Functional cure of chronic hepatitis B-hope or hype?

Chronic hepatitis B constitutes a substantial disease burden worldwide.The steps advocated by the World Health Organization in 2016 to eradicate hepatitis B by 2030 has failed to achieve significant progress,especially with respect to immu-nization coverage and linkage to care.The lack of governmental and public awar-eness regarding the long-term implications of hepatitis B burden cause under-funding of developmental projects.The presently approved treatment modalities have limited efficacy in complete viral eradication,hence the need for newer molecules to achieve functional cure(sustained undetectable hepatitis B surface antigen(HBsAg)and hepatitis B virus DNA in peripheral blood after a finite period of therapy).However,preliminary results from trials of novel therapies show their inadequacy to achieve this end by themselves but better performance with a low baseline serum HBsAg with nucleos(t)ide analogues(NA)treatment which need to be combined with/without pegylated interferon as an immu-nomodulator.Such therapy is limited by cost and adverse events and need to show incremental benefit over the standard of care(long-term NA therapy)with respect to efficacy and drug toxicities,making the development process tenuous.Thus,while such therapies continue to be tested,strategies should still focus on prevention of transmission by non-pharmaceutical measures,vaccination and increasing linkage to care.

Toward a new era of hepatitis B virus therapeutics:The pursuit of a functional cure

Hepatitis B virus(HBV)infection,although preventable by vaccination,remains a global health problem and a major cause of chronic liver disease.Although current treatment strategies suppress viral replication very efficiently,the optimal endpoint of hepatitis B surface antigen(HBsAg)clearance is rarely achieved.Moreover,the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored.Therefore,the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV,defined as undetectable HBV DNA and HBsAg loss over a limited treatment period.A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms,including inhibition of viral entry,transcriptional silencing,epigenetic manipulation,interference with capsid assembly,and disruption of HBsAg release.In parallel,another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses.Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment.Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses.In addition,several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting.Ultimately,it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs.This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.

Acceptance and Factors Associated With Participation in Functional Cure–Related Trials Among People Living With HIV: A Cross-sectional Study in Southern China

HIV remains a global health challenge,and research efforts directed towards a functional cure require people living with HIV(PLHIV)in-volvement in clinical trials.Our study assessed willingness to participate in HIV functional cure–related clinical trials and associated factors among PLHIV in Guangzhou,China,using a questionnaire survey approach.We analyzed responses from 718 questionnaires,finding that 71.2%were willing to participate in Phase Ⅲtrials,while 51.7%were willing to participate in Phase I trials and 42.9%expressed acceptability for analytic treatment interruption.Multivariate logistic regression demonstrated that male PLHIV,those with awareness of functional cure,and PLHIV,who had been on antiretroviral therapy(ART)for less than 1 year,were more willing to partic-ipate in Phase Ⅲtrials.Those with a body mass index greater than 24,and those without resistance to ART drug were more willing to participate in Phase I trials.The major motivations for participation in Phase Ⅲtrials were access to cutting-edge treatments(62.6%)and supporting research(55.3%).Safety was the main concern contributing to hesitancy.Our study revealed a high willingness to participate in HIV functional cure–related trials among PLHIV in Guangzhou,China,and willingness varied across different trial phases and was influenced by multiple factors.This study provides valuable references for future clinical trial recruitment strategies and public health policy formulation.

Reduction in Intrahepatic cccDNA and Integration of HBV in Chronic Hepatitis B Patients with a Functional Cure

