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doi:10.1111/jgh.12835
H E PAT O L O G Y
Randomized, three-arm study to optimize lamivudine efficacy in hepatitis B e antigen-positive chronic hepatitis B patients Xieer Liang,* Jun Cheng,† Yongtao Sun,‡ Xinyue Chen,§ Tong Li,¶ Hao Wang,** Jianning Jiang,†† Xiaoping Chen,‡‡ Hui Long,§§ Hong Tang,¶¶ Yanyan Yu,*** Jifang Sheng,††† Shijun Chen,‡‡‡ Junqi Niu,§§§ Hong Ren,¶¶¶ Junping Shi,**** Xiaoguang Dou,†††† Mobin Wan,‡‡‡‡ Jiaji Jiang,§§§§ Qing Xie,¶¶¶¶ Guangfeng Shi,***** Qin Ning,††††† Chengwei Chen,‡‡‡‡‡ Deming Tan,§§§§§ Hong Ma,¶¶¶¶¶ Jian Sun,* Jidong Jia,¶¶¶¶¶ Hui Zhuang¶ and Jinlin Hou* *State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, ‡‡Department of Infectious Diseases, Guangdong General Hospital, Guangzhou, †Beijing Ditan Hospital, Capital Medical University, §Beijing Youan Hospital, Capital Medical University, ¶¶¶¶¶Liver Research Center, Beijing Friendship Hospital, Capital Medical University, ¶Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, **Hepatology Unit, Peking University People’s Hospital, ***Department of Infectious Diseases, First Hospital of Peking University, Beijing, ‡Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ††Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, §§Department of Infectious Diseases, The First People Hospital of Foshan, Foshan, ¶¶Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, †††Department of Infectious Diseases, Zhejiang University 1st Affiliated Hospital, Hangzhou, ****The 6th People’s Hospital, Hangzhou, ‡‡‡Jinan Infectious Diseases Hospital, Ji’nan, §§§ Hepatology Unit, No. 1 Hospital Affiliated to Jilin University, Changchun, ¶¶¶Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, ††††Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, ‡‡‡‡ Department of Infectious Diseases, Changhai Hospital, The Second Military Medical University, ¶¶¶¶Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, *****Department of Infectious Diseases, Huashan Hospital, Fudan University, ‡‡‡‡‡ Department of Infectious Diseases, 85th People’s Liberation Army Hospital, Shanghai, §§§§Liver Center, First Affiliated Hospital of Fujian Medical University, Fuzhou, †††††Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, and §§§§§Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
Key words adefovir dipivoxil, hepatitis B e antigen, lamivudine, optimization strategy, virological response. Accepted for publication 14 October 2014. Correspondence Prof Jinlin Hou, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Email: [email protected] Declaration of conflict of interest: Q Ning has been a member of Advisory Committees or Review Panels; received consulting fees from Roche, Novartis, GlaxoSmithKline, Bristol-Myers Squibb; and has received grant/research support from Roche, Novartis, and Bristol-Myers Squibb. J Sheng has received grant/research support from Roche. J Jia has acted as a consultant for Novartis, Bristol-Myers Squibb, and Roche. J Hou has received consulting fees from Roche, Novartis, GlaxoSmithKline, and Bristol-Myers Squibb and has received grant/research support from Novartis. The other authors declare that they have no conflicts of interest. Funding: This study was funded by the National Science and Technology Major Project of China (2012ZX10002003).
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Abstract Background and Aim: Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE). Methods: Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 105 copies/mL, alanine aminotransferase 1.3–10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed. Results: At week 104, more patients in COMBO and OPTIMIZE groups achieved HBVDNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV-DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.5%). Patients under MONO with early virological response showed superior efficacy at week 104 (HBV-DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated. Conclusion: Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg-positive CHB patients. In lamivudinetreated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development. Author contributions: J Hou is the guarantor of the article. J Hou, J Jia, and J Sun were involved in the study design. X Liang, J Cheng, Y Sun, X Chen, T Li, H Wang, J Jiang, X Chen, H Long, H Tang, Y Yu, J Sheng, S Chen, J Niu, H Ren, J Shi, X Dou, M Wan, J Jiang, Q Xie, G Shi, Q Ning, C Chen, D Tan, H Ma, J Sun, J Jia, and H Zhuang collected data. J Hou, J Sun, and X Liang analyzed and interpreted the data and wrote the article. All authors had full access to the final version of the report and approved the submission.
Journal of Gastroenterology and Hepatology 30 (2015) 748–755 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
X Liang et al.
Optimization of lamivudine therapy
Introduction
Methods
Oral antiviral agents (nucleoside or nucleotide analogues) has been extensively proved to be an effective and potent way to inhibit hepatitis B virus (HBV) replication,1 which contributes to the reversion of liver fibrosis and decrease of liver complications.2–6 In spite of the convenient and well-tolerated virtue of oral antiviral agents, long-term antiviral therapy is usually needed to achieve durable viral suppression.5,7,8 The high genetic barrier drugs, such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), are recommended as firstline choices when initiating antiviral therapy to reduce the incidence of resistance to the extent possible.1,9 Although TDF has just been approved for chronic hepatitis B (CHB) in China, it is not yet easily accessible in mainland China. In addition, due to the high cost of TDF and ETV, low income and inadequate medical reimbursement of some patients, and an unawareness of medical care knowledge among patients and health-care departments, low genetic barrier antiviral agents, such as lamivudine (LAM) and adefovir dipivoxil (ADV), are still extensively used in China. Given the high resistance rate of treatment naïve CHB patients with lamivudine monotherapy (MONO),8,10 a previous study has been conducted to compare the antiviral efficacy of LAM monotherapy versus LAM plus ADV de novo combination therapy and demonstrated better viral control and lower resistance rate with combination therapy.11 Meanwhile, an optimization strategy, namely, the “roadmap concept,” was initially developed for low genetic barrier drugs to monitor and modify treatment strategy according to response.12,13 This strategy has been proven effective in our newly published randomized controlled study, in which, adding on ADV for suboptimal responder after 24 weeks of treatment with telbivudine (LdT) achieved significantly better viral suppression and lower resistance.14 Nevertheless, there is insufficient data to substantiate an optimization strategy for LAM therapy, compared with de novo LAM plus ADV therapy and LAM monotherapy. Therefore, the present study aimed to compare the efficacy and safety of the three abovementioned treatment strategies in hepatitis B e antigen (HBeAg)positive hepatitis B patients. The 2-year final results of this study are presented.
Study design. This was a randomized, open-label, controlled, multicenter, 2-year study in 24 centers of China from March 2010 to February 2013. Eligible patients were randomized 1:1:1 (by a central randomization center) to receive LAM plus ADV de novo combination therapy (COMBO), LAM-based optimized therapy (OPTIMIZE) or LAM monotherapy (MONO) for 104 weeks. Patients in OPTIMIZE group were initiated with LAM 100 mg once daily, and ADV 10 mg once daily was added to suboptimal responders (HBV-DNA > 1000 copies/mL [171.8 IU/mL] at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued LAM monotherapy until week 104. Patients in COMBO and MONO groups were initiated with combination therapy (LAM plus ADV) and LAM monotherapy from baseline to week 104, respectively. For all the patients receiving LAM monotherapy, ADV would be added if virological breakthrough was confirmed (Fig. 1). Clinical, laboratory, and adverse-event assessments were performed every 8–12 weeks from baseline to week 104. HBVDNA levels and HBV serological markers were measured using the Roche COBAS Taqman (Hoffmann-La Roche Ltd, Basel, Switzerland; lower limit of detection, 12 IU/mL [approximately 69.84 copies/mL]) and ARCHITECT i2000SR (Abbott Laboratoried, IL, USA) at the central laboratory set up by the research group. Virological breakthrough was defined as an increase of HBVDNA by ≥ 1 log10 above nadir on two consecutive occasions at least 1 month apart after achieving an initial response in a compliant patient. Patients who developed virological breakthrough just before withdrawing from the study (including at week 104) with no chance to confirm at least one month later were also treated as confirmed virological breakthrough cases. Genotyping and genotypic resistance, defined as virological breakthrough with identified treatment-emergent resistance mutations (M204I/V, L180M for LAM resistance; A181V/T, N236T for ADV resistance), was tested by polymerase chain reaction (PCR) sequencing at screening for all patients and at the timepoints of confirmed virological breakthrough. The study was conducted in accordance with the ethics principles of the Declaration of Helsinki and was consistent with good
Figure 1 The design of the study. Patients in OPTIMIZE (lamivudine [LAM]-based optimized therapy) group were initiated with LAM 100 mg once daily, and adefovir dipivoxil (ADV) 10 mg once daily was added to suboptimal responders (hepatitis B virus [HBV]DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued LAM monotherapy until week 104. *For all the patients receiving LAM monotherapy, ADV would be added if virological breakthrough was confirmed. CHB, chronic hepatitis B.
