• Adverse events
• Chronic hepatitis B
• Nucleotide/nucleoside analogues

Little clinical data are available about the effect of food on the antiviral efficacy of entecavir for chronic hepatitis B virus (HBV) infection. The present study evaluated whether entecavir administration in the fed state had comparable efficacy to the fasted condition for maintenance of viral suppression in HBV-infected patients with virological response on entecavir therapy.

In this multicenter, randomized, open-label, noninferiority study, patients who were currently receiving entecavir and showed a serum HBV DNA level of <20 IU/mL were randomized to take entecavir either under the fasted or fed condition for 48 weeks.

We randomly assigned 50 patients to the fasted group and 46 patients to the fed group. The full analysis set consisted of 49 patients in the fasted group and 44 patients in the fed group. At week 48, the proportion of patients with HBV DNA <20 IU/mL was not significantly different between the fasted and fed groups (98% vs 100%, P=1.00). The mean log₁₀ HBV DNA changes from baseline were similar between the two groups (−0.004 vs −0.012 log₁₀ IU/mL, P=0.43). There were no significant differences in the proportions of patients with normal alanine aminotransferase (87.8% vs 95.5%, P=0.27) and hepatitis B e-antigen seroconversion (0% vs 6.7%, P=0.47) between the two groups. None of the patients showed viral breakthrough. In pharmacokinetic analysis, the maximum concentration and the area under the concentration– time curve to the last quantifiable concentration decreased by 26.4% and 9.3%, respectively, in the fed group compared with the fasted group. However, the differences between two groups were not statistically significant (P=0.28 and 0.83, respectively).

In patients with virological response under entecavir therapy, concomitant food intake did not affect the antiviral efficacy. For patients with adherence problem, taking entecavir with food may be considered to improve compliance.

• chronic hepatitis B
• efficacy
• entecavir
• food effect

• Adefovir
• Adverse effects
• Adverse events
• Chronic hepatitis B
• Entecavir
• Hepatitis B infection
• Hepatitis B virus
• Lamivudine
• Nucleoside/nucleotide analogues
• Safety
• Side effects
• Telbivudine
• Tenofovir

• Hepatitis B, chronic
• Resistance
• Tenofovir
• Treatment failure

• Adenine/adverse effects
• Adenine/analogs & derivatives
• Adenine/therapeutic use
• Adult
• Aged
• Alanine Transaminase/blood
• Antiviral Agents/adverse effects
• Antiviral Agents/therapeutic use
• Biomarkers/blood
• Creatinine/blood
• DNA, Viral/blood
• Drug Resistance, Viral/genetics
• Drug Substitution
• Female
• Genotype
• Hepatitis B e Antigens/blood
• Hepatitis B virus/drug effects
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Hepatitis B virus/pathogenicity
• Hepatitis B, Chronic/blood
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/drug therapy
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation
• Phosphorous Acids/adverse effects
• Phosphorous Acids/therapeutic use
• Phosphorus/blood
• Retrospective Studies
• Time Factors
• Treatment Failure
• Viral Load
• Young Adult

Chronic infection with hepatitis B virus (HBV) constitutes a major global public health threat, causing substantial disease burdens such as liver cirrhosis and hepatocellular carcinoma, thus representing high unmet medical needs. Currently available therapies are safe, well tolerated, and highly effective in decreasing viremia and improving measured clinical outcomes with low rates of antiviral resistance. However, long-term management remains a clinical challenge, mainly due to the slow kinetics of HBV surface antigen clearance. In this article, we review emerging antivirals directed at novel targets derived from mechanisms of viral cellular entry, viral replication, viral assembly, and the host immune response, leading to preclinical and clinical trials for possible future therapeutic intervention. The recent therapeutic advances in the development of all categories of HBV inhibitors may pave the way for regimens of finite duration that result in long-lasting control of chronic hepatitis B infection.

• Hepatitis B
• Antiviral
• Nucleoside analogue
• Nucleotide analogue
• Non-nucleoside antivirals

• Antiviral Agents/therapeutic use
• Hepatitis B virus/drug effects
• Hepatitis B virus/pathogenicity
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/virology
• Humans
• Treatment Outcome

• chronic infection
• hepatitis B
• treatment

• 2'-fluoro-5-methylarabinosyluracil
• Adverse Effect
• Hepatitis B, Chronic
• Response Elements

• Adverse effects
• Hepatitis B
• Myopathy
• Telbivudine

AIM: To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients after multiple failures.

