Loss Of Hepatitis Research Articles

The loss of hepatitis B virus receptor NTCP/SLC10A1 in human liver cancer cells is due to epigenetic silencing.

HBV is a hepatotropic virus that infects human hepatocytes expressing the viral receptor hNTCP. Without effective antiviral therapy, chronic HBV infection poses a high risk of liver cancer. However, most liver cancer cell lines, including HepG2 and Huh7, do not support HBV infection due to the absence of hNTCP expression, and the mechanism underlying this defect remains unclear. This study demonstrates a significant reduction of hNTCP in hepatocellular carcinoma samples and HepG2 cells compared to normal liver tissues and primary human hepatocytes. Despite identical hNTCP genetic sequences, epigenetic analyses revealed a loss of the activating histone modification H3K27ac near the hNTCP transcription start site in cancer cells. Treatment with histone deacetylase inhibitors restored H3K27ac levels, reactivated hNTCP expression, and rendered HepG2 cells susceptible to HBV infection. These findings highlight the role of epigenetic modulation in hNTCP dysregulation, offering insights into hepatocarcinogenesis and its implications for chronic HBV infection.

Measuring HBV pregenomic RNA may be a potential biomarker to determine HBV functional cure in HIV/HBV-co-infected patients with HBsAg loss.

Functional cure of hepatitis B virus (HBV) is an optimal treatment goal for chronic hepatitis B, with the loss of hepatitis B surface antigen (HBsAg) being a crucial indicator. However, the adequacy of HBsAg loss for evaluating functional cure of HBV in patients co-infected with HBV/human immunodeficiency virus (HIV) remains controversial. In this study, we measured HBV pregenomic RNA (pgRNA), a potential biomarker that correlates with covalently closed circular DNA, in the frozen plasma of 98 patients with HBsAg loss from a large HIV/HBV co-infection cohort in Guangzhou, China. HBV pgRNA was still detected in 43.9% (44/98) of the patients, suggesting active HBV replication in individuals with HBsAg loss. Our observations imply that HBsAg loss may not be a reliable predictor of HBV functional cure in cases of HIV/HBV co-infection.

Perspective on Emerging Therapies to Achieve Functional Cure of Chronic Hepatitis B.

Advancements in our understanding of the hepatitis B viral (HBV) life cycle have paved the way for novel approaches to treat HBV infection. This review summarizes the various strategies being pursued to achieve a functional cure, defined as loss of hepatitis B surface antigen (HBsAg) and absence of viral replication 6 months off-therapy. Direct acting antiviral, host targeting antiviral, and immunological approaches are in various stages of development as treatment for chronic HBV infection. Novel treatments are being developed in pursuit of a cure for HBV. Current evidence suggests a single therapeutic agent alone may be insufficient, necessitating the need for combination therapy targeting HBV and the host immune response. Ongoing research focused on identifying the best therapeutic combination holds promise in achieving functional cure for HBV.

Relación entre adherencia a entecavir y efectividad en pacientes con hepatitis B crónica

Purposeto evaluate adherence of patients with chronic hepatitis B initiated on entecavir as first-line treatment and to correlate adherence with effectiveness. Methodsobservational retrospective study performed between January 2007 and June 2013. Patients treated with entecavir for at least one year were included. A patient was considered to be adherent if median adherence was > 95%. Virological response (HBV DNA < 20UI/ml by Polymerase Chain Reaction), biochemical response (normalized level of alanine amino transferase [AAT]) and serological response (loss of hepatitis B surface antigen [HBsAg]) was assessed at month 12. Results85 patients were included. The median adherence rate was 94.2 (SD 12.8)%. 85.7% of the adherent patients achieved a virological response in contrast with 71.4% of the nonadhe-rent patients (OR:2,40; IC95%:0,60-9,54;p = 0,19). 87.9% of the adherent patients and 85.7% of the nonadherent patients showed normalized level of AAT (OR:1,21; IC95%:0,22-6,60;p = 0,56). Two adherent patients showed clearance of hepatitis B surface antigen. Conclusionthe median adherence is not high. Nonadherent patients have a trend towards a higher rate of virological failure so it is necessary to promote improved adherence to treatment.

Predictors of therapeutic response to peginterferon α‑2a and nucleos(t)ide analog combination therapy for HBeAg‑negative chronic hepatitis B: 1‑year follow‑up after treatment.

