Hepatocellular carcinoma (HCC) is a primary liver cancer that originates from underlying inflammation, often associated with Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections. Despite the availability of treatments, there are high rates of tumour relapse due to the development of drug resistance in infected cells. Next-Generation Sequencing (NGS) plays a crucial role in overcoming this issue by sequencing both viral and host genomes to identify mutations and genetic heterogeneity. The knowledge gained from sequencing is then utilised to develop countermeasures against these mutants through different combination therapies. Advances in NGS have led to sequencing with higher accuracy and throughput, thereby enabling personalized and effective treatments. The purpose of this article is to highlight how NGS has contributed to precision medicine in HCC and the possible integration of artificial intelligence (AI) to bolster the advancement.

We conducted this study to describe whether mutations in the gene coding for the enzyme reverse transcriptase (RT) were related to drugs used in the treatment of hepatitis B in Vietnam.

Patients receiving antiretroviral therapy with evidence of treatment failure were included in the study. The RT fragment was cloned using the polymerase chain reaction technique after being extracted from patients' blood samples. The nucleotide sequences were analysed using Sanger method. The HBV drug resistance database contains mutations associated to resistance to existing HBV therapies. Medical records were accessed to collect information on patient parameters, such as treatment, viral load, biochemistry, and blood count.

Resistance mutations to lamivudine, telbivudine, and entecavir were found in the highest proportion (75-91.7%) of HBV samples from patients who had failed antiretroviral therapy. Only 20.8% of HBV strains had mutations exhibiting adefovir resistance, while none had mutations conferring tenofovir resistance. M204I/V, L180M, and L80I are frequent variants linked with resistance to lamivudine, telbivudine, and entecavir. In contrast, the A181L/T/V mutation was detected predominantly in tenofovir-resistant HBV strains. Following the drug resistance mutation test, patients achieved the greatest virological response after 24 weeks of therapy with tenofovir and entecavir at a daily dose of one tablet.

Lamivudine, telbivudine, and entecavir were all highly resistant to the RT enzyme modifications in 24 treatment failure patients, with M204I/V, L180M, and L80I being the most prevalent mutations. Tenofovir resistance mutations have not been found in Vietnam.

Clinical equivalence of generic antiviral agents for chronic hepatitis B (CHB) has not been demonstrated, particularly in cases with previous antiviral resistance. Entecavir 1 mg is prescribed frequently as a mono- or combination therapy in antiviral-resistant CHB patients. This study evaluated the efficacy and safety of switching to generic entecavir 1 mg (Baracle^®) in CHB patients taking brand-name entecavir 1 mg (Baraclude^®) alone or in combination with other nucleotide analogs after the development of antiviral resistance.

This study was a single-arm prospective study. The primary endpoint was undetectable HBV DNA (<20 IU/mL) at 12 months after switching treatment. The biochemical and serologic responses, virologic breakthrough, and antiviral resistance rates were also evaluated.

Forty CHB patients with undetectable HBV DNA through the brand-name entecavir 1 mg treatment as a mono- or combination therapy after developing antiviral resistance to nucleos(t)ide analogs were enrolled in this study. No significant difference in the HBV DNA non-detection rate was observed between the baseline and 12 months after switching therapy (p=0.324). Furthermore, non-inferiority of the generic entecavir 1 mg to the brand-name entecavir 1 mg with 10% margin in maintaining undetectable HBV DNA was demonstrated (95% CI -2.80 to 8.20%). Similarly, no difference in the biochemical response rate was observed after switching therapy. Serum hepatitis B e antigen loss was observed in 12.5%. No virologic breakthrough was reported.

Generic entecavir 1 mg is a reasonable alternative to the brand-name entecavir 1 mg in antiviral-resistant CHB patients with viral suppression.