Journal of Gastroenterology and Hepatology 30 (2015) 748–755 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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clinical practice guidelines and applicable local regulatory requirements. Institutional approval was obtained at all clinical sites, and written informed consent was provided by all screened patients. This study has been registered with ClinicalTrials.gov identifier NCT01088009 titled Efficacy Optimizing Research of Lamivudine Therapy. Patients. Eligible patients were aged 18–65 years, with detectable hepatitis B surface antigen (HBsAg) ≥ 6 months, HBeAgpositive, and HBeAb-negative at screening, HBV-DNA levels > 105 copies/mL (1.7 × 104 IU/mL), serum alanine aminotransferase (ALT) levels ≥ 1.3 but ≤ 10 × upper limit of normal (ULN) at screening and at least one ALT > 1 × ULN episode within 6 months but ≥ 14 days before screening, and without antiviral therapy within 6 months before screening. Patients who had a history of virological breakthrough or LAM/ETV/LdT-related genotypic resistance before screening were excluded. Additional exclusion criteria included other forms of liver disease; evidence of hepatic decompensation or hepatocellular carcinoma (HCC); serum creatinine level > 1.5 mg/dL; platelet count < 80 × 109/L; prothrombin time prolonged by > 4 s; serum albumin level < 3.5 g/dL; and bilirubin level > 2.0 mg/dL. Eligible patients with serum alpha fetoprotein level > 50 ng/mL required exclusion of underlying HCC. Efficacy and safety end-points. Efficacy analyses included all randomized patients who received at least one dose of study medication (intent to treat [ITT] population). The primary efficacy end-point was the proportion of patients with virological breakthrough and LAM-associated genotypic resistance. Secondary efficacy end-points included the proportion of patients achieving HBV-DNA < 300 copies/mL (51.5 IU/mL) at week 104, the reduction of HBV-DNA level from baseline and the proportion of patients with ALT normalization, serological response, virological breakthrough, and ADV-associated genotypic resistance. Safety analyses included all patients who underwent randomization and received at least one dose of study medication and underwent at least one safety assessment after the baseline assessment. Statistical analysis. The estimated proportion of patients with virological breakthrough and LAM-associated genotypic resistance in OPTIMIZE group and MONO group were 13% and 30%, respectively. Sample size of 120 per arm was calculated to detect a significant difference between the two groups with a dropout rate up to 25%, a two-sided significance level of 5%, and the power of 80%. In efficacy analyses of virological, serological, and biochemical response, ITT population with a missing value were considered as treatment failure for these end-points, and the chi-squared/Fisher’s exact tests were used to compare differences in response rates between the treatment groups. The last observation carried forward method was used to handle the missing values for continuous variables. Unplanned post hoc statistical analysis was performed for subgroups with early virological response and suboptimal response. All P values are two-sided, and all analyses were performed with SAS version 9.2 (SAS Institute, NC, USA). 750
Results Study population. Of the 413 screened patients, 366 were eligible and underwent randomization, 358 were included in the ITT population for efficacy analyses, with 120 in COMBO group, 120 in OPTIMIZE group, and 118 in MONO group. Eight patients were excluded from ITT population because of retracting inform consent form (ICF) without receiving any study drug. The most common reasons for treatment discontinuation were patient’s request (18 subjects) and lost contact (11 subjects). At the end of the study, 112, 111, and 100 patients in each group respectively completed the 104-week treatment (Fig. 2). Treatment groups were well matched at baseline with respect to demographics and other characteristics, with 77.1% male, 36.3% genotype B and 63.1% genotype C, mean baseline HBV-DNA level 8.6 log10 copies/mL, and mean ALT level 3.4 × ULN in overall patients (Table 1).
Virological breakthrough and resistance. Significantly lower proportion of patients in COMBO (8.3% [10/120]) and OPTIMIZE group (22.5% [27/120]) had virological breakthrough compared with MONO group (63.6% [75/118]). For the patients with virological breakthrough, resistance test showed that LAM-related resistance rates (M204I/V or L180M mutation) were 0.8% (1/120), 6.7% (8/120), and 58.5% (69/118) in the three groups, respectively (Table 2), accounting for 10.0% (1/10), 29.6% (8/27), and 92.0% (69/75) of patients with virological breakthrough in the three groups, respectively. Nine patients in COMBO group, 19 in OPTIMIZE group, and 6 in MONO group who developed virological breakthrough were found to have no M204I/V or L180M mutation. The possible reasons for these cases were noncompliance, low sensitivity of resistance testing, or mutations other than M204I/V or L180M. Regarding LAM-related mutation patterns, the vast majority of patients had M204I/V (50.0% [39/78]) or M204I/V + L180M (48.7% [38/78]) mutations, whereas only one had the pattern of L180M + A181V mutations from MONO group. Regarding ADVrelated mutations, only two developed ADV-related resistance. One patient in MONO group developed A181V mutation accompanied with L180M mutation at week 88 before adding on ADV. The other one in COMBO group showed A181V mutation at baseline and week 104; however, HBV-DNA declined from 2.2E + 07 copies/mL at baseline to 4.9E + 04 copies/mL at week 104 without other resistance mutations.
Virological response. At week 104, significantly more patients in COMBO and OPTIMIZE groups achieved HBVDNA < 300 copies/mL, 53.3% (64/120) in COMBO, and 48.3% (58/120) in OPTIMIZE group, respectively, compared with 34.8% (41/118) in MONO group (P = 0.012) (Table 2). Likewise, the mean reduction from baseline in serum HBV-DNA level was significantly greater in COMBO group (−5.9 log10 copies/mL) and OPTIMIZE group (−5.6 log10 copies/mL) than that in MONO group (−4.7 log10 copies/mL). Such difference occurred as early as week 36 (Fig. 3). Meanwhile, the virological responses were comparable between COMBO group and OPTIMIZE group.
Journal of Gastroenterology and Hepatology 30 (2015) 748–755 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
X Liang et al.
Optimization of lamivudine therapy
Figure 2 Flowchart of the study. COMBO; lamivudine plus adefovir dipivoxil de novo combination therapy; ICF, inform consent form; ITT, intent to treat; LOCF, last observation carried forward; MONO, lamivudine monotherapy; OPTIMIZE, lamivudine-based optimized therapy.
