Beyond Occam's Razor: Concurrent Non-functional Pituitary Macroadenoma and Metastatic Hepatocellular Carcinoma in a Patient With Functional Cure of Hepatitis B.

Occam's razor, the principle of parsimony, is frequently employed in medicine to derive a single diagnosis from a patient's myriad symptoms. Conversely, Hickam's dictum, which embraces the principle of plenitude by considering multiple diagnoses for a patient's presentation, is often underutilized or not as widely recognized as Occam's razor. The application of Hickam's dictum is particularly crucial when evaluating nonspecific symptoms such as fatigue, which can manifest in various diseases. This report describes the case of a 72-year-old man with a history of functional cure for hepatitis B who presented with chronic fatigue and hyponatremia. Initially, he was diagnosed with non-functional pituitary macroadenoma and panhypopituitarism. Two months following pituitary surgery, the onset of dyspepsia and the recurrence of fatigue revealed metastatic tumors in the liver, stomach, pancreas, left adrenal gland, and peri-pancreatic lymph nodes. A liver biopsy confirmed the diagnosis of hepatocellular carcinoma. This case highlights the importance of considering multiple, potentially co-existing conditions based on the patient's symptoms and risk factors to complete the thorough diagnoses. Additionally, it emphasizes the need to remain vigilant regarding the risk of liver cancer in patients with a history of chronic hepatitis B infection, irrespective of a functional cure.

Discovery of hepatitis B virus subviral particle biogenesis inhibitors from a bioactive compound library.

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.

Predictive models for functional cure in patients with CHB receiving PEG-IFN therapy based on HBsAg quantification through meta-analysis.

BACKGROUND AND AIMS: The efficacy of achieving HBsAg clearance through pegylated interferon (PEG-IFNα) therapy in patients with chronic hepatitis B (CHB) remains uncertain, especially regarding the probability of achieving functional cure among patients with varying baseline HBsAg levels. We aimed to investigate the predictive value of HBsAg quantification for HBsAg seroclearance in CHB patients undergoing PEG-IFNα treatment. METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library up to January 11, 2022. Subgroup analyses were performed for HBeAg-positive and HBeAg-negative patients, PEG-IFNα monotherapy and PEG-IFNα combination therapy, treatment-naive and treatment-experienced patients, and patients with or without liver cirrhosis. RESULTS: This predictive model incorporated 102 studies. The overall HBsAg clearance rates at the end of treatment (EOT) and the end of follow-up (EOF) were 10.6% (95% CI 7.8-13.7%) and 11.1% (95% CI 8.4-14.1%), respectively. Baseline HBsAg quantification was the most significant factor. According to the model, it is projected that when baseline HBsAg levels are 100, 500, 1500, and 10,000 IU/ml, the HBsAg clearance rates at EOF could reach 53.9% (95% CI 40.4-66.8%), 32.1% (95% CI 24.8-38.7%), 14.2% (95% CI 9.8-18.8%), and 7.9% (95% CI 4.2-11.8%), respectively. Additionally, treatment-experienced patients with HBeAg-negative status, and without liver cirrhosis exhibited higher HBsAg clearance rates after PEG-IFNα treatment. CONCLUSION: A successful predictive model has been established to predict the achievement of functional cure in CHB patients receiving PEG-IFNα therapy.

STOPPING NUCLEOS(T)IDE ANALOGUES IN CHRONIC HEPATITIS B USING HBSAG THRESHOLDS: A META-ANALYSIS AND META-REGRESSION.

