ABSTRACT
This letter to the editor relates to the study entitled "Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study", which was recently published by Peng et al. Hepatitis B virus infection represents a significant health burden worldwide and can lead to cirrhosis and even liver cancer. The antiviral drugs currently used to treat patients with chronic hepatitis B infection still have many side effects, so it is crucial to identify safe and effective drugs to inhibit viral replication.
Subject(s)
Antiviral Agents , Hepatitis B virus , Hepatitis B, Chronic , Tenofovir , Humans , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Tenofovir/therapeutic use , Tenofovir/analogs & derivatives , Tenofovir/adverse effects , Hepatitis B virus/drug effects , Treatment Outcome , Virus Replication/drug effects , Adenine/analogs & derivatives , Adenine/therapeutic use , Adenine/adverse effects , Alanine/analogs & derivatives , Alanine/therapeutic use , Alanine/adverse effectsABSTRACT
Background: About 20% of on-treatment patients with chronic hepatitis B (CHB) experienced low-level viraemia (LLV), which is associated with persistent low-grade inflammation, fibrosis progression, and increased risk of hepatocellular carcinoma. We aimed to investigate the high-risk factors related to LLV. Methods: In this retrospective study, patients receiving entecavir (ETV) treatment from January 2018 to January 2023 were enrolled, and were divided into a LLV (HBV DNA 20-2000 IU/mL) cohort and a complete virological response (CVR) (HBV DNA < 20 IU/mL) cohort according to the virological response at week 48 posttreatment. Treatment baseline characteristics were retrieved from electronic medical records. Multivariate logistic regression was performed. Results: Totally, 1653 patients were enrolled, male patients accounted for 73.0%; the median age was 44 years; the mean HBV DNA level was 5.9 Log10 IU/ml. Among them, 472 (28.6%) experienced LLV. Multivariate analysis showed that HBeAg positivity (OR = 2.650, 95% CI: 2.000-3.511, p < 0.001), HBV DNA ≥ 6.0 Log10 IU/mL (OR = 1.370, 95% CI: 1.054-1.780, p = 0.019), qHBsAg ≥ 9000 IU/mL (OR = 4.472, 95% CI: 3.410-5.866, p < 0.001), cirrhosis (OR = 1.650, 95% CI: 1.234-2.207, P = 0.001), LSM ≥ 13.0 kPa (OR = 1.644, 95% CI: 1.203-2.246, p = 0.002), and PLT < 100×109/L (OR = 1.450, 95% CI: 1.094-1.922, p = 0.010) at baseline were related to the development of LLV. Conclusions: High HBV DNA/HBsAg quantification/LSM, low PLT, HBeAg positivity, and liver cirrhosis were high-risk factors associated with LLV in patients receiving entecavir treatment.