Biochemical and serologic response. Among patients with ALT > 1 × ULN at baseline, 80.2% (93/116) and 82.2% (97/ 118) in COMBO group and OPTIMIZE group, respectively, achieved ALT normalization at week 104, compared with 59.5% (66/111) in MONO group (P < 0.0001). Comparable proportions of patients in COMBO group, OPTIMIZE group, and MONO group achieved HBeAg loss (24.2% versus 22.5% vs 22.0%, P = 0.919) and HBeAg seroconversion (16.7% vs 14.1% vs 17.0%, P = 0.811). One patient in each treatment group achieved HBsAg loss and HBsAg seroconversion (Table 2). Efficacy in subgroups. For the patients with suboptimal response (HBV-DNA > 1000 copies/mL at week 24) in OPTIMIZE group, adding on ADV from week 30 benefited them with 44.3% (43/97) achieving HBV-DNA < 300 copies/mL at week 104 and only 6.2% (6/97) developing LAM resistance. However, for the suboptimal responder allocated to MONO group who continued LAM monotherapy, only 21.2% (18/85) achieved HBVDNA < 300 copies/mL at week 104 and as high as 72.9% (62/85) developed LAM resistance. Of the patients who achieved early response (HBVDNA ≤ 1000 copies/mL) at week 24 in OPTIMIZE (n = 22) and MONO groups (n = 30), 73.1% (38/52) had HBV-DNA < 300
copies/mL at week 104, 40.4% (21/52) achieved HBeAg seroconversion. However, 17.3% (9/52) patients experienced LAM resistance over 104-week treatment. For the 33 nucleos(t)ide analogues (NAs) experienced patients (Table 1, COMBO 11, OPTIMIZE 6, MONO 16), the subsequent resistance rate is 0%, 33.3% (2/6), and 87.5% (14/16). Although the case number is not enough to draw any conclusion, LAM plus ADV combination therapy is strongly preferred over MONO. Safety. In the ITT population, one patient in OPTIMIZE group and one in MONO group retracted ICF and did not undergo at least one safety assessment after the baseline assessment. Therefore, safety analyses were at last performed in 356 patients. Among safety population, three treatment strategies were all well tolerated over the 104-week treatment period. The total adverse events were comparable and were reported in around 30% of the patients in the three treatment arms (Table 3). Most adverse events were not related to study drug as assessed by clinical investigators. Serious adverse events, none of which was considered as drug-related, were reported in 1 (0.8%), 3 (2.5%), and 4 (3.4%) patients in COMBO, OPTIMIZE, and MONO groups, respectively (Table 3).
Journal of Gastroenterology and Hepatology 30 (2015) 748–755 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Table 1
X Liang et al.
Baseline characteristics by treatment assignment
Characteristic †
Age (years) Male, n (%) HBV genotype, n (%) B C Others (A/D) Serum ALT level (ULN) Mean ± SD Median (range) Serum HBV-DNA level (log10 copies/mL)‡ Mean ± SD Median (range) Serum HBsAg level (log10 IU/mL)‡ Mean ± SD Median (range) Treatment-experienced§, n (%)
COMBO (n = 120)
OPTIMIZE (n = 120)
MONO (n = 118)
30 (18, 58) 94 (78.3)
28 (18, 59) 93 (77.5)
31 (18, 63) 89 (75.4)
39 (32.5) 80 (66.7) 1 (0.8)
47 (39.2) 73 (60.8) 0 (0.0)
44 (37.3) 73 (61.9) 1 (0.8)
3.3 ± 2.7 2.5 (0.6, 23.0)
3.4 ± 2.1 3.1 (0.6, 11.3)
3.6 ± 2.8 2.8 (0.7, 16.6)
8.6 ± 0.9 8.7 (4.9, 10.6)
8.6 ± 0.9 8.8 (6.1, 10.3)
8.6 ± 0.9 8.8 (5.2, 10.6)
4.3 ± 0.7 4.4 (0.9, 5.4) 18 (15.0)
4.2 ± 0.6 4.2 (2.5, 5.5) 8 (6.7)
4.1 ± 0.8 4.2 (0.8, 5.5) 26 (22.0)
†
Expressed as median (range). HBV-DNA levels and HBV serological markers were measured using the Roche COBAS Taqman (lower limit of detection [LLOD], 12 IU/mL [approximately 69.84 copies/mL]) and ARCHITECT i2000SR at the central laboratory set up by the research group. § Nineteen interferon-experienced patients (median duration of treatment 184 days [range 59–426]), 16 lamivudine-experienced patients (median duration 356 days [range 61–853]), 10 adefovir dipivoxil-experienced patients (median duration 365 days [range 51–365]), 4 entecavir-experienced patients (median duration 423 days [range 365–937]), and 3 telbivuidne-experienced patients (median duration 60 days [range 60–365]). A/D, genotype A or D; ALT, alanine aminotransferase; COMBO, lamivudine plus adefovir dipivoxil de novo combination therapy; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; MONO, lamivudine monotherapy; OPTIMIZE, lamivudine-based optimized therapy; SD, standard deviation; ULN, upper limit of normal. ‡
Table 2
Efficacy results at week 104 in the ITT population
Variables †
Lamivudine resistance, n (%)* Virological breakthrough, n (%)*† Virologic response, n (%)*‡ Serum HBV-DNA (mean reduction in log10 copies/mL from baseline)* ALT normalization, n (%)*§ HBeAg loss, n (%) HBeAg seroconversion, n (%) HBsAg loss, n (%) HBsAg seroconversion, n (%)
COMBO (n = 120)
OPTIMIZE (n = 120)
MONO (n = 118)
1 (0.8) 10 (8.3) 64 (53.3) −5.9
8 (6.7) 27 (22.5) 58 (48.3) −5.6
69 (58.5) 75 (63.6) 41 (34.8) −4.7
93/116 (80.2) 29 (24.2) 20 (16.7) 1 (0.8) 1 (0.8)
97/118 (82.2) 27 (22.5) 17 (14.1) 1 (0.8) 1 (0.8)
66/111 (59.5) 26 (22.0) 20 (17.0) 1 (0.9) 1 (0.9)
*COMBO/OPTIMIZE versus MONO: P < 0.05. For categorical end-points, missing values were considered as failure. For continuous end-points, the missing values were analyzed by LOCF method. † Virological breakthrough was defined as an increase of HBV-DNA by ≥ 1 log10 above nadir on two consecutive occasions at least 1 month apart after achieving an initial response in a compliant patient. Those patients who experienced virological breakthrough just before withdrawing from this study (including at week 104) with no chance to confirm at least 1 month later were also treated as confirmed virological breakthrough cases. Resistance was defined as virological breakthrough with identified treatment-emergent resistance mutations. ‡ Virological response was defined as serum HBV-DNA < 300 copies/mL. § For patients with serum ALT > 1 × ULN at baseline (n = 116, 118 and 111 in COMBO, OPTIMIZE, and MONO groups, respectively). ALT, alanine aminotransferase; COMBO, lamivudine plus adefovir dipivoxil de novo combination therapy; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; ITT, intent to treat; LOCF, last observation carried forward; MONO, lamivudine monotherapy; OPTIMIZE, lamivudine-based optimized therapy; ULN, upper limit of normal.
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Journal of Gastroenterology and Hepatology 30 (2015) 748–755 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Optimization of lamivudine therapy
Table 3
Summary of cumulative safety data
Outcomes at week 104
Figure 3 Mean serum hepatitis B virus (HBV)-DNA (log10 copies/mL) , COMBO (lamivudine plus adefovir dipivoxil de novo over time. combination therapy; n = 120); , OPTIMIZE (lamivudine-based optimized therapy; n = 120); , MONO (lamivudine monotherapy; n = 118).
Three patients had grade 3/4 aminotransferase elevation and one had blood platelet decrease, all of which were transient. One patient in MONO group had a transient elevation of serum creatinine greater than 0.5 mg/dL at week 96 as compared with baseline. No patient had creatinine clearance rate (calculated by Cockcroft– Gault formula) less than 50 mL/min, neither did a patient need to adjust the dose of study drug.
