HBeAg positive patients; Figure 2b: HBeAg negative patients) are provided in below. Figure 1a: Evidence network for virologic response for HBeAg positive patients Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; PEGPEG2: double duration of PEG; ADV2: additional dose of ADV;

12 12 Figure 1b: Evidence network for virologic response for HBeAg negative patients Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; PEGPEG2: double duration of PEG; ADV2: additional dose of ADV; Figure 2a: Evidence network for alt normalization for HBeAg positive patients Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; PEGPEG2: double duration of PEG; ADV2: additional dose of ADV;

13 13 Figure 2b: Evidence network for alt normalization for HBeAg negative patients Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; PEGPEG2: double duration of PEG; ADV2: additional dose of ADV; A variety of doses were found in the included studies. Treatment nodes in the network were assigned based on product brand name if available and by generic formulation if brand names were not available. Trial dosing strategies were collapsed for nodes except where specifically noted in this report. As the predicted probabilities of an outcome with a given treatment are more readily understood than the odd ratios (OR) comparing treatments, based on the NMA, we estimated these posterior probabilities. A summary of the efficacy results for the posterior probability of outcomes are provided in Figure 3 for HBeAg positive patients and in Figure 4 for HBeAg negative patients.

14 Figure 3: PREDICTED posterior probability of efficacy outcomes based on network meta-analysis for HBeAg positive patients Posterior probability of patients achieved virologic response for HBeAg+ patients LAM PLA ADV LDT TDF ETV PEG IFN Posterior probability of patients achieved ALT normalization for HBeAg+ patients LAM PLA ADV LDT TDF ETV PEG IFN Posterior probability of patients achieved HBeAg loss for HBeAg+ patients LAM PLA ADV LDT TDF ETV PEG IFN

15 15 Posterior probability of patients achieved HBeAg seroconversion for HBeAg+ patients LAM PLA ADV LDT TDF ETV PEG IFN Posterior probability of patients achieved HBsAg loss for HBeAg+ patients LAM PLA ADV LDT TDF ETV PEG IFN Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir;;

16 Figure 4: Predicted posterior probability of efficacy outcomes based on network meta-analysis for HBeAg negative patients Posterior probability of patients achieved virologic response for HBeAg- patients LAM PLA ADV LDT TDF ETV PEG IFN Posterior probability of patients achieved ALT normalization for HBeAg- patients LAM PLA ADV LDT TDF ETV PEG IFN Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; Exhibit 4: Serum testosterone level, quality of life, erectile dysfunction, libido, and depression: mean (SD) differences from Placebo based on network meta-analysis

17 17 Virologic response Virologic response was defined as attainment of undetectable levels of HBV DNA as determined by the PCR test for the particular study. Threshold values for undetectable DNA levels according to method of techniques used for measurement were documented, as they could be a source of heterogeneity. Only studies where the threshold of detection was 1,000 copies/milliliter were used in the analysis of undetectable HBV DNA levels. Thirty-six of the 40 included HBeAg positive studies reported 1,000 copies/milliliter at the end of treatment / fellow up, and were included in the NMA 8-15,17,19-25,27,28,30-33,35-47,61. In particular, LAM+ETV (0.952 ( )) and TDF (0.856 ( )), were associated with an over 70% virologic response rate at the end of treatment (Table 3). Twenty-one of the 22 included HBeAg negative studies reported 1,000 copies/milliliter at the end of treatment / follow up, and were included in the NMA 22,25,27,29,32,34,37,43,44, From the NMA, TDF (0.981 ( )), was associated with an over 70% virologic response rate at the end of treatment (Table 4). Some of the included studies used more than one scale to evaluate virologic response. Undetected scales were chosen over subscales if possible. ALT normalization ALT normalization was defined as normalization of alanine aminotransferase (ALT) levels to below the upper limit of normal for that study. Of the included HBeAg positive studies, 27 studies assessed the efficacy of CHB therapies on participants ALT normalization 9,10,13,14,19-28,30,31,33,34,36-42,44,47. From the NMA, LDT (0.722 ( )) and ETV (0.741 ( )), were associated with a higher chance of achieving normalization of ALT at the end of treatment/follow-up than the other treatment therapies. (Table 3). Of the included HBeAg negative studies, 19 studies assessed the efficacy of CHB therapy on participants ALT normalization 22,25,27,29,32,34,37,44,48-55,57,59,60. From the NMA, ETV (0.846 ( )), ETV+TDF (0.874 ( )) and IFN (0.863 ( )), were associated with a higher chance of achieving normalization of ALT at the end of treatment/follow-up than the other treatment therapies (Table 4). HBeAg Loss In HBeAg positive patients, HBeAg loss were defined as undetectable, using the threshold of detection used in each corresponding study. Twenty-four studies 11,13-15,19,20,22-25,27,28,30-32,34-36,38,41,42,44,47,61 assessed the efficacy of HBeAg loss for HBeAg positive patients. From the NMA, ADV+LDT (0.423 ( )) and PEG+ADV (0.499 ( )), were associated with a higher chance of achieving HBeAg loss at the end of treatment/follow-up than the other treatment therapies. (Table 3).

