HBV : Application of Roadmap-concept on Chronic Hepatitis B Patient with Entecavir Therapy Previously Exposed to Lamivudine: A Long Term Follow-up Study
Sang Jun SuhHyung Joon YimYeon Seok SeoChang Wook KimChang Don LeeSang Hoon ParkMyung Seok LeeChoong Kee ParkHee Bok ChaeMoon Young KimSoon Koo BaikYun Soo KimJu Hyun Ki
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Background/Aim: Many patients with lamivudine-resistant (LAM-R) chronic hepatitis B (CHB) had been treated by switching to entecavir (ETV) 1.0mg. Although rate of resistance to ETV (ETV-R) is reported high, current medical insurance system doesn`t pay-back for change from ETV to other agent in patients whose resistance to ETV was not identified. This study was aimed to stratify ETV therapy in LAM-R patients. Methods: One hundred and ten CHB patients who occurred LMV-R and received ETV 1.0mg up to 5 years were evaluated prospectively. At 12 months of switching to ETV, we divided subjects into non-detection group (HBV DNA<20 IU/mL) and detection group (HBV DNA≥20 IU/mL), which was subdivided into low viral load group (20≤HBV DNA<2,000 IU/mL) and high viral load group (2,000 IU/mL≤ HBV DNA). Virologic response rate (VR; HBV DNA<20 IU/mL) and ETV-R were evaluated as end point. Results: One hundred and ten patents were enrolled. The mean age was 45±11years, the proportion of male and HBeAgpositive patient was 71% (80/110) and 77% (85/110), respectively. The mean serum HBV DNA levels were 6.89±1.03, 3.26±1.81, 3.06±1.82, 2.49±1.53, 2.43±1.35 and 1.73±0.87 log10IU/ ml at baseline, month 12, 24, 36, 48 and 60, respectively. The VR (95% vs. 29%, P<0.001) was higher and ETV-R (10% vs. 54%, P=0.001) was lower in non-detection group than in detection group. The VR (27% vs. 29%, P=0.853) and ETV-R (45% vs. 57%, P=0.367) was not significantly different between low viral load and high viral load group. Resistance to ETV occurred at 26±10.3 months (median 24 months, 12-48 months) in detection group. Conclusion: Resistance rates were high in patients with detectable HBV DNA at 12 months of ETV therapy. Therefore, switching to or adding a potent nucleotide analogue (e.g. tenofovir) is warranted in LAM-R CHB patients whose HBV DNA is detected after 12 months of ETV therapy.Keywords:
Entecavir
Hepatitis B
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Abstract This study evaluated the efficacy of adefovir (ADV) plus lamivudine (LAM) or ADV add‐on therapy for patients with entecavir (ETV)‐refractory hepatitis B infection. Twenty‐nine ETV‐resistant and 8 patients with suboptimal response to ETV were enrolled. Twenty‐seven patients received ADV + LAM therapy and 10 patients received ADV + ETV therapy for >24 weeks. In 29 patients who were ETV‐resistant, the mean reduction in HBV DNA levels at 24 weeks was not different between the ADV + LAM and ADV + ETV groups (−1.98 log 10 IU/ml vs. −2.16 log 10 IU/ml; P = 0.792). Primary non‐response was observed in 52.2% (12/23) of ADV + LAM group and 33.3% (2/6) of ADV + ETV group ( P = 0.651). Initial virologic response (IVR) was observed in 17.4% (4/23) of ADV + LAM group and 33.3% (2/6) of ETV + ADV group ( P = 0.362). In eight patients with suboptimal response to ETV, the ADV + ETV group had a greater reduction in HBV DNA at 24 and 48 weeks than the ADV + LAM group (−2.29 log 10 IU/ml vs. −0.09 log 10 IU/ml and −2.04 log 10 IU/ml vs. −0.72 log 10 IU/ml; P = 0.020 and P = 0.012, respectively). Primary non‐response and IVR did not significantly differ between the two groups [100% (4/4) vs. 50% (2/4) and 0% (0/4) vs. 50% (2/4); P = 0.429 and P = 0.429, respectively]. The antiviral efficacies of ADV‐based therapy with ETV or LAM for patients with ETV‐resistant hepatitis B were limited and did not differ between the two groups. However, adding ADV to ETV may be more effective than ADV + LAM therapy in patients with suboptimal virologic response to ETV. J. Med. Virol. 84:18–25, 2011. © 2011 Wiley Periodicals, Inc.