Discussion In this study, which exclusively enrolled HBeAg-positive compensated CHB patients, LAM optimization strategy and de novo combination therapy of LAM plus ADV achieved better antiviral efficacy in terms of significantly reduced resistance rate and superior viral suppression, compared with LAM monotherapy. However, these strategies still cannot be recommended for treatment naïve patients when compared with ETV or TDF. Previous studies have confirmed that combination therapy of LAM with another noncross-resistant drug, such as peg-interferon alfa-2a or ADV, can significantly prevent the development of resistance.11,15 The results from the current randomized controlled study also confirmed the role of combination therapy in the prevention of resistance development. There was a sharp contrast of resistance rate in LAM monotherapy group and de novo combination group (58.5% vs 0.8%). However, the LAM resistance rate in combination group reported in this study (0.8%) was far lower than 15% in Sung et al.’s study,11 which can be ascribed to the difference of study design. First, the population for resistance testing is different. In our study, the presence of resistance mutation was assessed only in patients with confirmed virological breakthrough, whereas mutation assessments were performed in all enrolled patients at screening, baseline, week 16, week 52, and week 104 in Sung et al.’s study. Second, the methodology for resistance testing is different. The PCR reaction sequencing
Most frequent adverse events (≥ 2%) Any adverse event (%) Upper respiratory tract infection (%) Fatigue (%) Cough (%) Alopecie (%) Serious adverse event (%)† Death (%)‡ Grades 3/4 laboratory abnormalities (%)§ Alanine aminotransferase Aspartate aminotransferase Blood platelet degression
COMBO (n = 120)
OPTIMIZE (n = 119)
MONO (n = 117)
26.7 14.2
21.9 9.2
35.0 14.5
0.8 0.8 0.8 0.8 0.8
1.7 1.7 0 2.5 0
2.6 4.3 2.6 3.4 0
0 0 0
0 0 0
1.7 0.9 0.9
†
The outcome of SAEs were all reported as resolved without sequelae, except two (sudden deafness on the left ear and colon cancer) were reported as improved. ‡ The patient’s death was the outcome of an SAE of craniocerebral injury in a traffic accident and was considered to be not related to study drugs. § Patients are counted only once in each row. The severity of laboratory abnormalities was graded according to criteria adapted from the Division of AIDS, National Institute of Allergy and Infectious Diseases. Grades 3/4 elevations in aminotransferase levels are those > 5 times baseline; Grades 3/4 degression in blood platelet are those < 50 000/mm3. COMBO, lamivudine plus adefovir dipivoxil de novo combination therapy; MONO, lamivudine monotherapy; OPTIMIZE, lamivudinebased optimized therapy; SAEs, serious adverse events.
method was used in our study to assess resistance mutation versus a restriction fragment length polymorphism assay in Sung et al.’s study, which is much more sensitive to detect as low as 5% of resistant mutation in the virus population.16 Taken together, the drug resistance rate in our study was underestimated. However, Sung et al.’s study may have overestimated the resistance rate as they analyzed the resistance only in patients with available samples at week 104 (n = 41), whereas we calculated the rate of resistance based on the ITT population (n = 120). Apart from preventing drug resistance development, another benefit of combination therapy is the additive antiviral efficacy.11,17 At week 104, median serum HBV-DNA change form baseline (log10 copies/mL) for LAM plus ADV combination therapy were more significant than that of LAM monotherapy (−5.2 vs −3.4) in Sung et al.’ study.11 Similar results was observed in the current study evidenced by more patients achieved HBV-DNA < 300 copies/mL at week 104 in combination group (53.3% vs 34.8%). However, the additive viral suppression of LAM plus ADV combination therapy was far from satisfactory as compared with firstline potent antiviral agents. Of the HBeAg-positive CHB patients, 74% achieved HBV-DNA < 300 copies/mL after 96 weeks of ETV monotherapy,18 whereas 76% of those receiving 48 weeks of TDF monotherapy achieved HBV-DNA < 400 copies/mL.19 Although these were not head-to-head comparisons between LAM plus ADV combination therapy and potent NAs, LAM plus ADV
Journal of Gastroenterology and Hepatology 30 (2015) 748–755 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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combination therapy cannot be a preferred regimen when initiating antiviral therapy considering its inferior antiviral potency. In addition to de novo combination therapy, an optimization strategy was also included in our study design. This strategy was first proposed by a panel of hepatologists from US based post-hoc analysis of LdT registration data.12 Our newly published conceptproving study demonstrated that adding on ADV for suboptimal responders to LdT at week 24 could achieve better viral control and lower resistance in optimization group based on roadmap concept.14 It is still not sure whether the strategy can also be generalized to LAM. In the current study, a similar strategy was applied for LAM optimization group. However, the antiviral efficacy of LAM optimization strategy was inferior to that of LdT optimization strategy with less patients achieved HBV-DNA < 300 copies/mL (48.3% vs 76.7% in LdT optimization strategy) at week 104 and higher resistance rate (6.7% vs 2.7%). The unsatisfactory efficacy of LAM optimization strategy mainly depends on the inferior efficacy of LAM over LdT,20 leading to several important reasons why the roadmap concept could not be successfully applied to LAM. First, significantly fewer patients achieved early virological response at week 24. In this study, only 18.3% (22/120) of patients achieved HBV-DNA ≤ 1000 copies/mL at week 24 who continued MONO. If we lower the threshold from 1000 copies/mL to 300 copies/mL, over 90% of patients will need to add on ADV. Therefore, the strategy of optimization strategy was very close to de novo combination therapy without any additional benefit. Second, even in the subsets of patients with early virological response at week 24, 73% had HBV-DNA < 300 copies/mL at week 104 and around 40% achieved HBeAg seroconversion, still 17% developed LAM resistance. With these data, we prefer de novo combination therapy of LAM plus ADV to LAM optimization strategy. Nearly 60% of patients in LAM monotherapy group developed LAM resistance at week 104 with only 34.8% of patients achieving virological response. Hence, initial LAM monotherapy cannot be recommended. For patients on LAM monotherapy with incomplete virological responses (HBV-DNA > 1000 copies/mL at week 24), continuing LAM monotherapy will lead to 72.9% resistance, versus 6.2% resistance when early add on ADV at week 30. So, when LAM is to be used, promptly adding on ADV is necessary to prevent resistance development in suboptimal virological responders as early as week 24. It is encouraging to see no difference in the safety profile among the three treatment groups in the current study. However, safety and efficacy data of these treatment strategies in a head-to-head comparison with ETV/TDF monotherapy are not available. Another limitation of the current study are the treatment strategies based on LAM, which is not the preferred antiviral agent in western countries. However, this is the first proof of concept study of LAM optimization strategy providing data for the Asia-Pacific region, especially for China, where LAM is still extensively used. In conclusion, this study compared three treatment strategies over a 2-year period in Chinese HBeAg-positive CHB patients. LAM monotherapy is not recommended for initial treatment because of the high genotypic resistance rate and only moderate antiviral activity. The optimization strategy based on roadmap concept was not perfect when applied to LAM-treated patients; however, for patients who have been treated with LAM, adding on ADV is necessary and effective to prevent resistance development for the suboptimal responders. Although LAM plus ADV de novo 754
combination therapy showed acceptable viral control, low resistance, and a well-tolerated safety profile, these data are insufficient to change the first-line recommendation of TDF or ETV.
Acknowledgements Parts of this study were presented at the Asian Pacific Association for the Study of the Liver (APASL) Liver Week 2013, June 6–9, Singapore and at the 23rd Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2014), March 12–15, Brisbane, Australia. We thank the study investigators, coordinators, nurses, patients, and their families for their contributions. WuXiPRA Clinical Research Co., Ltd. provided professional monitoring, data management, and statistical analysis. GlaxoSmithKline provided free study drug and financially supported monitoring service.
References 1 European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J. Hepatol. 2012; 57: 167–85. 2 Woo G, Tomlinson G, Nishikawa Y et al. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses. Gastroenterology 2010; 139: 1218–29. 3 Wong GL, Chan HL, Mak CW et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology 2013; 58: 1537–47. 4 Liaw YF, Sung JJ, Chow WC et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N. Engl. J. Med. 2004; 351: 1521–31. 5 Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006; 131: 1743–51. 6 Chen CJ, Yang HI. Natural history of chronic hepatitis B revealed. J. Gastroenterol. Hepatol. 2011; 26: 628–38. 7 Chang TT, Lai CL, Kew YS et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010; 51: 422–30. 8 Lok AS, Lai CL, Leung N et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003; 125: 1714–22. 9 Sun J, Hou JL. Management of chronic hepatitis B: experience from China. J. Viral Hepat. 2010; 17 (Suppl. 1): 10–17. 10 Hann HW, Gregory VL, Dixon JS, Barker KF. A review of the one-year incidence of resistance to lamivudine in the treatment of chronic hepatitis B : lamivudine resistance. Hepatol. Int. 2008; 2: 440–56. 11 Sung JJ, Lai JY, Zeuzem S et al. Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J. Hepatol. 2008; 48: 728–35. 12 Keeffe EB, Zeuzem S, Koff RS et al. Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin. Gastroenterol. Hepatol. 2007; 5: 890–7. 13 Yu HC, Lin KH, Hsu PI et al. Real-world application of the roadmap model in chronic hepatitis B patients with telbivudine therapy. Clin. Ther. 2013; 35: 1386–99. 14 Sun J, Xie Q, Tan D et al. The 104-week efficacy and safety of telbivudine-based optimization strategy in chronic hepatitis B patients: a randomized, controlled study. Hepatology 2014; 59: 1283–92.