BACKGROUND AND AIMS: Recommendations for stopping nucleoside analogue(NA) therapy in HBeAg-negative Chronic Hepatitis B(CHB) are unclear. End-of-treatment quantitative HBsAg(EOTqHBsAg) thresholds<100IU/ml or <1000IU/ml have been proposed as stopping criterion. We assessed this by meta-analysis and meta-regression. DESIGN: We searched PubMed, EMBASE and conference abstracts for studies of HBeAg-negative CHB NA discontinuation. Extracted studies were analysed for risk-of-bias, pooled risk of HBsAg loss, virological(VR) and biochemical relapse(BR). Significant heterogeneity(I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariables, including EOTqHBsAg thresholds, ethnicity, duration of therapy and followup. RESULTS: We found 24 papers(3732 subjects), 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR and BR for stopping therapy at EOTqHBsAg<100IU/ml were 41.8%, 33.4% and 17.3%, versus 4.6%, 72.1% and 34.6% respectively for EOTqHBsAg≥100IU/ml. The pooled risks of HBsAg loss, VR and BR for stopping therapy at EOTqHBsAg<1000IU/ml were 22.0%, 52.7% and 15.9%, versus 3.4%, 63.8% and 26.4% respectively for EOTqHBsAg≥1000IU/ml. Multivariable analysis for HBsAg loss showed ethnicity, followup duration and EOTqHBsAg<100≥IU/ml explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg<100IU/ml had 28.2%, while non-Asians with EOTqHBsAg<1000IU/ml had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg<100≥IU/ml and other covariables only explained 43% and 63% of the variance in heterogeneity for VR and BR respectively, suggesting that other factors are also important for relapse. CONCLUSIONS: While EOTqHBsAg thresholds, ethnicity and followup duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.

[Therapeutic strategies, practice, and prospect of a clinical cure for chronic hepatitis B in China].

Clinical cure (herein referred to as functional cure) is currently recognized as the ideal therapeutic goal by the guidelines for the prevention and treatment of chronic hepatitis B (CHB) at home and abroad. China has achieved significant results in research and exploration based on pegylated interferon alpha therapeutic strategies to promote the effectiveness of CHB clinical cure rates in clinical practice. The summary and optimization of clinical cure strategies in different clinical type classifications, as well as the exploration of clinical cure continuity and long-term outcomes, are of great significance for solving the current bottleneck problem and our future efforts in the developmental directions of clinical cure in CHB populations.

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.

[Research progress on novel antiviral therapeutic drugs for chronic hepatitis B].

The ideal goal of hepatitis B treatment is to achieve a functional cure, and the persistent cccDNA in the liver is a barrier to functional cure. Currently, antiviral drugs represented by pegylated interferon-α and nucleos (t) ide analogues cannot eliminate cccDNA, which is difficult to achieve functional cure. With the deepening of the exploration of various mechanisms and drug targets, significant progress has been made in the research and development of several novel drugs targeting the hepatitis B virus's life cycle and immune system, offering hope for a functional cure. This article presents an overview of the new progress in clinical research on antiviral therapy for chronic hepatitis B based on the literature published in recent years and international conference materials.

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.

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

Purpose of Review: 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. Recent Findings: Direct acting antiviral, host targeting antiviral, and immunological approaches are in various stages of development as treatment for chronic HBV infection. Summary: 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.

A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection.

Allogeneic hematopoietic stem and progenitor cell transplant (HSCT) of CCR5 null (CCR5Δ32) cells can be curative for HIV-1-infected patients. However, because allogeneic HSCT poses significant risk, CCR5Δ32 matched bone marrow donors are rare, and CCR5Δ32 transplant does not confer resistance to the CXCR4-tropic virus, it is not a viable option for most patients. We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity in vivo, and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without CXCR4 locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a functional cure for both CCR5-tropic and CXCR4-tropic HIV-1 infections.

The Use of Tenofovir Disoproxil Fumarate in the Management of eAg-Negative Chronic Hepatitis B Infection.