The treatment of multidrug-resistant (MDR) chronic hepatitis B (CHB) is challenging. Herein, we report a multicenter prospective cohort study for the evaluation of tenofovir disoproxil fumarate (TDF)-based therapy for MDR CHB in a real-life setting. The inclusion criteria comprised patients with resistance to more than two nucleos(t)ide analogue (NA) classes and hepatitis B virus (HBV) DNA level of ≥200 IU/mL. The primary end-point was virologic response (VR), defined as undetectable HBV DNA (<20 IU/mL) after 60 months. A total of 236 patients met the inclusion criteria. The mean HBV DNA level was 4.16 ± 1.44 log IU/mL; 26.7% of patients had liver cirrhosis. Before the initiation of TDF, 33.5%, 44.9% and 21.6% of patients had mutations resistant to L-NA + adefovir, L-NA + entecavir (ETV) and L-NA + adefovir + ETV, respectively. A total of 184 patients received TDF-based combination therapy [TDF + ETV (n = 178) or TDF + L-NA (n = 6)], and 52 patients received TDF monotherapy. In the entire cohort, the VR rates were 77.2%, 89.9% and 92.2% at 12, 36 and 60 months, respectively. The VR rates were not significantly different between the combination therapy and the monotherapy group after 12 (76.2% vs 80.4%, P = .533), 36 (89.8% vs 90.3%, P = 1.000) or 60 (92.9% vs 87.5%, P = .499) months. Also, there was no significant difference in the cumulative VR rates for 5 years between the treatment groups (P = .910). Newly developed antiviral resistance was not observed. TDF-based therapy was effective for the treatment of MDR CHB. The efficacy of TDF monotherapy was not different from that of the TDF-based combination therapy.

HBsAg seroclearance occurs rarely in the natural history of chronic hepatitis B (CHB) infection and is associated with improved clinical outcomes. Many factors are associated with HBsAg seroconversion, including immune and viral factors. However, the immune mechanisms associated with HBsAg seroclearance are still difficult to elucidate. HBsAg seroclearance is the ideal aim of HBV treatment. Unfortunately, this goal is rarely achieved with current treatments. Understanding the mechanisms of HBsAg loss appears to be important for the development of curative HBV treatments. While studies from animal models give insights into the potential immune mechanisms and interactions occurring between the immune system and HBsAg, they do not recapitulate all features of CHB in humans and are subject to variability due to their complexity. In this article, we review recent studies on these immune factors, focusing on their influence on CHB progression and HBsAg seroconversion. These data provide new insights for the development of therapeutic approaches to partially restore the anti-HBV immune response. Targeting HBsAg will ideally relieve the immunosuppressive effects on the immune system and help to restore anti-HBV immune responses.

Suboptimal responses to lamivudine or telbivudine plus adefovir (LAM/LdT+ADV) rescue therapy are common in patients with LAM-resistant hepatitis B virus (HBV) infections. We compared patients switched to entecavir plus tenofovir (ETV+TDF) to those maintained on LAM/LdT+ADV.

This prospective randomized controlled trial examined 91 patients whose serum HBV DNA levels were greater than 60 IU/mL after at least 24 weeks of treatment with LAM/LdT+ADV for LAM-resistant HBV. Patients were randomized to receive a new treatment (ETV+TDF, n=45) or maintained on the same treatment (LAM/LdT+ADV, n=46) for 48 weeks. Patients with baseline ADV resistance were excluded.

Compared to LAM/LdT+ADV group, ETV+TDF group had more patients with a virologic response (42/45 [93.33%] vs. 3/46 [6.52%], P<0.001) and had a greater mean reduction in serum HBV DNA level from baseline (-4.16 vs. -0.37 log10 IU/mL, P<0.001). Multivariate analysis indicated that high baseline HBV DNA level (P=0.005) and LAM/LdT+ADV maintenance therapy (P=0.001) were negatively associated with virologic response. At week 48, additional ADV- or ETV-associated mutations were cleared in ETV+TDF group, but such mutations were present in 4.3% of patients in LAM/LdT+ADV group (P=0.106). The two groups had similar rates of adverse events.

ETV+TDF combination treatment led to a significantly higher rate of virologic response compared to LAM/LdT+ADV combination treatment in patients with LAM-resistant HBV who had suboptimal responses to LAM/LdT+ADV regardless of HBV genotypic resistance profile (NCT01597934).

The aim of this retrospective study was to compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) monotherapy and TDF + entecavir (ETV) combination therapy for chronic hepatitis B (CHB) patients with the partial virological response (PVR) to ETV.

CHB patients with PVR to ETV were switched to TDF monotherapy or TDF + ETV combination therapy. The primary efficacy outcome was a virological response (VR), and the secondary efficacy outcomes were hepatitis B e antigen (HBeAg) seroconversion and alanine aminotransferase (ALT) normalization. The primary safety outcomes were changes in serum creatinine and serum phosphorus levels.

