Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono‐rescue therapy (TDF group) and TDF plus entecavir (ETV) combination‐rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty‐three CHB patients with lamivudine and entecavir resistance were investigated. Ninety‐six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6‐24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono‐rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.     

Rapid re-emergence of YMDD mutation of hepatitis B virus with hepatic decompensation after lamivudine retreatment

Lamivudine has a high rate of antiviral resistance. Sequential treatment of anti-hepatitis B virus （HBV） is commonly used for lamivudine resistance. We report 4 cases of patients with rapid redetection of HBV mutants during the lamivudine retreatment. The four patients received lamivudine as an initial treatment of HBV and adefovir and lamivudine as a rescue therapy consecutively. HBV-DNA level, YMDD mutations and adefovir -resistant mutations （RFMP） were tested every 3 mo during the sequential treatment. All the patients showed YMDD mutations during the initial lamivudine therapy. After adefovir therapy for lamivudine resistance, they showed viral breakthrough. Adefovir was switched to lamivudine, however, it did not induce viral suppression at all, rather increased HBV-DNA with rapid reemergence of the YMDD mutations. All the patients had ALT flares, and hepatic decompensation occurred in two patients. After switching to adefovir combined with entecavir or lamivudine for a rescue therapy, the patients had reduction in HBV-DNA and ALT improvement. These cases demonstrated that lamivudine retreatment of patients with preexposed lamivudine resistance leads to rapid reemergence of YMDD mutation with significant viral rebounds and subsequent hepatic decompensation. Sequential administration of lamivudine in patients with a prior history of YMDD mutation should be abandoned.     

Viral response at 6 months is associated with treatment outcome of adefovir add-on therapy for lamivudine-resistance

Background and Aim: Adefovir add‐on therapy is recommended for patients infected with lamivudine‐resistant hepatitis B virus (HBV). We aimed to describe the long‐term treatment outcome and predictors for good response of adefovir add‐on therapy. Methods: A total of 559 chronic hepatitis B (CHB) patients who had been treated for at least 12 months with adefovir add‐on therapy due to resistance to lamivudine were retrospectively included. Complete virologic response (CVR) was defined as serum HBV DNA < 9 IU/mL. Viral responses at 6 months were classified as PCR negativity, partial virologic response (PVR, HBV DNA < 2000 IU/mL), or inadequate virologic response (IVR, HBV DNA ≥ 2000 IU/mL). Results: The median duration of follow‐up was 31.5 months (range, 12–56). The cumulative probabilities of CVR during adefovir add‐on therapy were 58%, 70%, 78%, and 80% at 12, 24, 36, and 43 months, respectively. The cumulative rates of resistance to adefovir were 0.4%, 0.8%, and 3.1% at 12, 24, and 36 months, respectively. The only baseline factor associated with CVR (hazard ratio 0.83, 95% confidence interval 0.62–0.91, P ≤ 0.001) and resistance to adefovir (hazard ratio 1.925, 95% confidence interval 1.13–3.30, P = 0.017) was serum HBV DNA level. Comparison of the cumulative rates of CVR and resistance to adefovir according to viral response at 6 months showed significant differences among the three groups (P < 0.0001 and P = 0.0005, respectively). Conclusions: Pre‐treatment HBV DNA level and viral response at 6 months is associated with treatment outcome for adefovir‐add on therapy in lamivudine resistance.     

Long-term efficacy of entecavir in adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance

This study aimed to evaluate the long-term efficacy of entecavir (ETV) in adefovir (ADV)-refractory chronic hepatitis B (CHB) patients with prior lamivudine (LMV) resistance. A total of 55 ADV-refractory CHB patients with prior LMV resistance, who received rescue therapy with ETV 1 mg daily for at least 12 months, were consecutively enrolled and analysed. Forty-four patients were men, and their median age was 47 (25-69). Ten patients had liver cirrhosis and 46 patients were positive for hepatitis B e antigen (HBeAg). Median hepatitis B virus DNA levels were 6.6 (4.3-8.0) log(10) copies/mL, and the median duration of ETV therapy was 24 (12-47) months. Cumulative virologic response rates at 6, 12, 24 and 36 months were 18%, 29%, 58% and 75%, respectively. HBeAg loss occurred in 10 (21.7%) of 46 HBeAg-positive patients. In multivariate analysis, only initial virologic response at 3 months remained as an independent predictor for virologic response (RR 3.143; 95% CI 1.387-7.120; P = 0.006). The patients with a virological response at 3 months had not only a significantly higher probability of achieving a virologic response (P < 0.001) but also lower probability of experiencing a virologic breakthrough (P = 0.043) than the patients without an early response. Viral breakthrough was observed in 29 patients during the follow-up period. Cumulative breakthrough rates at 6, 12, 24 and 36 months were 0%, 15%, 45% and 73%, respectively. ETV monotherapy may be considerably efficacious in cases with an initial virological response but its efficacy is attenuated by frequent emergence of ETV resistance in ADV-refractory CHB patients with prior LMV resistance.     

拉米夫定和阿德福韦酯抗乙型肝炎病毒耐药位点检测及临床意义

目的对应用拉米夫定或阿德福韦酯治疗后耐药的慢性乙型肝炎患者给予联合治疗,观察治疗前后乙型肝炎病毒（HBV）变异模式的变化及对疗效的影响。方法在142例对拉米夫定耐药患者中,给予72例拉米夫定联合阿德福韦酯、70例给予恩替卡韦联合阿德福韦酯冶疗,在72例对阿德福韦酯耐药患者中,给予36例联合拉米夫定、另36例联合恩替卡韦治疗,各组均治疗48 w,测定和比较治疗前后所有患者HBV DNA聚合酶逆转录区相关变异位点变化。结果在拉米夫定初治发生耐药的患者中,发生M204V和IL180M变异率分别为98.6%（140/142）和56.3%（80/142）,接受拉米夫定联合阿德福韦酯治疗患者HBV DNA阴转率为86.1%,与恩替卡韦联合阿德福韦酯治疗患者（97.1%）比,无显著性差异;在阿德福韦酯初治发生耐药的患者中,A181V和N236T变异频率分别为63.9%（46/72）和52.8%（38/72）,接受阿德福韦酯联合拉米夫定治疗患者HBV DNA阴转率为52.8%,显著低于阿德福韦酯联合恩替卡韦组（77.8%,P〈0.05）;在阿德福韦酯联合拉米夫定治疗的36例患者中,19例（52.8%）HBV DNA阴转,在阿德福韦酯联合恩替卡韦治疗的36例患者中,28例（77.8%）患者HBV DNA阴转,差异具有显著性（x2=4.963,P〈0.05）。结论以rtM204变异为主的拉米夫定耐药在联合阿德福韦酯进行挽救治疗后疗效确定;以rtA181变异为主的阿德福韦酯耐药患者在接受阿德福韦酯联合恩替卡韦治疗后的疗效优于联合拉米夫定。     

Rescue therapy for lamivudine‐resistant chronic hepatitis B: Comparison between entecavir 1.0 mg monotherapy,adefovir monotherapy and adefovir add‐on lamivudine combination therapy