Background/Objectives: Currently, there are insufficient data to recommend the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic infection who have normal ALT and low HBV DNA, since the prognosis is generally regarded as favorable. The aim of this pilot study was to determine whether the use of tenofovir disoproxil fumarate (TDF) 300 mg/day for 3 years was able to achieve functional cure (HBsAg loss) and HBsAg seroconversion in HBeAb-positive individuals. Methods: Fifty patients not on antiviral therapy (40% men, mean age 48.9 ± 10.9 years, 84% Asians) with minimal fibrosis were enrolled. Results: TDF reduced HBV DNA significantly to undetectable levels after 6 months. Overall, 48.3% of inactive carriers (baseline HBV DNA < 2000 IU/mL) remained HBV DNA negative 6 months after treatment withdrawal, which was significantly higher than the 5.6% in those who were not inactive carriers (baseline HBV DNA ≥ 2000 IU/mL) (p = 0.003). The HBsAg levels did not drop throughout the study period with no difference between inactive carriers versus those who were not. Five inactive carriers achieved functional cure, but none of these were amongst those who were not inactive carriers. No renal dysfunction or ALT flare on treatment withdrawal was observed. Conclusions: TDF could potentially be used to induce functional cure in patients who are inactive carriers with normal ALT, low HBV DNA and without advanced fibrosis.

Antiviral Therapy of Chronic Hepatitis B Virus between Present and Future.

Background/Objectives: The objective of this study was to analyze the results of clinical trials regarding long-term antiviral therapies in chronic hepatitis with HBV to compare current therapeutic protocols and to analyze the results of preliminary studies with new antiviral therapies for HBV. Methods: Clinical studies and meta-analyses from PubMed, Google Scholar, and Research Gate from 2011 to 2024 were analyzed on patients undergoing chronic antiviral therapy for HBV, and a retrospective observational study performed in our clinic on a group of 76 patients undergoing chronic therapy with entecavir was presented. Also, a summary of the results of preliminary studies with various innovative antiviral molecules for HBV was performed. Results: The results of extensive clinical trials reveal that current therapies for chronic HBV are well tolerated and maintain good viral suppression if the patient is adherent to therapy. Innovative therapies aim to eliminate HBsAg and, thus, significantly shorten the duration of treatment, and the preliminary results of the studies are promising. Conclusions: Being an asymptomatic condition that requires life-long therapy, adherence to therapy is a real problem. Also, the risk of decompensation of liver cirrhosis and adenocarcinoma remains important in these patients. Future research is needed to perfect some antiviral therapy schemes that shorten the treatment period but also decrease the rate of progression towards decompensated cirrhosis and liver adenocarcinoma.

Long-Term HBsAg Titer Kinetics with Entecavir/Tenofovir: Implications for Predicting Functional Cure and Low Levels.

The long-term kinetics of quantitative HBsAg levels in HBV-infected patients treated with entecavir or tenofovir, as well as the role of quantitative HBsAg in predicting functional cure (HBsAg loss) and low HBsAg levels (<2 log IU/mL) remain unclear. Of some 1661 consecutively enrolled patients newly treated with entecavir or tenofovir, we analyzed 852 patients who underwent serial HBsAg level checks every 6-12 months. The primary outcomes included long-term kinetics in HBsAg levels and the rate of functional cure and achieving low HBsAg levels. Over a mean 6.3-year follow-up, the functional cure rate was 2.28% (n = 19), and 12.9% (n = 108) achieved low HBsAg levels. A significant HBsAg level reduction was seen in the first treatment year (p < 0.05), with another stepwise decrease between year 6-7. These trends were pronounced in patients with chronic hepatitis and HBeAg-positivity compared to those with cirrhosis and HBeAg-negativity, respectively. Baseline HBsAg of ≤3 log IU/mL and the first-year HBsAg reduction were key predictors for both functional cure and low HBsAg levels (p < 0.05). In conclusion, our findings elucidate the stepwise reduction in quantitative HBsAg dynamics during high-potency NA therapy (entecavir or tenofovir) along with variations based on different conditions. We also underscore the significance of quantitative HBsAg titer in predicting functional cure and low-HBsAg levels.

[Research progress on the role of hepatitis B virus DNA integration in chronic hepatitis B].

Chronic hepatitis B virus (HBV) infection will greatly contribute to raising the occurrence probability of cirrhosis and hepatocellular carcinoma in patients. Although existing antiviral treatment regimens have a certain effect on delaying disease progression and improving prognosis, it is still not effective in attaining functional cures. Hepatitis B virus DNA integration may be one of the reasons for this phenomenon. Therefore, this paper reviews the possible mechanisms of HBV DNA integration in maintaining chronic inflammation of the liver, evading existing antiviral treatment methods, and inducing hepatocellular carcinoma so as to further deepen the understanding of the role of HBV DNA integration in the occurrence and development of chronic hepatitis B, providing ideas and references for formulating better treatment strategies.

ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B.

BACKGROUND & AIMS: Factors predicting HBsAg seroclearance after treatment cessation, irrespective of nucleos(t)ide analogue (NA) resumption, have important clinical implications. We evaluated predictors of long-term HBsAg seroclearance after entecavir cessation. METHODS: This study followed-up Chinese patients with chronic hepatitis B from two previous studies of entecavir cessation. All patients were non-cirrhotic, HBeAg-negative, with undetectable HBV DNA (<20 IU/ml) at end-of-treatment (EOT). They were monitored closely for 48 weeks with regular HBV DNA, quantitative HBsAg (qHBsAg) and alanine aminotransferase (ALT) measurements. Entecavir was resumed at HBV DNA >2,000 IU/ml, irrespective of ALT levels. After the initial 48 weeks, patients were assessed every 6 months, regardless of entecavir resumption, to monitor for HBsAg seroclearance. RESULTS: A total of 194 patients (63.4% male, mean age 49.9 years, on entecavir for a median of 47.2 months) were recruited; 94 (48.5%) and 158 (81.4%) patients had EOT qHBsAg <100 IU/ml and <1,000 IU/ml, respectively; 151 (77.8%) patients were eventually resumed on entecavir. After follow-up for a median of 70.7 (51.0-118.2) months, 28 (14.4%) patients had HBsAg seroclearance. qHBsAg levels at weeks 36 and 48 after EOT independently predicted HBsAg seroclearance (both p <0.01), whereas qHBsAg from EOT to week 24 only trended towards statistical significance. The ratio of ALT/qHBsAg at all time points from EOT to week 48 independently predicted HBsAg seroclearance (hazard ratios ranging from 1.003-1.028, all p <0.01) with excellent diagnostic performance (area under the receiver-operating characteristic curve 0.799-0.933, negative predictive value >90% at different time points), regardless of whether entecavir was resumed. CONCLUSIONS: The ALT/qHBsAg ratio after entecavir cessation predicts HBsAg seroclearance, even in patients who were resumed on treatment. Its use may mitigate the risk of severe hepatitis flares in patients managed by observation without treatment resumption. IMPACT AND IMPLICATIONS: Current predictors of HBsAg seroclearance after finite nucleos(t)ide analogue (NA) therapy have suboptimal predictive value. We demonstrated that the ALT/qHBsAg ratio may be able to reflect the balance between host control and virological activity. The ALT/qHBsAg ratio at different time points from end-of-treatment till week 48 independently and accurately predicted HBsAg seroclearance in patients who have stopped entecavir. The ALT/qHBsAg ratio may be utilized by clinicians for patient selection and retreatment decisions in finite NA therapy.

Peg-IFNα combined with hepatitis B vaccination contributes to HBsAg seroconversion and improved immune function.