Subject(s)
Antiviral Agents , DNA, Viral , Guanine , Hepatitis B virus , Hepatitis B, Chronic , Viremia , Humans , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/complications , Male , Guanine/analogs & derivatives , Guanine/therapeutic use , Female , Adult , Risk Factors , Antiviral Agents/therapeutic use , Retrospective Studies , Middle Aged , Hepatitis B virus/genetics , Hepatitis B virus/drug effects , DNA, Viral/blood , Hepatitis B e Antigens/blood , Liver Cirrhosis/virology , Viral Load/drug effectsABSTRACT
Hepatitis B virus (HBV) infection poses a considerable public health challenge in limited-resource settings especially in the sub-Saharan African region. Even though HBV infection is incurable, timely treatment is effective in preventing disease progression to liver cirrhosis or hepatocellular carcinoma. However, not all infected patients require treatment. The aim of the study was to determine the clinical, immunological, and virological profiles of treatment naïve patients with HBV infection, seen at the outpatient clinic of the Cape Coast Teaching Hospital. Additionally, the study sought to determine the antiviral treatment eligibility rate based on the 2015 guidelines of the World Health Organization (WHO) compared with the new 2024 guidelines. A hospital-based cross-sectional study involving total sampling of 220 treatment naïve HBV surface antigen positive clients was carried out. A structured questionnaire was used to collect data that were analyzed with STATA version 16. The median age at diagnosis was 34 years (IQR 26.0-41.5) with a male to female ratio of 1:1.5. A total of 138 participants (62.7%) were diagnosed with HBV infection following voluntary testing. There was a median delay of 8.5 months (IQR 3.0-22.5) between initial diagnosis and patients' presentation for medical care. In all, 24 patients (10.9%) had abnormal clinical examination findings, 172 patients (78.2%) had HBV DNA levels ≤ 2000 IU/ml whereas 8 (3.6%) were seropositive for the HBV envelope antigen. A few patients had concomitant human immunodeficiency virus (2.7%) and hepatitis C virus (1.4%) infections. Treatment eligibility rate based on the WHO 2015 guidelines was 6.4% (n = 14), however, with the updated 2024 guidelines, treatment eligibility was 42.3% (n = 93). Increasing the screening rate among the general population, early linkage to clinical care of screen positives and vaccination of screen negatives will help reduce HBV-related clinical conditions in resource-limited settings.
Subject(s)
Antiviral Agents , Hepatitis B , Hospitals, Teaching , Humans , Male , Female , Adult , Antiviral Agents/therapeutic use , Hepatitis B/drug therapy , Hepatitis B/prevention & control , Hepatitis B/diagnosis , Hepatitis B/epidemiology , Ghana/epidemiology , Cross-Sectional Studies , Hepatitis B virus/isolation & purification , Hepatitis B virus/drug effects , Middle AgedABSTRACT
BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.
Subject(s)
Antiviral Agents , Drug Therapy, Combination , Hepatitis B, Chronic , Interferon-alpha , Polyethylene Glycols , Recombinant Proteins , Tenofovir , Humans , Tenofovir/therapeutic use , Tenofovir/administration & dosage , Tenofovir/analogs & derivatives , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Male , Female , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/administration & dosage , Child , Recombinant Proteins/therapeutic use , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Polyethylene Glycols/therapeutic use , Polyethylene Glycols/adverse effects , Polyethylene Glycols/administration & dosage , Interferon-alpha/therapeutic use , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Child, Preschool , Treatment Outcome , Interferon alpha-2/therapeutic use , Interferon alpha-2/administration & dosage , Hepatitis B Surface Antigens/blood , Hepatitis B e Antigens/blood , Hepatitis B virus/genetics , Hepatitis B virus/drug effects , DNA, Viral/blood , Alanine/therapeutic use , Alanine/analogs & derivativesABSTRACT
BACKGROUND: Hepatitis B virus (HBV) infection is still a serious threat to global health and can lead to a variety of liver diseases, including acute and chronic hepatitis, liver cirrhosis, liver failure, hepatocellular carcinoma (HCC), and so on. At present, there are mainly two kinds of drugs for the treatment of hepatitis B at home and abroad: interferon (IFN) and nucleoside/nucleotide analogs (NAs). In recent years, natural compounds have been considered an important source for the development of new anti-HBV drugs due to their complex structure, diverse components, high efficiency, and low toxicity. Many studies have demonstrated that Solamargine has significant anticancer activity, but the antiviral effect is rarely studied. This study aimed to verify the anti-HBV effect of Solamargine and to explore the specific mechanism. METHOD: The relative expression of HBV pregenomic RNA (pgRNA) was detected by reverse transcription real-time fluorescence quantitative PCR (RT-qPCR). Northern blot and western blot were used to detect the relative expression of HBV pgRNA and target protein. PCR was used in the construction of HBV pg-promoter, ENII/BCP, and a series of gene deletion mutant fluorescent reporter vectors. The fluorescence relative expression of each mutant was detected by Renilla luciferase assay. RESULTS: By binding to MZF1 (Myeloid zinc finger protein 1, MZF1), Solamargine inhibits HBV core promoter activity, reduces pregenomic RNA level, and inhibits HBV, achieving antiviral effects.
