Entecavir Monotherapy Research Articles

Entecavir or tenofovir monotherapy prevents HBV recurrence in liver transplant recipients: A 5-year follow-up study after hepatitis B immunoglobulin withdrawal

Background/aims: Prophylaxis with HBIg + NUC remains the standard-of-care to prevent HBV reinfection after LT. Recent data suggest that 3rd generation NUC therapy may be effective as well. We investigated the 5-year efficacy/safety of ETV or TDF monoprophylaxis after HBIG withdrawal.

Entecavir monotherapy improves renal function in patients developing renal side effects during long-term tenofovir treatment without compromising virological response: A multicenter real-life study in 103 patients

Introduction: Tenofovir disoproxil fumarate (TDF) is a recommended first-line therapy for chronic hepatitis B (CHB) patients. However, reduced estimated glomerular filtration rate (eGFR), hypophosphatemia and Fanconi syndrome have been reported in some TDF-treated patients. We assessed whether entecavir (ETV) may be a safe and effective rescue strategy for such patients.

THU-442 - Entecavir or tenofovir monotherapy prevents hepatitis B virus recurrence in liver transplant recipients: a 5-year follow-up study after hepatitis B immunoglobulin withdrawal

THU-442 - Entecavir or tenofovir monotherapy prevents hepatitis B virus recurrence in liver transplant recipients: a 5-year follow-up study after hepatitis B immunoglobulin withdrawal

Entecavir monotherapy cost effective for CHB in China

Entecavir monotherapy cost effective for CHB in China

Cost-Effectiveness Comparison Between the Response-Guided Therapies and Monotherapies of Nucleos(t)ide Analogues for Chronic Hepatitis B Patients in China.

Nucleos(t)ide analogue (NA) monotherapies are typically used as the primary treatment for chronic hepatitis B (CHB) patients, including lamivudine (LAM), telbivudine (TBV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF). For high-resistance NAs (LAM, TBV, ADV), they can generate excellent clinical outcomes by using response-guided therapy; however, their pharmacoeconomic profiles remain unclear in China. We aimed to evaluate the cost effectiveness between response-guided therapies and monotherapies of NAs for Chinese hepatitis B e-antigen (HBeAg)-positive and -negative CHB patients. We constructed a Markov model to simulate CHB progression associated with 12 treatment strategies using effectiveness and cost data from the published literature. We measured the lifetime costs, quality adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way sensitivity (especially to extend the range of the TDF price) and probabilistic sensitivity analyses were used to explore the uncertainties of the model. For both HBeAg-positive and -negative patients, no treatment strategy generated the lowest lifetime costs (US$31,185-US$31,338) and QALYs (7.54-7.58). ETV and TDF monotherapies were not dominated by other treatments, whereas, the ICER of ETV monotherapy was the lowest (US$6112/QALY-US$8533/QALY). For each high-resistance NA, compared with its monotherapy, the ICERs of its response-guided therapies were below the willingness-to-pay threshold of US$22,833/QALY. Additionally, TDF monotherapy was the preferred treatment when its price dropped to US$1820/year or lower. Among 12 treatment strategies evaluated, ETV monotherapy is the most cost-effective treatment for treatment-naive CHB patients in China. The response-guided therapies of high-resistance NAs are more cost-effective than their monotherapies.

Flares during long-term entecavir therapy in chronic hepatitis B.

The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB). CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as > 3× increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT > 3× ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA). Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg (n = 3) and hepatitis B surface antigen (n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance (n = 2) and non-compliance (n = 1). The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares.

Circulating kidney injury molecule-1 is a novel diagnostic biomarker for renal dysfunction during long-term adefovir therapy in chronic hepatitis B.