18 18 HBeAg Seroconversion In HBeAg positive patients, seroconversion was defined as undetectable HBeAg and presence of anti-hbeag. Thirty studies 8,10,12-16,18-28,30-32,34,36,37,41,42,45,47,61 assessed the efficacy of HBeAg seroconversion for HBeAg positive patient. From the NMA, LAM+ETV (0.578 ( )) was associated with a higher chance of achieving HBeAg seroconversion at the end of treatment/follow-up than the other treatment therapies. (Table 3). HBsAg Loss HBeAg loss was defined as undetectable, using the threshold of detection used in each corresponding study. For the HBeAg positive patients, seventeen studies 9,14,22,24-26,28,32-35,37,38,41,45,47 assessed the efficacy of CHB therapies on HBsAg loss. From the NMA, TDF (0.202 ( )), LAM+PEG (0.246 ( )) and PEG+ADV (0.262 ( )), were associated with a higher chance of achieving HBsAg loss at the end of treatment/follow-up than the other treatment therapies. (Table 3). For the HBeAg negative patients, HBsAg loss was a rare event, and only four studies 22,29,37,60 assessed the efficacy of CHB therapies on HBsAg loss. NMA cannot be conducted due to limitation of data. Other efficacy outcomes were considered, but the data on these outcomes were limited: Histological Improvement Histological improvement of the liver was defined as a two point improvement on the Knodell inflammation score without an increase in fibrosis. In the HBeAg positive group, only eight studies assessed histological improvement as an efficacy outcome 9,14,20,24,26,27,36,37. Only four studies 27,29,37,51 assessed for the HBeAg negative patients. As the network was unstable due to limitation of the data, NMA was not performed on histological improvement for both HBeAg positive and HBeAg negative patients. HCC Incidence None of the included studies investigated HCC incidence as an outcome. Comparisons among the CHB therapies Summaries of the NMA comparisons among the included doses of CHB therapies are presented in Appendix F, for both HBeAg positive and HBeAg negative patients. Table 5 summaries the NMA comparisons among the monotherapies. In general for monotherapies:

19 19 Most of the treatment therapies are significantly better than PLA in terms of virologic response, normalization of ALT, HBeAg loss and HBeAg seroconversion. LAM for HBeAg positive patients LDT, TDF and ETV are significantly better than LAM in terms of virologic response. LDT, ETV are significantly better than LAM in terms of normalization of ALT. However, LAM is significantly better than PEG. LDT and PEG are significantly better than LAM in terms of HBeAg loss. LDT and PEG are significantly better than LAM in terms of HBeAg seroconversion. LAM for HBeAg negative patients ADV, LDT, TDF and ETV are significantly better than LAM in terms of virologic response. ETV is significantly better than LAM in terms of normalization of ALT. ADV for HBeAg positive patients LDT, TDF and ETV are significantly better than ADV in terms of virologic response. LDT and PEG are significantly better than ADV in terms of HBeAg loss. LDT for HBeAg positive patients LDT is significantly better than PEG and IFN in terms of virologic response. However, TDF is significantly better than LDT. LDT is significantly better than PEG and IFN in terms of normalization of ALT. LDT is significantly better than ETV in terms of HBeAg loss and HBeAg seroconversion. TDF for HBeAg positive patients TDF is significantly better than ETV, PEG and IFN in terms of virologic response. TDF is significantly better than PEG and IFN in terms of normalization of ALT. TDF for HBeAg negative patients TDF is significantly better than LAM, ADV, LDT, PEG and IFN in terms of virologic response. ETV for HBeAg positive patients ETV is significantly better than PEG and IFN in terms of virologic response normalization of ALT. However, PEG is significantly better than ETV in terms of HBeAg loss and HBeAg seroconversion. IFN for HBeAg positive or HBeAg negative patients PEG is NOT significantly better than IFN in terms of virologic response, normalization of ALT, HBeAg loss, HBeAg seroconversion and HBsAg loss. Note that some of the comparison have a large confidence interval due to the limitation of the data.