A total of 143 patients were investigated, including 63 patients in the TDF monotherapy group and 80 patients in the TDF + ETV combination therapy group. Baseline demographics and clinical characteristics were comparable between groups. The median age of patients was 44.5 years, and 76.2% of them were male. The VR rate in TDF + ETV group was higher than that of the TDF group at 48 weeks (88.8% vs 71.4%; P = .009). At 48 weeks, the HBeAg seroconversion rate of TDF + ETV group was higher than that of the TDF group (30% vs 15.9%; P = .049). There was no significant difference in the proportion of patients with elevated ALT in the TDF group and TDF + ETV group at 48 weeks (9.5% vs 7.5%; P = .665). After adjusting the treatment regimen, serum creatinine levels increased slightly and serum phosphorus level decreased slightly in both groups.

TDF + ETV combination therapy for 48 weeks had a higher VR rate than TDF monotherapy in CHB patients with PVR to ETV.

There are no globally agreed upon treatment guidelines for patients with chronic hepatitis B virus (HBV) with multidrug resistance (MDR). We conducted a multicenter, prospective, real-world cohort study of effects of tenofovir disoproxyl fumarate (TDF) monotherapy and TDF-based combination therapy, as rescue therapy, in patients with multidrug-resistant chronic HBV infections.

We recruited patients with chronic HBV infection with resistance to antivirals from 8 tertiary hospitals in Korea. Patients (n=423) received rescue therapy with TDF monotherapy (n=174) or TDF-based combination therapy (n=249). The median follow-up period was 180 weeks. A virologic response was defined as a serum HBV DNA level of <20 IU/mL.

Cumulative rates of virologic response did not differ significantly between the groups that received TDF monotherapy vs combination therapy at 48 weeks (71.7% vs 68.9%), 96 weeks (85.1% vs 84.2%), 144 weeks (92.1% vs 92.7%), 192 weeks (93.4% vs 95.7%), or 240 weeks (97.7% vs 97.2%). Serum levels of HBV DNA below 4.0 log₁₀ IU/mL (odds ratio, 2.478; 95% CI 1.959-3.135; P < .001) and the absence of mutations associated with resistance to adefovir (odds ratio, 1.570; 95% CI 1.279-1.926; P < .001) were associated with virologic response in patients with MDR. There was no significant difference of virologic response among patients of different ages, sex, patients with vs without cirrhosis, positivity for hepatitis B e antigen, or renal function (all P > .05).

In a multicenter, real-world cohort study, long-term use of TDF monotherapy showed non-inferior antiviral efficacy compared with that of TDF-based combination therapy in patients with MDR.

Nucleoside and nucleotide analogues (NAs) have a risk of mitochondrial toxicity and then inducing the increase of lactate. We aim to evaluate the impact of lactate on the effects of NAs therapy in hepatitis B virus-related hepatocellular carcinoma (HCC) patients after curative liver resection.

Five hundred and fifty-seven HBV-related HCC patients were divided into the treatment and control group according to whether they received NAs therapy or not. Perioperative and prognosis data were retrospectively reviewed.

The treatment group had a better overall survival rate (OS) than the control group (P = 0.017). The recurrence-free survival rate (RFS) did not significantly differ between the two groups (P = 0.174). NAs could improve the OS of early stage HCC patients (P = 0.028), as well as the OS of advanced stage HCC patients with low level of lactate in subgroup analysis stratified against the level of lactate (P = 0.037). Advanced stage HCC patients in the treatment group had a higher value of lactate than those in the control group (P = 0.024). Besides, advanced stage HCC patients had a higher value of lactate than early stage HCC patients in the treatment group (P < 0.001), as well as in the control group (P < 0.001).

NAs could improve the long-term outcomes of HBV-related HCC patients after curative liver resection. However, the improvement effect of NAs therapy is counteracted by the adverse effect of elevated lactate in advanced stage HBV-related HCC patients.

The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.

Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)-based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs). HBeAg positivity is associated with greater disease risk that may be moderately reduced upon HBeAg loss. The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome but also from transcripts arising from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. Our results uncover a heretofore underrecognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immunosurveillance. These results could alter trial design and endpoint expectations of new therapies for chronic HBV.

The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 ± 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean ± SEM, which were 1.53 ± 1.23, 1.75 ± 1.37, 2.07 ± 1.54, and 2.39 ± 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (χ = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment.

A complete virological response is closely related to the long-term outcome of patients with chronic hepatitis B and prevention of emerging HBV mutations. We aimed to evaluate the efficacy of tenofovir disoproxil fumarate (TDF) monotherapy compared to entecavir-adefovir dipivoxil (ETV-ADV) combination therapy in patients with suboptimal responses to long-term lamivudine-adefovir dipivoxil (LAM-ADV) therapy for nucleoside analogue-resistant chronic hepatitis B.