The aim of this study was to evaluate serum kidney injury molecule-1 (KIM-1) as a new diagnostic marker of renal dysfunction in chronic hepatitis B (CHB) patients receiving long-term adefovir dipivoxil (ADV) treatment.We retrospectively enrolled 85 patients treated with ADV and 85 patients treated with entecavir (ETV) monotherapy, for at least 6 months. The 2 groups were matched for baseline age (± 5 years), sex, and estimated glomerular filtration rate (eGFR). Serum creatinine, cystatin C, and KIM-1 concentrations were measured, and eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin C equation, at baseline and last follow-up.eGFR decreased by 10-20% from baseline in 11/85 (14.1%) patients, 20-30% in 5/85 (5.9%), and ≥ 30% in 2/85 (2.4%) patients treated with ADV. Serum KIM-1 was more significantly increased after ADV treatment 86.53 (10.20-355.40) pg/mL than ETV treatment 61.54 (10.53-200.56) pg/mL (P < 0.01). Furthermore, serum KIM-1 was positively correlated with serum cystatin C (r = 0.47; P < 0.001) and negatively correlated with eGFR (r = -0.46; P < 0.001). The area under the receiver operating characteristic curve (AUC-ROC) of serum KIM-1 for identifying renal dysfunction in all enrolled patients was 0.94 (95% confidence interval [95% CI], 0.87 to 1.02; P < 0.001), while the AUC-ROC of serum creatinine was only 0.82 (95% CI, 0.60 to 1.03; P < 0.01).Serum KIM-1 is a promising new diagnostic biomarker of renal dysfunction during long-term ADV therapy for CHB patients.

Efficacy of long-term tenofovir-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs.

Few studies have investigated the efficacy of long-term tenofovir disoproxil fumarate (TDF)-based rescue therapy in patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs. We retrospectively analyzed 40 Japanese patients with chronic hepatitis B refractory to nucleoside/nucleotide analogs who received TDF-based rescue therapy [TDF monotherapy, TDF plus lamivudine (LAM) combination therapy, or TDF plus entecavir (ETV) combination therapy] followed up for a median of 45 months (range 14-99months). Viral response, changes in hepatitis B surface antigen levels from the baseline, and viral breakthrough during therapy were analyzed. The proportion of patients with undetectable serum hepatitis B virus (HBV) DNA levels (less than 2.1 log copies per milliliter) (viral response) during TDF-based rescue therapy was 68, 78, 85, 88, 83, 81, 88, and 100% at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, and 4years respectively. There were no differences in the viral response rate between the TDF plus LAM group and the TDF plus ETV group. The mean reduction from the baseline in hepatitis B surface antigen levels in patients with LAM-resistant HBV was greater than the reductions in patients with adefovir dipivoxil (ADV)-resistant or ETV-resistant HBV at 2 and 3years (P=0.024, and P=0.025 respectively). However, two patients with ADV- or ETV-resistant HBV at the baseline developed viral breakthrough during TDF-based rescue therapy. Long-term therapy with a TDF-based rescue regimen demonstrated high viral suppression in patients in whom LAM plus ADV combination therapy, ETV plus ADV combination therapy, or ETV monotherapy had failed. However, patients with ADV- or ETV-resistant HBV at the baseline may develop viral breakthrough and resistance, and careful follow-up is advised.

HBIg-Induced Transient Hepatitis B Core Antibody in Liver Transplant Recipient: Misleading Serology Testing?