20 20 Table 5: NMA Results (EFFICACY): Odds ratios for Random Effects Model (Significant in Red Fonts) Odds ratios (95 % confidence interval) Tx Outcomes PLA ADV LDT TDF ETV PEG IFN HBeAg Positive LAM HBV DNA 0.09 ( ) 0.8 ( ) 2.43 ( ) ( ) 3 ( ) 0.65 ( ) 0.35 ( ) ALT norm 0.15 ( ) 0.98 ( ) 1.5 ( ) 1.53 ( ) 1.66 ( ) 0.46 ( ) 0.42 ( ) HBeAg loss 0.29 ( ) 0.79 ( ) 1.44 ( ) (-) 0.87 ( ) 1.6 ( ) 1.29 ( ) HBeAg sero 0.33 ( ) 0.87 ( ) 1.41 ( ) 0.97 ( ) 0.8 ( ) 1.51 ( ) 1.06 ( ) HBsAg loss 0.37 ( ) 0.73 ( ) 0.99 ( ) 3.78 (0-3442) 0.83 ( ) 6.56 ( ) 2.22 ( ) PLA HBV DNA 9.17 ( ) ( ) ( ) ( ) 7.47 ( ) 4.04 ( ) ALT norm 6.56 ( ) ( ) ( ) ( ) 3.1 ( ) 2.79 ( ) HBeAg loss 2.67 ( ) 4.89 ( ) (-) 2.92 ( ) 5.41 ( ) 4.37 ( ) HBeAg sero 2.64 ( ) 4.3 ( ) 2.94 ( ) 2.42 ( ) 4.58 ( ) 3.23 ( ) HBsAg loss 2.14 ( ) 2.71 ( ) ( ) 2.28 ( ) ( ) 6 ( ) ADV HBV DNA 3.02 ( ) ( ) 3.74 ( ) 0.81 ( ) 0.44 ( ) ALT norm 1.53 ( ) 1.56 ( ) 1.69 ( ) 0.47 ( ) 0.42 ( ) HBeAg loss 1.83 ( ) (-) 1.1 ( ) 2.03 ( ) 1.64 ( ) HBeAg sero 1.62 ( ) 1.11 ( ) 0.91 ( ) 1.73 ( ) 1.21 ( ) HBsAg loss 1.36 ( ) 4.83 ( ) 1.11 ( ) 9.17 ( ) 2.86 ( ) LDT HBV DNA 4.13 ( ) 1.23 ( ) 0.27 ( ) 0.15 ( ) ALT norm 1.02 ( ) 1.11 ( ) 0.31 ( ) 0.28 ( ) HBeAg loss (-) 0.6 ( ) 1.11 ( ) 0.89 ( ) HBeAg sero 0.68 ( ) 0.57 ( ) 1.07 ( ) 0.75 ( ) HBsAg loss 3.73 ( ) 0.84 ( ) 6.63 ( ) 2.21 ( ) TDF HBV DNA 0.3 ( ) 0.07 ( ) 0.04 ( ) ALT norm 1.09 ( ) 0.3 ( ) 0.27 ( ) HBeAg loss (-) (-) (-) HBeAg sero 0.83 ( ) 1.56 ( ) 1.09 ( ) HBsAg loss 0.22 ( ) 1.86 ( ) 0.57 ( ) ETV HBV DNA 0.22 ( ) 0.12 ( ) ALT norm 0.28 ( ) 0.25 ( ) HBeAg loss 1.85 ( ) 1.5 ( ) HBeAg sero 1.89 ( ) 1.32 ( ) HBsAg loss 7.66 ( ) 2.68 ( ) PEG HBV DNA 0.54 ( ) ALT norm 0.9 ( ) HBeAg loss 0.81 ( ) HBeAg sero 0.7 ( )

