anti-HBV Agents Research Articles

HBV disease: HBsAg carrier and occult B infection reactivation in haematological setting

HBV reactivation in patients with haematological malignancies undergoing chemoimmunotherapy is a serious and frequent complication. This is linked to either the high frequency of inactive HbsAg carriers and occult B infection among oncohaematological patients or the profound immunosuppression caused by high dose chemotherapy, monoclonal antibody therapy or auto- and allo-haematopoietic stem cell (HSC) transplantations. Identifying the patients at risk is mandatory in this clinical setting and prophylaxis with antiviral drugs or close monitoring may reduce and/or eliminate the HBV reactivation risk and the serious consequences. In general, preemptive anti-HBV therapy is more effective than treatment at reactivation. Prompt lamivudine prophylaxis should be given to HBsAg positive patients (inactive carriers) undergoing chemotherapy-immunochemotherapy and continued after cessation of immunosuppression even though long-term lamivudine therapy involves a risk of developing drug resistance. Use of newer anti-HBV agents may be considered. HBV reactivation has also been observed in occult B infection (HBcAb positive) and the optimal management of this group of patients requires special attention.

Helioxanthin Analogue 8-1 Inhibits Duck Hepatitis B Virus Replication in Cell Culture

Current approved anti-HBV treatment cannot completely eliminate HBV infection, and emergence of resistant virus is an important treatment issue. Effective anti-HBV agents with different mechanisms of action on novel target sites are needed for the treatment of HBV infection and for combating the resistant virus, alone or in combination with current anti-HBV strategies. Helioxanthin analogue 8-1 displayed potent anti-HBV activity in human HBV in vitro and in animal models, with a unique antiviral mechanism. Its antiviral activity in other HBV system needs further study. The anti-duck hepatitis B virus (DHBV) activity of 8-1, an analogue of a natural product, helioxanthin, was studied in the DHBV inducible cell line, dstet5, in comparison to and in combination with the nucleoside analogue, lamivudine (3TC). Helioxanthin analogue 8-1 exhibited anti-DHBV activity as demonstrated by quantification of viral DNA, RNA, covalently closed circular DNA and protein synthesis. Analogue 8-1 did not affect the stability of cellular macromolecules and did not have a sustained antiviral effect after drug removal. When DHBV replication was induced, virus-harbouring cells were more susceptible to the cytotoxicity of 8-1 than non-induced cells. 8-1 exhibited effective inhibition on DHBV replication. The combination of 8-1 with 3TC resulted in additional anti-DHBV activity. Viral induced cells displayed higher susceptibility to 8-1 treatment than non-induced cells. HBV X protein might not be an essential factor in the initiation of the biological activity of 8-1, as demonstrated by its absence in DHBV. These findings warrant further development of 8-1 for the treatment of chronic hepatitis B and its associated diseases.

Review of Hepatitis B Therapeutics

Currently, there are 7 approved therapies for chronic hepatitis B virus (HBV) infection, an increase from just 3 agents 5 years ago. This review will focus on the pharmacology, potency, and adverse events associated with immunomodulatory agents and nucleos(t)ide analogues, with an emphasis on targets of therapy within the HBV life cycle. We will also offer guidelines for the use of available anti-HBV agents and review the emerging challenges in hepatitis B management, including HBV drug resistance, its management, and the potential role of combination therapy.

Design and Development of Anti-Hepatitis B Virus Agents

Hepatitis B virus (HBV) infected hepatitis is the common infectious disease. In the World Conservative Estimate Plan, the number of persons chronically infected with HBV is more than 300 million. Current regimen of treatment is far from satisfactory, as it is associated with certain side effects and viral resistance capacity. Therefore, a serious attention has recently been paid to the design and development of new potent anti-HBV agents. A variety of drugs have been synthesized and screened for their anti-HBV effects. These include nucleosides, natural compounds, quinolines, benzodiazepines, indoles, etc. Many of them are in wide trend in current treatment regimen. In this review, we have presented the recent development on the design and development of all categories HBV inhibitors studied.

Antiviral activity of 2,3′-anhydro and related pyrimidine nucleosides against hepatitis B virus

Various 2,3′-anhydro analogs of 5-substituted 1-(2-deoxy-β-d-lyxofuranosyl)uracils (10–15) and a related 1-(3-O-mesyl-2-deoxy-β-d-lyxofuranosyl) pyrimidine nucleoside analog (18) have been synthesized for evaluation as a new class of potential anti-HBV agents. The compounds 10, 12, and 15 demonstrated most potent anti-HBV activities against duck HBV (DHBV) and human HBV with EC50 values in the range of 2.5–10 and 5–10μg/mL, respectively, at non-toxic concentrations (CC50=>200μg/mL). The nucleoside 18 also demonstrated significant anti-HBV activity against DHBV with an EC50 value of 2.5μg/mL, however, it was less active against HBV in 2.2.15 cells (EC50=>10μg/mL).