Introduction: The rate of HBV transmission in liver transplantation from donors with positive Hepatitis B core Antibodies is reported to be higher in liver transplants when compared to other solid organ transplants due to the fact that HBV resides in donor hepatocytes. The administration of hepatitis B immune globulins (HBIg) and effective antiviral therapy has been successful in reducing the rate of is transmission. In this case, we describe a patient who received a deceased donor liver transplant from an HBcAb positive donor and developed a transient seropositive HBcAb from HBIg administration. Case Presentation: A 61-year-old woman with a history of end-stage liver disease secondary to hepatitis C genotype 1a liver cirrhosis who underwent a deceased donor orthotopicliver transplant on August 7th,2015. HCV viral PCR on August 13th, 2015 was 54,787 IU/mL. She was treated with simeprevir plus sofosbuvir for 12 weeks with sustained viral response. RepeatHCV viral PCRs in October and November 2015 as well as February2016 were all undetectable. Patient's donor serology was noted to have negative Hepatitis B Surface Antigen (HBsAg) and a positive HBcAb total but and a negative HBcAbIgM while HBV PCR, and HCV PCR were both negative. The transplant procedure was uneventful. The recipient received a single dose of 10,000 units of HBIg intravenously during the hospitalization per protocol and was continued on entecavir 0.5 mg daily.Of note, she was immunized with hepatitis B vaccine series (total 3 doses) and acquired immunity to Hepatitis B in March 2013 but lost her immunity to hepatitis B in February 2015 prior liver transplant. Upon follow up in transplant infectious disease clinic 1 month following her liver transplant, she was doing well. Interestingly enough, hepatitis B serology during that time showed positive HBsAb and HBcAb testsand negative HBsAg and HBV DNA. We continued to monitor recipient hepatitis B serology (table1) and found that her HBcAb which was positive became negative 9 months after the transplant and her HBsAb which was positive became negative after 9 months following the transplant despite after receiving a hepatitis B booster dose in December 2015. In our patient, she was initially non-immune to hepatitis B and received HBIg plue entecavir after the transplant. A recent study of 80 consecutive patients with chronic HBV undergoing liver transplantation on an HBIg-free regimen of entecavir monotherapy found a 91% loss of HBsAg and 98.8% achievement of serum HBV DNA clearance over a median follow-up time of 26 months post orthotopic liver transplant makes the role of HBIg diminish. HBIg is a polyclonal purified preparation of human anti-HBs (hepatitis B surface antibody) derived from pooled plasma and has maximum benefit during the first 6-12 months after the transplant when recipients were receiving intense immunosuppressant. In our patient, she initially was non-immune toHBV and then her HBcAb became positive, however HBV DNA was negative and HBsAb was positive for the first 6-7 months after the transplant. HBsAb seropositive may be explained by passive immunity from HBIg which can last long for 6-12 months.Figure 1

On-treatment and off-treatment efficacy of entecavir in a real-life cohort of chronic hepatitis B patients.

Entecavir (ETV) is a potent nucleoside analogue with high genetic barrier to resistance. In this study, real-life clinical experiences in the long-term use of ETV and the durability of its off-treatment effectiveness were analyzed. This study was based on a large real-life cohort of 2240 chronic hepatitis B patients treated with ETV between January 2006 and December 2012 using a centralized electronic data repository. Among 2240 patients, 804 patients were treatment naive and underwent ETV monotherapy. Their mean treatment duration was 712±493 days, with a cumulative proportion of patients achieving HBV DNA less than 300 copies/ml in 85.8, 95.7, and 97.6% at years 1, 2, and 3, respectively. Predictors for earlier virologic response were female sex, lower HBV DNA, higher alanine transaminase, lower platelet count, and HBeAg negativity at baseline. In patients who achieved virologic response and HBeAg loss, the cumulative relapse rate was 91.3% in 2 years after the cessation of treatment. During the treatment, 34 patients developed hepatocellular carcinoma, among whom 30 patients had cirrhosis before treatment initiation. ETV treatment showed efficient virologic response as the treatment duration was extended, but off-treatment efficacy was not durable, and the antiviral treatment showed some limitation in preventing hepatocellular carcinoma among liver cirrhosis patients, implying that treatment cessation should be taken into consideration more carefully. This study from a real-life cohort may provide data on treating chronic hepatitis B patients more close to everyday clinical practice.

Changes in serum β2-microglobulin, retinol-binding protein, and cystatin C and their value in identifying early renal dysfunction in patients with chronic hepatitis B undergoing tenofovir or entecavir monotherapy: a comparative analysis

