User Experience of a Just-in-Time Smartphone Resonance Breathing Application for Substance Use Disorder: Acceptability, Appropriateness, and Feasibility.

BACKGROUND: Addressing the negative impact of substance use disorders (SUDs) on individuals, families, and communities is a public health priority. Most treatments and interventions require engagement with a healthcare provider or someone who can offer recovery support. The need for interventions that facilitate self-management of relapse triggers at the moment they occur is also critical. Our study aimed to explore the user experience of individuals using a just-in-time smartphone episodic resonance breathing (eRPB) intervention to address stress, anxiety, and drug cravings. METHODS: We conducted an 8-week pilot study of the eRPB with 30 individuals in recovery from SUD. Data on 3 indicators of user experience-acceptability, appropriateness, and feasibility-were collected using survey questions (n = 30) and semi-structured interviews (n = 11). We performed univariate analysis on the survey data and deductive thematic analysis on the qualitative data. RESULTS: A majority of the survey respondents agreed that the application (app) was acceptable (> 77%), appropriate (> 82%), and feasible (> 89%). Several interview participants stated that the app helped them relax and manage stress and cravings and expressed appreciation for the simplicity of its design. Participants also reported barriers to feasibility (such as forgetting to use the app) and recommendations for improvement (such as the addition of motivational messages). CONCLUSIONS: Our findings show that individuals in recovery from SUD had highly positive experiences with the eRPB app. A positive user experience may improve adherence to the intervention and, ultimately, the self-management of stress, anxiety, and craving relapse triggers.

Characterisation of HBV and co-infection with HDV and HIV through spatial transcriptomics.

Background and aims: The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection. Method: The NanoString GeoMx digital spatial profiling platform was employed to assess expression of HBV surface antigen and CD45 in formalin-fixed paraffin-embedded (FFPE) biopsies from three treatment-naïve patients with chronic HBV and HDV or HIV co-infection. The GeoMx Human Whole Transcriptome Atlas assay quantified the expression of genes enriched in specific regions of interest (ROIs). Cell type proportions within ROIs were deconvoluted using a training matrix from the human liver cell atlas. A weighted gene correlation network analysis evaluated transcriptomic signatures across sampled regions. Results: Spatially discrete transcriptomic signatures and distinct biological pathways were associated with HBV infection/disease status and immune responses. Shared features including 'cytotoxicity' and 'B cell receptor signalling' were consistent across patients, suggesting common elements alongside individual traits. HDV/HBV co-infection exhibited upregulated genes linked to apoptosis and immune cell recruitment, whereas HIV/HBV co-infection featured genes related to interferon response regulation. Varied cellular characteristics and immune cell populations, with an abundance of γδT cells in the HDV/HBV sample, were observed within analysed regions. Transcriptional differences in hepatocyte function suggest disrupted metabolic processes in HDV/HBV co-infection potentially impacting disease progression. Conclusion: This proof-of-principle study shows the value of this platform in investigating the complex immune landscape, highlighting relevant host pathways to disease pathogenesis.

Hepatitis B Virus DNA integration: Implications for diagnostics, therapy, and outcome.

HBV DNA integration originally recognized as a non-functional byproduct of the HBV life cycle has now been accepted as a significant contributor to HBV pathogenesis and HDV persistence. Integrated HBV DNA is derived from linear genomic DNA present in virus particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of HBsAg and HBx. DNA integration events accumulate over the course of viral infection ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infection. HBV DNA integration events have primarily been investigated in the context of HCC development where they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and presumably epigenetic alterations promoting tumor growth. More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response. Integrated DNA provides a source for envelope proteins required for HDV replication and hence represents a means for HDV persistence. Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection which relies on HBsAg as a diagnostic marker. Integrated HBV DNA has been useful in assessing the turnover of infected hepatocytes which occurs during all phases of chronic hepatitis B including the initial phase of infection historically termed immune tolerant. HBV DNA integration was also shown to impact the development of novel therapies targeting viral RNAs.