Background and Aim: There have been no reports comparing the therapeutic results of adefovir (ADV) and entecavir (ETV) rescue therapy for patients with lamivudine (LAM)‐resistant chronic hepatitis B (CHB). We aimed to compare the cumulative efficacy and resistance of ETV 1.0 mg monotherapy, ADV monotherapy and ADV add‐on LAM combination therapy in LAM‐refractory patients. Methods: One hundred and four patients were included in the following three treatment groups; group 1 (n = 24), LAM was switched to ETV (1.0 mg once a day); group 2 (n = 44), LAM was switched to ADV (10 mg once a day); and group 3 (n = 36), ADV was added to LAM (10 mg once a day). Results: After 6 months of rescue treatment, alanine aminotransferase normalization was observed in 75.0%, 65.9% and 74.3% of patients receiving ETV monotherapy, ADV monotherapy and ADV add‐on therapy, respectively. A significantly higher log₁₀HBV‐DNA drop at 6 months occurred in the ADV add‐on group compared with the ETV group. The rate of HBV‐DNA polymerase chain reaction undetectability (<300 copies/mL) 6 months after initiation of ETV monotherapy, ADV monotherapy and ADV add‐on therapy was 33.3%, 27.3% and 68.6%, respectively (P = 0.003). The cumulative HBeAg seroconversion rate was significantly higher in ADV add‐on/ADV monotherapy groups compared with the ETV monotherapy group (P = 0.022). Viral breakthrough and genotypic resistance were detected in six (25.0%) and six (13.6%) patients in the ETV and ADV monotherapy groups, whereas no cases of genotypic resistance were detected in ADV add‐on group 24 months after initiation of antiviral treatment (P < 0.01). Conclusion: Adefovir add‐on treatment in patients with LAM‐resistant CHB suppresses HBV replication more effectively than ETV or ADV monotherapy. Additionally, no genotypic resistance was detected in the ADV add‐on group.     

Development of HCC in patients receiving adefovir dipivoxil for lamivudine‐resistant hepatitis B virus mutants

Aim: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add‐on lamivudine for treatment of lamivudine‐resistant hepatitis B virus (HBV) mutants. Methods: A total of 247 patients who developed lamivudine‐resistant HBV mutants, with an increase of HBV DNA ≥ 1 log copies/mL, received adefovir dipivoxil 10 mg add‐on lamivudine 100 mg daily during a median of 115 weeks (range: 25–282 weeks). They were followed for the development of HCC by imaging modalities every 3?6 months. Results: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and α‐fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan‐Meier analysis, AST levels ≥ 70 IU/L, YIDD mutants, cirrhosis and age ≥ 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). Conclusion: HCC can develop in cirrhotic patients receiving adefovir add‐on lamivudine. Hence, the patients with baseline AST ≥ 70 IU/L and YIDD mutants would need to be monitored closely for HCC.     

Antiviral effect of entecavir in nucleos(t)ide analogue‐naïve and nucleos(t)ide analogue‐experienced chronic hepatitis B patients without virological response at week 24 or 48 of therapy

We investigated the antiviral effect of entecavir in nucleos(t)ide analogue (NA)‐naïve and NA‐experienced chronic hepatitis B patients without virological response (VR, HBV DNA < 300 copies/mL) at week 24 or 48. A total of 369 NA‐naïve and 181 NA‐experienced patients treated with entecavir monotherapy were analysed. Of the 369 NA‐naïve patients, 34 did not achieve VR at week 48. Of them, patients with HBV DNA ≤2000 copies/mL at week 48 achieved a higher VR rate than those with HBV DNA >2000 copies/mL (18/23 vs 3/11, P = 0.004). Two naïve patients with HBV DNA >2000 copies/mL developed entecavir‐ or lamivudine‐resistant mutants. In 98 lamivudine‐experienced patients without ever having lamivudine resistance, most patients with VR (72/72) and partial VR (300–10⁴ copies/mL; 20/23) at week 24 or VR at week 48 (89/91) could maintain or achieve VR after prolonged therapy. In 75 patients with prior resistance to lamivudine, prolonged entecavir therapy led to low VR rate in those without VR at week 24 (13/45) or 48 (4/34) and high entecavir‐resistance rate in those with or without VR at week 24 (6/30 with and 23/45 without) and 48 (8/41 with and 21/34 without). VR at week 48 was an independent predictor (HR 0.14, 95% CI 0.06–0.33) for entecavir‐resistant mutant development among the 75 patients with prior lamivudine‐resistant mutants. In conclusion, prolonged entecavir treatment resulted in a poor response in naïve patients with HBV DNA >2000 copies/mL at week 48 and patients with prior lamivudine‐resistant mutants without VR at week 24 or 48.     

Current antiviral therapies for chronic hepatitis B.