Objective: To investigate the dynamic changes in serum β2-microglobulin, retinol-binding protein, and cystatin C in chronic hepatitis B(CHB)patients treated with tenofovir or entecavir alone as the anti-HBV therapy, as well as their value in identifying early renal dysfunction. Methods: A total of 61 previously untreated CHB patients who were diagnosed and treated in the Department of Infectious Diseases in Henan Provincial People's Hospital from June 2013 to August 2015 were enrolled and divided into tenofovir group and entecavir group. The serum levels of β2-microglobulin, retinol-binding protein, cystatin C, and creatinine and estimated glomerular filtration rate(eGFR)were compared between the two groups at baseline and 4, 8, 39, 52, 78, and 104 weeks after antiviral therapy. The independent samples t-test was used for comparison of continuous data, and the chi-square test was used for comparison of categorical data. P < 0.05 was considered statistically significant. Results: A total of 61 CHB patients were enrolled, with 31 in the tenofovir group and 30 in the entecavir group. The two groups had comparable serum levels of β2-microglobulin, retinol-binding protein, and cystatin C at baseline, but there were significant differences in β2-microglobulin and retinol-binding protein over time(both P < 0.05). There was a significant difference in cystatin C at 78 weeks(t = -2.062, P = 0.044), but there was no significant difference at 104 weeks(t = -1.544, P = 0.128). There were no significant differences in serum creatinine or eGFR at any time point between the two groups(P > 0.05). At 104 weeks, there were no significant differences in HBV-DNA clearance rate or the level of virologic breakthrough between the two groups(P > 0.05). Conclusion: Serum β2-microglobulin, retinol binding protein, and cystatin C are more sensitive than eGFR in the monitoring of early renal dysfunction during the anti-HBV therapy with tenofovir or entecavir alone.

Pegylated interferon combined with entecavir in treatment of HBeAg positive chronic hepatitis B

Objective To evaluate the efficacy of pegylated interferon α-2a and entecavir (ETV) combination therapy for patients with HBeAg positive chronic hepatitis B(CHB). Methods Fifty eight HBeAg positive CHB patients were assigned to two groups: 29 patients received ETV 0.5 mg daily for 72 weeks (ETV group) and 29 patients received ETV and pegylated interferon α-2a 180 μg weekly for 48 weeks followed by ETV alone for 24 weeks (combination group). Serum samples were collected from all patients every 12 weeks for assessment of biochemical, virological and serological responses to treatment. Results Fifty four patients completed the 72-week study, including 28 in ETV group and 26 in combination group. There were no significant differences in week 24, week 48 and week 72 of ALT normalization [72%(21/29) vs. 93%(27/29), χ2=2.104; 90%(26/29) vs. 97%(28/29), χ2=0.269; 90%(26/29) vs. 97%(28/29), χ2=0.269], HBV DNA undetectable rate [31%(8/26) vs. 46%(13/28), χ2=1.391; 62%(16/26) vs. 57%(16/28), χ2=0.108; 77%(20/26) vs. 75%(21/28), χ2=0.027], HBeAg loss rate[12%(3/26) vs. 25%(7/28), χ2=0.850; 31%(8/26) vs. 32%(9/28), χ2=0.012; 46%(12/26) vs. 36%(10/28), χ2=0.609] and HBsAg levels(log10 IU/ml)(3.63±0.45 vs. 3.36±1.18, t=-1.066; 3.45±0.43 vs. 3.23±1.15, t=-0.915; 3.36±0.58 vs. 2.88± 1.28, t=-1.762)between two regimens (all P>0.05). Among 58 patients, 15 were HBeAg and anti-HBe double-positive (26%)and 43 were HBeAg mono-positive patients. The baseline HBV DNA level [(5.07±1.50) vs. (6.40±1.47) log10 IU/ml, t=2.858, P<0.05] and HBeAg titer [14(4-45) vs. 732(296-1 012)S/CO, Z=-5.031, P=0.05] in double-positive patients were lower than those in mono-positive patients. The HBV DNA undetectable rate of double-positive patients was significantly higher than that of mono-positive patients in 24 weeks [10/15 vs. 26%(10/39), χ2=7.819, P<0.05] and 72 weeks [15/15 vs. 69%(27/39), χ2=4.287, P=0.05]. The HBeAg loss rate of double-positive patients was higher than that of mono-positive patients in 12 weeks [6/15 vs. 10%(4/39), χ2=4.533, P=0.05] and 48 weeks [9/15 vs. 26%(10/39), χ2=5.608, P=0.018]. This tendency was more significant in the combination therapy group, but the difference was not statistically significant. (5/6 vs. 4/9, P=0.065). Conclusions Compared with Entecavir monotherapy, entecavir combined with interferon may not improve the therapeutic effect in HBeAg positive chronic hepatitis B patients. However, the therapeutic response of HBeAg /anti-HBe double-positive patients may better than that of HBeAg mono-positive patients. Key words: Hepatitis B, chronic; Peginterferon Alfa-2a; Entecavir; Drug therapy, combined

