HBV DNA Undetectable Rate Research Articles

First year real life experience with tenofovir alafenamide fumarate: The pythagorean cohort.

In chronic hepatitis B infection, antiviral therapy significantly reduces the incidence of complications. This study aimed to present real-life 12-month effectiveness and safety data for TAF. This Pythagoras Retrospective Cohort Study included patients from 14 centers in Turkiye. The study presents 12-month results of 480 patients treated with TAF as initial therapy or after switching from another antiviral drug. The study shows treatment of about 78.1% patients with at least one antiviral agent (90.6% tenofovir disoproxil [TDF]). The rate of undetectable HBV DNA increased in both treatment-experienced and naive patients. In TDF-experienced patients, the rate of alanine transaminase (ALT) normalization increased slightly (1.6%) within 12 months, but the change was not statistically significant (p=0.766). Younger age, low albumin, and high body mass index and cholesterol were identified as risk factors for abnormal ALT after 12 months, but no linear relationship was detected. In TDF-experienced patients, renal and bone function indicators showed significant improvement three months after the transition to TAF and remained stable for 12 months. Real-life data demonstrated effective virological and biochemical responses with TAF therapy. After switching to TAF treatment, gains in kidney and bone functions were achieved in the early period.

The effectiveness of combination therapy with interferon and nucleoside analogs in pediatric patients with chronic hepatitis B: a systematic review and meta-analysis.

It is a challenging issue regarding the optimal antiviral treatment of children with chronic hepatitis B (CHB). The efficacy comparison of interferon (IFN) or nucleos(t)ide analogs (NAs) monotherapy with their combination could better understand this issue. PubMed, EMBASE, Cochrane Library, Wanfang, CNKI, and abstracts of major international hepatology meetings were searched from inception to Feb 8, 2022. Randomized control trials and observational studies reporting the efficacy of combination therapy with IFN and NAs in children with CHB were eligible. A total of 17 studies were included. Compared with IFN monotherapy, combination therapy with IFN and NAs was significantly associated with increased rates of HBV DNA undetectable, HBeAg clearance, HBeAg seroconversion, alanine transaminase (ALT) normalization as well as the composite treatment response both at the end of treatment and during the follow-up period (RRs ranged from 1.23 to 1.75). A favorable trend for HBsAg seroconversion was found in IFN plus NAs-treated children, but not for the HBsAg clearance at the end of treatment. Although a similar trend towards the superiority of the combination therapy versus NAs monotherapy was observed (RRs ranged from 1.24 to 2.33) except for the HBV DNA undetectable rate at the end of treatment, the number of reported studies was limited. Combination therapy with IFN and NAs is more effective than IFN monotherapy in viral suppression and serological response for children with CHB. More studies were still needed to reveal the efficacy of this combination therapy compared with NAs monotherapy.

Analysis of antiviral efficacy after switching from brand to generic entecavir in patients with treatment-naïve chronic hepatitis B

Background/AimsEntecavir (ETV) can suppress chronic hepatitis B (CHB) virus replication as a standard of treatment drugs. For the treatment of CHB, affordable generic drugs may be more widely used in developing and undeveloped countries. However, there is little real-world data regarding the clinical efficacy of switching from entecavir-brand-name drugs (ETV-Brand) to entecavir generic drugs (ETV-Generic) with 0.5 mg once daily. The aim of the study was to evaluate the antiviral activity and safety of ETV-Generic in comparison to ETV-Brand in CHB-patients.MethodsIn this single-center, retrospective, 175 treatment-naïve—CHB-patients were assigned to receive 0.5 mg of ETV-Brand per day for a least 2 years and then switched to ETV-Generic for 6 months for analysis. The primary efficacy endpoint was a sustained virological response in comparison of the rate of undetectable serum Hepatitis B deoxyribonucleic acid (HBV DNA) as the sustained virologic response at baseline and 6 months after switching. Secondary efficacy endpoints were the comparison of the alanine aminotransferase (ALT) levels between before and after switching and ALT normalization. Renal safety consideration was reported on changing the estimated glomerular filtration rate.ResultsFrom baseline to 6 months, the rate of undetectable HBV DNA and ALT levels remained stable as compared ETV-Brand period with ETV-Generic for 6 months. The rate of undetectable HBV DNA were 81.1%in ETV-Brand versus 88.0%in ETV-Generic (p = 0.05 CI 0.1–13.5%). ALT levels were 27.2 IU/L (CI 24.8–29.6 IU/L) in ETV-Brand versus 26.2 IU/L (CI 24.0–28.4 IU/L) in ETV-Generic (p = 0.55). Both endpoints were not significantly different between ETV-Brand and ETV-Generic treatments. Kidney function did not significantly differ from ETV-Brand (80.8, interquartile range [IQR]: 66.6–95.3 mL/min/1.73 m2) to ETV-Generic treatment period (80.3, IQR: 65.6–93.5 mL/min/1.73 m2).ConclusionIn treatment-naïve CHB-patients, the efficacy and safety profiles of switching from ETV-Brand to ETV-Generic showed no difference. Concluding the ETV-Generic comes to exciting virologic responses and rare adverse events.