Patients (n=60) were randomized to TDF monotherapy or ETV-ADV combination therapy for 96 weeks. All patients had the rt204I/V mutation and serum HBV DNA was measured (>60 IU/ml) during LAM-ADV therapy. The primary end point was a complete virological response (HBV DNA <20 IU/ml) at week 96.

The median duration of prior LAM-ADV rescue therapy was 43 (7-108) months. A complete virological response was achieved in 86.6% and 53.3% of patients in the TDF and ETV-ADV groups, respectively, at week 96 (P=0.005). Reduction in serum HBV DNA was significantly greater in the TDF group than in ETV-ADV group (-3.2 ±1.2 versus -2.6 ±1.2; P=0.01). Hepatitis B e antigen loss (22.2% versus 16.6%; P=0.731) and biochemical responses (76.7% versus 73.3%; P=0.766) were not different between the TDF and ETV-ADV groups. No newly emerged mutations were detected. Both therapies demonstrated favourable safety profiles.

TDF therapy achieved a better complete virological response than ETV-ADV therapy in chronic hepatitis B patients with suboptimal response to long-term LAM-ADV rescue therapy. (KCT0000627).

The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues.

One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy.

None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class.

None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.

Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All patients should be monitored for risk of disease progression and HCC. Treated patients should be monitored for therapy response and adherence. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.

Tenofovir disoproxil fumarate (TDF) monotherapy for 48 weeks provided a virological response comparable to that of TDF and entecavir (ETV) combination therapy in patients infected with ETV-resistant hepatitis B virus (HBV). Little long-term data in routine clinical practice are available regarding the optimal treatment of patients with ETV-resistant HBV.

We investigated the long-term antiviral efficacy of combination therapy of TDF+lamivudine (LAM) or TDF+ETV compared to that of TDF monotherapy in 73 patients with resistance to both LAM and ETV.

Patients were treated with TDF monotherapy (n=12), TDF+LAM (n=19), or TDF+ETV (n=42) for more than 6 months. The median duration of TDF-based rescue therapy was 37 months. Virologic response (VR) was found in 63 patients (86.3%). The rates of VR among the three groups (TDF monotherapy, TDF+LAM, and TDF+ETV) were not statistically different (log-rank P=0.200) at 12 months (59.3%, 78.9%, and 51.8%, respectively) or at 24 months (88.4%, 94.7%, and 84.2%). In addition, treatment efficacy of TDF-based combination or TDF monotherapy was not statistically different with ETV-resistant strains or exposure to other antiviral agents. In multivariate analysis, only lower baseline HBV DNA level was an independent predictor for VR (hazard ratio, 0.723; 95% confidence interval, 0.627-0.834; P<0.001).

TDF monotherapy was as effective as combination therapy of TDF+LAM or TDF+ETV in maintaining long-term viral suppression in chronic hepatitis B patients with resistance to both LAM and ETV. HBV DNA level at the start of TDF rescue therapy was the only independent predictor of subsequent VR.

Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance.

A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared.

There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ²  = 0.749, P = 0.862) and hepatitis B e antigen-positivity (χ²  = 0.099, P = 0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37 ± 1.07 log₁₀ IU ml^-1 , -2.16 ± 0.81 log₁₀ IU ml^-1 , -1.17 ± 1.23 log₁₀ IU ml^-1 and -2.49 ± 1.10 log₁₀ IU ml^-1 , respectively (F = 4.078, P = 0.011). The TDF group and ETV (0.5 mg) + TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg) + ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence.

TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.

Chronic Hepatitis B continues as a significant public health problem despite the availability of safe and effective antivirals and a highly effective protective vaccine. Current therapy, however rarely leads to cure and lifelong therapy is often required, contributing to poor uptake and ongoing morbidity. New insights into the hepatitis B viral life cycle and the host immune response have expanded the potential targets for drug therapies with interesting antiviral candidates and novel immunotherapeutic approaches in early stage development. Yet, HBV persistence is multifactorial - due to an intrahepatic reservoir and ongoing HBV-mediated immune dysregulation, making "cure" unlikely to be realized through even the most efficacious monotherapy. Building on the success seen in the treatment of hepatitis C (HCV) and human immunodeficiency virus (HIV), combination therapy may be an essential strategy to improve efficacy and decrease viral breakthrough. Combinations acting on immune and viral targets are particularly attractive. However, creating synergy while balancing efficacy and safety remains a clear challenge. Various approaches to combination therapy are reviewed, highlighting strengths and challenges of each potential strategy. Overall, combination therapies are attractive as the next step towards cure and are a key strategy for achieving treatment with finite durations and durable endpoints.