Entecavir
Adefovir
Refractory (planetary science)
Hepatitis B
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Objective Evaluation of safety and efficacy of one year treatment of entecavir (ETV)in Chinese patients with chronic hepatitis B(CHB)who had failed to lamivudine(LVD)treat- ment.Methods One hundred and forty-five eligible patients were enrolled who had documented LVD failure.In the double-blind phase,patients were randomized(4:1)to ETV 1.0 mg/d(n=116)or placeho(n=29)for 12 weeks.In the open-label phase,all patients received ETV 1.0 mg/d for 36 weeks.HBV DNA level,liver biochemical tests,HBV seromarkers and safety assessments were con- ducted.Results The mean reduction in HBV DNA levels at week 12 was 4.30 log_(10)copies/ml in ETV group compared to 0.15 log_(10)copies/ml in placebo group(P＜0.01).Among patients with ab- normal alanine aminotransferase(ALT)at baseline,a significantly higher percentage of patients in the ETV group had achieved ALT normalization at week 12 than in the placebo group(68% vs 6%,P＜0.01).In 12 weeks period,the overall incidence of adverse events was comparable between treat- ment groups:33% of ETV patients and 28% of placebo patients reported adverse events.All patients treated in the double-blind phase entered the open-label dosing phase.Among patients initially treated with ETV in the double-blind phase,the mean reduction in HBV DNA levels after 48 weeks of ETV treatment was 5.08 log_(10)copies/ml.In patients initially treated with placebo in double-blind phase, the mean reduction in HBV DNA levels after 36 weeks of ETV treatment was 4.86 log_(10)copies/ml. Normalization of ALT levels was observed in more than 85% of patients with abnormal ALT at base line.HBeAg seroconversion occurred in 6.2%(8/129)at week 48.No mutations associated with re sistance to ETV were detected.ETV 1.0 mg per day for up to 48 weeks was safe and well tolerated. Conelusions The findings from this study demonstrated the antiviral activity and safety of ETV in a- dults with CHB who have failed LVD.
Entecavir
Hepatitis B
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To evaluate the virological, serological and biochemical outcomes of 3 years of entecavir (ETV) treatment in nucleoside-naive chronic hepatitis B patients.This study was divided into two stages: Patients receiving either ETV 0.5 mg/d (n = 258) or lamivudine (LAM) 100 mg/d (n = 261) entered the initial 96-week randomized, double blind, controlled efficacy study. Patients not achieving a consolidated response (HBV DNA less than 0.7 MEq/ml, ALT less than 1.25 times*ULN, and if HBeAg-positive at baseline, loss of HBeAg for >or= 24 weeks), or those experienced viral breakthrough or relapse, entered a 48-week entecavir rollover study.96 weeks after the treatment, 79% of ETV treated and 46% of LAM treated patients had HBV DNA less than 300 copies/ml (P < 0.0001), 96% of ETV treated and 92% of LAM treated patients had normalized ALT (P = 0.06). 21% of ETV treated and 23% of LAM treated patients achieved HBeAg seroconversion. Among the 160 patients received continuous ETV for 144 weeks, 89% had undetectable serum HBV DNA, 86% showed ALT normalization, and 27% achieved HBeAg seroconversion. ETV resistance was rare: only 3 patients showed ETV resistance 96 weeks after the treatment, and additional 2 patients developed ETV resistance during the following 48 weeks, genotyping indicated the ETV resistance was caused by gene mutation. Adverse event rates in ETV-treated patients were similar to those in LAM-treated patients, but fewer ALT flares were observed in ETV-treated patients.This study demonstrates that ETV treatment results in long-term HBV suppression and ALT normalization in Chinese CHB patients, and is associated with low rate of drug resistance.