Among current treatment options for chronic hepatitis B, nucleoside/nucleotide analog therapy has better tolerability and most patients respond to the therapy, while interferon (IFN) therapy has rather severe side‐effects and a lower response rate. However, nucleoside/nucleotide analog therapies have problems of the emergence of drug resistance and poor sustainability of response after discontinuation. After the first nucleoside/nucleotide analog lamivudine, adefovir and entecavir are now utilized in many countries. Adefovir has efficacy for lamivudine resistant patients and current data suggests that adding adefovir to ongoing lamivudine is better than switching to adefovir in terms of viral suppression and the occurrence of resistance. Entecavir can be the first choice for naïve patients, although cross‐resistance has been known for lamivudine resistant patients and mutational screening should take place before using entecavir with such patients. Many other new nucleoside/nucleotide analogs are being developed such as telbivudine, clevudine and tenofovir; the details of each drug will be disclosed in near future.     

乙型肝炎病毒YMDD变异的治疗对策

目的 探讨慢性乙型肝炎患者发生YMDD病毒变异后的治疗策略. 方法 2005年6月-2007年6月在门诊和住院的经拉米夫定治疗后出现YMDD变异的慢性乙型肝炎患者120例,随机分为4组,A组单用阿德福韦酯10 mg/d,治疗48周;B组采用阿德福韦酯10 mg/d,拉米夫定100 mg/d,联合治疗12周,后单用阿德福韦酯10mg/d治疗36周;C组采用阿德福韦酯10mg/d、拉米夫定100mg/d,联合治疗48周;D组接受恩替卡书1 mg/d,治疗48周.根据资料不同,分别采用方差分析、q检验和χ2检验.结果 4组患者治疗12周内ALT水平进一步反弹升高的患者比例分别为30.0%(9/30)、10.0%(3/30)、6.7%(2/30)、10.0%(3/30)(A组与B组、D组间比较χ2=3.750,P=0.053;A组与C组比较χ2=5.455,P<0.05).A组1例患者出现重型肝炎;治疗12周时4组患者YMDD变异株检测阳性率分别为17.2%、0、0、0;治疗48周时4组患者间ALT水平、HBeAg阳性患者血清转换率比较,差异均无统计学意义.C组、D组患者ALT复常率、HBVDNA达到检测水平以下的百分率与A组患者比较,χ2值分别为7.131、5.516、5.260、6.748,P值均<0.05,差异有统计学意义.4组患者的基因型耐药率分别为6.9%(2/29)、6.7%(2/30)、0、0,A组2例耐药患者测序为rtN236T变异,B组rtA181V和rtN236T变异各1例.结论 YMDD变异后采用阿德福韦酯与拉米夫定联合治疗或恩替卡韦治疗更安全有效.     

Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks

In hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who were refractory to current lamivudine therapy, switching to entecavir was superior to continued lamivudine at week 48 for histologic improvement, viral load reduction by polymerase chain reaction and alanine aminotransferase normalization. We assessed the efficacy, safety, and resistance profile of entecavir through 96 weeks of treatment. A total of 286 patients were randomized and treated with entecavir 1 mg (n = 141) or continued lamivudine 100 mg (n = 145). At week 52, 77 entecavir-treated patients who had a protocol-defined virologic response (HBV branched DNA [bDNA] < 0.7 MEq/mL but HBeAg-positive) continued blinded therapy for up to 96 weeks. Patients were assessed for efficacy, safety, and emerging resistance. Cumulative proportions of all treated patients who achieved confirmed efficacy endpoints were also analyzed. Between week 48 and the end of dosing, the proportions of patients with HBV DNA <300 copies/mL by polymerase chain reaction increased from 21% to 40%, and alanine aminotransferase normalization (< or =1x upper limit of normal) increased from 65% to 81%. In the second year, HBeAg seroconversion was achieved by 10% of patients. Of the 77 patients in the second year treatment cohort, entecavir resistance emerged in six patients, and seven experienced virologic breakthrough (five with genotypic resistance acquired before year 2). The safety profile of entecavir in the second year of therapy was consistent with that reported during year 1. CONCLUSION: Through 96 weeks of treatment, 1 mg entecavir resulted in continued clinical benefit in lamivudine-refractory HBeAg-positive chronic hepatitis B patients with a safety profile comparable to lamivudine.     

Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus

BACKGROUND AND AIMS: Prolonged lamivudine therapy is associated with treatment-resistant YMDD mutant hepatitis B virus (HBV). We evaluated the efficacy and safety of adding adefovir dipivoxil to lamivudine in 135 patients with chronic hepatitis B (CHB) and YMDD mutant HBV. METHODS: Ninety-five patients with compensated CHB (group A) were randomized to adefovir 10 mg daily (n = 46) or placebo (n = 49) for 52 weeks while continuing treatment with lamivudine. Forty patients with decompensated hepatitis B or post-liver transplantation (group B) received adefovir and lamivudine. The primary end point was a decline in serum HBV DNA level to 10(5) copies/mL or a >2 log(10) reduction from baseline at weeks 48 and 52. RESULTS: HBV DNA response occurred in 85% of patients (39 of 46) in group A given combined therapy versus 11% (5 of 46) receiving lamivudine alone (P < 0.001), with a significant change in HBV DNA level from baseline (P < 0.001) between treatment groups (median, -4.6 vs. +0.3 log(10) copies/mL, respectively). Normalization of alanine aminotransferase levels occurred in 31% of patients (14 of 45) receiving combined therapy versus 6% (3 of 48) receiving lamivudine alone (P = 0.002). Ninety-two percent of patients (36 of 39) in group B had an HBV DNA response (median change of -4.6 log(10) copies/mL) and improved liver chemistries (P < or = 0.001). Both treatment regimens were well tolerated, and renal function abnormalities were not observed in either group. CONCLUSIONS: The addition of adefovir dipivoxil to lamivudine in patients with CHB with compensated or decompensated liver disease due to YMDD mutant HBV is associated with virologic and biochemical improvement during 52 weeks of treatment and is well tolerated.     

Emergence of adefovir-resistant mutants after reversion to YMDD wild-type in lamivudine-resistant patients receiving adefovir monotherapy

Background:  To evaluate the effect of reversion to YMDD wild-type on emergence of adefovir (ADV)-resistant mutation and antiviral activity of ADV in lamivudine (LAM)- resistant patients.
Methods:  We determined YMDD mutations and ADV-resistant mutations before and every 3 months during ADV monotherapy in 33 LAM-resistant patients using the restriction fragment mass polymorphism (RFMP) method.
Results:  Reversion to pure YMDD wild-type hepatitis B virus (HBV) occurred in 6% (2/33), 9% (3/33), 20% (4/20) and 35% (6/17) of patients after 12, 24, 36 and 48 weeks, respectively. Five (29%) patients were found to have pure YMDD mutants at 48 weeks of therapy. Among 33 patients, 4 (12%) patients developed ADV-resistant mutations at 48 weeks of therapy. Adefovir-resistant mutants emerged in all patients after reversion to YMDD wild-type HBV. The mean serum HBV reductions, evaluated at 24 weeks of therapy, were not different between patients with and without reversion to YMDD wild-type HBV (−3.1 log₁₀ copies/mL vs −3.4 log₁₀ copies/mL, P  > 0.05).
Conclusions:  ADV-resistant mutations emerged after reversion to YMDD wild-type in LAM-resistant patients who received ADV monotherapy. Thus, ADV add-on therapy may be necessary to reduce the incidence of developing ADV resistance in patients with LAM resistance.     

HBV YMDD变异者采用阿德福韦和恩替卡韦治疗144周临床比较

目的 评价阿德福韦(ADV)和恩替卡韦(ETV)治疗慢性乙型肝炎HBV YMDD变异患者144周的疗效和安全性.方法 2005年6月至2007年6月在门诊和住院的经拉米夫定(LAM)治疗后出现HBV YMDD变异的慢性乙型肝炎患者120例,随机分为4组,A组单用ADV 10 mg/d治疗144周;B组采用ADV 10 ...     