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 14-99 months). 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 4 years 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 3 years (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.

Virological breakthrough (VBT) could be a manifestation of chronic hepatitis B (CHB) in patients treated with long-term nucleot(s)ide analogues. We aimed to determine the association of on-treatment serum hepatitis B virus (HBV) DNA with VBT in HBeAg-positive CHB patients receiving entecavir (ETV) treatment.

A retrospective cohort study, including 162 consecutive patients (95 men and 67 women; mean age, 43.1±13.4 years) with HBeAg-positive CHB treated with ETV for at least 48 weeks between August 2008 and May 2015, was conducted. Univariate and multivariate cox regression analysis were used to identify associations with VBT and clinical factors, including HBV DNA and HBeAg serum status.

Among the 162 ETV-treated HBeAg-positive CHB patients, eighteen patients (11.1%) experienced VBT (VBT group), whereas the other 144 patients were without VBT (non-VBT group). The cumulative rate of HBV DNA < 100 IU/mL in the VBT group and the non-VBT group at week 48 were 44.44% and 70.14%, and at week 96 were 58.33% and 92.56%, respectively (p = 0.015). The cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group at week 48 and week 96 were statistically significant (p = 0.014). Multivariate analysis disclosed that failure to achieve HBeAg seroclearance were the factors significantly associated with VBT.

Our results demonstrated that on-treatment HBV DNA could probably predict VBT in ETV-treated HBeAg-positive chronic hepatitis B patients. Failure to achieve HBeAg seroclearance was associated with VBT in ETV-treated HBeAg-positive CHB patients. HBV DNA >100IU/mL at 48 weeks is potentially a predictor for VBT.

The primary goal of therapy for chronic hepatitis B (CHB) is to prevent liver disease progression. Hepatitis B surface antigen (HBsAg) seroclearance or seroconversion is regarded as an optimal endpoint to discontinue treatment. However, HBsAg seroclearance occurs very rarely with nucleos(t)ide analog (NUC) treatment, and long-term, almost indefinite, NUC treatment is required for the majority of patients. In patients with drug-resistant hepatitis B virus (HBV), a combination of tenofovir disoproxil fumarate (TDF) and entecavir (ETV), which is currently regarded as the strongest combination therapy against HBV, would be potentially safe to prevent the emergence of additional HBV resistance mutations. However, long-term tolerance data are lacking, and cost may be an issue for combination therapies. Several recent, well-designed, randomized controlled trials have shown that TDF monotherapy provides similar antiviral efficacy compared with the combination of TDF and ETV. Furthermore, no additional HBV resistance mutations emerged during TDF monotherapy for up to 96 weeks. Considering a comparable antiviral efficacy, extremely low risk of TDF-resistance, lower cost, and better safety potential, TDF monotherapy would be a reasonable choice for the treatment of drug-resistant patients with CHB.

Tenofovir disoproxil fumarate (TDF) plays a pivotal role in the management of drug-resistant chronic hepatitis B. However, it remains unclear whether TDF-nucleoside analogue combination therapy provides better outcomes than TDF monotherapy. This study aimed to compare the efficacy of TDF monotherapy with that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B.

This retrospective cohort study included 76 patients receiving TDF-based rescue therapy for more than 12 months. Suboptimal response was defined as serum HBV-DNA level of > 60 IU/mL during prior rescue therapy. Multi-drug resistance was defined as the presence of two or more drug resistance-related mutations confirmed by mutation detection assay. The relationship between baseline characteristics and virologic response (HBV DNA < 20 IU/mL) at 12 months were evaluated using logistic regression analysis.

Fifty-five patients (72.4%) were suboptimal responders to prior rescue therapy, and 26 (34.2%) had multi-drug resistance. Forty-two patients (55.3%) received combination therapy with nucleoside analogues. Virologic response at 12 months was not significantly different between the TDF monotherapy group and TDF-nucleoside analogue combination therapy group (p = 0.098). The serum HBV DNA level was reduced to -4.49 ± 1.67 log10 IU/mL in the TDF monotherapy group and to -3.97 ± 1.69 log10 IU/mL in the TDF-nucleoside analogue combination therapy group at 12 months (p = 0.18). In multivariate analysis, female sex (p = 0.032), low baseline HBV-DNA level (p = 0.013), and TDF monotherapy (p = 0.046) were predictive factors for virologic response at 12 months.

TDF monotherapy showed similar efficacy to that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B.