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Seroconversion
HBeAg
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Objective To study the antiviral efficacy of entecavir (ETV) compared with lamivudine (LAM) in patients with chronic hepatitis B. Methods Eighty four patients with chronic hepatitis B were divided into ETV group (0.5 mg/d) and LAM group (100 mg/d) for at least 48 weeks. After 4,12,24,48 weeks treatment,serum samples of the patients were tested for alanine aminotransferase levels and HBV viral loads according to PCR assay,respectively. HBV serological markers were tested before and after 48 weeks treatment. Results After 48 weeks treatment,the ALT normalization rate in ETV and LAM groups were 90.5% and 73.8%,respectively (P0.05 ). The proportion of patients with HBV DNA undetectable (HBV DNA 103 copies/ml ) was higher in ETV group than in LAM group (92.7% vs 71.4%,P0.05). There were no significant difference in proportion of HBeAg seroconversion between two groups,but the HBeAg loss rate in ETV group was higher than LAM group (39.4% vs 17.7%,P0.05 ). No patient was resistant to ETV,while 8 cases (19.0% ) occoured viral rebound and YMDD mutations were confirmed by examination. Conclusions The rates of virologic response,normalization of alanine aminotransferase levels and HBeAg loss in ETV group were significantly higher than LAM group.
Entecavir
HBeAg
Alanine aminotransferase
Seroconversion
Hepatitis B
BDNA test
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Clinical characteristics of patients with chronic hepatitis B (CHB) who developed genotypic resistance to entecavir (ETV) were compared to those without resistance.Two hundred fifty eight CHB patients who underwent ETV treatment in our institution from July 2007 to May 2013 were included.Eight (3.1%) patients developed genotypic resistance to ETV during the follow-up period. The patterns of genotypic resistance to ETV were as follows: L180M + M204V + S202G (n=3); M204I + V173M (n=1); I169V + V173M (n=1); L180M + M204V + V173L (n=1); L180M + M204V + V173L + M250V (n=1); M204I + V214A + P237H (n=1). The cumulative occurrence rates of genotypic resistance to ETV were not significantly different between CHB patients with prior nucleos(t)tide analogues (NA) exposure (NA experienced, n=56) and NA naïve patients (n=202, P=0.823 by log rank comparison). Older age, higher baseline log10hepatitis B virus-deoxynucleic acid (log10HBV-DNA), higher log10HBV-DNA at 3, 6, 12 and 24 months after baseline, and complete virologic response (CVR, undetectable serum HBV-DNA by polymerase chain reaction 6 months after ETV treatment) were significant contributors to the development of genotypic resistance to ETV. Multivariate analyses showed higher log10HBV-DNA 6 months after baseline and absence of CVR were independent and significant contributors to the development of ETV resistance.Clinical characteristics of patients who developed ETV resistance were higher log10HBV-DNA 6 months after baseline and absence of CVR during the ETV treatment.
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Background/Aim: Entecavir (ETV) is a first-line agent in the treatment of chronic hepatitis B (CHB) because of its highly potent antiviral effect with a high genetic barrier to resistance. The optimal management of patients with partial virologic response (PVR) to ETV is currently not well defined. The aims of this study were to assess the efficacy of prolonged ETV monotherapy and predictive factor of PVR in CHB patients with a PVR to ETV therapy. Methods: A total of 268 treatment-naive CHB patients, who were treated with ETV 0.5 mg daily for at least 48 weeks, were included in this study. PVR was defined as a decrease in serum HBV DNA of more than 2 log10 IU/mL but detectable HBV DNA by real-time PCR assay at week 48. All patients were monitored at baseline and at 3-month intervals during treatment. Results: The mean age was 49.9±12.0 years, and 149 patients (55.4%) were men. 161 patients (60.1%) were HBeAg-positive, and 99 patients (36.9%) had cirrhosis. Forty-one of 268 patients (15.3%) showed PVR to 48 weeks of ETV treatment, and 24 patients were followed up for over 18 months. Among them, 13 of 24 patients (54.2%) achieved a complete virologic response (HBV DNA 7 log10 IU/mL) at baseline, HBV DNA >2000 IU/mL at week 12, and detectable HBV DNA at week 24 were independently associated with a PVR during ETV therapy. Conclusions: This study showed that baseline and on-treatment early HBV DNA levels were predictor of PVR to ETV in treatment-naive patients with CHB. Long-term ETV therapy may be effective for achieving viral suppression in treatmentnaive CHB patients with a PVR to ETV.