Chronic hepatitis B (CHB) is a major global health concern. Guidelines for the management of hepatitis B virus (HBV) indicate that the loss of hepatitis B surface antigen (HBsAg) is a key endpoint of interest. The present study aimed to examine long-term changes in HBsAg levels in HBV-DNA-negative, hepatitis B e-antigen (HBeAg)-negative patients treated with peginterferon (Peg-IFN) α-2a and nucleos(t)ide analog (NA), and to examine the conditions that make them susceptible to HBsAg decline. A total of 17 patients with CHB treated with NA and Peg-IFN were observed for 96 weeks (48 weeks of Peg-IFN therapy and 48 weeks of post-treatment follow-up). In this study, responders were defined as those with a 50% or greater decrease in HBsAg levels from baseline at week 96. Beginning at week 16 of Peg-IFN therapy, there was a significant difference in the decrease in HBsAg levels from baseline between the responders and non-responders. In responders, HBsAg levels tended to be >60% lower 16 weeks after Peg-IFN initiation than before initiation. Age at the start of NA use and the duration of NA use before Peg-IFN treatment initiation were significant pretreatment factors associated with HBsAg response. In conclusion, Peg-IFN was revealed to be more effective in HBeAg-negative patients with CHB who started NA at a young age and have been on long-term treatment, particularly if the HBsAg levels decreased to less than 60% of the starting level at week 16 after starting Peg-IFN treatment.

Plain Language Summary of the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Infection

What is this summary about? This is a summary for the hepatitis B community providing straightforward information on the results of a study called ‘B-Clear’. Hepatitis B is an infection of the liver caused by a virus. Chronic hepatitis B is a long-lasting infection and occurs when the body is unable to fight off the virus and it persists in the blood and liver. Chronic hepatitis B virus infection is a major global health problem affecting approximately 296 million people. Current standard therapies, such as nucleotide analogs (antiviral therapy), rarely lead to a cure. This study investigated a new treatment for chronic hepatitis B virus infection, called bepirovirsen, alone or in combination with nucleotide analogs (antiviral therapy), in participants with chronic hepatitis B virus infection. The duration of treatment was 6 months. What were the results? In this study, bepirovirsen was tested to see if it could decrease the levels of hepatitis B surface antigen and viral DNA to the point where they cannot be detected anymore in the blood and whether participants would maintain undetectable levels for 6 months after the end of treatment. Six (9%) participants who were currently on nucleotide analogs (antiviral therapy) and also received bepirovirsen and 7 (10%) participants who only received bepirovirsen, achieved undetectable levels of hepatitis B surface antigen and viral DNA for 6 months after the end of treatment. What do the results mean? These results show that bepirovirsen could be an effective treatment for chronic hepatitis B virus infection. The loss of hepatitis B surface antigen seen in some participants means that bepirovirsen has the potential to reduce the risk of liver complications, such as liver failure and liver cancer and provide patients with an alternative option to lifelong treatment. Achieving undetectable levels of hepatitis B surface antigen and viral DNA may also have a positive impact on the quality of life of participants by reducing stigma and discrimination related to hepatitis B and offer relief from the hopelessness that often comes with a chronic hepatitis B virus infection diagnosis and need for lifelong therapy. Larger and longer studies are needed to confirm the results of the B-Clear study and to further evaluate how well bepirovirsen works in treating chronic hepatitis B virus infection as well as to assess its safety.

A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D

BackgroundCoinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes.MethodsIn this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group.ResultsA total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P=0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups.ConclusionsAfter 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.)

Functional Cure of Chronic Hepatitis B with Antiviral Treatment in Children having High-level Viremia and Normal or Mildly Elevated Serum Aminotransferase.