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15 Lau GK, Piratvisuth T, Luo KX et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 2005; 352: 2682–95. 16 Allen MI, Gauthier J, DesLauriers M et al. Two sensitive PCR-based methods for detection of hepatitis B virus variants associated with reduced susceptibility to lamivudine. J. Clin. Microbiol. 1999; 37: 3338–47. 17 Lok AS, Trinh H, Carosi G et al. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naïve patients with chronic hepatitis B. Gastroenterology 2012; 143: 619–28.e1.
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18 Gish RG, Lok AS, Chang TT et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007; 133: 1437–44. 19 Marcellin P, Heathcote EJ, Buti M et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N. Engl. J. Med. 2008; 359: 2442–55. 20 Lai CL, Gane E, Liaw YF et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N. Engl. J. Med. 2007; 357: 2576–88.
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H E PAT O L O G Y
Randomized, three-arm study to optimize lamivudine efficacy in hepatitis B e antigen-positive chronic hepatitis B patients Xieer Liang,* Jun Cheng,† Yongtao Sun,‡ Xinyue Chen,§ Tong Li,¶ Hao Wang,** Jianning Jiang,†† Xiaoping Chen,‡‡ Hui Long,§§ Hong Tang,¶¶ Yanyan Yu,*** Jifang Sheng,††† Shijun Chen,‡‡‡ Junqi Niu,§§§ Hong Ren,¶¶¶ Junping Shi,**** Xiaoguang Dou,†††† Mobin Wan,‡‡‡‡ Jiaji Jiang,§§§§ Qing Xie,¶¶¶¶ Guangfeng Shi,***** Qin Ning,††††† Chengwei Chen,‡‡‡‡‡ Deming Tan,§§§§§ Hong Ma,¶¶¶¶¶ Jian Sun,* Jidong Jia,¶¶¶¶¶ Hui Zhuang¶ and Jinlin Hou* *State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, ‡‡Department of Infectious Diseases, Guangdong General Hospital, Guangzhou, †Beijing Ditan Hospital, Capital Medical University, §Beijing Youan Hospital, Capital Medical University, ¶¶¶¶¶Liver Research Center, Beijing Friendship Hospital, Capital Medical University, ¶Department of Microbiology and Infectious Disease Center, Peking University Health Science Center, **Hepatology Unit, Peking University People’s Hospital, ***Department of Infectious Diseases, First Hospital of Peking University, Beijing, ‡Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi’an, ††Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, §§Department of Infectious Diseases, The First People Hospital of Foshan, Foshan, ¶¶Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, †††Department of Infectious Diseases, Zhejiang University 1st Affiliated Hospital, Hangzhou, ****The 6th People’s Hospital, Hangzhou, ‡‡‡Jinan Infectious Diseases Hospital, Ji’nan, §§§ Hepatology Unit, No. 1 Hospital Affiliated to Jilin University, Changchun, ¶¶¶Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, ††††Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, ‡‡‡‡ Department of Infectious Diseases, Changhai Hospital, The Second Military Medical University, ¶¶¶¶Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, *****Department of Infectious Diseases, Huashan Hospital, Fudan University, ‡‡‡‡‡ Department of Infectious Diseases, 85th People’s Liberation Army Hospital, Shanghai, §§§§Liver Center, First Affiliated Hospital of Fujian Medical University, Fuzhou, †††††Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, and §§§§§Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
Key words adefovir dipivoxil, hepatitis B e antigen, lamivudine, optimization strategy, virological response. Accepted for publication 14 October 2014. Correspondence Prof Jinlin Hou, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Email: [email protected] Declaration of conflict of interest: Q Ning has been a member of Advisory Committees or Review Panels; received consulting fees from Roche, Novartis, GlaxoSmithKline, Bristol-Myers Squibb; and has received grant/research support from Roche, Novartis, and Bristol-Myers Squibb. J Sheng has received grant/research support from Roche. J Jia has acted as a consultant for Novartis, Bristol-Myers Squibb, and Roche. J Hou has received consulting fees from Roche, Novartis, GlaxoSmithKline, and Bristol-Myers Squibb and has received grant/research support from Novartis. The other authors declare that they have no conflicts of interest. Funding: This study was funded by the National Science and Technology Major Project of China (2012ZX10002003).
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Abstract Background and Aim: Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE). Methods: Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 105 copies/mL, alanine aminotransferase 1.3–10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed. Results: At week 104, more patients in COMBO and OPTIMIZE groups achieved HBVDNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV-DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.5%). Patients under MONO with early virological response showed superior efficacy at week 104 (HBV-DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated. Conclusion: Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg-positive CHB patients. In lamivudinetreated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development. Author contributions: J Hou is the guarantor of the article. J Hou, J Jia, and J Sun were involved in the study design. X Liang, J Cheng, Y Sun, X Chen, T Li, H Wang, J Jiang, X Chen, H Long, H Tang, Y Yu, J Sheng, S Chen, J Niu, H Ren, J Shi, X Dou, M Wan, J Jiang, Q Xie, G Shi, Q Ning, C Chen, D Tan, H Ma, J Sun, J Jia, and H Zhuang collected data. J Hou, J Sun, and X Liang analyzed and interpreted the data and wrote the article. All authors had full access to the final version of the report and approved the submission.
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Introduction
Methods
Oral antiviral agents (nucleoside or nucleotide analogues) has been extensively proved to be an effective and potent way to inhibit hepatitis B virus (HBV) replication,1 which contributes to the reversion of liver fibrosis and decrease of liver complications.2–6 In spite of the convenient and well-tolerated virtue of oral antiviral agents, long-term antiviral therapy is usually needed to achieve durable viral suppression.5,7,8 The high genetic barrier drugs, such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV), are recommended as firstline choices when initiating antiviral therapy to reduce the incidence of resistance to the extent possible.1,9 Although TDF has just been approved for chronic hepatitis B (CHB) in China, it is not yet easily accessible in mainland China. In addition, due to the high cost of TDF and ETV, low income and inadequate medical reimbursement of some patients, and an unawareness of medical care knowledge among patients and health-care departments, low genetic barrier antiviral agents, such as lamivudine (LAM) and adefovir dipivoxil (ADV), are still extensively used in China. Given the high resistance rate of treatment naïve CHB patients with lamivudine monotherapy (MONO),8,10 a previous study has been conducted to compare the antiviral efficacy of LAM monotherapy versus LAM plus ADV de novo combination therapy and demonstrated better viral control and lower resistance rate with combination therapy.11 Meanwhile, an optimization strategy, namely, the “roadmap concept,” was initially developed for low genetic barrier drugs to monitor and modify treatment strategy according to response.12,13 This strategy has been proven effective in our newly published randomized controlled study, in which, adding on ADV for suboptimal responder after 24 weeks of treatment with telbivudine (LdT) achieved significantly better viral suppression and lower resistance.14 Nevertheless, there is insufficient data to substantiate an optimization strategy for LAM therapy, compared with de novo LAM plus ADV therapy and LAM monotherapy. Therefore, the present study aimed to compare the efficacy and safety of the three abovementioned treatment strategies in hepatitis B e antigen (HBeAg)positive hepatitis B patients. The 2-year final results of this study are presented.