Anti-viral effect in chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase

Background & aimsNormal/mildly elevated ALT (<2 × ULN) CHB patients are potentially at risk of progression to cirrhosis and/or hepatocellular carcinoma (HCC). We aimed to assess the outcomes of anti-viral therapy for normal/mild elevation of ALT CHB patients. MethodsCHB patients (n = 432) who have had liver biopsied were determined. It was determined that the outcomes of anti-viral therapy in CHB patients with normal/mild elevation of ALT, in response to nucleoside/nucleotide analogues (NAs) (n = 190) and pegylated interferon (PEG-IFN) (n = 30) treatment for up to 72 weeks. Non-anti-viral treated patients were used as control (n = 40). ResultsThere was about 50% of the CHB patients showed hepatic inflammatory necrosis ≥ G2 and/or fibrosis ≥ S2 among >30-years-old. The rate of undetectable HBV DNA in NAs and PEG-IFN groups was ~50%, ~80% or ~90% at week 24, 48 or 72, respectively. HBeAg clearance rate was lower in NAs treated than that in PEG-IFN group at week 48 (6% vs 20%, P < 0.05). ALT normalization rate was increased by 1.18-fold at week 72. HBsAg decline in HBeAg+ patients treated with NAs or PEG-IFN was 0.418 or 1.217 log IU/mL (P < 0.0001) at week 48; whereas HBsAg decline was 0.176 or 0.816 log IU/mL (P < 0.001) in HBeAg− patients. HBsAg at baseline and week 24 were strong predictors of “low HBsAg at week 48”. ConclusionLong term anti-viral therapy inhibits HBV replication effectively in ALT<2 × ULN CHB patients. PEG-IFN therapy is recommended for HBeAg+ patients with baseline HBsAg<4.37 log IU/ml and HBeAg− patients with baseline HBsAg<2.66 log IU/ml to achieve “low HBsAg at week 48”.

Long-term data on entecavir treatment for treatment-naive or lamivudine-resistant chronic hepatitis B infection in kidney transplant recipients.

Entecavir (ETV) showed short-term efficacy and safety in HBsAg-positive kidney transplant recipients (KTRs), but long-term data are lacking. We retrospectively reviewed 30 HBsAg-positive KTRs who received ETV during 2007-2017. Eighteen treatment-naïve (Group I) and 12 lamivudine-resistant (Group II) patients received ETV for 48.4±35.2 and 66.0±26.0months, respectively. Both groups show significant HBV DNA decline, but Group I achieved earlier undetectability after 11.9±9.6months (compared with 28.8±24.2months in Group II, P=.033). Group I showed higher rates of undetectable HBV DNA (89%, 94%, 94%, 100%, and 100% at 12, 24, 36, 48, and 60months, respectively, compared with 25%, 50%, 50%, 91%, and 91% in Group II, P=.003). ALT normalized after 6.0±1.9 and 6.8±2.1months in Group I and Group II, respectively. Four patients (33.3%) in Group II developed drug resistance (2 had persistent viraemia and 2 had virological breakthrough, at 40.3±15.0months). Group II showed higher liver stiffness after 5years (7.7±4.1kPa, compared with 5.0±1.6kPa in Group I, P=.046) and incidence of cirrhosis (4 patients [33.3%], compared with 1 [5.6%] patient in Group I, P=.049). Two patients (one in each group) developed hepatocellular carcinoma. Renal allograft function remained stable during follow-up of 63.2±33.4months for both groups. There was no difference in patient and graft survival between two groups at 5years (P=.62 and .36, respectively). ETV showed favorable long-term efficacy and tolerability in treatment-naïve KTRs. One-third of lamivudine-resistant subjects showed non-response or viral breakthrough after ETV treatment.

Entecavir-based combination therapies for chronic hepatitis B: A meta-analysis.