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HBeAg
Hepatitis B
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Abstract The subsequent maintenance therapy in chronic hepatitis B (CHB) patients after long‐term viral replication suppression is still uncertain. We aim to evaluate the efficacy of lamivudine (LAM) maintenance therapy in CHB patients achieving undetectable hepatitis B virus (HBV) DNA after 3 years of entecavir (ETV) therapy. Consecutive CHB patients who received at least 3 years of ETV and achieved HBV DNA negativity were allocated either LAM switch therapy or stopped ETV therapy in a prospective, open‐label study. Another group of sex‐ and age‐matched patients with continuous ETV therapy for at least 4 years served as historical control group. The primary outcome measurement of the study was relapse of HBV DNA (defined as serum HBV DNA level ≥ 2000 IU/mL). A total of 74 patients, including 42 of LAM switch and 32 of the nonswitch group, were enrolled. There were no significant differences in demographics, except a higher proportion of patients with positive hepatitis B envelope antigen in the nonswitch group at the initiation of ETV therapy. The LAM switch group had significantly lower 1‐year relapse rate of HBV within 1 year compared to the nonswitch group (14.3% vs. 75%, p < 0.001). However, none of the 48 historical control patients developed relapse of HBV, which was significantly lower than the rate in LAM switch group ( p < 0.001). LAM switch was the only factor associated with HBV DNA relapse. In conclusion, continuous long‐term potent nucleot(s)ide analogue therapy is mandatory for prevention of viral relapse in CHB patients.
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Hepatitis B
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In the 2007-2008 guidelines of the study group (Ministry of Health, Labor and Welfare of Japan), lamivudine (LAM)-continuous treatment was recommended in patients treated with LAM for more than 3 years who maintained hepatitis B virus (HBV) DNA less than 2.6 log copies/mL, because in these patients LAM resistance might exist and switching treatment to entecavir (ETV) might cause ETV resistance. However, there was no evidence on whether switching treatment to ETV- or LAM-continuous treatment was better in those patients. In the present study, we performed a randomized controlled trial of LAM-to-ETV switching treatment. Twenty-seven patients treated with LAM for more than 3 years whose HBV DNA levels were less than 2.6 log copies/mL were enrolled and randomly divided into two groups, LAM-continued group or switching to ETV group. Then, we examined incidence of virological breakthrough (VBT) and breakthrough hepatitis (BTH) in each group. There was no BTH in any of the patients. VBT was observed in six patients of the LAM group (6/15, 40%), and no patient of the ETV group (0/11, 0%) (P = 0.02). The differences of the proportion of cumulated VBT using a log-rank test with Kaplan-Meier analysis were significant between the LAM and ETV groups (P = 0.025). In patients treated with LAM for more than 3 years maintaining HBV DNA less than 2.6 log copies/mL, switching treatment to ETV is recommended at least during the 2 years' follow-up period.