There is a lack of data supporting the notion that antiviral treatments can benefit children with chronic hepatitis B (CHB) having high viremia and normal or mildly elevated serum alanine aminotransferase (ALT) levels. We aimed to analyze the efficacy of antiviral treatments in children with CHB and explore the factors associated with functional cure. Forty-eight children with CHB having high viremia and normal or mildly elevated serum ALT levels were screened in this real-world study. Thirty-two children received either interferon-alpha (IFN-α) monotherapy, IFN-α therapy with a nucleoside analog (NA) add-on, or IFN-α and NA combination therapy. The 16 children in the control group did not receive antiviral treatment. All 48 children were available for follow-up assessments for the entire 36-month study period. We identified a functional cure with respect to hepatitis B virus (HBV) DNA loss, loss /seroconversion of circulating hepatitis B e antigen (HBeAg), and loss of hepatitis B surface antigen (HBsAg) with or without seroconversion. Cox regression analysis was employed to evaluate the factors that may have influenced the functional cure. After 36 months, the cumulative functional cure rate was 56.25% (18/32) in the treated group and 0% (0/16) in the control group (p<0.001). In the treated group, the serum HBV DNA levels declined rapidly at the end of a 6-month visit and the cured children achieved a loss rate of 100% (18/18) within 16 months of beginning treatment, compared with 64.29% (9/14) of the uncured children (p<0.001). The rates of HBeAg seroconversion were significantly higher among the cured children than among the uncured children (p<0.001). All 16 children in the control group maintained high levels of serum HBV DNA and were positive for both serum HBeAg and HBsAg during the entire 36 months of the study period. Functional cure was associated with younger ages (1-6 vs. 7-14 years, p=0.013), CD8+ T lymphocyte counts (p=0.013), and B lymphocyte counts (p=0.003). No serious adverse events were observed. Antiviral treatment achieved a functional cure of CHB in a high proportion of children having high-level viremia and normal or mildly elevated ALT levels. Younger age and high peripheral lymphocyte counts were associated with this functional cure.

Hepatitis D virus infection: Progress on the path toward disease control and cure.

This article discusses the impact of Hepatitis D virus (HDV) infection as a major cause of liver-related morbidity and mortality in people with Hepatitis B virus (HBV) infection. The article reviews the current knowledge and unanswered questions about the epidemiology, pathogenesis, and natural history of HDV infection. Although effective treatments for HDV infection have been elusive, interferon alfa is recommended for at least 48 weeks. However, response rates with standard-of-care peginterferon alfa are suboptimal, leading to few patients with a sustained virologic response. The article proposes novel approaches to treating HDV and HBV, including targeting reduction or loss of hepatitis B surface antigen (HBsAg) reduction, and discusses potential strategies for achieving HBsAg loss in patients with chronic HBV infection. Finally, the article discusses the landmark decision of accepting viral and biochemical surrogates by regulatory authorities, opening the door for the clinical development of drugs for patients with HDV infection.

A Systematic Review on Current Trends in the Treatment of Chronic Hepatitis B to Predict Disease Remission and Relapse.

Despite decreasing the prevalence of chronic hepatitis B (CHB), it is still a major health care challenge. Current antiviral regimens aim to suppress hepatitis B virus (HBV) deoxyribonucleic acid (DNA) activity to prevent the risk of hepatic decompensation, liver cirrhosis, and hepatocellular carcinoma (HCC). Currently, pegylated interferon (Peg-IFN) and nucleos(t)ide analogs (NA) are the first-line choices of drugs. Peg-IFN is now discontinued due to its mode of application and side effects. NA is used once daily to suppress HBV DNA activity but has little effect on covalently closed circular DNA (cccDNA), so continuous long-term therapy is required to suppress HBV DNA. Due to this effect, disease remission, relapse, and even clinical flare are common phenomena after the end of treatment (EOT). This review aimed to analyze the current regimens for treating chronic hepatitis B. Their mode of action, duration of treatment, and events after stopping therapy. The review was performed using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) 2020 guidelines. A search was undertaken in PubMed, PubMed Central, Google Scholar, and ScienceDirect. Screening of articles was carried out to find relevant and appropriate articles. Articles were then quality-checked before inclusion. Our analysis showed that long-term finite therapy with nucleoside analogs could improve clinical outcomes and suppress viral DNA activity. However, a functional cure, loss of hepatitis B surface antigen (HBsAg), is rarely achieved. The decision to end treatment depends on quantitative HBsAg level (qHBsAg), alanine aminotransferase (ALT), HBV DNA (deoxyribonucleic acid), hepatitis B e antigen (HBeAg), and fibrosis assessment. It is concluded that patients with HBeAg negative without cirrhosis can be easily withdrawn from treatment if they have long-term viral remission and a high HBsAg loss rate. However, patients with positive HBeAg should continue treatment because there is a high chance of disease relapse and even acute flare. To predict whether patients will benefit from EOT, some immunomodulatory markers are studied, including interleukin (IL-20, IL-8), fas ligand (FASGL), and IFN gamma. Although these factors are reliable, none pose an independent effect on disease remission. Combination therapy (IFN alpha + oral nucleoside analogs) is promising but has clinical shortcomings.