Currently, there is no consensus on the efficacy and safety of the entecavir (ETV) monotherapy versus the ETV-based combination therapy for chronic hepatitis B. A comprehensive literature search was performed on the comparison of ETV-based combination therapy and monotherapy for chronical hepatitis B (CHB) patients in the PubMed, Embase, Web of Science, the Cochrane Libraries, and the Chinese BioMedical Literature Database. Both dichotomous and continuous variables were extracted, and pooled outcomes were expressed as odds ratio (OR) or mean difference (MD). We included randomized clinical trials (RCTs) and cohorts involving Group A: nucleos(t)ide-naive patients (four RCTs, n = 719 patients), Group B: nucleos(t)ide-resistant patients (four cohorts, n = 196 patients), and Group C: entecavir-treated patients with undetectable hepatitis B virus DNA (two RCTs and two cohorts, n = 297). Group A. ETV monotherapy was better for rates of undetectable HBV DNA, while the rates of the HBV DNA levels at the end of treatment, HBeAg Loss, ALT normalization were similar between the two groups [MD, -0.85 (95% CI, -0.173-0.03); OR, 0.92 (95% CI, 0.24-3.56); OR, 1.31 (95% CI, 0.17-9.82)]; Group B. ETV monotherapy was better for rates of undetectable HBV DNA, while the rates of the HBV DNA levels at the end of treatment, HBeAg Loss, ALT normalization were similar; Group C. The ETV-based combination therapy was better for the rate of HBV DNA relapse. Based on the current data, ETV-based combination therapy seemed to be no better than ETV monotherapy. Further studies are needed to verify this conclusion.

Long-term outcome of entecavir treatment of nucleos(t)ide analogue-naïve chronic hepatitis B patients in Japan.

We determined the antiviral potency and viral breakthrough rate after 10years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection. The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1logcopies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10years were calculated. The median age was 50years and follow-up period was 5.5years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was - 0.08logIU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan-Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment. Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment.

Clinical effect of entecavir versus tenofovir in treatment of HBeAg-positive chronic hepatitis B patients with a high viral load: a comparative analysis

Objective: To investigate the clinical effect and safety of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in the treatment of previously untreated HBeAg-positive chronic hepatitis B (CHB) patients with a high viral load. Methods: A retrospective analysis was performed for the clinical data of 152 HBeAg-positive CHB patients with a high viral load (HBV DNA≥10(6) IU/ml) who were firstly treated with ETV (ETV group) or TDF (TDF group), with 76 patients in each group. The serum levels of alanine aminotransferase (ALT), HBV DNA, HBeAg, anti-HBe, creatinine, and creatine kinase were measured at baseline, and the patients were followed up and evaluated at weeks 4, 12, 24, 36, 48, 60, 72, 84, and 96 of treatment. The Kaplan-Meier survival curves were used to analyze cumulative complete virologic response, HBeAg seroconversion, and ALT normalization rate. The Cox proportional hazards regression model was used to identify the influencing factors for virologic response. P < 0.05 was considered statistically significant. Results: There were no significant differences in ALT normalization rate between the ETV group and the TDF group at weeks 4, 12, 24, 48, 72, and 96 of treatment (18.1%/55.6%/83.3%/90.3%/93.1%/97.2% vs 16.0%/53.6%/75.4%/94.2%/100%/100%, P > 0.05). There were also no significant differences in virologic response rate between the ETV group and the TDF group at weeks 48 and 96 of treatment (89.5%/97.3% vs 93.4%/98.7%, P > 0.05). The multivariate analysis showed that the baseline parameters were not predictive factors for virologic response. At week 48 of treatment, the TDF group had a significantly higher HBeAg seroconversion rate than the ETV group (14.5% vs 3.9%, P = 0.048); at week 96 of treatment, there was no significant difference in HBeAg seroconversion rate between the two groups (15.8% vs 7.9%, P = 0.132). The Kaplan-Meier survival analysis showed that there were no significant differences between the two groups in cumulative ALT normalization rate, cumulative HBV DNA undetectable rate, and cumulative seroconversion rate. Only one patient in the ETV group experienced virologic breakthrough from weeks 60 to 72 of treatment, and there were no serious adverse reactions. Conclusion: TDF and ETV had similar clinical effects, HBeAg seroconversion rate, and safety in previously untreated HBeAg-positive CHB patients with a high viral load.

Continuous up to 4 Years Entecavir Treatment of HBV-Infected Adolescents - A Longitudinal Study in Real Life.