Subject(s)
Antiviral Agents , Hepatitis B virus , Promoter Regions, Genetic , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Humans , Antiviral Agents/pharmacology , Hep G2 Cells , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Virus Replication/drug effects , Hepatitis B/drug therapy , Hepatitis B/virologyABSTRACT
Background and aims: Limited data have been reported on achieving functional cure using pegylated interferon (Peg-IFN) alpha-2b treatment for postpartum hepatitis B e antigen (HBeAg)-negative women with chronic hepatitis B virus (HBV) infection. This study was to assess the effectiveness and safety of Peg-IFN alpha-2b in HBV postpartum women without HBeAg and identify factors linked to the functional cure. Methods: A total of 150 HBeAg-negative postpartum women were retrospectively recruited.47 patients received Peg-IFN alpha-2b [Peg-IFN(+) group] and 103 patients did not [Peg-IFN(-) group]. Propensity score matching (PSM) was used to adjust the baseline imbalance between the two groups. The patients were followed for at least 48 weeks. The primary endpoints were hepatitis B surface antigen(HBsAg) loss and HBsAg seroconversion at 48 weeks. Logistic regression analysis was used to assess factors associated with HBsAg loss at 48 weeks. Results: At week 48,the HBsAg loss and seroconversion rate in Peg-IFN(+) group were 51.06%(24/47) and 40.43%(19/47), respectively. Even after PSM, Peg-IFN(+) group still showed higher HBsAg loss rate (50.00% vs 7.14%,p<0.001) and higher HBsAg seroconversion rate (38.10% vs 2.38%,p<0.001). Baseline HBsAg levels (Odds Ratio [OR]: 0.051, 95% Confidence Interval [CI]: 0.003-0.273, P=0.010), HBsAg at week 24 (OR:0.214, 95%CI:0.033-0.616, P=0.022), HBsAg decline at week 24 (OR:4.682, 95%CI: 1.624-30.198, P=0.022) and postpartum flare (OR:21.181, 95%CI:1.872-633.801, P=0.030) were significantly associated with HBsAg loss at week 48 after Peg-IFN alpha-2b therapy. Furthermore, the receiver operating characteristic curve (ROC) showed that the use of baseline HBsAg<182 IU/mL, HBsAg at week24 < 4 IU/mL and HBsAg decline at week24>12IU/mL were good predictors of HBsAg loss. No serious adverse events were reported. Conclusion: Peg-IFN alpha-2b treatment could achieve a high rate of HBsAg loss and seroconversion in HBeAg-negative postpartum women with reliable safety, particularly for patients experience postpartum flare and have low baseline HBsAg levels.
Subject(s)
Antiviral Agents , Hepatitis B Surface Antigens , Hepatitis B e Antigens , Hepatitis B, Chronic , Interferon alpha-2 , Interferon-alpha , Polyethylene Glycols , Postpartum Period , Recombinant Proteins , Humans , Female , Hepatitis B, Chronic/drug therapy , Polyethylene Glycols/therapeutic use , Recombinant Proteins/therapeutic use , Adult , Hepatitis B e Antigens/blood , Antiviral Agents/therapeutic use , Interferon-alpha/therapeutic use , Retrospective Studies , Interferon alpha-2/therapeutic use , Hepatitis B Surface Antigens/blood , Treatment Outcome , Hepatitis B virus/immunology , Hepatitis B virus/drug effects , Young Adult , SeroconversionABSTRACT
Hepatitis B surface antigen (HBsAg) is not only the biomarker of hepatitis B virus (HBV) infection and expression activity in hepatocytes, but it also contributes to viral specific T cell exhaustion and HBV persistent infection. Therefore, anti-HBV therapies targeting HBsAg to achieve HBsAg loss are key approaches for an HBV functional cure. In this study, we found that YZH-106, a rupestonic acid derivative, inhibited HBsAg secretion and viral replication. Further investigation demonstrated that YZH-106 promoted the lysosomal degradation of viral L- and M-HBs proteins. A mechanistic study using Biacore and docking analysis revealed that YZH-106 bound directly to the PreS2 domain of L- and M-HBsAg, thereby blocking their entry into the endoplasmic reticulum (ER) and promoting their degradation in cytoplasm. Our work thereby provides the basis for the design of a novel compound therapy to target HBsAg against HBV infection.