Long-term efficacy of entecavir therapy in chronic hepatitis B patients with antiviral resistance to lamivudine and adefovir

No studies have reported the long-term effects of entecavir switching in patients with multidrug resistance who developed resistance after lamivudine/adefovir sequential therapy. We evaluated the efficacy of 96 weeks of entecavir therapy in patients with resistance to lamivudine/adefovir sequential therapy. In total, 33 patients with chronic hepatitis B virus (HBV) infection with evidence of active viral replication (HBV DNA levels ≥ 10(5) copies/mL) or a history of treatment failure to lamivudine/adefovir sequential therapy between April 2007 and July 2009 were treated with entecavir (1.0 mg daily) for at least 48 weeks. The rates of alanine transaminase (ALT) normalization and HBV DNA negativity were 66.7% (14/21) and 24.2% (8/33) at 48 weeks, respectively. The initial HBV DNA level was the only factor that was inversely associated with serum HBV DNA negativity after 48 weeks of entecavir therapy (P < 0.023). At 96 weeks, the rates of ALT normalization and HBV DNA negativity were 77.8% (7/9) and 16.7% (3/18), respectively. Viral breakthrough occurred in 21.2% (7/33) and 78.9% (15/19) of patients at 48 and 96 weeks, respectively. Patients who achieved a HBV DNA level of <4 log(10) copies/mL at 48 weeks maintained a similar HBV DNA level and a normal ALT level until 96 weeks. Entecavir monotherapy for 96 weeks was not efficacious for patients with lamivudine/adefovir-resistant HBV. The initial HBV DNA level was the only predictive factor for antiviral efficacy. However, patients who achieved a HBV DNA level of <4 log(10) copies/mL with a normal ALT level at 48 weeks should maintain, rather than stop, entecavir therapy.     

Evolution of multi-drug resistant hepatitis B virus during sequential therapy

Multi-drug resistant hepatitis B virus (HBV) has been reported in hepatitis B patients who received sequential antiviral therapy. In vitro studies showed that HBV constructs with mutations resistant to lamivudine and adefovir have marked reduction in sensitivity to combination of lamivudine and adefovir, whereas constructs with mutations resistant to either drug remain sensitive to the other drug. We conducted this study to determine whether mutations conferring resistance to multiple antiviral agents co-locate on the same HBV genome in vivo and to describe the evolution of these mutations. Sera from six patients who had been found to have multi-drug resistant HBV mutations to lamivudine+adefovir, lamivudine+hepatitis B immunoglobulin (HBIG), or lamivudine+entecavir on direct sequencing were cloned after nested polymerase chain reaction (PCR). Analysis of 215 clones from 11 samples with multi-drug resistant mutations on direct sequencing showed that 183 (85%) clones had mutations to both therapies on the same genome; 31 clones had lamivudine-resistant mutants only. Clonal analysis of serial samples from three patients showed progressive evolution from all clones with lamivudine-resistant HBV mutations only to mixtures of clones that have multi-drug resistant mutations and clones that have lamivudine-resistant HBV mutations only, and ultimately all clones having multi-drug resistant HBV mutations. In conclusion, mutations conferring resistance to multiple antiviral agents co-locate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multi-drug resistant HBV. De novo combination therapy may prevent the emergence of multi-drug resistant mutants.     

A comparison of 4-year entecavir efficacy in nucleos(t)ide analog-naïve and -experienced adult Taiwanese chronic hepatitis B patients

Purpose

To compare the efficacy of entecavir (ETV) monotherapy up to 4 years in nucleos(t)ide analog (NA)-experienced and -naïve subjects.

Methods

One hundred sixty NA-experienced and 282 naïve chronic hepatitis B patients who were treated with ETV were enrolled. Of the 160 NA-experienced patients, 49 had prior lamivudine (LAM)-resistant mutants, 18 had resistant mutants to LAM followed by adefovir (ADV) after switching to ADV sequential therapy (LAM/ADV resistance), and 9 had prior ADV-resistant mutants. NA-resistant mutants were detected by line probe assay.