Cautious optimism in anticipation of hepatitis B curative therapies.

Despite relative effectiveness of current hepatitis B therapies, there is still no curative agents available. The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen. Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection, which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.

Bushen Jianpi Formula Combined with Entecavir for the Treatment of HBeAg-Negative Chronic Hepatitis B: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background Bushen Jianpi formula (BSJPF, also known as Lingmao formula) is a traditional Chinese medicine for chronic hepatitis B (CHB). The previous study has suggested that the treatment combination of BSJPF and entecavir (ETV) can achieve a significant loss of hepatitis B e antigen (HBeAg) and a significant decrease in serum level of hepatitis B virus (HBV) DNA in HBeAg-positive CHB patients with mildly elevated alanine aminotransferase. Objective This study aimed to evaluate the efficacy and safety of BSJPF combined with ETV for treating HBeAg-negative CHB patients. Methods A total of 640 patients were assigned randomly to the treatment group (receiving BSJPF combined with ETV for 96 weeks) or the control group (receiving a placebo combined with ETV for 96 weeks) in a 1 : 1 ratio. The primary endpoints are the rate of loss of hepatitis B surface antigen (HBsAg). The secondary outcomes included the rate of decrease in the HBsAg concentration to ≥1 lg·IU/mL, the HBV DNA suppression, the decline of the level of covalently closed circular DNA (cccDNA) in the liver, histological improvements, and the rate of ALT normalization. Results The rate of HBsAg loss in the treatment group was significantly higher than that of the control group (5.5% versus 1.8%, P=0.031). There were 11.1% of patients in the treatment group who recorded a reduction in HBsAg ≥1 lg·IU/mL, which is better than 5.9% of patients in the control group (P=0.043). There was no significant difference between the two groups with regard to the rate of HBV DNA clearance, the reduction in intrahepatic cccDNA, and the rate of ALT normalization (P > 0.05). The rate of liver fibrosis improvement in the treatment group was better than that of the control group (35.5% versus 11.8%, P=0.031), but there was no difference in necroinflammatory improvement (P > 0.05). The adverse events (AEs) were similar between the two groups, except for the abnormal kidney function, with 2.2% in the control group and 0.0% in the treatment group (P=0.028). Conclusion The combination of BSJPF and ETV can increase the rate of HBsAg loss and the rate of histological fibrosis improvement without serious adverse events in CHB patients. Trial Registration. This trial is registered with ChiCTR-IOR-16009880 on November 16, 2016—retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=16836.

Loss of hepatitis D virus infectivity upon farnesyl transferase inhibitor treatment associates with increasing RNA editing rates revealed by a new RT-ddPCR method

Chronic hepatitis D is the most severe form of chronic viral hepatitis and to date, efficient therapeutic approaches against hepatitis D virus (HDV) are limited. Among the antiviral molecules currently tested in clinical trials, the farnesyl transferase inhibitor (FTI) Lonafarnib inhibits the prenylation of the large delta antigen (L-HDAg), blocking virus assembly. Given the importance of L-HDAg in the virus life cycle, we hypothesized that Lonafarnib treatment may have side effects on virus replication. Here, we setup an innovative method for the quantification of HDV RNA allowing the independent quantification of edited and non-edited versions of the HDV genome upon infection. We demonstrated that FTI treatment of HBV/HDV co-infected dHepaRG or primary human hepatocytes leads to an accumulation of intracellular HDV RNAs and a marked increase in the levels of edited RNAs non only within the infected cells but also in the viral particles that are produced. Interestingly, these viral particles were less infectious, probably due to an enrichment in edited genomes that are packaged, leading to unproductive infection given the absence of S-HDAg synthesis after viral entry. Taken together, we setup an innovative quantification method allowing the investigation of RNA editing during HDV infection in a simple, fast, clinically-relevant assay and demonstrated for the first time the dual antiviral activity of FTI on HDV infection.

Chronic Hepatitis B Treatment Strategies Using Polymerase Inhibitor-Based Combination Therapy.

Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed circular (ccc) DNA. More recently, therapeutic strategies targeting various stages of the HBV lifecycle have been attempted. Although cccDNA-targeted therapies are attractive, there are still many problems to be overcome, and the development of novel polymerase inhibitors remains an important issue. Interferons and nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the only therapeutic options currently available for HBV infection. Many studies have reported that the combination of interferons and NRTI causes the loss of hepatitis B surface antigen (HBsAg), which is suggestive of seroconversion. Although NRTIs do not directly target cccDNA, they can strongly reduce the serum viral DNA load and could suppress the recycling step of cccDNA formation, improve liver fibrosis/cirrhosis, and reduce the risk of hepatocellular carcinoma. Here, we review recent studies on combination therapies using polymerase inhibitors and discuss the future directions of therapeutic strategies for HBV infection.

Usefulness of a Hepatitis B Surface Antigen-Based Model for the Prediction of Functional Cure in Patients with Chronic Hepatitis B Virus Infection Treated with Nucleos(t)ide Analogues: A Real-World Study.

In patients with chronic hepatitis B (CHB) under long-term treatment with nucleso(t)ide analogues (NAs), the loss of hepatitis B surface antigen (HBsAg) is a rare event. A growing body of evidence supports the use of quantitative HBsAg for the prediction of functional cure, although these results are mainly derived from studies performed on Asian patients with hepatitis B e antigen (HBeAg)-positive CHB. Here, we investigated the clinical role of quantitative HBsAg in a real-life cohort of CHB patients under treatment with NAs in a tertiary care center from North-West Italy. A total of 101 CHB patients (HBeAg-negative, n = 86) undergoing NAs treatment were retrospectively enrolled. HBsAg was measured at baseline (T0), 6 months (T1), 12 months (T2) and at the last follow-up (FU). Median FU was 5.5 (3.2–8.3) years; at the end of FU, 11 patients lost the HBsAg (annual incidence rate = 1.8%). Baseline HBsAg levels were significantly different between patients with no HBsAg loss and those achieving a functional cure (3.46, 2.91–3.97 vs. 1.11, 0.45–1.98 Log IU/mL, p < 0.001). Similarly, the HBsAg decline (Δ) from T0 to T2 was significantly different between the two groups of patients (0.05, −0.04–0.13, vs. 0.38, 0.11–0.80 Log IU/mL, p = 0.002). By stratified cross-validation analysis, the combination of baseline HBsAg and ΔHBsAg T0–T2 showed an excellent accuracy for the prediction of HBsAg loss (C statistic = 0.966). These results corroborate the usefulness of quantitative HBsAg in Caucasian CHB patients treated with antivirals for the prediction of HBsAg seroclearance.

Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus.

Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.

Functional Cure of Hepatitis B Virus Infection in Individuals With HIV-Coinfection: A Literature Review.

In individuals infected with hepatitis B virus (HBV), the loss of hepatitis B surface antigen (HBsAg) is the ultimate therapeutic goal, which defines “functional cure.” For individuals living with human immunodeficiency virus (HIV), functional cure occurs roughly 2 per 100 person-years during potent anti-HBV containing antiretroviral therapy. Although this rate may be higher than expected in treated HBV mono-infected individuals, rates of functional cure widely vary between studies (0.6–10.5 per 100 person-years). Similar to HBV mono-infection, the phase of HBV infection, HBV (sub-)genotypes and hepatitis B “e” Ag-negative variants are associated with functional cure in treated HIV-HBV co-infection. In specifically HIV-HBV co-infected individuals, strong increases in CD4+ T cell counts after treatment initiation have also been linked to functional cure, yet this finding is inconsistent across studies. Several markers directly or indirectly reflecting HBV activity are being developed to predict functional cure, such as quantification of HBsAg, hepatitis B core-related antigen, HBsAg protein composition, anti-hepatitis B core antibodies and interferon-gamma-inducible protein 10. Few have been assessed during treatment in HIV-HBV co-infected individuals and none have been validated to predict functional cure. Novel therapeutics for HBV cure are essential for individuals with HIV-HBV co-infection and need to be separately evaluated in this population.

What Should Be Done to Re-evaluate Cessation of Nucleos(t)ide Analog Therapy for Chronic Hepatitis B Infection?