21 21 Odds ratios (95 % confidence interval) Tx Outcomes PLA ADV LDT TDF ETV PEG IFN HBsAg loss 0.31 ( ) HBeAg Negative LAM HBV DNA 0.21 ( ) 20.4 ( ) 3.08 ( ) ( ) 5 ( ) 3.04 ( ) 3.31 ( ) ALT norm 0.39 ( ) 2.61 ( ) 1.03 ( ) 2.51 ( ) 3.06 ( ) 1.93 ( ) 4.8 ( ) PLA HBV DNA ( ) ( ) ( ) ( ) ( ) ( ) ALT norm 6.8 ( ) 2.66 ( ) 6.56 ( ) 7.92 ( ) 4.99 ( ) ( ) ADV HBV DNA 0.15 (0-3.1) 8.05 ( ) 0.24 (0-5.32) 0.14 (0-4.1) 0.16 (0-3.8) ALT norm 0.39 ( ) 0.96 ( ) 1.16 ( ) 0.75 ( ) 1.81 ( ) LDT HBV DNA 54.8 ( ) 1.61 ( ) 0.98 ( ) 1.07 ( ) ALT norm 2.45 ( ) 2.97 ( ) 1.89 ( ) 4.64 ( ) TDF HBV DNA 0.03 (0-1.04) 0.02 (0-0.78) 0.02 (0-0.77) ALT norm 1.2 ( ) 0.77 ( ) 1.9 ( ) ETV HBV DNA 0.61 ( ) 0.66 ( ) ALT norm 0.64 ( ) 1.56 ( ) PEG HBV DNA 1.09 ( ) ALT norm 2.5 ( ) Abbreviations: Tx: Treatment; PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; HBV DNA, undetectable HBV DNA levels; ALT norm, normalization of serum alanine aminotransferase levels; HBeAg sero, hepatitis B e antigen seroconversion; HBeAg loss, hepatitis B e antigen loss; HBsAg loss, hepatitis B surface antigen loss; Histo Improv, histological improvement of the liver

22 22 Safety NMA were conducted for 3 safety outcomes: serious adverse events, any adverse events and withdrawal due to adverse events. Serious adverse events Twenty trials 9,10,12,14,25,27,29-32,34,36,37,44,47,50,51,54,55,60 reported serious adverse events (SAE; as defined by the authors). Table 6 summarizes the posterior probability of the serious adverse events, Table 7 summarizes the head-to-head comparison among mono-therapies, and Appendix G summarizes the full head-to-head comparison. In terms of serious adverse events, PEG has significantly more serious adverse events than LAM, LDT, and ETV. Any adverse events Twenty trials 9,14,17,22,25-29,31,32,34,36,37,42,44,51,54,55 reported any adverse events (AE; as defined by the authors). Table 6 summarizes the posterior probability of the any adverse events, Table 7 summarizes the headto-head comparison among mono-therapies, and Appendix G summarizes the full head-to-head comparison. In terms of any adverse events, PEG has statistically significantly more any adverse events than LAM, PLA, ADV, LDT, TDF and ETV. Withdrawal due to adverse events Seventeen trials 9-11,14,15,25,29-31,34,36,37,42,44,47,55,60 reported withdrawal due to adverse events (as defined by the authors). Table 6 summarizes the posterior probability of the withdrawal due to adverse events, Table 7 summarizes the head-to-head comparison among mono-therapies, and Appendix G summarizes the full head-to-head comparison. In terms of the results, PEG has significantly more withdrawal due to adverse events than ETV. In addition, ETV has significantly fewer withdrawal due to adverse events than LAM.