Study design. This was a randomized, open-label, controlled, multicenter, 2-year study in 24 centers of China from March 2010 to February 2013. Eligible patients were randomized 1:1:1 (by a central randomization center) to receive LAM plus ADV de novo combination therapy (COMBO), LAM-based optimized therapy (OPTIMIZE) or LAM monotherapy (MONO) for 104 weeks. Patients in OPTIMIZE group were initiated with LAM 100 mg once daily, and ADV 10 mg once daily was added to suboptimal responders (HBV-DNA > 1000 copies/mL [171.8 IU/mL] at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued LAM monotherapy until week 104. Patients in COMBO and MONO groups were initiated with combination therapy (LAM plus ADV) and LAM monotherapy from baseline to week 104, respectively. For all the patients receiving LAM monotherapy, ADV would be added if virological breakthrough was confirmed (Fig. 1). Clinical, laboratory, and adverse-event assessments were performed every 8–12 weeks from baseline to week 104. HBVDNA levels and HBV serological markers were measured using the Roche COBAS Taqman (Hoffmann-La Roche Ltd, Basel, Switzerland; lower limit of detection, 12 IU/mL [approximately 69.84 copies/mL]) and ARCHITECT i2000SR (Abbott Laboratoried, IL, USA) at the central laboratory set up by the research group. Virological breakthrough was defined as an increase of HBVDNA by ≥ 1 log10 above nadir on two consecutive occasions at least 1 month apart after achieving an initial response in a compliant patient. Patients who developed virological breakthrough just before withdrawing from the study (including at week 104) with no chance to confirm at least one month later were also treated as confirmed virological breakthrough cases. Genotyping and genotypic resistance, defined as virological breakthrough with identified treatment-emergent resistance mutations (M204I/V, L180M for LAM resistance; A181V/T, N236T for ADV resistance), was tested by polymerase chain reaction (PCR) sequencing at screening for all patients and at the timepoints of confirmed virological breakthrough. The study was conducted in accordance with the ethics principles of the Declaration of Helsinki and was consistent with good
Figure 1 The design of the study. Patients in OPTIMIZE (lamivudine [LAM]-based optimized therapy) group were initiated with LAM 100 mg once daily, and adefovir dipivoxil (ADV) 10 mg once daily was added to suboptimal responders (hepatitis B virus [HBV]DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued LAM monotherapy until week 104. *For all the patients receiving LAM monotherapy, ADV would be added if virological breakthrough was confirmed. CHB, chronic hepatitis B.
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clinical practice guidelines and applicable local regulatory requirements. Institutional approval was obtained at all clinical sites, and written informed consent was provided by all screened patients. This study has been registered with ClinicalTrials.gov identifier NCT01088009 titled Efficacy Optimizing Research of Lamivudine Therapy. Patients. Eligible patients were aged 18–65 years, with detectable hepatitis B surface antigen (HBsAg) ≥ 6 months, HBeAgpositive, and HBeAb-negative at screening, HBV-DNA levels > 105 copies/mL (1.7 × 104 IU/mL), serum alanine aminotransferase (ALT) levels ≥ 1.3 but ≤ 10 × upper limit of normal (ULN) at screening and at least one ALT > 1 × ULN episode within 6 months but ≥ 14 days before screening, and without antiviral therapy within 6 months before screening. Patients who had a history of virological breakthrough or LAM/ETV/LdT-related genotypic resistance before screening were excluded. Additional exclusion criteria included other forms of liver disease; evidence of hepatic decompensation or hepatocellular carcinoma (HCC); serum creatinine level > 1.5 mg/dL; platelet count < 80 × 109/L; prothrombin time prolonged by > 4 s; serum albumin level < 3.5 g/dL; and bilirubin level > 2.0 mg/dL. Eligible patients with serum alpha fetoprotein level > 50 ng/mL required exclusion of underlying HCC. Efficacy and safety end-points. Efficacy analyses included all randomized patients who received at least one dose of study medication (intent to treat [ITT] population). The primary efficacy end-point was the proportion of patients with virological breakthrough and LAM-associated genotypic resistance. Secondary efficacy end-points included the proportion of patients achieving HBV-DNA < 300 copies/mL (51.5 IU/mL) at week 104, the reduction of HBV-DNA level from baseline and the proportion of patients with ALT normalization, serological response, virological breakthrough, and ADV-associated genotypic resistance. Safety analyses included all patients who underwent randomization and received at least one dose of study medication and underwent at least one safety assessment after the baseline assessment. Statistical analysis. The estimated proportion of patients with virological breakthrough and LAM-associated genotypic resistance in OPTIMIZE group and MONO group were 13% and 30%, respectively. Sample size of 120 per arm was calculated to detect a significant difference between the two groups with a dropout rate up to 25%, a two-sided significance level of 5%, and the power of 80%. In efficacy analyses of virological, serological, and biochemical response, ITT population with a missing value were considered as treatment failure for these end-points, and the chi-squared/Fisher’s exact tests were used to compare differences in response rates between the treatment groups. The last observation carried forward method was used to handle the missing values for continuous variables. Unplanned post hoc statistical analysis was performed for subgroups with early virological response and suboptimal response. All P values are two-sided, and all analyses were performed with SAS version 9.2 (SAS Institute, NC, USA). 750
Results Study population. Of the 413 screened patients, 366 were eligible and underwent randomization, 358 were included in the ITT population for efficacy analyses, with 120 in COMBO group, 120 in OPTIMIZE group, and 118 in MONO group. Eight patients were excluded from ITT population because of retracting inform consent form (ICF) without receiving any study drug. The most common reasons for treatment discontinuation were patient’s request (18 subjects) and lost contact (11 subjects). At the end of the study, 112, 111, and 100 patients in each group respectively completed the 104-week treatment (Fig. 2). Treatment groups were well matched at baseline with respect to demographics and other characteristics, with 77.1% male, 36.3% genotype B and 63.1% genotype C, mean baseline HBV-DNA level 8.6 log10 copies/mL, and mean ALT level 3.4 × ULN in overall patients (Table 1).
Virological breakthrough and resistance. Significantly lower proportion of patients in COMBO (8.3% [10/120]) and OPTIMIZE group (22.5% [27/120]) had virological breakthrough compared with MONO group (63.6% [75/118]). For the patients with virological breakthrough, resistance test showed that LAM-related resistance rates (M204I/V or L180M mutation) were 0.8% (1/120), 6.7% (8/120), and 58.5% (69/118) in the three groups, respectively (Table 2), accounting for 10.0% (1/10), 29.6% (8/27), and 92.0% (69/75) of patients with virological breakthrough in the three groups, respectively. Nine patients in COMBO group, 19 in OPTIMIZE group, and 6 in MONO group who developed virological breakthrough were found to have no M204I/V or L180M mutation. The possible reasons for these cases were noncompliance, low sensitivity of resistance testing, or mutations other than M204I/V or L180M. Regarding LAM-related mutation patterns, the vast majority of patients had M204I/V (50.0% [39/78]) or M204I/V + L180M (48.7% [38/78]) mutations, whereas only one had the pattern of L180M + A181V mutations from MONO group. Regarding ADVrelated mutations, only two developed ADV-related resistance. One patient in MONO group developed A181V mutation accompanied with L180M mutation at week 88 before adding on ADV. The other one in COMBO group showed A181V mutation at baseline and week 104; however, HBV-DNA declined from 2.2E + 07 copies/mL at baseline to 4.9E + 04 copies/mL at week 104 without other resistance mutations.
Virological response. At week 104, significantly more patients in COMBO and OPTIMIZE groups achieved HBVDNA < 300 copies/mL, 53.3% (64/120) in COMBO, and 48.3% (58/120) in OPTIMIZE group, respectively, compared with 34.8% (41/118) in MONO group (P = 0.012) (Table 2). Likewise, the mean reduction from baseline in serum HBV-DNA level was significantly greater in COMBO group (−5.9 log10 copies/mL) and OPTIMIZE group (−5.6 log10 copies/mL) than that in MONO group (−4.7 log10 copies/mL). Such difference occurred as early as week 36 (Fig. 3). Meanwhile, the virological responses were comparable between COMBO group and OPTIMIZE group.