Background and Aims:Functional cure(FC)is characterized by the clearance of the hepatitis B surface antigen from the serum of patients with chronic hepatitis B(CHB).However,the level of intrahepatic covalently closed circular DNA(cccDNA)and hepatitis B virus(HBV)integration remains unclear.We conducted this study to determine them and reveal their value in the treatment of CHB.Methods:There were two sessions to elucidate the changes in intrahepatic cccDNA and HBV integration after antiviral therapy.In the first session,116 patients were enrolled and divided into FC,non-functional cure(NFC),and CHB groups,including 48 patients with functionally cured CHB,27 with CHB without functional cure after antiviral treatment,and 41 with treatment-naïve CHB.Patients were tested for both intrahepatic cccDNA and other viral markers.All patients in the FC group were followed up for at least 24 weeks to observe relapse.In the second session,another ten patients were included for in-depth whole-genome sequencing to analyze HBV integration.Results:Thirteen patients in the FC group were negative for intrahepatic cccDNA.Intrahepatic cccDNA was much higher in the CHB group compared with the FC group.Seven patients had HBsAg seroreversion,including two with virological relapse.Integration of HBV was detected in one(33.3%)functionally cured patients and in seven(100%)with CHB.28.0%of the HBV breakpoints were assigned in the 1,500 nt to 1,900 nt range of the HBV genome.Conclusions:After achieving an FC,the rate of intrahepatic cccDNA and HBV integration was significantly reduced in patients with CHB.For those patients who cleared intrahepatic cccDNA,the chances of developing virological relapse were even lower.

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

Background and Aims:There is a lack of data supporting the notion that antiviral treatments can beneft children with chronic hepatitis B(CHB)having high viremia and normal or mildly elevated serum alanine aminotransferase(ALT)levels.We aimed t analyze the efficacy of antiviral treatments in children with CHB and explore the factors associated with functional cure.Methods: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)monother-apy,IFN-a 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 chil-dren 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/seroconver-sion of circulating hepatitis B e antigen(HBeAg),and loss of hepatitis B surface antigen(HBsAg)with or without serocon-version.Cox regression analysis was employed to evaluate the factors that may have influenced the functional cure.Re-sults: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.Func tional 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.Conclusions: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 as sociated with this functional cure.

Immunomodulatory and Antiviral Therapy Improved Functional Cure Rate in CHB Patients with High HBsAg Level Experienced NA

Background and Aims:A functional cure,or hepatitis B virus(HBV)surface antigen(HBsAg)loss,is difficult to achieve in patients with hepatitis B virus e antigen(HBeAg)-positive chronic hepatitis B.The HBV vaccine and granulocyte-macrophage colony-stimulating factor(GM-CSF)have been reported to help reduce HBsAg levels and promote HBsAg loss.In this prospective randomized trial,we evaluated HBsAg loss in patients receiving pegylated interferon α2b(PEGIFN-α2b)and tenofovir disoproxil fumarate(TDF),with and without GM-CSF and HBV vaccination.Methods:A total of 287 patients with HBeAg positive chronic hepati-tis B and seroconversion after nucleot(s)ide analog treat-ment were assigned randomly to three treatment groups for 48 weeks,TDF alone(control),PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine.The prima-ry endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.Resu/ts:The cumulative HBsAg loss rates in the control,PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine groups at week 48 were 0.0%,28.3%,and 41.1%,respec-tively.The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%,21.7%,and 33.9%,respec-tively.Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss(p=0.017)and seroconversion(p=0.030).Con-clusions:In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment,immunomodulatory/antiviral treatment regimens effective-ly improved HBsAg loss,and the regimen including GM-CSF and HBV vaccination was most effective.

Expanding indications for chronic hepatitis B treatment: Is it really desirable to treat everyone?

Chronic viral hepatitis causes an increased risk of progressive liver disease and hepatocellular carcinoma.On the wave of the World Health Organization’s goal to reduce new cases and deaths from hepatitis B and C by 2030,there is an increasing call to expand the indications for treatment of chronic hepatitis B.Currently,the main goal of treatment is to achieve a functional cure due to the inability of current drugs to completely eradicate the virus.There are still many discrepancies between available guidelines in terms of eligibility for treatment as well as an uncertainty about the appropriate treatment duration.This editorial addresses key questions about the topic and whether indications for treatment should be expanded.

Past,present,and future of long-term treatment for hepatitis B virus

The estimated world prevalence of hepatitis B virus(HBV)infection is 316 million.HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma(HCC)despite universal vaccination programs,and effective antiviral therapy.Long-term administration of nucleos(t)ide analogues(NA)has been the treatment of choice for chronic hepatitis B during the last decades.The NA has shown a good safety profile and high efficacy in controlling viral replication,improving histology,and decreasing the HCC incidence,decompensation,and mortality.However,the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment.The knowledge,in recent years,about the different phases of the viral cycle,and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches.Consequently,several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results.This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B,the present of NA treatment and withdrawal,and the future perspectives with combined molecules to achieve a functional cure.

Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Global prophylactic vaccination programmes have helped to curb new hepatitis B virus(HBV)infections.However,it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma.As such,HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed.Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA(cccDNA)which establishes itself as a minichromosome in the nucleus of hepatocytes.As the viral transcription intermediate,the cccDNA is responsible for producing new virions and perpetuating infection.HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications.Two HBV proteins,X(HBx)and core(HBc)promote viral replication by modulating the cccDNA epigenome and regulating host cell responses.This includes viral and host gene expression,chromatin remodeling,DNA methylation,the antiviral immune response,apoptosis,and ubiquitination.Elimination of the cccDNA minichromosome would result in a sterilizing cure;however,this may be difficult to achieve.Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure.This review explores the cccDNA epigenome,how host and viral factors influence transcription,and the recent epigenetic therapies and epigenome engineering approaches that have been described.

Heterogeneity of immune control in chronic hepatitis B virus infection:Clinical implications on immunity with interferon-αtreatment and retreatment

Hepatitis B virus(HBV)infection is a global public health issue.Interferon-α(IFN-α)treatment has been used to treat hepatitis B for over 20 years,but fewer than 5%of Asians receiving IFN-αtreatment achieve functional cure.Thus,IFN-αretreatment has been introduced to enhance antiviral function.In recent years,immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks,including both innate and adaptive immunity,triggering immune responses that control HBV replication.However,heterogeneity of the immune system to control HBV infection,particularly HBV-specific CD8^(+)T cell heterogeneity,has consequential effects on T cell-based immunotherapy for treating HBV infection.Altogether,the host’s genetic variants,negative-feedback regulators and HBV components affecting the immune system's ability to control HBV.In this study,we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-αtreatment and retreatment.

Nationwide retrospective study of hepatitis B virological response and liver stiffness improvement in 465 patients on nucleos(t)ide analogue

BACKGROUND Hepatitis B virus(HBV)nucleos(t)ide analog(NA)therapy reduces liver disease but requires prolonged therapy to achieve hepatitis B surface antigen(HBsAg)loss.There is limited North American real-world data using non-invasive tools for fibrosis assessment and few have compared 1st generation NA or lamivudine(LAM)to tenofovir disoproxil fumarate(TDF).AIM To assess impact of NA on virological response and fibrosis regression using liver stiffness measurement(LSM)(i.e.,FibroScan®).METHODS Retrospective,observational cohort study from the Canadian HBV Network.Data collected included demographics,NA,HBV DNA,alanine aminotransferase(ALT),and LSM.Patients were HBV monoinfected patients,treatment naïve,and received 1 NA with minimum 1 year follow-up.RESULTS In 465(median 49 years,37%female,35%hepatitis B e antigen+at baseline,84%Asian,6%White,and 9%Black).Percentage of 64(n=299)received TDF and 166 were LAM-treated with similar median duration of 3.9 and 3.7 years,respectively.The mean baseline LSM was 11.2 kPa(TDF)vs 8.3 kPa(LAM)(P=0.003).At 5-year follow-up,the mean LSM was 7.0 kPa in TDF vs 6.7 kPa in LAM(P=0.83).There was a significant difference in fibrosis regression between groups(i.e.,mean-4.2 kPa change in TDF and-1.6 kPa in LAM,P<0.05).The last available data on treatment showed that all had normal ALT,but more TDF patients were virologically suppressed(<10 IU/mL)(n=170/190,89%)vs LAM-treated(n=35/58,60%)(P<0.05).None cleared HBsAg.CONCLUSION In this real-world North American study,approximately 5 years of NA achieves liver fibrosis regression rarely leads to HBsAg loss.