Abstract Anti-viral therapy with nucleos(t)ide analogs (NUCs) for chronic hepatitis B (CHB) is generally considered to be a long-term treatment. Relevant guidelines issued by Asian Pacific Association for the Study of the Liver, European Association for the Study of the Liver, and American Association for the Study of Liver Diseases have recently proposed requirements and standards for cessation of NUCs, but it remains unclear which proportion of CHB patients on long-term or prolonged treatment of NUCs will relapse after NUCs cessation. Recently, paradoxical increase in loss of hepatitis B surface antigen (HBsAg) with or without the development of anti-hepatitis B surface antibody has been observed in NUCs’ treated CHB patients with cessation of therapy. Hence, it is of great clinical relevance to identify CHB who might have been over-treated with NUCs and might even benefit HBsAg loss or seroconversion with cessation of therapy. To address these issues, our review comprehensively analyzed the data from recent clinical trials in which the antiviral efficacy in the long-term or prolonged treatment of NUCs and/or interferon-α for CHB patients were evaluated. Furthermore, the relevant problems and deficiencies existing in the study design of previous clinical studies were also described. To solve the unmet issues in the field, a prospective study with a large-enough sample size would be required to understand the related virologic and immunological markers that can accurately predict the outcome and prognosis of the CHB patients who stop the NUCs treatment. With the rapid advancement of antiviral drug development for CHB patients, the future ideal regimens should include multiple targets for antiviral drug therapy combined with efficient immune-modulatory therapy, which will help more CHB patients to obtain functional cure with NUCs cessation.

A novel piperazine derivative that targets hepatitis B surface antigen effectively inhibits tenofovir resistant hepatitis B virus

Chronic hepatitis B virus (HBV) infection is a global problem. The loss of hepatitis B surface antigen (HBsAg) in serum is a therapeutic end point. Prolonged therapy with nucleoside/nucleotide analogues targeting the HBV-polymerase may lead to resistance and rarely results in the loss of HBsAg. Therefore, inhibitors targeting HBsAg may have potential therapeutic applications. Here, we used computational virtual screening, docking, and molecular dynamics simulations to identify potential small molecule inhibitors against HBsAg. After screening a million molecules from ZINC database, we identified small molecules with potential anti-HBV activity. Subsequently, cytotoxicity profiles and anti-HBV activities of these small molecules were tested using a widely used cell culture model for HBV. We identified a small molecule (ZINC20451377) which binds to HBsAg with high affinity, with a KD of 65.3 nM, as determined by Surface Plasmon Resonance spectroscopy. Notably, the small molecule inhibited HBsAg production and hepatitis B virion secretion (10 μM) at low micromolar concentrations and was also efficacious against a HBV quadruple mutant (CYEI mutant) resistant to tenofovir. We conclude that this small molecule exhibits strong anti-HBV properties and merits further testing.

Thyroid dysfunction is associated with the loss of hepatitis B surface antigen in patients with chronic hepatitis B undergoing treatment with α-interferon.

ObjectiveTo investigate the influence of thyroid dysfunction on the antiviral efficacy of α-interferon in adult patients with chronic hepatitis B (CHB).MethodsWe performed a retrospective study of 342 patients with CHB who underwent interferon treatment for >12 weeks. Patients with thyroid dysfunction before or during treatment were defined as the thyroid dysfunction group (n = 141) and those with normal thyroid function were defined as the normal thyroid function group (n = 201). The prevalences of hepatitis B virus (HBV) DNA undetectability, low hepatitis B surface antigen (HBsAg) titre (<250 IU/mL), HBsAg loss, and hepatitis B envelope antigen loss were compared.ResultsDuring interferon treatment, 69 of 270 (25.6%) participants with normal thyroid function at baseline developed thyroid dysfunction, whereas 11 of 72 (15.3%) with thyroid dysfunction at baseline regained normal thyroid function. The thyroid dysfunction group had significantly higher prevalences of low HBsAg titre (29.8% vs. 18.9%) and HBV DNA undetectability (66.0% vs. 40.3%). Multivariate logistic regression analysis showed that thyroid dysfunction was associated with HBsAg loss (odds ratio 4.945, 95% confidence interval 1.325–18.462).ConclusionsThese results suggest that thyroid dysfunction is not an absolute contraindication, but is associated with HBsAg loss, in patients with CHB undergoing α-interferon treatment.