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Figure 2 Flowchart of the study. COMBO; lamivudine plus adefovir dipivoxil de novo combination therapy; ICF, inform consent form; ITT, intent to treat; LOCF, last observation carried forward; MONO, lamivudine monotherapy; OPTIMIZE, lamivudine-based optimized therapy.
Biochemical and serologic response. Among patients with ALT > 1 × ULN at baseline, 80.2% (93/116) and 82.2% (97/ 118) in COMBO group and OPTIMIZE group, respectively, achieved ALT normalization at week 104, compared with 59.5% (66/111) in MONO group (P < 0.0001). Comparable proportions of patients in COMBO group, OPTIMIZE group, and MONO group achieved HBeAg loss (24.2% versus 22.5% vs 22.0%, P = 0.919) and HBeAg seroconversion (16.7% vs 14.1% vs 17.0%, P = 0.811). One patient in each treatment group achieved HBsAg loss and HBsAg seroconversion (Table 2). Efficacy in subgroups. For the patients with suboptimal response (HBV-DNA > 1000 copies/mL at week 24) in OPTIMIZE group, adding on ADV from week 30 benefited them with 44.3% (43/97) achieving HBV-DNA < 300 copies/mL at week 104 and only 6.2% (6/97) developing LAM resistance. However, for the suboptimal responder allocated to MONO group who continued LAM monotherapy, only 21.2% (18/85) achieved HBVDNA < 300 copies/mL at week 104 and as high as 72.9% (62/85) developed LAM resistance. Of the patients who achieved early response (HBVDNA ≤ 1000 copies/mL) at week 24 in OPTIMIZE (n = 22) and MONO groups (n = 30), 73.1% (38/52) had HBV-DNA < 300
copies/mL at week 104, 40.4% (21/52) achieved HBeAg seroconversion. However, 17.3% (9/52) patients experienced LAM resistance over 104-week treatment. For the 33 nucleos(t)ide analogues (NAs) experienced patients (Table 1, COMBO 11, OPTIMIZE 6, MONO 16), the subsequent resistance rate is 0%, 33.3% (2/6), and 87.5% (14/16). Although the case number is not enough to draw any conclusion, LAM plus ADV combination therapy is strongly preferred over MONO. Safety. In the ITT population, one patient in OPTIMIZE group and one in MONO group retracted ICF and did not undergo at least one safety assessment after the baseline assessment. Therefore, safety analyses were at last performed in 356 patients. Among safety population, three treatment strategies were all well tolerated over the 104-week treatment period. The total adverse events were comparable and were reported in around 30% of the patients in the three treatment arms (Table 3). Most adverse events were not related to study drug as assessed by clinical investigators. Serious adverse events, none of which was considered as drug-related, were reported in 1 (0.8%), 3 (2.5%), and 4 (3.4%) patients in COMBO, OPTIMIZE, and MONO groups, respectively (Table 3).
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Table 1
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Baseline characteristics by treatment assignment
Characteristic †
Age (years) Male, n (%) HBV genotype, n (%) B C Others (A/D) Serum ALT level (ULN) Mean ± SD Median (range) Serum HBV-DNA level (log10 copies/mL)‡ Mean ± SD Median (range) Serum HBsAg level (log10 IU/mL)‡ Mean ± SD Median (range) Treatment-experienced§, n (%)
COMBO (n = 120)
OPTIMIZE (n = 120)
MONO (n = 118)
30 (18, 58) 94 (78.3)
28 (18, 59) 93 (77.5)
31 (18, 63) 89 (75.4)
39 (32.5) 80 (66.7) 1 (0.8)
47 (39.2) 73 (60.8) 0 (0.0)
44 (37.3) 73 (61.9) 1 (0.8)
3.3 ± 2.7 2.5 (0.6, 23.0)
3.4 ± 2.1 3.1 (0.6, 11.3)
3.6 ± 2.8 2.8 (0.7, 16.6)
8.6 ± 0.9 8.7 (4.9, 10.6)
8.6 ± 0.9 8.8 (6.1, 10.3)
8.6 ± 0.9 8.8 (5.2, 10.6)
4.3 ± 0.7 4.4 (0.9, 5.4) 18 (15.0)
4.2 ± 0.6 4.2 (2.5, 5.5) 8 (6.7)
4.1 ± 0.8 4.2 (0.8, 5.5) 26 (22.0)
†
Expressed as median (range). HBV-DNA levels and HBV serological markers were measured using the Roche COBAS Taqman (lower limit of detection [LLOD], 12 IU/mL [approximately 69.84 copies/mL]) and ARCHITECT i2000SR at the central laboratory set up by the research group. § Nineteen interferon-experienced patients (median duration of treatment 184 days [range 59–426]), 16 lamivudine-experienced patients (median duration 356 days [range 61–853]), 10 adefovir dipivoxil-experienced patients (median duration 365 days [range 51–365]), 4 entecavir-experienced patients (median duration 423 days [range 365–937]), and 3 telbivuidne-experienced patients (median duration 60 days [range 60–365]). A/D, genotype A or D; ALT, alanine aminotransferase; COMBO, lamivudine plus adefovir dipivoxil de novo combination therapy; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; MONO, lamivudine monotherapy; OPTIMIZE, lamivudine-based optimized therapy; SD, standard deviation; ULN, upper limit of normal. ‡
Table 2
Efficacy results at week 104 in the ITT population
Variables †
Lamivudine resistance, n (%)* Virological breakthrough, n (%)*† Virologic response, n (%)*‡ Serum HBV-DNA (mean reduction in log10 copies/mL from baseline)* ALT normalization, n (%)*§ HBeAg loss, n (%) HBeAg seroconversion, n (%) HBsAg loss, n (%) HBsAg seroconversion, n (%)
COMBO (n = 120)
OPTIMIZE (n = 120)
MONO (n = 118)
1 (0.8) 10 (8.3) 64 (53.3) −5.9
8 (6.7) 27 (22.5) 58 (48.3) −5.6
69 (58.5) 75 (63.6) 41 (34.8) −4.7
93/116 (80.2) 29 (24.2) 20 (16.7) 1 (0.8) 1 (0.8)
97/118 (82.2) 27 (22.5) 17 (14.1) 1 (0.8) 1 (0.8)
66/111 (59.5) 26 (22.0) 20 (17.0) 1 (0.9) 1 (0.9)
*COMBO/OPTIMIZE versus MONO: P < 0.05. For categorical end-points, missing values were considered as failure. For continuous end-points, the missing values were analyzed by LOCF method. † Virological breakthrough was defined as an increase of HBV-DNA by ≥ 1 log10 above nadir on two consecutive occasions at least 1 month apart after achieving an initial response in a compliant patient. Those patients who experienced virological breakthrough just before withdrawing from this study (including at week 104) with no chance to confirm at least 1 month later were also treated as confirmed virological breakthrough cases. Resistance was defined as virological breakthrough with identified treatment-emergent resistance mutations. ‡ Virological response was defined as serum HBV-DNA < 300 copies/mL. § For patients with serum ALT > 1 × ULN at baseline (n = 116, 118 and 111 in COMBO, OPTIMIZE, and MONO groups, respectively). ALT, alanine aminotransferase; COMBO, lamivudine plus adefovir dipivoxil de novo combination therapy; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; ITT, intent to treat; LOCF, last observation carried forward; MONO, lamivudine monotherapy; OPTIMIZE, lamivudine-based optimized therapy; ULN, upper limit of normal.
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Table 3
Summary of cumulative safety data
Outcomes at week 104
Figure 3 Mean serum hepatitis B virus (HBV)-DNA (log10 copies/mL) , COMBO (lamivudine plus adefovir dipivoxil de novo over time. combination therapy; n = 120); , OPTIMIZE (lamivudine-based optimized therapy; n = 120); , MONO (lamivudine monotherapy; n = 118).