Subject(s)
Hepatitis B Surface Antigens , Hepatitis B virus , Lysosomes , Virus Replication , Humans , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Hepatitis B Surface Antigens/metabolism , Lysosomes/metabolism , Virus Replication/drug effects , Hepatitis B/virology , Hepatitis B/drug therapy , Antiviral Agents/pharmacology , Proteolysis , Hep G2 Cells , Hepatocytes/virology , Hepatocytes/metabolism , Molecular Docking Simulation , Protein Binding , Protein PrecursorsABSTRACT
This editorial commented on an article in the World Journal of Gastroenterology titled "Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis" by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.
Subject(s)
Antiviral Agents , Hepatitis B virus , Neoplasms , Protein Kinase Inhibitors , Virus Activation , Humans , Virus Activation/drug effects , Hepatitis B virus/drug effects , Hepatitis B virus/immunology , Hepatitis B virus/isolation & purification , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Neoplasms/drug therapy , Hepatitis B/diagnosis , Hepatitis B/virology , Hepatitis B/drug therapy , Risk Factors , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Hepatitis B Surface Antigens/bloodABSTRACT
Optimising treatment outcomes for people living with hepatitis B virus (HBV) is key to advancing progress towards international targets for the elimination of viral hepatitis as a public health threat. Nucleos/tide analogue agents (most commonly tenofovir or entecavir) are well-tolerated and suppress viraemia effectively in the majority of those who are offered therapy. However, outcomes are not consistent, and we explore the factors that may contribute to incomplete therapeutic responses. We discuss situations in which therapy is not accessible, affordable or acceptable, reflecting the impact of social, cultural and economic barriers, stigma and discrimination, low awareness, poor access to health systems and comorbidity. These challenges are amplified in certain vulnerable populations, increasing the risk of adverse outcomes-which include liver cirrhosis and hepatocellular carcinoma-among people who already experience marginalisation and health inequities. We also tackle the physiological and biological mechanisms for incomplete virological suppression in individuals receiving HBV treatment, considering the possible impact of inadequate tissue drug levels, poor drug-target avidity and genomic resistance. These factors are interdependent, leading to a complex landscape in which socioeconomic challenges increase the challenge of consistent daily therapy and set the scene for selection of drug resistance. By putting a spotlight on this neglected topic, we aim to raise awareness, prompt dialogue, inform research and advocate for enhanced interventions. As criteria for HBV treatment eligibility relax, the population receiving therapy will expand, and there is a pressing need to optimise outcomes and close the equity gap.