This study evaluated the long-term (up to 4 years) efficacy and safety of entecavir ETV treatment and analysed the significance of baseline and on-treatment factors in long-term ETV outcomes in adolescents with chronic hepatitis B (CHB). We determined the cumulative virological and serological outcomes of 44 adolescents with CHB receiving ETV for up to 4 years. To investigate the dynamics of HBV DNA, ALT activity and hepatitis B e antigen (HBeAg) seroconversion over time and their associations with the considered factors, generalized estimating equation (GEE) models were used. The cumulative rates of undetectable HBV DNA (<20 IU/ml) and HBeAg seroconversion after 4 years were 89.7% and 55.4%, respectively. In the study group, we showed that having undetectable HBV DNA at the 6th or 12th month of therapy predicted the achievement of a sustained response rate (SRR, defined as the loss of HBV DNA, loss of HBeAg and ALT normalization) at year 3 of ETV therapy (P = 0.048, OR = 5.83; P = 0.012; OR = 14.57, respectively). The GEE analysis indicated that of the different factors, the duration of ETV therapy had a strong impact on the achievement of virological suppression, HBeAg seroconversion and SRR in adolescents. Each month after the initiation of therapy, the odds of loss of HBV DNA increased by approximately 5% (OR = 1.05, P<0.0001), on average. Additionally, the GEE analysis revealed that adolescents with an age at infection of ≥10 years had 3 times higher odds of achieving undetectable HBV DNA than patients with a younger infection age (OR = 3.67, P = 0.028). None of the ETV-treated patients reported significant adverse effects. ETV is an effective and safe treatment option for adolescents with CHB. Undetectable HBV DNA in the 6th and/or 12th month of ETV treatment and older age at infection could predict maintained virological suppression.

A Meta-Analysis of the Efficacy of Interferon Monotherapy or Combined with Different Nucleos(t)ide Analogues for Chronic Hepatitis B.

Background: The aim of the present study was to compare the efficacy of interferon (IFN) with or without different nucleos(t)ide analogues (NAs). Methods: The PubMed, Wan Fang and CNKI databases were searched to identify relevant trials up to May 2015. Meta-analysis was performed with Review Manager 5.0. The stability and reliability were evaluated by publication bias tests. Results: Fifty-six studies fulfilled the criteria for the meta-analysis. Compared with IFN monotherapy, combination therapy were superior in HBV DNA undetectable rate (Risk Ratio (RR) = 1.55, 95% confidence interval (CI): 1.44–1.66, p < 0.00001), HBeAg and HBsAg loss rate (RR = 1.38, 95% CI: 1.22–1.56, p < 0.00001; RR = 1.69, 95% CI: 1.03–2.78, p = 0.04, respectively) at the end of week 48 treatment. Sub-analysis showed the RRs of virological response for entecavir (ETV), adefovir (ADV), and lamivudine (LAM) were 1.64, 1.61 and 1.52, respectively; RRs of HBeAg loss rate were 1.34, 1.71 and 1.34, respectively. However, at the end of follow-up, IFN plus NAs therapy was better than IFN monotherapy only in terms of HBV DNA undetectable rate (p = 0.0007). Conclusions: Combination therapy was better than IFN monotherapy in virological and serological responses at the end of treatment. After follow-up, only HBV DNA undetectable rate was superior for combination therapy.

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

Antiviral Therapy in Lamivudine-Resistant Chronic Hepatitis B Patients: A Systematic Review and Network Meta-Analysis.

The relative efficacy of different strategies for chronic hepatitis B (CHB) patients with lamivudine resistance (LAM-R) has not yet been systematically studied. Clinical trials were searched in PUBMED, MEDLINE, EMBASE, and CNKI databases up to February 15, 2016. Nine trials including 764 patients met the entry criteria. In direct meta-analysis, TDF showed a stronger antiviral effect than any one of ETV, LAM/ADV, and ADV against LAM-R hepatitis B virus. LAM/ADV therapy was superior to ADV in suppressing viral replication. ETV achieved similar rate of HBV DNA undetectable compared to ADV or LAM/ADV. In network meta-analysis, TDF had higher rates of HBV DNA undetectable compared to ETV (OR, 24.69; 95% CrI: 5.36–113.66), ADV (OR, 37.28; 95% CrI: 9.73–142.92), or LAM/ADV (OR, 21.05; 95% CrI: 5.70–77.80). However, among ETV, ADV, and LAM/ADV, no drug was clearly superior to others in HBV DNA undetectable rate. Moreover, no significant difference in the rate of ALT normalization or HBeAg loss was observed compared the four rescue strategies with each other. TDF appears to be a more effective rescue therapy than LAM/ADV, ETV, or ADV. LAM plus ADV therapy was a better treatment option than ETV or ADV alone for patients with LAM-R.