Evaluating GPT-V4 (GPT-4 with Vision) on Detection of Radiologic Findings on Chest Radiographs.

Background Generating radiologic findings from chest radiographs is pivotal in medical image analysis. The emergence of OpenAI's generative pretrained transformer, GPT-4 with vision (GPT-4V), has opened new perspectives on the potential for automated image-text pair generation. However, the application of GPT-4V to real-world chest radiography is yet to be thoroughly examined. Purpose To investigate the capability of GPT-4V to generate radiologic findings from real-world chest radiographs. Materials and Methods In this retrospective study, 100 chest radiographs with free-text radiology reports were annotated by a cohort of radiologists, two attending physicians and three residents, to establish a reference standard. Of 100 chest radiographs, 50 were randomly selected from the National Institutes of Health (NIH) chest radiographic data set, and 50 were randomly selected from the Medical Imaging and Data Resource Center (MIDRC). The performance of GPT-4V at detecting imaging findings from each chest radiograph was assessed in the zero-shot setting (where it operates without prior examples) and few-shot setting (where it operates with two examples). Its outcomes were compared with the reference standard with regards to clinical conditions and their corresponding codes in the International Statistical Classification of Diseases, Tenth Revision (ICD-10), including the anatomic location (hereafter, laterality). Results In the zero-shot setting, in the task of detecting ICD-10 codes alone, GPT-4V attained an average positive predictive value (PPV) of 12.3%, average true-positive rate (TPR) of 5.8%, and average F1 score of 7.3% on the NIH data set, and an average PPV of 25.0%, average TPR of 16.8%, and average F1 score of 18.2% on the MIDRC data set. When both the ICD-10 codes and their corresponding laterality were considered, GPT-4V produced an average PPV of 7.8%, average TPR of 3.5%, and average F1 score of 4.5% on the NIH data set, and an average PPV of 10.9%, average TPR of 4.9%, and average F1 score of 6.4% on the MIDRC data set. With few-shot learning, GPT-4V showed improved performance on both data sets. When contrasting zero-shot and few-shot learning, there were improved average TPRs and F1 scores in the few-shot setting, but there was not a substantial increase in the average PPV. Conclusion Although GPT-4V has shown promise in understanding natural images, it had limited effectiveness in interpreting real-world chest radiographs. © RSNA, 2024 Supplemental material is available for this article.

HIV/HBV coinfection remodels the immune landscape and natural killer cell ADCC functional responses.

BACKGROUND AND AIMS: HBV and HIV coinfection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to immune dysregulation including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. Here we used high-throughput single-cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV coinfection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets that can be therapeutically harnessed. APPROACH AND RESULTS: Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV coinfection was characterized by an over-representation of adaptive, KLRC2 -expressing NK cells, including a higher abundance of a chemokine-enriched ( CCL3/CCL4 ) adaptive cluster. The NK cell remodeling in HIV/HBV coinfection was reflected in enriched activation pathways, including CD3ζ phosphorylation and ZAP-70 translocation that can mediate stronger antibody-dependent cellular cytotoxicity responses and a bias toward chemokine/cytokine signaling. By contrast, HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of "exhaustion" with higher circulating levels of HBsAg. Phenotypic alterations in the NK cell pool in coinfection were consistent with increased "adaptiveness" and better capacity for antibody-dependent cellular cytotoxicity compared to HBV mono-infection. Overall, an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort. CONCLUSIONS: This study provides new insights into the differential signature and functional profile of NK cells in HBV and HIV/HBV coinfection, highlighting pathways that can be manipulated to tailor NK cell-focused approaches to advance HBV cure strategies in different patient groups.

Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.

Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here we describe the high-throughput, functional assessment of phosphorylation sites through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally resolved phosphoproteomics. Using T cell activation as a model, we observe hundreds of unstudied phosphorylation sites that modulate NFAT transcriptional activity. We identify the phosphorylation-mediated nuclear localization of PHLPP1, which promotes NFAT but inhibits NFκB activity. We also find that specific phosphosite mutants can alter gene expression in subtle yet distinct patterns, demonstrating the potential for fine-tuning transcriptional responses. Overall, base editor screening of PTM sites provides a powerful platform to dissect PTM function within signaling pathways.