Subject(s)
Antiviral Agents , Hepatitis B virus , Tenofovir , Humans , Antiviral Agents/therapeutic use , Drug Resistance, Viral , Guanine/analogs & derivatives , Guanine/therapeutic use , Health Services Accessibility , Hepatitis B/drug therapy , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Tenofovir/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: The efficacy of different nucleos(t)ide analogs in the treatment of chronic hepatitis B virus (CHB) with severe acute exacerbation (SAE) remained unclear. Thus, this study aimed to compare the short-term efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients having CHB with SAE. METHODS: We analyzed consecutive patients with treatment-naive CHB receiving TDF (nâ =â 36) or ETV (nâ =â 65) for SAE. The primary endpoint was overall mortality or receipt of liver transplantation (LT) by 24 weeks. The secondary endpoints are the comparison of ETV vs. TDF influences on renal function and virological and biochemical responses at 4, 12, 24, and 48 weeks. RESULTS: The baseline characteristics were comparable between the two groups. By 24 weeks, 8 (22%) patients in the TDF group and 10 (15%) patients in the ETV group had either died (nâ =â 15) or received LT (nâ =â 3) ( P â =â 0.367). Cox-regression multivariate analysis revealed age ( P â =â 0.003), baseline international normalized ratio of prothrombin time ( Pâ =â 0.024), and early presence of hepatic encephalopathy ( P â =â 0.003) as independent factors associated with mortality or LT. The two groups of patients achieved comparable biochemical and virological responses at 48 weeks. No significant difference was found in the estimated glomerular filtration rate (eGFR) between the TDF and the ETV groups. However, a significant reduction in the eGFR at 48 weeks, as compared with the baseline, was found in each group. CONCLUSION: TDF and ETV achieved similar short-term clinical outcomes and treatment responses in CHB patients with SAE.
Subject(s)
Antiviral Agents , Guanine , Hepatitis B, Chronic , Tenofovir , Humans , Guanine/analogs & derivatives , Guanine/therapeutic use , Guanine/adverse effects , Female , Male , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/mortality , Tenofovir/therapeutic use , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Middle Aged , Adult , Treatment Outcome , Liver Transplantation , Retrospective Studies , Disease Progression , Severity of Illness Index , Glomerular Filtration Rate/drug effects , DNA, Viral/blood , Viral Load , Time Factors , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Proportional Hazards ModelsABSTRACT
High levels of hepatitis B virus (HBV) surface antigen (HBsAg) in the blood of chronic HBV carriers are considered to drive the exhaustion of antigen-specific T and B lymphocytes and thus responsible for the persistence of infection. Accordingly, therapeutic elimination of HBsAg may facilitate the activation of adaptive antiviral immune responses against HBV and achieve a functional cure of chronic hepatitis B. We discovered recently that an amphipathic alpha helix spanning W156 to R169 of HBV small envelope (S) protein plays an essential role in the morphogenesis of subviral particles (SVPs) and metabolism of S protein. We thus hypothesized that pharmacological disruption of SVP morphogenesis may induce intracellular degradation of S protein and reduce HBsAg secretion. To identify inhibitors of SVP biogenesis, we screened 4417 bioactive compounds with a HepG2-derived cell line expressing HBV S protein and efficiently secreting small spherical SVPs. The screen identified 24 compounds that reduced intracellular SVPs and secreted HBsAg in a concentration-dependent manner. However, 18 of those compounds inhibited the secretion of HBsAg and HBeAg in HBV replicon transfected HepG2 cells at similar efficiency, suggesting each of those compounds may disrupt a common cellular function required for the synthesis and/or secretion of these viral proteins. Interestingly, lycorine more efficiently inhibited the secretion of HBsAg in HepG2 cells transfected with HBV replicons, HepG2.2.15 cells and HBV infected - HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). The structure activity relationship and antiviral mechanism of lycorine against HBV have been determined.