METHODS: A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue (NA) treatments were included. Study subjects were treated with TDF alone (n = 13) or in combination with lamivudine (LAM, n = 12) or entecavir (ETV, n = 4) for ≥ 6 mo. Complete virologic response (CVR) was defined as an achievement of serum hepatitis B virus (HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment. Safety assessment was based on serum creatinine and phosphorus level. Eleven patients had histories of LAM and adefovir dipivoxil (ADV) treatment and 18 patients were exposed to LAM, ADV, and ETV. Twenty-seven patients (93.1%) were hepatitis B e antigen (HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL. The median treatment duration was 16 mo (range 7 to 29 mo).

RESULTS: All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it. Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV. One patient had a resistance to both ADV and ETV. The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%, respectively. Although one patient failed to achieve CVR, serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL, achieving near CVR. No patients in this study showed viral breakthrough or primary non-response during the follow-up period. The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%, 12%, and 27% at 6, 12, and 18 mo of treatment, respectively. Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations. History of prior exposure to specific antiviral agents did not make a difference to treatment outcome. Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV. No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed. There were no other adverse events related to TDF therapy observed in the study subjects.

CONCLUSION: TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.

• Tenofovir
• Chronic hepatitis B
• Treatment failure

AIM: To evaluate the treatment outcomes of clevudine compared with entecavir in antiviral-naive patients with chronic hepatitis B (CHB).

METHODS: We retrospectively analyzed the clinical data of CHB patients treated with clevudine 30 mg/d and compared their clinical outcomes with patients treated with entecavir 0.5 mg/d. The biochemical response, as assessed by serum alanine aminotransferase (ALT) activity, virologic response, as assessed by serum hepatitis B virus DNA (HBV DNA) titer, serologic response, as assessed by hepatitis B e antigen (HBeAg) status, and virologic breakthrough with genotypic mutations were assessed.

RESULTS: Two-hundred and fifty-four patients [clevudine (n = 118) vs entecavir (n = 136)] were enrolled. In clevudine-treated patients, the cumulative rates of serum ALT normalization were 83.9% at week 48 and 91.5% at week 96 (80.9% and 91.2% in the entecavir group, respectively), the mean titer changes in serum HBV DNA were -6.03 and -6.55 log₁₀ copies/mL (-6.35 and -6.86 log₁₀ copies/mL, respectively, in the entecavir group), and the cumulative non-detection rates of serum HBV DNA were 72.6% and 83.1% (74.4% and 83.8%, respectively, in the entecavir group). These results were similar to those of entecavir-treated patients. The cumulative rates of HBeAg seroconversion were 21.8% at week 48 and 25.0% at week 96 in patients treated with clevudine, which was similar to patients treated with entecavir (22.8% and 27.7%, respectively). The virologic breakthrough in the clevudine group occurred in 9 (7.6%) patients at weeks 48 and 15 (12.7%) patients at week 96, which primarily corresponded to genotypic mutations of rtM204I and/or rtL180M. There was no virologic breakthrough in the entecavir group.

CONCLUSION: In antiviral-naive CHB patients, long-term treatment outcomes of clevudine were not inferior to those of entecavir, except for virologic breakthrough.

• Chronic hepatitis B
• Hepatitis B virus
• Clevudine
• Entecavir
• Treatment outcomes

• 2'-Fluoro-5-methylarabinosyluracil
• Chronic hepatitis B
• Muscular diseases
• Viral breakthrough

Hepatitis D virus (HDV) is a defective virus with circular, single-stranded genomic RNA which needs hepatitis B virus (HBV) as a helper virus for virion assembly and infectivity. HDV virions are composed of a circular shape HDV RNA and two types of viral proteins, small and large HDAgs, surrounded by HBV surface antigen (HBsAg). The RNA polymerase II from infected hepatocytes is responsible for synthesizing RNAs with positive and negative polarities for HDV, as the virus does not code any enzyme to replicate its genome. HDV occurs as co-infection or super-infection in up to 5% of HBsAg carriers. A recent multi-center study highlighted that pegylated interferon α-2a (PEG-IFN) is currently the only treatment option for delta hepatitis. Nucleotide/nucleoside analogues, which are effective against HBV, have no relevant effects on HDV. However, additional clinical trials combining PEG-IFN and tenofovir are currently ongoing. The molecular interactions between HDV and HBV are incompletely understood. Despite fluctuating patterns of HBV viral load in the presence of HDV in patients, several observations indicate that HDV has suppressive effects on HBV replication, and even in triple infections with HDV, HBV and HCV, replication of both concomitant viruses can be reduced. Additional molecular virology studies are warranted to clarify how HDV interacts with the helper virus and which key cellular pathways are used by both viruses. Further clinical trials are underway to optimize treatment strategies for delta hepatitis.

• Hepatitis D virus
• Hepatitis B virus
• Delta hepatitis
• Liver cirrhosis
• Hepatocellular carcinoma
• Hepatitis B virus surface antigen