Three patients had grade 3/4 aminotransferase elevation and one had blood platelet decrease, all of which were transient. One patient in MONO group had a transient elevation of serum creatinine greater than 0.5 mg/dL at week 96 as compared with baseline. No patient had creatinine clearance rate (calculated by Cockcroft– Gault formula) less than 50 mL/min, neither did a patient need to adjust the dose of study drug.
Discussion In this study, which exclusively enrolled HBeAg-positive compensated CHB patients, LAM optimization strategy and de novo combination therapy of LAM plus ADV achieved better antiviral efficacy in terms of significantly reduced resistance rate and superior viral suppression, compared with LAM monotherapy. However, these strategies still cannot be recommended for treatment naïve patients when compared with ETV or TDF. Previous studies have confirmed that combination therapy of LAM with another noncross-resistant drug, such as peg-interferon alfa-2a or ADV, can significantly prevent the development of resistance.11,15 The results from the current randomized controlled study also confirmed the role of combination therapy in the prevention of resistance development. There was a sharp contrast of resistance rate in LAM monotherapy group and de novo combination group (58.5% vs 0.8%). However, the LAM resistance rate in combination group reported in this study (0.8%) was far lower than 15% in Sung et al.’s study,11 which can be ascribed to the difference of study design. First, the population for resistance testing is different. In our study, the presence of resistance mutation was assessed only in patients with confirmed virological breakthrough, whereas mutation assessments were performed in all enrolled patients at screening, baseline, week 16, week 52, and week 104 in Sung et al.’s study. Second, the methodology for resistance testing is different. The PCR reaction sequencing
Most frequent adverse events (≥ 2%) Any adverse event (%) Upper respiratory tract infection (%) Fatigue (%) Cough (%) Alopecie (%) Serious adverse event (%)† Death (%)‡ Grades 3/4 laboratory abnormalities (%)§ Alanine aminotransferase Aspartate aminotransferase Blood platelet degression
COMBO (n = 120)
OPTIMIZE (n = 119)
MONO (n = 117)
26.7 14.2
21.9 9.2
35.0 14.5
0.8 0.8 0.8 0.8 0.8
1.7 1.7 0 2.5 0
2.6 4.3 2.6 3.4 0
0 0 0
0 0 0
1.7 0.9 0.9
†
The outcome of SAEs were all reported as resolved without sequelae, except two (sudden deafness on the left ear and colon cancer) were reported as improved. ‡ The patient’s death was the outcome of an SAE of craniocerebral injury in a traffic accident and was considered to be not related to study drugs. § Patients are counted only once in each row. The severity of laboratory abnormalities was graded according to criteria adapted from the Division of AIDS, National Institute of Allergy and Infectious Diseases. Grades 3/4 elevations in aminotransferase levels are those > 5 times baseline; Grades 3/4 degression in blood platelet are those < 50 000/mm3. COMBO, lamivudine plus adefovir dipivoxil de novo combination therapy; MONO, lamivudine monotherapy; OPTIMIZE, lamivudinebased optimized therapy; SAEs, serious adverse events.
method was used in our study to assess resistance mutation versus a restriction fragment length polymorphism assay in Sung et al.’s study, which is much more sensitive to detect as low as 5% of resistant mutation in the virus population.16 Taken together, the drug resistance rate in our study was underestimated. However, Sung et al.’s study may have overestimated the resistance rate as they analyzed the resistance only in patients with available samples at week 104 (n = 41), whereas we calculated the rate of resistance based on the ITT population (n = 120). Apart from preventing drug resistance development, another benefit of combination therapy is the additive antiviral efficacy.11,17 At week 104, median serum HBV-DNA change form baseline (log10 copies/mL) for LAM plus ADV combination therapy were more significant than that of LAM monotherapy (−5.2 vs −3.4) in Sung et al.’ study.11 Similar results was observed in the current study evidenced by more patients achieved HBV-DNA < 300 copies/mL at week 104 in combination group (53.3% vs 34.8%). However, the additive viral suppression of LAM plus ADV combination therapy was far from satisfactory as compared with firstline potent antiviral agents. Of the HBeAg-positive CHB patients, 74% achieved HBV-DNA < 300 copies/mL after 96 weeks of ETV monotherapy,18 whereas 76% of those receiving 48 weeks of TDF monotherapy achieved HBV-DNA < 400 copies/mL.19 Although these were not head-to-head comparisons between LAM plus ADV combination therapy and potent NAs, LAM plus ADV
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combination therapy cannot be a preferred regimen when initiating antiviral therapy considering its inferior antiviral potency. In addition to de novo combination therapy, an optimization strategy was also included in our study design. This strategy was first proposed by a panel of hepatologists from US based post-hoc analysis of LdT registration data.12 Our newly published conceptproving study demonstrated that adding on ADV for suboptimal responders to LdT at week 24 could achieve better viral control and lower resistance in optimization group based on roadmap concept.14 It is still not sure whether the strategy can also be generalized to LAM. In the current study, a similar strategy was applied for LAM optimization group. However, the antiviral efficacy of LAM optimization strategy was inferior to that of LdT optimization strategy with less patients achieved HBV-DNA < 300 copies/mL (48.3% vs 76.7% in LdT optimization strategy) at week 104 and higher resistance rate (6.7% vs 2.7%). The unsatisfactory efficacy of LAM optimization strategy mainly depends on the inferior efficacy of LAM over LdT,20 leading to several important reasons why the roadmap concept could not be successfully applied to LAM. First, significantly fewer patients achieved early virological response at week 24. In this study, only 18.3% (22/120) of patients achieved HBV-DNA ≤ 1000 copies/mL at week 24 who continued MONO. If we lower the threshold from 1000 copies/mL to 300 copies/mL, over 90% of patients will need to add on ADV. Therefore, the strategy of optimization strategy was very close to de novo combination therapy without any additional benefit. Second, even in the subsets of patients with early virological response at week 24, 73% had HBV-DNA < 300 copies/mL at week 104 and around 40% achieved HBeAg seroconversion, still 17% developed LAM resistance. With these data, we prefer de novo combination therapy of LAM plus ADV to LAM optimization strategy. Nearly 60% of patients in LAM monotherapy group developed LAM resistance at week 104 with only 34.8% of patients achieving virological response. Hence, initial LAM monotherapy cannot be recommended. For patients on LAM monotherapy with incomplete virological responses (HBV-DNA > 1000 copies/mL at week 24), continuing LAM monotherapy will lead to 72.9% resistance, versus 6.2% resistance when early add on ADV at week 30. So, when LAM is to be used, promptly adding on ADV is necessary to prevent resistance development in suboptimal virological responders as early as week 24. It is encouraging to see no difference in the safety profile among the three treatment groups in the current study. However, safety and efficacy data of these treatment strategies in a head-to-head comparison with ETV/TDF monotherapy are not available. Another limitation of the current study are the treatment strategies based on LAM, which is not the preferred antiviral agent in western countries. However, this is the first proof of concept study of LAM optimization strategy providing data for the Asia-Pacific region, especially for China, where LAM is still extensively used. In conclusion, this study compared three treatment strategies over a 2-year period in Chinese HBeAg-positive CHB patients. LAM monotherapy is not recommended for initial treatment because of the high genotypic resistance rate and only moderate antiviral activity. The optimization strategy based on roadmap concept was not perfect when applied to LAM-treated patients; however, for patients who have been treated with LAM, adding on ADV is necessary and effective to prevent resistance development for the suboptimal responders. Although LAM plus ADV de novo 754
combination therapy showed acceptable viral control, low resistance, and a well-tolerated safety profile, these data are insufficient to change the first-line recommendation of TDF or ETV.
Acknowledgements Parts of this study were presented at the Asian Pacific Association for the Study of the Liver (APASL) Liver Week 2013, June 6–9, Singapore and at the 23rd Annual Conference of the Asian Pacific Association for the Study of the Liver (APASL 2014), March 12–15, Brisbane, Australia. We thank the study investigators, coordinators, nurses, patients, and their families for their contributions. WuXiPRA Clinical Research Co., Ltd. provided professional monitoring, data management, and statistical analysis. GlaxoSmithKline provided free study drug and financially supported monitoring service.
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