23 23 Table 6: Posterior probability of safety outcomes based on network meta-analysis Posterior probability of an outcome Treatment Any AE Serious AE Withdrawal due to AE LAM ( ) ( ) 0.02 ( ) PLA ( ) ( ) ( ) ADV ( ) ( ) ( ) LDT ( ) 0.04 ( ) ( ) TDF ( ) ( ) ( ) ETV ( ) ( ) ( ) PEG 0.93 ( ) ( ) ( ) LAMPEG ( ) ( ) ( ) LAMLDT ( ) (-) (-) PEGADV (-) ( ) ( ) ETVTDF ( ) ( ) ( ) IFNLAM (-) (-) ( ) ADVLDT (-) (-) 0.08 (0-0.64) ADV2 (-) ( ) ( ) PEGPEG ( ) ( ) (-) Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir; PEGPEG2: double duration of PEG; ADV2: additional dose of ADV;

24 24 Table 7: NMA Results (SAFTY): Odds ratios for Random Effects Model (Significant in Red Fonts) Odds ratios (95 % confidence interval) Tx Outcomes PLA ADV LDT TDF ETV PEG LAM Any AE 0.92 ( ) 1.14 ( ) 1.19 ( ) 1.18 ( ) 1.09 ( ) 6.91 ( ) Serious AE 3.85 ( ) 3.9 ( ) 0.73 ( ) 3.91 ( ) 0.85 ( ) 2.19 ( ) Withdrawal due to AE 0.45 ( ) 0.71 ( ) 0.19 (0-2.83) 0.76 ( ) 0.25 ( ) 4.2 ( ) PLA Any AE 1.24 ( ) 1.3 ( ) 1.28 ( ) 1.18 ( ) 7.54 ( ) Serious AE 1.04 ( ) 0.19 ( ) 1.02 ( ) 0.23 ( ) 0.57 ( ) Withdrawal due to AE 1.56 ( ) 0.37 ( ) 1.58 ( ) 0.54 ( ) 9.07 ( ) ADV Any AE 1.05 ( ) 1.04 ( ) 0.96 ( ) 6.1 ( ) Serious AE 0.19 (0.01-2) 0.98 ( ) 0.22 ( ) 0.57 ( ) Withdrawal due to AE 0.23 ( ) 0.98 ( ) 0.35 ( ) 5.76 ( ) LDT Any AE 0.99 ( ) 0.92 ( ) 5.82 ( ) Serious AE 5.35 ( ) 1.16 ( ) 3.01 ( ) Withdrawal due to AE 4.06 ( ) 1.29 ( ) ( ) TDF Any AE 0.93 ( ) 5.84 ( ) Serious AE 0.22 ( ) 0.57 ( ) Withdrawal due to AE 0.34 (0-11.6) 5.59 ( ) ETV Any AE 6.35 ( ) Serious AE 2.57 ( ) Withdrawal due to AE 17.3 ( ) Abbreviations: AE: adverse event; PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir

25 25 Observational Studies Selection of Observational studies A total of 4,530 studies were identified from the original literature, and, upon screening the titles and abstracts, 452 potentially relevant publications were retrieved for further screening. Of the 452 potentially relevant reports, a total of 52 studies, were selected for inclusion (See Appendix D for selection detail). Note that these studies were for mono-infected treatment naïve patients only. A summary of the included studies can be found in Table 8. A detailed description of the included observational studies can be found in Appendix E. Table 8: Summary of observational studies Interventions Publications (n) Patients (n) Publication Years Lamivudine (LAM) Adefovir (ADV) Telbivudine (LDT) Tenofovir (TDF) Entecavir (ETV) pegylated interferon (PEG) Conventional interferon (IFN) Combination therapies TOTAL 52 11,256 Abbreviations: PLA, placebo; LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir Results of Observational studies A summary of the efficacy results based on meta-analysis for the observation studies are provided in Figure 5 for both HBeAg positive and negative patients in a forest plot in terms of virologic response and normalization of ALT.

26 26 Figure 5: Meta-analyses results from observational studies proportion of patients achieved virologic response for HBeAg positive patients LAM LDT TDF ETV PEG IFN proportion of patients achieved ALT normalization for HBeAg positive patients LAM LDT TDF ETV PEG IFN proportion of patients achieved virologic response for HBeAg negative patients LAM LDT TDF ETV PEG IFN proportion of patients achieved ALT normalization for HBeAg negative patients LAM LDT TDF ETV PEG IFN Abbreviations: LAM, lamivudine; IFN, conventional interferon; PEG, pegylated interferon; LdT, telbivudine; ETV, entecavir; ADV, adefovir; TDF, tenofovir;