Dynamic Characteristics of Serum Hepatitis B Surface Antigen in Chinese Chronic Hepatitis B Patients Receiving 7 Years of Entecavir Therapy.

Background:The ultimate goal of hepatitis B treatment is hepatitis B surface antigen (HBsAg) seroclearance. Several factors have been suggested to be associated with the rate of HBsAg reduction in antiviral-naive or lamivudine therapy cohorts. However, there are few studies evaluating the factors during long-term entecavir (ETV) therapy. In the present study, we aimed to evaluate the factors to predict the outcome of ETV therapy for 7 years.Methods:A total of 47 chronic hepatitis B (CHB) patients treated with ETV monotherapy were included in this study. Liver biochemistry, hepatitis B virus (HBV) serological markers, serum HBV DNA, and HBsAg titers were tested at baseline, 3 months, 6 months, and yearly from 1 to 7. The associations between factors and HBsAg reduction were assessed using multivariate tests with repeated measure analysis of variance.Results:At baseline, serum HBsAg levels showed a positive correlation with baseline HBV DNA levels (r = 0.625, P < 0.001). The mean HBsAg titers after ETV treatment were significantly lower than the baseline titers (P ranges from 0.025 to 0.000,000,6). The HBsAg reduction rate during the 1st year was greater compared to after 1 year of treatment (P < 0.05). Multivariate test showed that hepatitis B e antigen (HBeAg) seroclearance and/or HBsAg reduction ≥0.5 log10 IU/ml at 6 months had a high negative predictive value (96.77%) for HBsAg seroclearance (P = 0.002, P = 0.012, respectively).Conclusions:The HBsAg reduction rate during the 1st year was greater than that after 1 year of treatment. Further, HBeAg status and HBsAg levels at month 6 are the optimal factors for the early prediction of HBsAg seroclearance after long-term ETV therapy in CHB patients.

Alternative Therapies for Chronic Hepatitis B Patients With Partial Virological Response to Standard Entecavir Monotherapy.