Discovery and Development of Anti-HBV Agents and Their Resistance

Hepatitis B virus (HBV) infection is a prime cause of liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma. The current drugs clinically available are nucleot(s)ide analogues that inhibit viral reverse transcriptase activity. Most drugs of this class are reported to have viral resistance with breakthrough. Recent advances in methods for in silico virtual screening of chemical libraries, together with a better understanding of the resistance mechanisms of existing drugs have expedited the discovery and development of novel anti-viral drugs. This review summarizes the current status of knowledge about and viral resistance of HBV drugs, approaches for the development of novel drugs as well as new viral and host targets for future drugs.

Long-term Therapy With Tenofovir Is Effective for Patients Co-Infected With Human Immunodeficiency Virus and Hepatitis B Virus

We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy. We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF. At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 41-63 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m(2), which was most pronounced shortly after TDF therapy was initiated. TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.

A promising alternative anti-HBV agent: The targeted ribonuclease

HBV-targeted ribonuclease (TR) is a fusion of HBV core protein (HBVc) and human eosinophil-derived neurotoxin (hEDN). Introduction of TR by transfection or transduction into HepG2.2.15 cells (a cell model of HBV infection) revealed that it significantly reduces serological markers of HBV replication (including HBsAg, HBeAg and HBV DNA) in cell supernatants, suggesting that the targeted ribonuclease inhibits HBV replication. To further our understanding of the molecular mechanism of the anti-HBV effect of TR, we expressed TR in E. coli and found that purified TR possesses RNase activity and targeting activity. Furthermore, the antiviral effect of TR depends both on an enzymatically active hEDN and on the core domain. In or out of HepG2.2.15 cells, TR coassembles with the wild-type capsid protein into particles with internal hEDN domains. Our data suggest an intracellular ribonuclease activation mechanism that, owing to the characteristics of HBV morphogenesis, is highly virus specific. HBV may therefore be particularly vulnerable to the capsid-targeted viral inactivation approach.

Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection

ObjectivesThe aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection.Methods14 patients with...

Synthesis and the Biological Evaluation of Arylnaphthalene Lignans as Anti‐hepatitis B Virus Agents

We have previously shown that helioxanthin can suppress human hepatitis B virus gene expression. A series of helioxanthin analogues were synthesized and evaluated for their anti‐hepatitis B virus activity. Modifications at the lactone rings and methylenedioxy unit of helioxanthin can modulate the antiviral activity. Among them, compound 32 is the most effective anti‐HBV agent. Compound 32 can suppress the secretion of viral surface antigen and e antigen in HepA2 cells with EC50 values of 0.06 and 0.14 μM, respectively. Compound 32 not only inhibited HBV DNA with wild‐type and lamivudine‐resistant strain but also suppressed HBV mRNA, core protein and viral promoters. In this study, a full account of the preparation, structure‐activity relationships of helioxanthin analogues, and the possible mechanism of anti‐HBV activity of this class of compounds are presented. This type of compounds possesses unique mode of action differing from existing therapeutic drugs. They are potentially new anti‐HBV agents.

Hepatitis B resistance in Iran.

Emerging new medications in the treatment of HBV produces hope and promises for curing of HBV. Over the past decade, the development of oral nucleoside/nucleotide analogs (NAs) with favorable potencies and tolerabilities has led to substantial advances in chronic hepatitis B (CHB) therapy. The oral anti-HBV agents currently approved are lamivudine, adefovir dipivoxil , entecavir , telbivudine, clevudine, and tenofovir. Treatment algorithms have been developed to assist in identification of suitable candidates for treatment and to determine and initiate appropriate treatment . In this review the problem of drug resistance in the course of chronic hepatitis B treatment are discussed in detail from both aspects of clinical and genetics.

Application of hepatitis B virus replication mouse model

To evaluate the value of the hepatitis B virus (HBV) replication mouse model with regard to several aspects of the study of HBV biology. To evaluate the HBV replication mouse model in detecting the efficacy of anti-HBV agents, the interferon inducer polyinosinic-polytidylin acid (polyIC) and nucleotide analogues adefovir and entecavir were administered to mice injected with wild type pHBV4.1, and the inhibiting effect of these agents on HBV DNA replication was evaluated. To identify the model's value in a replication ability study of HBV drug-resistant mutants and a HBx-minus mutant, telbivudine resistance mutants (rtM204I, ayw subtype), adefovir resistance mutants (rtA181V + rtN236T, ayw subtype) and HBx-minus mutants were injected respectively, and their corresponding HBV DNA replication intermediates in mouse liver were assessed. Compared with the wild type HBV replication mouse model without antiviral agent treatment, the HBV DNA replication intermediates of the polyIC-treated group were decreased 1-fold; while in the entecavir- and adefovir-treated groups, the levels of HBV DNA replication intermediates were inhibited 13.6-fold and 1.4-fold, respectively. For the mouse models injected with telbivudine resistance mutant, adefovir resistance mutant and HBx-minus mutant, HBV DNA replication intermediates could still be detected, but the levels of HBV DNA replication intermediates of these mutants decreased 4.5-fold, 5.6-fold and 2.9-fold respectively, compared with the mouse model with wild type HBV plasmid. The HBV replication mouse model we established was a useful and convenient tool to detect the efficacy of antiviral agents and to study the replication ability of HBV mutants in vivo.