27 27 A total of four studies reported outcomes for IFN treatment. Only one study 65 reported virologic response (34%) and ALT normalization (34%). Two studies 62,63 reported HBeAg loss (47.1%-70%). One study 64 reported HBeAg seroconversion (20.5%-36.8%) and HBsAg loss (3.2%-5.7%). A total of five studies reported outcomes for PEG treatment. One study 69 reported virologic response (28%) for HBeAg+ patients, and three studies 67,68,70 for HBeAg- patients (19.2%-61.1%); One study 70 reported ALT normalization (27%) for HBeAg+ patients and two studies 68,70 reported for HBeAgpatients (33.3%-47%). Three studies 66,69,70 reported HBeAg loss (25%-46.7%), and one reported 69 HBeAg seroconversion (35%). A total of four studies 66,68-70 reported HBsAg loss (6.7%-13% for HBeAg+ patients; 2.8%-14% for HBeAg- patients). A total of fifteen studies 62,68,71-83 reported outcomes for LAM treatment. Five studies 71,76,78,82,83 reported virologic response (38.1%-93.1%%) for HBeAg+ patients, and six studies 68,73,75-77,81 reported for HBeAgpatients (10%-91.6%). Four studies 71,78,82,83 reported ALT normalization for HBeAg+ patients (52.6%- 83.1%) while only three studies 68,77,81 reported for HBeAg- patients (24%-72.4%). Seven studies 62,71,74,76,78,82,83 reported HBeAg loss (4.1%-80.3%), and six reported 71,74,76,78,82,83 HBeAg seroconversion (6.7%-80.3%). A total of five studies 72,73,75,79,82 reported HBsAg loss (0%-2.1% for HBeAg+ patients; 4.8%-11.7% for HBeAg- patients). Five studies 74,84-87 reported outcomes for LDT treatment. Four studies reported virologic response (25.6%-85.7%) for HBeAg+ patients, and three studies 84,86,87 reported for HBeAg- patients (77.2%- 93.1%). Three studies reported ALT normalization for HBeAg+ patients (81.0%-100%) while only two studies 84,86 reported for HBeAg- patients (79.3%-82.8%). Two studies 74,84 reported HBeAg loss (13.3%- 51.9%), and three 74,84,86 reported HBeAg seroconversion (8.9%-57.1%). A total of two studies 84,86 reported HBsAg loss (0%-1.6% for HBeAg+ patients; 0% for HBeAg- patients). Only two studies 88,89 for TDF were included. The main reason for exclusion was co-infection. Among this two studies, virologic response was reported (71.4%-72% for HBeAg+ patients and 27.3%-91% for HBeAg- patients). ALT normalization (82% for HBeAg+ patients and 70% for HBeAg- patients) and HBeAg seroconversion (5.1%) were reported from one study 88. A total of seventeen studies 86,88, reported outcomes for ETV treatment. Thirteen studies 86,88,91-97,99,100,103,104 reported virologic response (39%-82.5%) for HBeAg+ patients, and eleven studies 86,88,91-95,97,98,100,104 reported for HBeAg- patients (61.7%-100%). Nine studies 86,88,93-97,99,103 reported ALT normalization for HBeAg+ patients (31.4%-98%) while only six studies 86,93-95,97,98 reported for HBeAgpatients (60.9%-95%). Seven studies reported 91,94-97,99 HBeAg loss (3.5%-48.9%), and six reported 88,90,93,97,99 HBeAg seroconversion (2.2%-68%). A total of three studies 86,93,98 reported HBsAg loss (0% for both HBeAg+ patients and HBeAg- patients). Only three observation studies 68,69,99 reported for outcomes for combination treatment. The combination included PEG+LAM and LAM+ADV.