Rates and determinants of hepatitis B 'e' antigen and hepatitis B surface antigen seroclearance during long-term follow-up of patients coinfected with HIV and hepatitis B virus.

This study determines rates and risk factors associated with hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg) seroclearance, two important prognostic indicators during infection with hepatitis B virus (HBV), in a large contemporary cohort of patients coinfected with HIV-HBV. Prospective cohort study of predominately antiretroviral therapy (ART) experienced, coinfected patients. Participants enrolled in the French HIV-HBV Cohort had complete HBV serological battery conducted at inclusion and every yearly visit. Piecewise-exponential survival models were used to determine risk factors associated with seroclearance. A total of 290 patients, of whom 151 (52.1%) were HBeAg positive, had been followed for a median 7.4 years (interquartile range [IQR] = 3.1-8.0). Tenofovir (TDF) containing ART became increasingly more frequent, as rates of undetectable HBV-DNA increased accordingly (at baseline = 39.3%, end of follow-up = 91.0%). In HBeAg-positive patients, 60 of 151 had HBeAg seroclearance (cumulative 46.4% at end of follow-up) after a median 3.0 years (IQR = 2.0-4.9). Overall, 17 of 290 patients had HBsAg seroclearance (cumulative 7.4% at end of follow-up) after a median 4.6 years (IQR = 2.1-7.2). Lower levels of time-averaged cumulative HBV-DNA were significantly associated with both HBeAg and HBsAg seroclearance (P < 0.001 and P = 0.01, respectively). In post hoc analysis among patients initiating TDF, incidence rates of HBeAg seroclearance peaked at year 4 of TDF treatment (13.1/100 person-years), whereas a steep drop in HBsAg seroclearance incidence rates occurred after year 3 (at year 3 = 1.2/100 person-years versus thereafter = 0.6/100 person-years). HBsAg seroclearance and, to a lesser extent, HBeAg seroclearance remain difficult endpoints for patients coinfected with HIV-HBV to achieve. HBV-DNA suppression, associated with effective treatment, is strongly linked to seroclearance, but this mostly occurs within the first years of ART-containing highly potent anti-HBV activity.

A randomized clinical trial of peginterferon alpha‐2b with or without entecavir in patients with HBeAg‐negative chronic hepatitis B: Role of host and viral factors associated with treatment response

Combining peginterferon (PEG-IFN) and a potent nucleoside/nucleotide analogue might improve treatment response in patients with chronic hepatitis B (CHB). The aims of this study were to compare the efficacy of PEG-IFN alpha-2b with or without entecavir in HBeAg-negative CHB and to investigate predictors of response. A total of 126 treatment-naïve patients were randomly assigned to receive monotherapy (n = 63) or combination therapy (n = 63) for 48 weeks. Virological response (VR) was defined as HBV DNA level <2000 IU/mL at week 96. Baseline factors including polymorphisms in the IFNL3 (rs12979860) and HLA-DPA1 (rs3077) genes and on-treatment viral kinetics were determined. At week 48, rates of undetectable HBV DNA were lower in the monotherapy than combination groups, but rates of HBsAg clearance and decline were comparable. At week 96, there was no difference between the corresponding groups regarding virological response (41.3% vs 38.1%, P = 0.856), HBsAg clearance (9.5% vs 4.8%, P = 0.491) and HBsAg decline. Baseline HBsAg level [odds ratio (OR): 3.14 (1.34-7.69), P = 0.012] and rs3077 polymorphism [OR: 2.78 (1.27-6.11), P = 0.011] were independent predictors of response. Patients carried GG genotype of rs3077 with low baseline HBV (<1000 IU/mL) had high probability of achieving VR (76.5%) and HBsAg clearance (29.4%). None of the patients without decrease in HBsAg combined with <2 log10 HBV DNA decline at week 12 achieved a virological response. In conclusion, the combination therapy lead to greater on-treatment HBV DNA suppression but did not improve virological response and HBsAg clearance/decline over monotherapy. Host and viral factors could help optimize decision-making at baseline and during PEG-IFN-based therapy.

A Better Antiviral Efficacy Found in Nucleos(t)ide Analog (NA) Combinations with Interferon Therapy than NA Monotherapy for HBeAg Positive Chronic Hepatitis B: A Meta-Analysis.