Chronic hepatitis B:New potential therapeutic drugs target

liverrelated morbidity and mortality worldwide.It impacts nearly 300 million people.The current treatment for chronic infection with the hepatitis B virus(HBV)is complex and lacks a durable treatment response,especially hepatitis B surface antigen(HBsAg)loss,necessitating indefinite treatment in most CHB patients due to the persistence of HBV covalently closed circular DNA(cccDNA).New drugs that target distinct steps of the HBV life cycle have been investigated,which comprise inhibiting the entry of HBV into hepatocytes,disrupting or silencing HBV cccDNA,modulating nucleocapsid assembly,interfering HBV transcription,and inhibiting HBsAg release.The achievement of a functional cure or sustained HBsAg loss in CHB patients represents the following approach towards HBV eradication.This review will explore the up-to-date advances in the development of new direct-acting anti-HBV drugs.Hopefully,with the combination of the current antiviral drugs and the newly developed direct-acting antiviral drugs targeting the different steps of the HBV life cycle,the ultimate eradication of CHB infection will soon be achieved.

An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients:High-sensitivity Quantitative HBsAg Loss

In the era of antiviral therapy,the main goal of treatment has shifted from the persistent inhibition of hepatitis B virus(HBV)replication to the pursuit of serological clearance of HBs surface antigen(HBsAg).Based on the life cycle of HBV,HBsAg originates from covalently closed circular DNA(cccDNA)and integrated HBV DNA,thus reflecting their transcriptional activity.Complete HBsAg loss may mean elimination or persistent inactivity of the HBV genome including cccDNA and integrated HBV DNA.HBsAg loss improves the recovery of abnormal immune function,which in turn,may further promote the clearance of residual viruses.Combined with functional cure and the great improvement of clinical outcomes,the continuous seroclearance of high-sensitivity quantitative HBsAg may represent the complete cure of chronic hepatitis B(CHB).For many other risk factors besides HBV itself,patients with HBsAg loss still need regular monitoring.In this review,we summarized the evolution of CHB treatment,the origin of serum HBsAg,the pattern of HBsAg seroclearance,and the effect of HBsAg loss on immune function and disease outcomes.In addition,we discuss the significance of high-sensitivity HBsAg detection and its possibility as a surrogate of complete cure.

Targeting the HIV reservoir:chimeric antigen receptor therapy for HIV cure

Although antiretroviral therapy(ART)can reduce the viral load in the plasma to undetectable levels in human immunodeficiency virus(HIV)-infected individuals,ART alone cannot completely eliminate HIV due to its integration into the host cell genome to form viral reservoirs.To achieve a functional cure for HIV infection,numerous preclinical and clinical studies are underway to develop innovative immunotherapies to eliminate HIV reservoirs in the absence of ART.Early studies have tested adoptive T-cell therapies in HIV-infected individuals,but their effectiveness was limited.In recent years,with the technological progress and great success of chimeric antigen receptor(CAR)therapy in the treatment of hematological malignancies,CAR therapy has gradually shown its advantages in the field of HIV infection.Many studies have identified a variety of HIV-specific CAR structures and types of cytolytic effector cells.Therefore,CAR therapy may be beneficial for enhancing HIV immunity,achieving HIV control,and eliminating HIV reservoirs,gradually becoming a promising strategy for achieving a functional HIV cure.In this review,we provide an overview of the design of anti-HIV CAR proteins,the cell types of anti-HIV CAR(including CAR T cells,CAR natural killer cells,and CAR-encoding hematopoietic stem/progenitor cells),the clinical application of CAR therapy in HIV infection,and the prospects and challenges in anti-HIV CAR therapy for maintaining viral suppression and eliminating HIV reservoirs.

Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics

The achievement of a functional cure for chronic hepatitis B(CHB)remains limited to a minority of patients treated with currently approved drugs.The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB.A critical prerequisite for the functional cure of CHB is a substantial reduction,or even eradication of covalently closed circular DNA(cccDNA).Within this context,the changes in cccDNA levels during treatment become as a pivotal concern.We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics.In this review,we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA.Building upon this foundation,we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe.