Subject(s)
Antiviral Agents , Hepatitis B Surface Antigens , Hepatitis B virus , Humans , Hepatitis B virus/drug effects , Antiviral Agents/pharmacology , Hepatitis B Surface Antigens/metabolism , Hep G2 Cells , Virus Assembly/drug effects , Virion/drug effects , Drug Discovery , Virus Replication/drug effects , Small Molecule Libraries/pharmacology , Viral Envelope Proteins/metabolism , Hepatitis B e Antigens/metabolismABSTRACT
In this editorial, we discussed the apparent discrepancy between the findings described by Colapietro et al, in their case report and data found in the literature. Colapietro et al reported a case of hepatitis B virus (HBV)-related hepatic decompensation in a patient with chronic myeloid leukemia and a previously resolved HBV infection who was receiving Bruton's tyrosine kinase (BTK) inhibitor therapy. First of all, we recapitulated the main aspects of the immune system involved in the response to HBV infection in order to underline the role of the innate and adaptive response, focusing our attention on the protective role of anti-HBs. We then carefully analyzed literature data on the risk of HBV reactivation (HBVr) in patients with previous HBV infection who were treated with either tyrosine kinase inhibitors or BTK inhibitors for their hematologic malignancies. Based on literature data, we suggested that several factors may contribute to the different risks of HBVr: The type of hematologic malignancy; the type of therapy (BTK inhibitors, especially second-generation, seem to be at a higher risk of HBVr than those with tyrosine kinase inhibitors); previous exposure to an anti-CD20 as first-line therapy; and ethnicity and HBV genotype. Therefore, the warning regarding HBVr in the specific setting of patients with hematologic malignancies requires further investigation.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Hematologic Neoplasms , Hepatitis B virus , Protein Kinase Inhibitors , Virus Activation , Humans , Virus Activation/drug effects , Virus Activation/immunology , Hepatitis B virus/drug effects , Hepatitis B virus/immunology , Hepatitis B virus/pathogenicity , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Hematologic Neoplasms/immunology , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/virology , Hepatitis B/virology , Hepatitis B/diagnosis , Hepatitis B/drug therapy , Hepatitis B/immunology , Risk Factors , Antiviral Agents/therapeutic use , Hepatitis B Antibodies/blood , Hepatitis B Antibodies/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/virology , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic useABSTRACT
Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B virus , Liver Neoplasms , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Reactive Oxygen Species , Signal Transduction , Sorafenib , Superoxide Dismutase-1 , TOR Serine-Threonine Kinases , Sorafenib/pharmacology , Sorafenib/therapeutic use , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/virology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/virology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Reactive Oxygen Species/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Superoxide Dismutase-1/metabolism , Superoxide Dismutase-1/genetics , Animals , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/drug effects , Mice , Hepatitis B virus/drug effects , Cell Line, Tumor , Xenograft Model Antitumor Assays , Apoptosis/drug effects , Hepatitis B/complications , Hepatitis B/drug therapy , Hepatitis B/virology , Ditiocarb/pharmacology , Drug Resistance, Neoplasm/drug effects , Mice, Nude , Cell Proliferation/drug effects , Trans-Activators , Viral Regulatory and Accessory ProteinsABSTRACT
BACKGROUND: HBV infects ~257 million people and can cause hepatocellular carcinoma. Since current drugs are not curative, novel therapies are needed. HBV infects chimpanzee and human livers. However, chimpanzee studies are severely restricted and cost-prohibitive, while transgenic/chimeric mouse models that circumvent the species barrier lack natural HBV infection and disease progression. Thus, in vitro human models of HBV infection are useful in addressing the above limitations. Induced pluripotent stem cell-derived hepatocyte-like cells mitigate the supply limitations of primary human hepatocytes and the abnormal proliferation/functions of hepatoma cell lines. However, variable infection across donors, deficient drug metabolism capacity, and/or low throughput limit iHep utility for drug development. METHODS: We developed an optimal pipeline using combinations of small molecules, Janus kinase inhibitor, and 3',5'-cAMP to infect iHep-containing micropatterned co-cultures (iMPCC) with stromal fibroblasts within 96-well plates with serum-derived HBV and cell culture-derived HBV (cHBV). Polyethylene glycol was necessary for cell-derived HBV but not for serum-derived HBV infection. RESULTS: Unlike iHep monocultures, iMPCCs created from 3 iHep donors could sustain HBV infection for 2+ weeks. Infected iMPCCs maintained high levels of differentiated functions, including drug metabolism capacity. HBV antigen secretion and gene expression patterns in infected iMPCCs in pathways such as fatty acid metabolism and cholesterol biosynthesis were comparable to primary human hepatocyte-MPCCs. Furthermore, iMPCCs could help elucidate the effects of interferons and direct-acting antiviral drugs on the HBV lifecycle and any hepatotoxicity; iMPCC response to compounds was similar to primary human hepatocyte-MPCCs. CONCLUSIONS: The iMPCC platform can enable the development of safe and efficacious drugs against HBV and ultimately help elucidate genotype-phenotype relationships in HBV pathogenesis.