Entecavir
Christian ministry
Hepatitis B
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To evaluate the efficacy of entecavir (ETV) 1.0 mg/d or ETV plus adefovir dipivoxil (ADV) in adults with chronic hepatitis B virus (HBV) infection who had previously resisted lamivudine (LAM) and failed with rescue treatment of LAM + ADV.40 patients were enrolled. 14 patients were treated with ETV 1.0 mg/d monotherapy while 26 patients were treated with ETV 1.0 mg/d + ADV 10 mg/d. The HBV DNA level, liver function, HBV serology and renal function were observed.There was no statistically significant difference with baseline situation between group ETV 1.0 mg and group ETV + ADV. HBV DNA level in group ETV 1.0 mg was (5.768 ± 0.709) log10 copies/ml on baseline, and it declined to (4.712 ± 0.846) log10 copies/ml, (3.914 ± 0.996) log10 copies/ml, (3.702 ± 0.934) log10 copies/ml, (3.879 ± 0.913) log10 copies/ml and (3.855 ± 1.070) log10 copies/ml at 4, 8, 12, 24 and 48 weeks. HBV DNA level in group ETV + ADV was (5.703 ± 0.845) log10 copies/ml on baseline, and it declined to (4.476 ± 0.905) log10 copies/ml, (3.590 ± 0.884) log10 copies/ml, (2.987 ± 0.673) log10 copies/ml and (2.933 ± 0.535) log10 copies/ml at 4, 8, 12 and 24 weeks. At 24 weeks, there were 28.6% patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but there were 80.8% patients in group ETV + ADV achieved this level. Statistically significant difference existed between (x(2) = 8.469, P = 0.004 ). At 48 weeks, there were still 4 patients achieved HBV DNA < 500 copies/ml in group ETV 1.0 mg, but patients in group ETV + ADV all achieved it. At 24 weeks, ALT levels of 42.9% patients in group ETV 1.0 mg were back to normal, but there were 92.3% patients' ALT levels back to normal in group ETV + ADV. There was statistically significant difference (x(2) = 9.337, P = 0.002). At 48 weeks, ALT levels of 57.1% patients in group ETV 1.0 mg were back to normal, but all patients' ALT levels were back to normal in group ETV + ADV. At 48 weeks, there was 1 patient with HBeAg seroconversion in group ETV 1.0 mg while there were 4 patients in group ETV + ADV.As rescue treatment for patients with chronic hepatitis B who had previously resisted LAM and failed with treatment of LAM + ADV, ETV + ADV was more efficient than ETV 1.0 mg monotherapy, and it can achieve better virological and biochemical response.
Adefovir
Entecavir
Hepatitis B
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Background/Aims The optimal management of patients exhibiting a partial virologic response (PVR) to entecavir (ETV) has not been determined. The aim of this study was to determine the long-term efficacy of prolonged ETV monotherapy in treatment-naïve chronic hepatitis B (CHB) patients exhibiting a PVR to ETV therapy. Methods This study included 364 treatment-naïve CHB patients treated with ETV for â¥48 weeks and who received continuous ETV monotherapy for â¥96 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log10 IU/mL from baseline but with detectable HBV DNA by real-time PCR assay at week 48. Results Fifty-two of the 364 patients (14.3%) showed a PVR. Among them, 41 patients received continuous ETV monotherapy for â¥96 weeks (median duration 144 weeks, range 96-312 weeks), and 40 of these patients (95%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged ETV monotherapy (median duration 78 weeks, range 60-288 weeks). The cumulative probabilities of a VR at weeks 96, 144, and 192 from treatment initiation were 78.0%, 92.7%, and 95.1%, respectively. The VR rate was 97.2% (35/36) in HBeAg-positive patients and 100% (5/5) in HBeAg-negative patients. In multivariate analysis, HBeAg positivity (odds ratio [OR], 9.231; 95% confidence interval [CI], 1.03-82.91; P=0.047) and a high baseline HBV DNA level (OR, 0.170; 95% CI, 0.08-0.37; P=0.000) were independently associated with a delayed virologic response. No patient developed genotypic resistance to ETV during follow-up. Conclusions Long-term ETV monotherapy is effective for achieving a VR in treatment-naïve CHB patients exhibiting a PVR to ETV. HBeAg positivity and high baseline HBV DNA level were independently associated with a delayed virologic response. Keywords: Chronic hepatitis B; Entecavir; Partial virologic response
Entecavir
HBeAg
Hepatitis B
Combination therapy
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