Synthesis and the biological evaluation of arylnaphthalene lignans as anti-hepatitis B virus agents

We have previously shown that helioxanthin can suppress human hepatitis B virus gene expression. A series of helioxanthin analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Modifications at the lactone rings and methylenedioxy unit of helioxanthin can modulate the antiviral activity. Among them, compound 32 is the most effective anti-HBV agent. Compound 32 can suppress the secretion of viral surface antigen and e antigen in HepA2 cells with EC 50 values of 0.06 and 0.14 μM, respectively. Compound 32 not only inhibited HBV DNA with wild-type and lamivudine-resistant strain but also suppressed HBV mRNA, core protein and viral promoters. In this study, a full account of the preparation, structure–activity relationships of helioxanthin analogues, and the possible mechanism of anti-HBV activity of this class of compounds are presented. This type of compounds possesses unique mode of action differing from existing therapeutic drugs. They are potentially new anti-HBV agents.

Evaluation of genotoxicity of Yanhuanglian dehydrocavidine (YHL-DC) in vitro and in vivo

It is reported that dehydrocavidine (DC), the main component of a traditional Chinese medicine, Yanhuanglian (YHL), can protect hepatic tissue against HBV and HAV impairment. As part of a safety evaluation on YHL-DC for use in the treatment of HBV, the present study evaluated the potential genotoxicity of YHL-DC by using the standard battery of tests (i.e., bacterial reverse mutation, chromosomal aberrations, and mouse micronucleus assays) recommended by the State Food and Drug Administration of China. The results showed that YHL-DC was not genotoxic under the conditions of the reverse mutation, chromosomal aberrations, and mouse micronucleus assay conditions. The anticipated clinical dose should be smaller than the doses used in the genotoxicity assays. With confirmation from further toxicity studies, YHL-DC would hopefully prove to be a useful anti-HBV agent.

2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1 H)-one derivatives as anti-HBV agents targeting at capsid assembly

A series of novel 2,4-diaryl-4,6,7,8-tetrahydroquinazolin-5(1 H)-one derivatives were designed and synthesized as potent inhibitors of HBV capsid assembly. These compounds arose from efforts to rigidify an earlier series of heteroaryldihydropyrimidines (HAPs), and compounds 12, 13, 20, 24, 30 and 32 showed potent inhibition of HBV capsid assembly, especially 24 with IC 50 value at sub-micromolar range.

Results of up to 2 years of entecavir vs lamivudine therapy in nucleoside‐naïve HBeAg‐positive patients with chronic hepatitis B

Entecavir is a potent inhibitor of hepatitis B virus (HBV) polymerase. The efficacy and safety of entecavir in nucleoside-naïve patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B was established in a large, international, double-dummy study (ETV-022) where patients were randomized to entecavir 0.5 mg/day (n = 354) or lamivudine 100 mg/day (n = 355) once daily. ETV-022 had a 52-week blinded treatment phase, followed by an extended blinded treatment phase for up to 44 additional weeks (96 weeks total). Treatment was discontinued for patients achieving a protocol-defined response as determined by patient management criteria that intended to test the possibility of finite therapy, which has not previously been studied for entecavir or other anti-HBV agents in a large trial. Early results from this study have been previously presented/published separately. This paper compiles the results of up to 2 years of treatment for protocol-defined responders, virologic responders and nonresponders. For responders who discontinued therapy (per protocol), 24-week off-treatment evaluation is presented to provide a more 'complete picture' of what clinicians can expect when treating nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. For patients who discontinued therapy because of nonresponse (nonresponders) and subsequently entered the rollover study ETV-901, follow-up results, including resistance profile, are provided.