PURPOSE: The purpose of this study was to investigate immunological variations between a group that received the hepatitis B vaccine and a non-vaccine group. We focused on a cohort that achieved HBsAg seroclearance after Peg-IFNα treatment of CHB. METHODS: We enrolled twenty-eight individuals who achieved HBsAg seroclearance after Peg-IFNα treatment. They were divided into two groups: a vaccine group (n = 14) and a non-vaccine group (n = 14). We assessed lymphocyte subpopulations, B cell- and T cell-surface costimulatory/inhibitory factors, cytokines and immunoglobulin levels were detected at different time points to explore immune-function differences between both groups. RESULTS: The seroconversion rate in the vaccine group at 24 weeks post-vaccination was 100%, which was significantly higher (p = 0.006) than that of the non-vaccine group (50%). Additionally, more individuals in the vaccine group exhibited anti-HBs levels exceeding 100 IUs/L and 300 IUs/L compared to the non-vaccine group (p < 0.05). The vaccine group demonstrated significantly increase total B cells and class-switched B cells at 24 weeks and plasma cells, CD80+B cells, Tfh cells, and ICOS+Tfh cell at 12 weeks, compared with baseline levels (p < 0.05). Conversely, Bregs (CD24+CD27+ and CD24+CD38high) decreased significantly at 24 weeks (p < 0.05). None of the above changes were statistically significance in the non-vaccine group (p > 0.05). Total IgG increased significantly in the vaccine group, and IL-2, IL-5, and IL-6 concentrations increased significantly at week 24 (p < 0.05). Differences in various types of cytokines and immunoglobulins in the plasma of the non-vaccine group were not significant (p > 0.05). Anti-HBs titers positively correlated with Th1/Th2 cells at 24 weeks (r = 0.448 and 0.458, respectively, p = 0.022 and 0.019, respectively), and negatively with CD24+CD38highBreg cells (r = -0.402, p = 0.042). CONCLUSIONS: After achieving HBsAg seroclearance through Peg-IFNα treatment for CHB, administering the hepatitis B vaccine significantly increased anti-HBs-seroconversion rates and antibody levels. We also observed significant immunological differences between the vaccine and non-vaccine groups. Specifically, the vaccine group exhibited significant increases in B cells, plasma cells, and Tfh cells, while Breg levels was significantly lower. These immunological changes are likely conducive to the production of anti-HBs antibodies. However, in the non-vaccine group, the observed changes were not significantlly significant.

Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B.

BACKGROUND AND AIMS: Functional cure is difficult to achieve using current antiviral therapies; moreover, limited data are available regarding treatment outcomes in children. This retrospective study aimed to assess the frequency of functional cure among children undergoing antiviral treatment for active chronic hepatitis B (CHB). METHODS: A total of 372 children aged 1-16 years, with active CHB were enrolled and underwent either nucleos(t)ide analog monotherapy or combination therapy with interferon-α (IFN-α) for 24-36 months. All children attended follow-up visits every 3 months. Functional cure was defined as evidence of hepatitis B virus (HBV) DNA loss, circulating hepatitis B e antigen (HBeAg) loss/seroconversion, and hepatitis B surface antigen (HBsAg) loss. RESULTS: After 36 months of antiviral treatment and/or follow-up visits, children with CHB aged 1- < 7 years exhibited higher rates of HBV DNA clearance, HBeAg seroconversion, and HBsAg loss than CHB children ≥ 7-16 years of age (93.75% versus [vs.] 86.21% [p < 0.0001]; 79.30% vs. 51.72% [p < 0.0001]; and 50.78% vs. 12.93% [p < 0.0001], respectively). Longitudinal investigation revealed more rapid dynamic reduction in HBV DNA, HBeAg, and HBsAg levels in children aged 1-7 years than in those aged ≥ 7-16 years with CHB. According to further age-stratified analysis, HBsAg loss rates were successively decreased in children with CHB who were 1- < 3, 3- < 7, 7- < 12, and 12-16 years of age (62.61% vs. 41.13% vs. 25.45% vs. 1.64%, respectively; p < 0.0001) at 36 months. In addition, baseline HBsAg level < 1,500 IU/mL was found to favor disease cure among these pediatric patients. No serious adverse events were observed throughout the study period. CONCLUSION: Results of the present study demonstrated that children aged 1- < 7 years, with active CHB can achieve a high functional cure rate by undergoing antiviral therapy compared to those aged ≥ 7 years, who undergo antiviral therapy. These data support the use of antiviral treatment at an early age in children with CHB. However, future prospectively randomized controlled trials are necessary to validate the findings of this study.

Inhibition of cellular factor TM6SF2 suppresses secretion pathways of Hepatitis B, Hepatitis C and Hepatitis D viruses.

Chronic viral hepatitis is caused by hepatitis B virus, hepatitis C virus or hepatitis D virus (HBV, HCV, and HDV). Despite different replication strategies, all these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions and HBV subviral particles. Moreover, in a cohort of people with hepatitis B a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis.

Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.

Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.