We investigated the durability of virological response after lamivudine (LAM) discontinuation in LAM-resistant chronic hepatitis B (CHB) patients with complete virological response after LAM-adefovir (ADV) combination therapy. We enrolled 58 patients switched to ADV monotherapy with undetectable viral loads (<12 IU/ml) and normal alanine aminotransferase levels after ADV add-on combination treatment for at least 6 months in LAM-resistant CHB patients. Virologic relapse was defined as HBV DNA detection at more than 20 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. During median 40.9 months of follow-up (range 11.5-79.0 months), seven (12.1%) patients experienced virological relapse. The cumulative rate of virological relapse at 3 and 5 years was 5.5% and 22.4%, respectively. Two patients had elevated alanine aminotransferase during virological relapse. These seven patients with virological relapse had undetectable HBV DNA after switching to tenofovir therapy. In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 87.9% of the patients during median 40.9 months follow-up. This adapting step-down strategy, switching from combination therapy to monotherapy in virologically suppressed CHB patients with stable liver disease, may reduce the cost burden and the risk of potentially harmful effects of combination therapy. J. Med. Virol. 89:85-90, 2017. © 2016 Wiley Periodicals, Inc.

Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide. Currently available antiviral treatment options for chronic hepatitis B include pegylated interferon alpha2a (PegIFN) or nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of sustained on-treatment response to therapy. The advantages of PegIFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. Furthermore, PegIFN is the only approved agent known to be active against hepatitis D virus (HDV). The use of these two antiviral agents with different mechanisms of action in combination against hepatitis B is theoretically an attractive approach for treatment. Although several studies have confirmed certain virological advantages of combination therapies, data supporting a long-term clinical benefit for patients are lacking and monotherapy with PegIFN or NAs remains the therapy of choice. Moreover, with the current treatment approaches, only a limited number of patients achieve hepatitis B surface antigen (HBsAg) loss. HBsAg loss is considered a "functional cure", but does not mean viral eradication. There is a need for novel therapeutic approaches that enable not only suppression of viral replication, but resolution of HBV infection. A key challenge is to target covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. The recent development and availability of innovative in vitro and in vivo systems and sensitive molecular techniques has opened new possibilities to study the complex network of interactions that HBV establishes with the host in the course of infection and to define new targets for antiviral strategies. Several new antiviral or immunomodulatory compounds have reached preclinical or clinical testing with the aim of silencing or eradicating cccDNA to achieve functional cure. Many of these strategies may also be effective for the treatment of HDV, which is dependent on HBsAg for its life cycle. This Clinical Trial Watch summarizes the most recent therapeutic strategies designed to directly target the viruses B and D or to improve immune responses during chronic HBV infection.

Multiple clinical trials have demonstrated the efficacy and safety of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB). However, long-term efficacy and safety data for TDF in real-life clinical practice are limited.

Prospective German field practice study in CHB-mono-infected patients. Patients were TDF-naïve but could have been treated previously with other HBV antivirals.

Efficacy analysis included 400 patients; 301 (75 %) completed 36 months of TDF treatment. Both treatment-naïve and treatment-experienced patients showed a rapid decline in HBV DNA within 3 months of TDF initiation. After 36 months, HBV DNA < 69 IU/mL was achieved by 91 % of treatment-naïve patients (90 and 92 % in hepatitis B "e" antigen [HBeAg]-positive and [HBeAg]-negative, respectively) and 96 % of treatment-experienced patients (93 and 97 %, respectively). Three patients experienced virologic breakthrough, all with reported non-compliance. Overall, 5.7 % HBeAg-positive and 2.2 % HBeAg-negative patients lost hepatitis B surface antigen. Safety data were consistent with the known TDF safety profile; the most commonly reported adverse events possibly related to TDF were fatigue (2.0 %) and headache (2.0 %). Few patients (1.3 %) experienced renal-related adverse reactions. Creatinine clearance remained relatively stable over time; patients responded favorably where TDF was dose adjusted per label for decreased creatinine clearance.

TDF showed a favorable tolerability profile and induced rapid and sustained suppression of HBV DNA in patients with CHB treated for up to 3 years in routine clinical practice, irrespective of treatment history. Efficacy and safety in this heterogeneous patient population were consistent with data from clinical trials.