Anti-HBV agents. Part 3: Preliminary structure–activity relationships of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors

Thirty-two tetra-acylated derivatives of alisol A were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in vitro. Among the series of alisol A derivatives examined, five analogues were active against HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion in HepG 2.2.15 cells. These results also provide interesting structure–activity relationships of tetra-acylalisol A derivatives. Compounds tetra-acetyl alisol A ( A1), tetra-methoxyacetyl alisol A ( A23), and tetra-ethoxyacetyl alisol A ( A24) exhibited high activities against secretion of HBsAg with IC 50 values of 0.0048, 0.0044, and 0.014 mM, respectively, HBeAg with IC 50 values of 0.011, 0.012, and 0.018 mM, respectively, and remarkable selective index values SI HBsAg >333, SI HBeAg >145; SI HBsAg = 209, SI HBeAg = 77; and SI HBsAg >200, SI HBeAg >156, respectively. Additional studies in rats showed that compound A1 has favorable pharmacokinetic prosperities for further development purpose, with elimination half-time ( t 1/2) of 1.63 h and oral bioavailability ( F) of 40.9%.

HBIg Discontinuation with Maintenance Oral Anti-viral Therapy and HBV Vaccination in Liver Transplant Recipients

Hepatitis B (HBV) is an uncommon indication for liver transplantation in the US accounting for approximately 5% of cases. Recurrence prophylaxis is typically long-term hepatitis B immune-globulin (HBIg) and an oral anti-HBV agent. Because of high HBIg costs and improving efficacy of new oral agents, there is increasing interest in HBIg discontinuation. To describe results of a protocol at our center including HBV vaccination and HBIg discontinuation. All patients received HBIg therapy and an oral anti-viral agent from the time of transplant. Patients transplanted for HBV with a stable post-operative clinical course underwent HBV vaccination and HBIg discontinuation. After HBIg discontinuation, patients were monitored for HBV recurrence for at least one year. Recurrence was defined as either viral (HBV-DNA 10(4) copies/ml on two consecutive occasions) or hepatitis (viral recurrence with elevated liver transaminases). Of 1182 recipients, 36 (3%) had HBV. Twenty-four were excluded from the protocol, and the remaining 12 patients underwent HBIg withdrawal. Median age at HBIg discontinuation was 56 (range, 36-70) years, median time from transplant to HBIg discontinuation was 62.8 (range, 27.5-128) months, and median time of follow-up after discontinuation was 27.4 (range, 13-69) months. Of the 12 patients vaccinated, no patients maintained HBSAb >or= 10 IU/l at last follow-up. There was no viral or hepatitis recurrence and no deaths or graft loss. HBIg discontinuation with maintenance oral anti-viral monotherapy is safe and effective for HBV liver transplant recipients. Vaccination is not effective in this population.

Tenofovir for the Treatment of Hepatitis B Virus

Tenofovir disoproxil fumarate is a nucleotide analog reverse transcriptase inhibitor recently approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B virus (HBV) infection in adults. Tenofovir has been available in the United States for the treatment of human immunodeficiency virus (HIV) since 2001. It blocks HBV replication in liver cells and is available as a once-daily oral formulation. The efficacy of tenofovir for the treatment of chronic HBV has been demonstrated to be superior to adefovir in randomized controlled trials, which led to its FDA approval for use in chronic HBV. Because of its potent antiviral activity, favorable safety profile, and higher barrier to the development of resistance, tenofovir should replace adefovir as a first-line monotherapy option in the treatment of HBV in monoinfected patients. In the HIV-HBV-coinfected population, tenofovir is already a preferred agent in combination with other anti-HBV agents (lamivudine or emtricitabine), which are cotreatments for HIV as well. In addition, tenofovir monotherapy or in combination with nucleoside analogs are options for patients who have developed resistance to other therapies for chronic HBV, including lamivudine and adefovir.

Current management of hepatitis B virus infection before and after liver transplantation

The progress in treatment against hepatitis B virus (HBV) has substantially improved the outcome of all HBV-infected patients. We systematically reviewed the existing data in the management of HBV transplant patients in order to assess the optimal regimen in the pretransplant setting, for post-transplant prophylaxis and for therapy of HBV recurrent infection. All data suggest that an effective pretransplant anti-HBV therapy prevents post-transplant HBV recurrence. Pretransplant therapy has been based on lamivudine with addition of adefovir upon lamivudine resistance, but the use of newer, potent high-genetic barrier agents is expected to improve long-term efficacy. Moreover, it may lead to improvement of liver function, which sometimes removes the need for transplantation, although more objective criteria for removal from waiting lists are required. After liver transplantation, the combination of HBV immunoglobulin and one nucleos(t)ide analogue, mostly lamivudine, is currently the best approach, almost eliminating the probability of HBV recurrence. Treatment of post-transplant HBV recurrence has been mainly studied with lamivudine, but it will be most effective with entecavir and tenofovir, which have a low risk of resistance. In conclusion, the newer anti-HBV agents improve the treatment of HBV both pretransplant and post-transplant. HBV immunoglobulin is still used in combination with an anti-HBV agent for post-transplant prophylaxis. Monoprophylaxis with one of the new anti-HBV agents might be possible, particularly in patients preselected as having a low risk of HBV recurrence, but further data are needed and strategies to ensure compliance must be used.