Subject(s)
Hepatitis B virus , Hepatocytes , Induced Pluripotent Stem Cells , Humans , Hepatocytes/virology , Induced Pluripotent Stem Cells/virology , Induced Pluripotent Stem Cells/metabolism , Hepatitis B virus/genetics , Hepatitis B virus/physiology , Hepatitis B virus/drug effects , Hepatitis B/virology , Hepatitis B/drug therapy , Coculture Techniques , Janus Kinase Inhibitors/pharmacology , Antiviral Agents/pharmacology , Cells, CulturedABSTRACT
Chronic hepatitis B virus (HBV) infection is due to the failure of host immune system to resolve the viral infection. Accordingly, restoration or reconstitution of a functional antiviral immune response to HBV is essential to achieve durable control of HBV replication leading to a functional cure of chronic hepatitis B (CHB). Noninfectious subviral particles (SVPs), comprised of HBV surface antigen (HBsAg), are the predominant viral products secreted by HBV-infected hepatocytes. The high levels of SVPs in the circulation induce immune tolerance and contribute to the establishment of chronic HBV infection. The current standard-of-care medications for CHB efficiently suppress HBV replication but fail to reduce the levels of HBsAg in majority of treated patients. Further understanding the mechanisms underlying SVP morphogenesis, secretion and regulation by viral and host cellular factors are critical for the discovery of therapeutics that can inhibit SVP production and/or induce the degradation of HBV envelope proteins. We describe herein a protocol for intracellular SVP detection by a native agarose gel electrophoresis-based particle gel assy. The method is suitable for quantitative detection of intracellular HBV SVPs and can be applied in dissecting the molecular mechanism of SVP morphogenesis and the discovery of antiviral agents targeting SVP formation in hepatocytes.
Subject(s)
Hepatitis B virus , Virion , Hepatitis B virus/physiology , Hepatitis B virus/drug effects , Humans , Hepatocytes/virology , Hepatocytes/metabolism , Hepatitis B Surface Antigens/metabolism , Virus Replication/drug effects , Electrophoresis, Agar Gel/methods , Cells, Cultured , Hepatitis B, Chronic/virology , Hepatitis B, Chronic/drug therapyABSTRACT
While certain human hepatitis B virus-targeting nucleoside analogs (NAs) serve as crucial anti-HBV drugs, HBV yet remains to be a major global health threat. E-CFCP is a 4'-modified and fluoromethylenated NA that exhibits potent antiviral activity against both wild-type and drug-resistant HBVs but less potent against human immunodeficiency virus type-1 (HIV-1). Here, we show that HIV-1 with HBV-associated amino acid substitutions introduced into the RT's dNTP-binding site (N-site) is highly susceptible to E-CFCP. We determined the X-ray structures of HBV-associated HIV-1 RT mutants complexed with DNA:E-CFCP-triphosphate (E-CFCP-TP). The structures revealed that exocyclic fluoromethylene pushes the Met184 sidechain backward, and the resultant enlarged hydrophobic pocket accommodates both the fluoromethylene and 4'-cyano moiety of E-CFCP. Structural comparison with the DNA:dGTP/entecavir-triphosphate complex also indicated that the cyclopentene moiety of the bound E-CFCP-TP is slightly skewed and deviated. This positioning partly corresponds to that of the bound dNTP observed in the HIV-1 RT mutant with drug-resistant mutations F160M/M184V, resulting in the attenuation of the structural effects of F160M/M184V substitutions. These results expand our knowledge of the interactions between NAs and the RT N-site and should help further design antiviral NAs against both HIV-1 and HBV.