Persistent hepatitis B virus (HBV) infections affect about 240 million patients worldwide that are at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes and a unique life cycle, which involves the generation of an RNA template for replication via reverse transcription. Mutations occur frequently during chronic infection, and particular selection pressures select distinct mutants. Nucleoside and nucleotide analogues like lamivudine (LMV), entecavir (ETV), telbivudine (LdT), adefovir dipivoxil (ADV) and tenofovir (TDF) are used to achieve long-term suppression of viral replication. Importantly, these drugs have different barriers to resistance, explaining the higher incidence of treatment failure in the past due to drug resistant viral strains for the older compounds LMV, LdT and ADV. On a molecular level, drug resistant mutations usually affect the reverse transcriptase domain of the HBV polymerase protein. Secondary compensatory mutations restore the replication fitness of the mutant virus. From a clinical point of view, patients undergoing antiviral therapy require regular testing for HBV DNA (every 3-6 months). In case of insufficient viral suppression or viral breakthrough (>1 log increase in HBV DNA above nadir), strict adherence to therapy needs to be ensured. If drug resistance is suspected or even molecularly confirmed, rescue therapy strategies exist, usually switching to a noncross-resistant antiviral drug. LMV, LdT and ETV resistant HBV can be treated with TDF monotherapy, ADV resistance with ETV or TDF, and insufficient responses to TDF may require ETV either as mono- or combination therapy. Complex treatment histories with many antivirals may sometimes necessitate the combination of highly effective antivirals like ETV and TDF. Novel treatment targets such as core (capsid) inhibitors, siRNA targeting protein translation, entry inhibitors or immune modulators aim at improving the efficacy of antivirals in order to (functionally) cure hepatitis B.

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

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

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

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

Sequential therapy posed a high risk of emergence of multidrug resistance and presented a management issue in chronic hepatitis B (CHB) treatment. We evaluated the antiviral efficacy and safety of entecavir (ETV) plus tenofovir (TDF) combination therapy in multidrug-resistant (MDR) CHB patients.

In this prospective, multicentre study, MDR CHB patients, defined as measurable serum HBV DNA (≥60 IU/ml) while on any rescue treatment regimen for at least 24 weeks and the presence of documented prior genotypic resistance to both nucleoside analogue(s) and nucleotide analogue, were treated with ETV 1.0 mg and TDF 300 mg combination therapy for 48 weeks.

A total of 64 eligible patients who had previously failed to a median three lines of antiviral therapy (range, 2-6) were included. At baseline, median age was 47.0 years, 89.1% were HBeAg(+), and median HBV DNA was 4.24 (range, 2.11-6.73) log10 IU/ml. By week 4, 12, 24 and 48, 15/64 (23.4%), 36/64 (56.3%), 43/64 (67.2%) and 55/64 (85.9%) patients achieved a HBV DNA <60 IU/ml respectively. The mean reduction of HBV DNA from baseline to 4 and 48 weeks was 1.23 log10 IU/ml and 2.38 log10 IU/ml respectively. Although five patients experienced virological breakthrough, all were transient and no resistant mutation to TDF or novel mutation was detected in any patients.

In difficult-to-treat MDR CHB patients with a high exposure to multiple antiviral drugs, ETV plus TDF combination therapy can provide a very high rate of viral suppression through 48 weeks of treatment.

Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination.

We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy.

The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy.

The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases.

Most guidelines suggest combination therapy including nucleoside and nucleotide analogues for the treatment of chronic hepatitis B (CHB) with multidrug resistance (MD-R). However, long-term combination treatment can evoke high costs and safety problems. Therefore, we investigated the efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy for viral suppression in patients with CHB exhibiting MD-R. We reviewed patients with CHB exhibiting antiviral drug resistance treated by TDF mono-rescue therapy from December 2012 to June 2014. The patients were categorized into three groups: lamivudine-resistance (LAM-R) group (n = 290), and LAM-R + adefovir-resistance (ADV-R) group (n = 43), and LAM-R + entecavir-resistance (ETV-R) group (n = 113). We compared the virologic response rate according to the multiplicity of resistance and investigated the predictive factors of a virologic response. For a median of 15 months (range, 6-24 months) of TDF mono-rescue therapy, the cumulative virologic response rates were 82.8, 81.4, and 84.1% in the LAM-R, LAM-R + ADV-R, and LAM-R + ETV-R groups, respectively (P = 0.239). Multivariate analysis revealed that multiplicity of resistance did not influence the achievement of a virologic response (P = 0.218). However, the baseline HBV DNA level significantly influenced the achievement of a virologic response for the treatment of CHB with MD-R (P < 0.001). TDF mono-rescue therapy is an appropriate treatment for CHB with MD-R, and the baseline HBV DNA level is a significant predictive factor for a virologic response. These factors should be considered before treating CHB with MD-R.

Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV.

In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks.

Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (-3.03 log10 IU/mL vs -3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups.