Background: The clinical efficacy of nucleos(t)ide analogues (NAs) combined with interferon (IFN) therapy vs. NAs monotherapy for chronic hepatitis B (CHB) remains inconclusive. The aim of this meta-analysis was to determine whether the NAs plus IFN regimen offers synergistic efficacy that justifies the cost and burden of such a combination therapy in CHB patients. Methods: Related publications covering the period of 1966 to July 2014 were identified through searching MEDLINE, EMBASE, Cochrane library, Chinese Biomedical Literature Database, WANFANG, and CNKI database. A total of 17 studies were enrolled, including 6 in English and 11 in Chinese. Then, we established a final list of studies for the meta-analysis by systematically grading the quality and eligibility of the identified individual studies. We used hepatitis B antigen (HBeAg) loss, HBV-DNA undetectable rate, HBeAg seroconversion, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, and histological score at the end of treatment for efficacy evaluation. A quantitative meta-analysis (Review Manager, Version 5.1.0) was performed to assess the differences between NAs and IFN combination therapy and NAs monotherapy. Results: Our analysis demonstrated that HBeAg loss (RR = 1.73, 95% CI = 1.32–2.26, p < 0.001), HBV-DNA undetectable rate (RR = 1.58, 95% CI = 1.22–2.04, p < 0.001), HBeAg seroconversion (RR = 1.68, 95% CI = 1.36–2.07, p < 0.001), and HBsAg loss (RR = 2.51, 95% CI = 1.32–4.75, p < 0.001) in the combination therapy group were significantly higher than those in the monotherapy group. However, there were no significant differences in HBsAg seroconversion (RR = 4.25, 95% CI = 0.62–29.13, p = 0.14), sustained virological response rates, and biochemical response rates observed between the two groups. The results showed that the combination therapy group had more improved HBV histology than the NAs monotherapy group (RR = 1.14, 95% CI = 0.93–1.39, p = 0.22). Conclusions: NAs and IFN or Peg-IFN combination therapy had a better efficacy in terms of HBeAg loss, HBV-DNA undetectable rate, HBeAg seroconversion, and HBsAg loss, compared to the NA monotherapy group at the end of treatment; however, there was no significant difference in HBsAg seroconversion between the two regimens.

LAM add-on ADV combination therapy or ETV monotherapy for CHB patients with suboptimal response to ADV

Introduction. Among the available nucleos(t)ide analogues adefovir dipivoxil (ADV) is relatively cheap and widely used in rural area in China. However, there are insufficient data on recommendation for patients with suboptimal response to ADV after 48 weeks of treatment in order to reduce the resistance rate in the long term. The aim of this study was to compare the efficacy and safety of LAM add-on combination therapy versus ETV monotherapy for patients with suboptimal response to ADV.Material and methods. 136 patients with suboptimal response to ADV were randomly assigned to the add-on LAM with ADV combination therapy (68 patients) group and the ETV monotherapy (68 patients) group. Patients in the add-on group were prescribed 100 mg LAM and 10 mg ADV per day, while the monotherapy group received 0.5 mg ETV per day for 48 weeks. Tests for liver and kidney function, HBV serum markers, HBV DNA load, were performed every 3 months.Results. The mean patient age in LAM add-on group and ETV monotherapy was 38.59 ± 7.65 and 37.56 ± 8.67 years respectively. The HBV DNA undetectable rate in the LAM add-on group and the ETV group were not significant difference at week 4, 12 and 24 (P > 0.05). However, the HBV undetectable rate in the ETV group was higher than that in the LAM add-on group at week 36 and 48 (P = 0.043 for week 36 and P = 0.038 for week 48). There was no significant difference both for HBeAg loss and HBeAg seroconversion between two groups (P > 0.05) at 48 weeks. Meanwhile, our study also demonstrated that the mean eGFR levels in LAM add-on group was decreased from 99.6 ± 8.71 at baseline to 86.4 ± 9.83 at the end of 48 weeks, which was significantly higher than that in the ETV monotherapy group (P < 0.05). 8.8% of patients in LAM add-on group experienced eGFR reduction by 20-30% from baseline at 48 weeks. No patients developed hyposphosphatemia in our study.Conclusion. Our study clearly showed that switch to ETV monotherapy was the more effective and more safe than that of LAM add-on combination therapy for patients with suboptimal response to ADV.