Results

Four years of ETV therapy resulted in virological response (VR, HBV DNA < 300 copies/ml), HBeAg seroconversion, and ETV-resistant mutants development in 98.2, 45.2, and <1 % of naïve patients, respectively. LAM- and ADV-experienced patients who never developed LAM-resistant mutants had similar VR and ETV-resistant mutant rates to NA-naïve patients. In contrast, prior LAM-resistant mutants were significantly associated with higher ETV-resistant mutants development and reduced VR rates. Patients with prior LAM-resistant mutants but not at baseline had a lower rate of ETV-resistant mutants compared to those with baseline LAM-resistant mutants [hazard ratio (HR): 0.58, 95 % confidence interval (CI): 0.35–0.95] and those who had LAM/ADV resistance (HR:0.16, 95 % CI:1.0.03–0.76). Early add-on ADV achieved VR in eight of nine patients with ETV-resistant mutants when HBV DNA was <2 × 10⁵ copies/ml.

Conclusions

Entecavir was highly efficacious and low resistance in NA-naïve, LAM-, or ADV-experienced patients without LAM-resistant mutants. Patients with prior LAM-resistant mutants but not at baseline had lower ETV-resistant mutant rates compared to those with baseline LAM-resistant mutants or LAM/ADV resistance.     

Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure

Background and aims

In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen.

Methods

In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks.

Results

At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log₁₀IU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed.

Conclusions

In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.

     

Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B

BACKGROUND & AIMS: Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV. METHODS: In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal). RESULTS: Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was -5.11 log(10) copies/mL for entecavir-treated patients and -0.48 log(10) copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment. CONCLUSIONS: In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile.     

拉米夫定和阿德福韦酯双重耐药HBV株临床检出特点与表型特性分析

目的分析拉米夫定(lamivudine,LAM)和阿德福韦酯(adefovir,ADV)双重耐药HBV株临床检出特点和表型特性,为临床优化抗病毒方案提供参考。方法回顾性分析26 553例慢性HBV感染者血清样本中HBV反转录酶区与LAM和ADV耐药相关的突变类型及频率,采用PCR产物直接测序法和克隆测序法(≥20个克隆/样本)对双重耐药HBV株进行鉴定,采用表型耐药方法分析强效核苷(酸)类似物[nucleos(t)ide analogues,NAs]对双重耐药HBV的抑制效果。结果 26 553例慢性HBV感染者的血清样本中,LAM/ADV双重耐药HBV突变株的检出率为0.6%(147/26 553),主要突变类型为rt L180M+A181V+M204V(65.3%)和rt A181V+M204I(10.2%)。多数患者经历了LAM→ADV(40.8%)或LAM→ADV→ETV(38.8%)单药序贯/联合治疗,平均抗病毒时间为63个月。其中2例代表性LAM和ADV双重耐药患者的动态血清样本克隆结果显示,在恩替卡韦(entecavir,ETV)+ADV联合挽救治疗期间,随着获得完全病毒学应答后维持时间的延长,病毒准种池中LAM/ADV双重耐药株逐渐消失,病毒株以单一NAs耐药株或野生株为主。体外表型结果显示,各种双重耐药HBV突变株的体外复制力均低于野生株,ETV+ADV联合、替诺福韦酯(tenofovir,TDF)单独或TDF+ETV联合可有效抑制野生株复制(抑制率为98.5%~99.5%),而对各种LAM/ADV双重耐药突变株的抑制率分别为80.6%~92.5%、86.1%~97.9%和89.2%~97.5%。结论长期LAM和ADV单一序贯治疗可促进LAM/ADV双重耐药HBV发生,ETV+ADV联合、TDF单独或TDF+ETV联合均可有效抑制LAM/ADV双重耐药HBV复制,而基于TDF的挽救治疗效果更佳。