In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks.

NCT01639066.

Despite effective preventive primary prevention with vaccination, many people remain infected with hepatitis B virus (HBV) and suffer from its complications. Effective treatments such as interferon-based regimens and oral nucleoside/nucleotides have been developed over the last 30 years, but they are not perfect. Each of the treatments has its own merits, but none can eradicate HBV from the host. As a result, regular monitoring of the response during treatment and after treatment is required. The choice and monitoring of selected treatments, new potential therapeutic agents, and treatment options for drug resistance are discussed in this review.

Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV.

In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=45) or TDF and ETV (1 mg/day) combination therapy (n=45) for 48 weeks.

Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log10 IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs. 73%; p>0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (-3.66 vs. -3.74 log10 IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p>0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups.

TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV.

ClinicalTrials.gov ID NCT01639092.

Chronic hepatitis B virus (HBV) infection and hepatitis delta virus (HDV) co-infection lead to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).

We review the current knowledge of the management of HBV mono-infection and HBV/HDV co-infection with a special emphasis on liver cirrhosis.

Treatment options for chronic hepatitis B are pegylated interferon (PEG-IFN) alfa and nucleos(t)ide analogues (NUC). PEG-IFN is a finite option to achieve hepatitis B surface antigen loss in compensated cirrhosis. However, this goal is rare. NUC are potent to achieve HBV DNA suppression but long-term treatment is mandatory in most cases. Long-term treatment with NUC can lead to reversion of liver cirrhosis, improve liver function, prevent liver transplantation, and reduces but does not eliminate the risk for development of HCC. Treatment options for hepatitis D are limited to PEG-IFN. Although late relapse is common, treatment with PEG-IFN reduces disease progression. However, new treatments are urgently needed for HDV infection.

Early treatment of chronic hepatitis B and D is important to prevent complications of cirrhosis. HCC surveillance remains important in patients with cirrhosis.

There are about 350 million hepatitis B virus (HBV) carriers worldwide and chronic HBV is considered a major public health problem. The objective of the present study was to assess the effectiveness of the nucleos(t)ide analogues tenofovir (TDF) and entecavir (ETV) in the treatment of chronic HBV. A cross-sectional study was carried out from March-December 2013, including all patients with chronic HBV, over 18 years of age, undergoing therapy through the public health system in southern Brazil. Only the data relating to the first treatments performed with TDF or ETV were considered. Retreatment, co-infection, transplanted or immunosuppressed patients were excluded. Six hundred and forty patients were evaluated, of which 336 (52.5%) received TDF and 165 (25.8%) ETV. The other 139 (21.7%) used various combinations of nucleos(t)ide analogues and were excluded. The negativation of viral load was observed in 87.3% and 78.8% and the negativation of hepatitis B e antigen was achieved in 79% and 72% of those treated with ETV or TDF, respectively. Negativation of hepatitis B surface antigen was not observed. There was no occurrence of adverse effects. This is a real-life study demonstrating that long-term treatment with ETV and TDF is both safe and effective.

Chronic hepatitis B virus (HBV) infection evolves from immune-tolerance phase, through immune clearance phase to a quiescent phase or reactivation as hepatitis B e antigen-negative hepatitis. Persistent infection may result in the development of cirrhosis and hepatocellular carcinoma (HCC). Host factors including gender, age, family history, HLA-DP, and viral factors including HBV DNA, genotypes, precore mutations, pre-S deletions, and hepatitis B surface antigen (HBsAg) level are associated with the development of these complications. Risk scores for the development of HCC have been derived. Patients with persistently elevated alanine aminotransferase levels (>30 for males; >19 U/L for females) and HBV DNA levels >2000 IU/mL should be treated. Patients with established cirrhosis with detectable HBV DNA should also be treated. The recommended first-line agents include pegylated interferon and 2 nucleos(t)ide analogs, entecavir and tenofovir. NAs require long-term treatment to maintain suppression of HBV DNA. They have been shown to decrease hepatic fibrosis, or reverse cirrhosis and to reduce the development of HCC. They have very low rates (0% to 1.2%) of resistance. HBsAg seroclearance, although the ideal endpoint, is only achievable in 10% to 12% of patients by multicenter trials usually studying relatively young patients. Patients on long-term treatment should be monitored for viral breakthrough that may be due to noncompliance or the development of resistance. Newer agents are under trials to enhance the rate of HBsAg seroclearance. However, even with the current NAs, long-term treatment of >6 years can markedly reduce the covalently closed circular DNA, the viral component responsible for initiation of viral replication.

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.