Efficacy of 48-week tenofovir disoproxil fumarate therapy in patients who were unresponsive to nucleoside-analogue treatments

To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) after failure of nucleoside-analogues (NAs). A total of 30 CHB patients who had been previously treated with NAs and had subsequently completed a 48-week course of TDF were retrospectively investigated. Patients' data of HBV DNA level (log10 copies/ml) and rate of undetectable HBV DNA at treatment weeks 0 (baseline), 4, 12, 24, 36 and 48 were collected for evaluation. The lower limit of HBV DNA detection was 100 IU/ml. The serum alanine aminotransferase (ALT) normalization rate, hepatitis B e antigen (HBeAg) seroconversion rate, viral breakthrough (VBT) rate, viral response (VR) rate, and adverse events were determined upon treatment completion. Statistical analyses were carried out using the Student's t-test, the x² test or the Kaplan-Meier method. Over the 48-week treatment period, HBV DNA levels declined significantly from baseline (week 4:(2.11 ± 0.38) log10 IU/ml, t =5.582; week 12:(0.93 ± 0.31) log10 IU/ ml, t =9.303; week 24:(0.75 ± 0.20) log10 IU/ml, t =3.123; week 36:(0.16 ± 0.19) log10 IU/ml, t =10.759; week 48:(0.14 ± 0.25) log10 IU/ml, t =12.202) (all P less than 0.01). However, the rates of HBV DNA reduction and of cumulative reduction were comparable at weeks 24, 36 and 48 (all P more than 0.05). The most robust decline in HBV DNA levels was observed at week 4 ((2.11 ± 0.38) log10 IU/ml) and the highest cumulative HBV DNA reduction was observed at week 24 ((3.79 ± 0.37) log10 IU/ml). The rate of undetectable HBV DNA at week 4 (26.7%) was significantly lower than that at weeks 24 (87.5%, P less than 0.01), 36 (80.0%, P=0.007), and 48 (88.9%, P=0.001). The median time to achieving undetectable HBV DNA was 10.4 weeks (range:3.43-34.0 weeks). At week 48, the rates of VR, HBeAg seroconversion, and VBT were 88.9% ,6.7%, and 0% respectively. During treatment, the levels of creatine kinase were more than two times the upper limit normal in 9.2% of the patients, and were comparable at each time point examined (all P more than 0.05). All patients showed a normal level of serum creatinine throughout the treatment period. For CHB patients with non-response to NAs, TDF can suppress HBV DNA replication very quickly and achieve a high rate of ALT normalization with a low rate of adverse events.

The Change of Quantitative of HBeAg Can Predict the Efficacy of Peg-IFN-α 2a in HBeAgpositive CHB Patients

Abstract Objective To investigate the quantitation of hepatitis B e antigen (HBeAg) at week 24 in predicting the efficacy of pegylated-interferon alfa-2a (Peg-IFN-α 2a) in HBeAg-positive chronic hepatitis B (CHB) patients at week 48 and to find a useful predictor for treatment efficacy and investigate individualized treatment of antiviral therapy. Methods Ninety-six HBeAg-positive CHB patients with detectable HBeAg who were treated with Peg-IFN-α 2a were enrolled in this trial. They were categorized into 3 groups according to the changes of HBeAg in week 24: HBeAg decline &gt; 2 log10 group (group A), HBeAg decline between 1 1og10 - 2 log10 (group B), HBeAg decline &lt; 1 log10 group (group C), and group C was randomly distributed into C1 and C2. The patients in group A, group B, and group C1 continued the original therapy and the patients in group C2 were given lamivudine plus Peg-IFN-α 2a for 24 weeks. At week 48, the treatment efficacy and hepatitis B virus covalently closed circular DNA (HBV cccDNA) in liver biopsies were analyzed. Results At week 48, mean reduction of serum HBV DNA: group A: 5.8 log10 copies/ml, group B: 3.8 log10 copies/ml, group C1: 2.8 log10 copies/ml, group C2: 5.7 log10 copies/ml, the reduction of HBV DNA in group A was greater than groups B and C1 (P &lt; 0.01), that in group C1 was greater than group C2 (P &lt; 0.01), the difference between groups B and C1 had no statistical significance (P = 0.19). Mean reduction of HBeAg: group A: 2.7 log10S/CO, group B: 1.9 log10S/CO, group C1: 0.9 log10S/CO, group C2: 1.5 log10S/CO, the difference among groups A, B and C1 and between groups C1 and C2 were statistically significant (P &lt; 0.01). At week 48, HBV DNA undetectable rate in group A, group B, group C1 and group C2 were 87.5%, 34.5%, 17.4% and 81.9%, respectively, the rate in group A was greater than groups B and C1 (P &lt; 0.01)，that in group C1 was greater than group C2 (P &lt; 0.01). HBeAg seroconversion rate were 75.0%, 24.1%, 13.0% and 22.7%, respectively, that in group A was greater than groups B and C1 (P &lt; 0.01). Group A had lower cccDNA in liver tissue than group B and group C1 (P &lt; 0.01). The difference of HBV cccDNA between groups B and C1 and that between groups C1 and C2 had no statistical significance. Conclusions HBeAg decline &gt; 2 log10 at week 24 in Peg-IFN-α 2a-treated hepatitis B patients suggested a better efficacy at week 48; HBeAg decline &lt; 2 log10 at week 24 suggests a worse efficacy at week 48, the combined therapy of Peg-IFN-α and lamivudine could improve the clinical responses. The change of quantitative of HBeAg at week 24 may be used as a predictor of treatment effects at week 48.