Entecavir (ETV) is a first-line, oral antinucleoside agent for the treatment of chronic hepatitis B patients. Despite its high potency, some patients may still be viremic after prolonged therapy with ETV monotherapy. Long-term outcome data comparing maintained ETV monotherapy to alternative therapies in persistently viremic patients are limited. Our goal was to compare complete viral suppression (CVS) rates [hepatitis B DNA (HBV DNA)<40 to 60 IU/mL] with alternative therapies to continued ETV monotherapy in ETV partial responders. This is a retrospective cohort study consisting of 86 consecutive treatment-naive, ETV=0.5 mg partial responders (detectable HBV DNA after ≥12 mo on ETV) who maintained ETV=0.5 mg daily (n=29) or switched to either ETV=1.0 mg daily (n=32) or ETV/tenofovir (TDF)=0.5 mg/300 mg (n=25) in 3 US GI/liver clinics from January 2005 to January 2012. Patients were identified by International Classification of Diseases, Ninth Revision query and data were collected by individual chart review. For those who remained on ETV=0.5 mg, comparison at regimen "switch time" was done using values at 12 months from initial ETV therapy. Rates of CVS were evaluated using Kaplan-Meier methods. Multivariate Cox proportional hazard models were used to estimate hazard ratio (HR) relating to potential predictors to the desirable outcomes of CVS. In all therapy groups, the majority of patients were Asian (93.1% to 100.0%), male (64.0% to 68.8%), and hepatitis B e antigen-positive (95.8% to 100.0%) and had similar baseline alanine aminotransferase (ALT) levels. However, baseline HBV DNA (7.0 vs. 7.9 vs. 7.8 log10 IU/mL, P=0.05) and HBV DNA at regimen switch point (2.9 vs. 3.7 vs. 3.6 log10 IU/mL, P=0.0014) were lower in the ETV=0.5 mg cohort compared with those switched to ETV=1.0 mg or ETV/TDF, respectively. The ETV=0.5 mg cohort also had the shortest duration of ETV=0.5 mg therapy before switch (11.8 vs. 13.5 vs. 19.2 mo, P<0.0001). After the switch point, more patients on ETV/TDF achieved CVS compared with those on ETV=0.5 mg or ETV=1.0 mg at month 6 (77.3% vs. 13.8% vs. 9.4%), month 12 (86.4% vs. 40.5% vs. 25.0%), and month 18 (100% vs. 70.2% vs. 33.3%). Compared with the ETV=0.5 mg and ETV=1.0 mg groups, the ETV/TDF group also had higher rates of ALT normalization at month 6 (73.0% vs, 46.4% vs. 63.0%), month 12 (79.7% vs. 69.5% vs. 77.9%), and month 18 (100.0% vs. 69.5% vs. 86.8%), respectively. The multivariate analyses, inclusive of baseline age and treatment duration on initial therapy with ETV=0.5 mg, indicated that the ETV/TDF combination (HR=12.19, P<0.0001) was independently and positively associated with CVS, whereas high HBV DNA levels at baseline (HR=0.77, P=0.02) and at switch point (HR=0.46, P=0.002) were negatively associated with CVS. ETV=1.0 mg dose was not a predictor for CVS compared with ETV=0.5 mg. Following adjustments for HBV DNA levels and prior treatment duration, ETV/TDF combination therapy independently predicted superior viral suppression and ALT normalization in partial responders to ETV=0.5 mg daily compared with ETV=0.5 mg or ETV=1.0 mg monotherapy. In patients who continued to be viremic after 12 months of ETV=0.5 mg, one third were still viremic after another 18 months on the same therapy. Alternative therapies should be considered for these patients.

Liver transplantation and hepatitis B virus infection: towards an immunoglobulin-free antiviral treatment after transplantation.

This article provides an update on the latest development on deploying oral nucleosides in an immunoglobulin-free regime against hepatitis B virus (HBV) recurrence after liver transplantation. Entecavir and tenofovir are the two newer oral nucleosides that are associated with a low virological rebound rate at less than 2% at 5 years. As a result, they have been applied as standalone treatment against HBV recurrence after liver transplantation without immunoglobulin. Recent evidence has shown that a hepatitis B surface antigen seroclearance rate of 86% and 91% after 1 and 2 years was achievable with entecavir monotherapy. Moreover, none of the patients had histological graft damage because of HBV recurrence and an overall survival over 80% at 7 years has been reported. With newer and more potent oral nucleos(t)ide (NA) available, a hepatitis B immune globulin-free regimen after liver transplantation has become safe and feasible for suppression of HBV recurrence after liver transplantation, and for avoidance of HBV-related graft complications.

Profile of HBV polymerase gene mutations during entecavir treatment in patients with chronic hepatitis B

We investigated the efficacy of entecavir (ETV) monotherapy in 54 naïve patients and 27 lamivudine (LMV) and/or adefovir (ADV) experienced patients. Eighty-one chronic hepatitis B patients with a viral load above 4 log 10 copies/ml and high levels of serum alanine aminotransferase were treated with ETV 0.5mg daily. The viruses of patients were sequenced before ETV therapy and after every three months of ETV therapy. Eight LAM-experienced and ADV-experienced patients emerged mutations in the ETV treatment. In one of these experienced patients, the ETV-resistant mutations were detected during ETV treatment, with the virological and the biochemical breakthrough. Two LAM-experienced and ADV-naïve patients were detected mutation during 1-2 years ETV therapy. All three LAM-naïve and ADV-experienced patients were detected mutations in the ETV treatment. Five in fifty for LAM-naïve and ADV-naïve patients showed mutations in the ETV monotherapy. ETV has a high genetic barrier to resistance and the efficacy in LAM-experienced and/or ADV-experienced patients were much lower than in naïve patients.