28 28 Discussion In this study, we identified the available evidence on comparable benefits and harms of the available CHB treatments through systematic reviews and synthesized this evidence using network metaanalysis (NMA). We used NMA to evaluate the relative efficacy of all available treatments across 5 surrogate clinical outcomes and 3 safety outcomes. We consolidated the information of all RCTs that included the treatments of interest to provide the probability of an outcome. The framework of our analysis was largely based on our previous publication 105. We expanded our review to studies with a standard interferon arm as well as to scientific abstracts. The total number of the included RCT studies in the NMA was increased from 15 to 40 for HBeAg positive patients, and from 8 studies to 22 studies for HBeAg negative patients. With additional evidence serving as input to the NMA, our study was able to provide narrower confidence intervals than the previous study. However, the main conclusion on most of the results did not change. In terms of mono-therapies, TDF, ETV and LDT were still the most effective in terms of virologic response and ALT normalization for HBeAg positive patients; TDF, ETV and ADV were the most effective treatments in terms of the same outcomes for HBeAg negative patients. In the five years since our previous review, a number of combination therapies studies were conducted and reported. New combination therapies included ADV+LDT, ETV+LAM and ETV+TDF. Our study had limitations. Firstly, given that our review was limited to studies written in English, a number of useful studies that were written in other languages might have been ignored. For example, a number of clinical studies of CHB have been conducted and published in Chinese and Japanese. Other limitations include variation in outcome definition, especially in terms of virologic response viral load, duration of study treatment and follow up and patient characteristics. These variations may increase the risk of bias in the NMA estimates. In addition, the number of studies included for some pair-wise comparisons was small. This is particularly true for tenofovir, standard interferon and most of the combination therapies. Thus, it will create wide confidence intervals in the NMA for these therapies. Statistical significant inconsistency was not observed within the networks. However, some of the inconsistency estimates presented wide confidence intervals, indicating the likelihood of a type II error in some of the inconsistency tests. We were not able to test for heterogeneity and subgroup analysis due to time constraints. Finally, NMAs for some of the outcomes with rare events that were infrequently reported were characterized by large parameter uncertainty especially in indirect comparisons. The comparisons in these outcomes were also limited due to lack of connectivity in the study network for some of the treatments. In conclusion, our systematic review of RCT studies and network meta-analysis show that for HBeAg positive patients, tenofovir is the most effective treatment followed by entecavir, in terms of virologic response and ALT normalization. In terms of HBeAg loss and HBeAg seroconversion, pegylated interferon is the most effective treatment. In terms of HBsAg loss, pegylated interferon is the most effective treatment followed by tenofovir. For HBeAg negative patients, tenofovir is also the most

29 effective treatment, followed by adefovir and entecavir, in terms of virologic response and ALT normalization. Findings of the observational studies show that the probability of achieving virologic response and ALT normalization in a real-world setting is high among the oral agents assessed, while the probability of achieving HBeAg loss, HBeAg seroconversion, and HBsAg loss was generally low. However, direct comparisons between the treatments with respect to their relative effectiveness could not be achieved through the observation studies. More research on the comparative effectiveness of the treatments in a real-world setting is needed. 29 Key Messages PEG is not significantly better than IFN in both HBeAg positive and negative patients. When we compare with LAM for HBeAg positive patients, LDT, TDF and ETV are significantly better than LAM in terms of virologic response. LDT and ETV are significantly better than LAM in terms of normalization of ALT. However, LAM is significantly better than PEG in terms of normalization of ALT. LDT and PEG are significantly better than LAM in terms of HBeAg loss and HBeAg seroconversion. When we compare with LAM for HBeAg negative patients, ADV, LDT, TDF and ETV are significantly better than LAM in terms of virologic response. ETV is significantly better than LAM in terms of normalization of ALT. When we compare with TDF for HBeAg positive patients, TDF is significantly better than LAM, ADV, LDT, ETV, PEG and IFN in terms of virologic response. TDF is significantly better than PEG and IFN in terms of normalization of ALT. When we compare with TDF for HBeAg negative patients, TDF is significantly better than LAM, ADV, LDT, PEG and IFN in terms of virologic response. When we compare with PEG and IFN for HBeAg positive patients: LDT, TDF and ETV are significantly better than PEG and IFN in terms of virologic response. LDT and ETV are significantly better than PEG and IFN in terms of normalization of ALT. On the other hand, PEG is significantly better than ETV in terms of HBeAg loss and HBeAg seroconversion. In terms of safety, PEG has significantly more serious adverse events than LAM, LDT, and ETV. PEG also has statistically significantly more any adverse events than LAM, PLA,

30 ADV, LDT, TDF and ETV. PEG has significantly more withdrawal due to adverse events than ETV. LAM has significantly more withdrawal due to adverse events than ETV. Beside this, there are no significant different in terms of safety among all other oral agents. 30

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