Sa1014 Meta-Analysis and Systematic Review of Chronic Hepatitis B Patients With Minimally Elevated Alanine Aminotransferase (ALT): Nearly Half With ALT 1-2x Upper Limit of Normal Have Significant Fibrosis

Background and Aim: Entecavir (ETV) is a potent antiviral drug to treat chronic hepatitis B (CHB) patients with high genetic barrier. Aim of this study was to assess the effectiveness, safety, and rate of antiviral resistance of ETV monotherapy in nucleos(t)ide analogues (NUC) naive CHB patients in clinical practice. Methods: Charts of CHB patients were reviewed. CHB patients who were treated with ETV at least one year were included in this study. Clinical symptoms, liver function test and HBV DNA were monitored every 3-6 months. Virological breakthrough was defined as . 1 log IU/mL increase from nadir. Antiviral resistance testing was performed in patients who had confirmed virological breakthrough. Imaging studies using ultrasonography or CT of liver was monitored every 6 months for hepatocellular carcinoma (HCC) screening. Results: 535 patients were included. At baseline, mean age was 51.8 years, 58.5% was male, 35.1% was HBeAg positive, mean HBV DNA was 6.8 log IU/mL, 87% had elevation of ALT, and 37.1% was cirrhosis. Mean of follow up was 40 months. The rates of undetectable HBV DNA progressively increased to more than 90% in both HBeAg positive and negative patients at year 5. HBeAg seroconversion and HBsAg loss was found in 10.5% and 1.7% at year 5, respectively. No virological breakthrough or antiviral resistance mutations was found in 5 years. Among 337 noncirrhotic patients, 20 patients (5.9%) developed cirrhosis using imaging criteria during follow up; however, no patients in this group developed clinical decompensation. Of 198 cirrhotic patients, clinical decompensation was developed in 5 patients (2.5%). HCC occurred 12 patients (2.2%) in 5 years. No serious adverse event was demonstrated. Serum creatinine remained unchanged during ETV treatment. Conclusion: ETV was safe and effectively suppressed hepatitis B virus without virological breakthrough throughout 5 years of treatment.

Combination lamivudine and adefovir versus entecavir for the treatment of naïve chronic hepatitis B patients: A pilot study

BackgroundThe aim of this study was to compare the effect of combination lamivudine (LAM) and adefovir dipivoxil (ADV) versus entecavir (ETV) monotherapy for naïve HBeAg-positive chronic hepatitis B (CHB) patients.Material/MethodsFifty enrolled patients with CHB were evenly divided into 2 groups: a group treated with of lamivudine (LAM) (100 mg/day) plus adefovir (ADV) (10 mg/day) combination, and a group treated with entecavir (ETV) (0.5 mg/day). Serum levels of ALT, AST, creatinine, bilirubin, HBsAg, HBeAg and HBV viral load, and genotypic resistance were analyzed at 0, 12, 24, 52, and 104 weeks. HBV DNA levels were determined by real-time PCR and HBsAg and HBeAg by chemiluminescence. Serum levels of ALT, AST, creatinine, and bilirubin were measured by an automatic biochemical analyzer. Data analysis was performed with SPSS 12.0 software.ResultsThere were no significant differences in the virological response (VR) rates between LAM+ADV and ETV cohorts at 24, 52, and 104 weeks (P>0.05). The HBeAg seroconversion rates were 28% and 20%, and the biochemical response (BR) rates were 88% and 84% at week 104 in the LAM+ADV and ETV groups, respectively. The rates of undetectable HBV DNA, HBeAg seroconversion, and ALT normalization rates were similar in both cohorts. No virological breakthrough or serious adverse effects were noted for any patient during the study period.ConclusionsBoth LAM + ADV combination therapy and ETV monotherapy were effective and safe in the treatment of naïve HBeAg-positive CHB patients. However, further studies are needed to obtain long-term results.