An evaluation of entecavir for the treatment of chronic hepatitis B infection in adults

ABSTRACTEntecavir is a nucleoside analogue of 2ʹ-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naïve patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance.

Comparable efficacy with entecavir monotherapy and tenofovir–entecavir combination in chronic hepatitis B patients

ObjectivesThe long-term goal for chronic hepatitis B patients is to maintain viral suppression in order to reduce disease progression risk. Because patients with previous treatment failure may have multiple viral...

Peginterferon Is Superior to Nucleos(t)ide Analogues for Prevention of Hepatocellular Carcinoma in Chronic Hepatitis B.

Clinical factors associated with hepatocellular carcinoma (HCC) have been extensively studied in antiviral treatment-naive patients with chronic hepatitis B virus (HBV) infection but not in treatment-experienced patients. Owing to the wide availability of antiviral agents that effectively suppress HBV replication, we investigated HCC risk factors in treatment-experienced patients. In a cohort of 330 patients who underwent pretherapeutic liver biopsy, we analyzed the HCC incidence in relationship to clinical parameters. Ultra-deep sequencing of the viral genome was performed on 11 entecavir-treated and pegylated interferon (peginterferon)-treated patients. Initial univariate/multivariate explorations indicated that cirrhosis and antiviral treatment were independently associated with HCC occurrence. The peginterferon-experienced patients had a lower HCC incidence than the nucleos(t)ide analogue-treated patients (P = .011). The peginterferon and entecavir monotherapy groups also differed in HCC incidence (P = .018). Results of analysis of baseline-matched subgroups concurred with cohort analysis (P = .009 for comparison of peginterferon-experienced vs nucleotide analogue-treated patients; P = .022 for comparison of peginterferon- vs entecavir-treated patients). Viral loads of entecavir-treated patients were constantly suppressed to levels lower than those of peginterferon-treated patients (P < .001). Oncogenic surface antigen truncation mutations were detected in entecavir-treated patients with HCC but not in peginterferon-treated patients (P = .015). Treatment by peginterferon was associated with a lower HCC incidence than nucleos(t)ide-analogue treatment in chronic HBV infection.

Evolution of entecavir-resistant hepatitis B virus during entecavir and adefovir dipivoxil combination therapy.

The emergence of entecavir (ETV) resistance is rare, particularly in a longitudinal study. The aim of the present study was to characterize the evolution of ETV-resistant variants during antiviral therapy using entecavir monotherapy followed by ETV-adefovir dipivoxil (ADV) combination therapy. The study included a prospective cohort of 53 consecutive chronic hepatitis B (CHB) patients. During the 60-month period of ETV therapy, 2 patients exhibited ETV resistance and their medical records were comprehensively reviewed. A total of 25 consecutive serum samples were regularly collected from the 2 patients. All the samples were used to characterize the evolution of the polymerase gene mutations using pyrosequencing. The linkage of the variants was analyzed from 87 reverse transcriptase sequences of 3 selective samples using clone sequencing. The 2 patients presented with viral breakthrough during ETV monotherapy. In patient A, the rtL180M, rtS202G and rtM204V mutant variants were detected using pyrosequencing prior to virological breakthrough. Although the viral load declined following the administration of ADV, the ETV-resistant variants were persistently dominant in the viral populations. In patient B, the rtL180M, rtM204I and rtM204V mutants were present in ~70, 30 and 10% of the viral populations, respectively, at the time of study entry. In addition, rtT184F was present in ~20% of the viral population during virological breakthrough, at month 24. The rtL180M, rtT184F and rtM204V were predominant during the combination treatment. Clonal analysis further revealed that the rtS202G or rtT184F was in all cases co-localized with rtL180M and rtM204V in any single virus isolate clone. The results of the present study indicate that the addition of ADV therapy with ETV for treating ETV-resistant mutation may not inhibit the replication of ETV-resistant variants that developed previously in lamivudine-treated CHB patients.