Current advances in the elimination of hepatitis B in China by 2030

With its 78 million chronic carriers, hepatitis B virus （HBV） infection is still one of the leading public health challenges in China. Over the last two decades, China has made great progress on the prevention of HBV transmission through national vaccination programs. Zero transmission from mother to infant has been proposed as the current goal. Available anti-HBV therapy is efficacious in suppressing HBV replication; however, it fails to completely cure patients with chronic hepatitis B and even requires Hfelong treatment. To reduce the costs and improve the efficacy, several trials have been recently conducted in China to optimize the current anti-HBV managements. Novel biomarkers were identified to predict treatment outcomes, and new promising treatment strategies were developed. Reports also indicate that coinfections of HBV with other hepatotropic viruses and human immunodeficiency virus are common in China and cause severe liver diseases, which should be recognized early and treated properly. Work is still needed to eliminate hepatitis B in China by 2030.

Consolidation treatment needed for sustained HBsAg-negative response induced by interferon-alpha in HBeAg positive chronic hepatitis B patients

Hepatitis B surface antigen(HBsAg)clearance is considered as functional cure in patients with chronic hepatitis B(CHB).This study aimed to assess the durability of HBsAg clearance achieved by interferon-based therapies in patients with CHB who were originally positive for hepatitis B envelope antigen(HBeAg).In this prospective study,HBeAg-positive CHB patients with confirmed HBsAg loss under interferon-based therapies were enrolled within 12 weeks from end of treatment and followed up for 48 weeks.Virological markers,biochemical indicators,and liver imaging examinations were observed every 3–6 months.Sustained functional cure was analysed as primary outcome.Factor associated with sustained HBsAg loss or reversion was also investigated.The rate of HBsAg loss sustainability was 91.8%(212/231).Patients receiving consolidation treatment for 12–24weeks or≥24 weeks had higher rates of sustained HBsAg negativity than those receiving consolidation treatment for<12 weeks(98.3%and 91.2%vs.86.7%,P=0.068),and the former groups had significantly higher anti-HBs levels than the later(P<0.05).The cumulative incidence of HBsAg reversion and HBV DNA reversion was 8.2%and 3.9%,respectively.Consolidation treatment of≥12 weeks[odd ratio(OR)3.318,95%confidence interval(CI)1.077–10.224,P=0.037)was a predictor of sustained functional cure,and HBeAg-positivity at cessation of treatment(OR 12.271,95%CI 1.076–139.919,P=0.043)was a predictor of HBsAg reversion.Interferon-alpha induced functional cure was durable and a consolidation treatment of≥12–24 weeks was needed after HBsAg loss in HBeAg-positive CHB patients.

Advances in new antivirals for chronic hepatitis B

Chronic hepatitis B virus(HBV)infection remains a global health burden.Timely and effective antiviral therapy is beneficial for patients with HBV infection.With existing antiviral drugs,including nucleos(t)ide analogs and interferon-alfa,patients can achieve viral suppression with improved prognosis.However,the rate of hepatitis B surface antigen loss is low.To achieve a functional cure and even complete cure in chronic hepatitis B patients,new antivirals need to be developed.In this review,we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.

HIV reservoir: antiviral immune responses and immune interventions for curing HIV infection

Antiretroviral therapy against human immunodeficiency virus (HIV) is effective in controlling viral replication but cannot completely eliminate HIV due to the persistence of the HIV reservoir. Innate and adaptive immune responses have been proposed to contribute to preventing HIV acquisition, controlling HIV replication and eliminating HIV-infected cells. However, the immune responses naturally induced in HIV-infected individuals rarely eradicate HIV infection, which may be caused by immune escape, an inadequate magnitude and breadth of immune responses, and immune exhaustion. Optimizing these immune responses may solve the problems of epitope escape and insufficient sustained memory responses. Moreover, immune interventions aimed at improving host immune response can reduce HIV reservoirs, which have become one focus in the development of innovative strategies to eliminate HIV reservoirs. In this review, we focus on the immune response against HIV and how antiviral immune responses affect HIV reservoirs. We also discuss the development of innovative strategies aiming to eliminate HIV reservoirs and promoting functional cure of HIV infection.