Subject(s)
Antiviral Agents , Catalytic Domain , Drug Resistance, Viral , HIV-1 , Hepatitis B virus , Mutation , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Drug Resistance, Viral/genetics , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , HIV-1/drug effects , HIV-1/genetics , Nucleosides/pharmacology , Nucleosides/chemistry , Nucleosides/metabolism , HIV Reverse Transcriptase/metabolism , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Crystallography, X-Ray , RNA-Directed DNA Polymerase/metabolism , RNA-Directed DNA Polymerase/genetics , RNA-Directed DNA Polymerase/chemistry , Binding Sites , Protein Binding , Models, MolecularABSTRACT
Lappanolides A-N (1-14), 14 undescribed sesquiterpenoids, along with 23 known ones (15-37), were isolated from the roots of Saussurea costus, which were primarily categorized into eudesmane, guaiane, and germacrane types. Lappanolide A (1) possessed an unprecedented pseudo-disesquiterpenoids. Their structures and absolute configurations were established using physical data analyses (HRESIMS, IR, 1D and 2D NMR) and ECD calculations. All isolated compounds were tested for anti-hepatitis B virus (anti-HBV) activity. Ten compounds (1, 9, 11, 12, 19, 22, 28, 29, 31, and 36) exhibited activities against HBsAg secretions as determined by ELISA assay, with IC50 values ranging from 5.2 to 45.7 µM. In particular, compounds 28 and 29 showed inhibition of HBsAg secretion with IC50 values of 5.28 and 5.30 µM, and CC50 values of 9.85 and 6.37 µM, respectively, though they all exhibited low selectivity. Several compounds displayed cytotoxicity in the MTT assay. Among them, compound 28 was the most notable and was chosen for further study using flow cytometry. The result showed that it significantly induced HepG2 cell arrest in the S phase and induced apoptosis.
Subject(s)
Antiviral Agents , Hepatitis B virus , Saussurea , Sesquiterpenes , Saussurea/chemistry , Humans , Hepatitis B virus/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Hep G2 Cells , Molecular Structure , Hepatitis B Surface Antigens/metabolism , Hepatitis B Surface Antigens/drug effects , Structure-Activity Relationship , Plant Roots/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Apoptosis/drug effectsABSTRACT
INTRODUCTION: Hepatitis B virus (HBV) reactivation (HBVr) induced by chemotherapy in patients with resolved or chronic infection can lead to severe consequences. Despite recommendations, rates of HBV screening before chemotherapy are low due to poor recognition of risk factors by clinicians. The aim of the study is to assess whether routine HBV screening using universal HBV screening on chemotherapy orders (CO) could reduce HBVr incidence. METHODS: This is a 1-year retrospective single-center observational study of patients who received intravenous chemotherapy post implementation of CO. We compared the incidence of HBVr in three groups of patients: those screened through CO (group 1), those screened by the medical team (group 2), and those not screened (group 3). RESULTS: On a total of 1374 patients, 179 of 206 patients were screened as requested on CO (group 1) and 421 by the medical team (group 2), whereas 747 patients were not screened (group 3). Only one HBVr occurred, and no difference was seen on the incidence of HBVr between group 1 and group 3 (0% vs 0.1%; p = 1.00), probably because of a lack of follow-up after chemotherapy. Follow-up for HBVr was imperfect in group 1 and group 2 (16.7% vs 5.6%; p = 0.32). Screening was done for 92% of patients on anti-CD20 therapy. In group 3, 89 patients had ALT elevation during chemotherapy but only 17 (19%) were tested for HBVr. CONCLUSION: Systematic HBV detection requested on CO is an effective way to obtain a high percentage of patients with adequate screening, particularly when chemotherapy is at high risk of HBVr. Nevertheless, this screening method do not guarantee optimal follow-up and requires improvements.