A conceptual model for chronic hepatitis B and content validity of the Hepatitis B Quality of Life (HBQOL) instrument.

BACKGROUND: There is increased emphasis on incorporating patient perspectives and patient-relevant endpoints in drug development. We developed a conceptual model of the impact of chronic hepatitis B (CHB) on patients' lives and evaluated the content validity of the Hepatitis B Quality of Life (HBQOL) instrument, a patient-reported outcome tool for use in clinical studies, as a patient-relevant endpoint to measure health-related quality of life in patients with CHB. METHODS: A literature review of qualitative studies of patient experience with CHB and concept elicitation telephone interviews with patients with CHB in the United Kingdom were used to develop a conceptual model of the experience and impact of living with CHB. The content validity of the HBQOL was evaluated using cognitive debriefing techniques. RESULTS: The qualitative literature review (N = 43 publications) showed that patients with CHB experience emotional/psychological impacts. During concept elicitation interviews (N = 24), fatigue was the most commonly reported symptom, and most participants were worried/anxious about virus transmission and disease progression/death. A conceptual model of patients' experiences with CHB was developed. The conceptual relevance and comprehensibility of the HBQOL were supported, though limitations, including the lack of a self-stigma item and recall period, were noted for future improvement. CONCLUSIONS: The conceptual model shows that patients with CHB experience emotional/psychological impacts that affect their lifestyles, relationships, and work/schooling. The cognitive debriefing interviews support the content validity of the HBQOL as a conceptually relevant patient-reported outcome measure of health-related quality of life.

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.

The O- GlcNAc transferase OGT interacts robustly with all three mammalian TET methylcytosine dioxygenases. We show here that deletion of the Ogt gene in mouse embryonic stem cells (mESC) results in a widespread increase in the TET product 5-hydroxymethylcytosine (5hmC) in both euchromatic and heterochromatic compartments, with concomitant reduction of the TET substrate 5-methylcytosine (5mC) at the same genomic regions. mESC engineered to abolish the TET1-OGT interaction likewise displayed a genome-wide decrease of 5mC. DNA hypomethylation in OGT-deficient cells was accompanied by de-repression of transposable elements (TEs) predominantly located in heterochromatin, and this increase in TE expression was sometimes accompanied by increased cis -expression of genes and exons located 3' of the expressed TE. Thus, the TET-OGT interaction prevents DNA demethylation and TE expression in heterochromatin by restraining TET activity genome-wide. We suggest that OGT protects the genome against DNA hypomethylation and impaired heterochromatin integrity, preventing the aberrant increase in TE expression observed in cancer, autoimmune-inflammatory diseases, cellular senescence and ageing.

Mobile resonance frequency breathing smartphone application to support recovery among people with opioid use disorder: Study protocol for feasibility study.

BACKGROUND: Experiencing drug cravings is an aspect of substance use disorders that frequently compromises the recovery efforts of people who use drugs. Most treatment approaches that address drug cravings either involve cognitive strategies or medication. Few interventions directly address the physiological aspects of craving, such as increased heart rate. Previous research has demonstrated that slow-paced breathing may be effective in managing drug cravings by manipulating an individual's heart rate. The purpose of this paper is to describe a study protocol for an intervention that offers resonance frequency breathing training for managing cravings via a smartphone application (app). METHODS: This trial is registered in ClinicalTrials.gov (Identifier: NCT05830773). The intervention focuses on persons in recovery from opioid use disorder who receive services from the Texas Health and Human Service Commission Recovery Support Services division. Participants will be trained to use Camera Heart Rate Variability (CHRV), a resonance frequency breathing app. The CHRV app measures heart rate and the volumetric variations of blood circulation. When experiencing stress, anxiety, or cravings, participants will use the app to practice breathing exercises. Participants (N = 60) will also complete surveys at baseline, 4 weeks, and 8 weeks; the survey questions, covers demographic characteristics, personal trauma history, substance use experience, and utilization of substance use treatment services. The surveys will also include psychosocial measures of craving, stress, and anxiety to allow the study team to assess changes between baseline and study completion. Participants who complete the full 8-week intervention will be invited to participate in a 30-minute interview about their experience with the app. Interviews will provide details on implementation outcomes, including acceptability, appropriateness, and feasibility. CONCLUSION: Many evidence-based interventions for opioid use require interpersonal communication with individuals in one's recovery network. However, individuals may be unable to engage others in their recovery network in the moments when they are experiencing cravings or stress- and anxiety-related triggers. Therefore, recovery support interventions that emphasize individual self-management of cravings, stress, and anxiety when they occur can empower individuals in recovery and enhance existing interventions.

Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.

Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.

Association of hepatitis delta virus with liver morbidity and mortality: A systematic literature review and meta-analysis.

BACKGROUND AND AIMS: Studies have suggested that patients with chronic hepatitis B, either co- or superinfected, have more aggressive liver disease progression than those with the HDV. This systematic literature review and meta-analysis examined whether HDV RNA status is associated with increased risk of advanced liver disease events in patients who are HBsAg and HDV antibody positive. APPROACH AND RESULTS: A total of 12 publications were included. Relative rates of progression to advanced liver disease event for HDV RNA+/detectable versus HDV RNA-/undetectable were extracted for analysis. Reported OR and HRs with 95% CI were pooled using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. The presence of HDV RNA+ was associated with an increased risk of any advanced liver disease event [random effect (95% CI): risk ratio: 1.48 (0.93, 2.33); HR: 2.62 (1.55, 4.44)]. When compared to the patients with HDV RNA- status, HDV RNA+ was associated with a significantly higher risk of progressing to compensated cirrhosis [risk ratio: 1.74 (1.24, 2.45)] decompensated cirrhosis [HR: 3.82 (1.60, 9.10)], HCC [HR: 2.97 (1.87, 4.70)], liver transplantation [HR: 7.07 (1.61, 30.99)], and liver-related mortality [HR: 3.78 (2.18, 6.56)]. CONCLUSIONS: The patients with HDV RNA+ status have a significantly greater risk of liver disease progression than the patients who are HDV RNA-. These findings highlight the need for improved HDV screening and linkage to treatment to reduce the risk of liver-related morbidity and mortality.

Evaluation of the Panbio™ COVID-19 IgG rapid test device performance.

Background: The Panbio™ COVID-19 IgG Rapid Test Device ("Panbio™") detects IgG antibodies against the SARS-CoV-2 spike protein from viral infection or vaccination. Objectives: To determine the diagnostic sensitivity and specificity of the Panbio™ professional use test, using fingerstick whole blood and venous plasma. Study design: Fingerstick whole blood and venous plasma from each participant were tested with Panbio™ and compared against the SARS-CoV-2 IgG II assay on the Abbott Architect™ platform (Europe) or the equivalent AdviseDx SARS-CoV-2 IgG II Abbott Alinity i™ platform (US). 447 evaluable participants were enrolled across 6 US and 9 European clinical centers. Results: For unvaccinated participants with PCR-confirmed infection ≥21 days post-symptom onset, the Panbio™ sensitivity with fingerstick whole blood was 92.6 % (95 % CI: 85.9, 96.7), and the specificity was 97.0 % (95 % CI: 93.1, 99.0). For venous plasma, the sensitivity was 90.0 % (95 % CI: 79.5, 96.2) for participants with PCR-confirmed infection and symptom onset 22-180 days ago; the specificity was 96.3 % (92.2, 98.6). For vaccinated participants, the sensitivity was 98.4 % (95 % CI: 91.2, 100.0) for fingerstick whole blood and 96.7 % (95 % CI: 88.7, 99.6) for venous plasma. Conclusion: The Panbio™ test had high sensitivity and specificity for detecting IgG against the SARS-CoV-2 spike protein.

Measuring Instructional Interactions During Reading Instruction for Students Receiving Intervention in Middle School.

More than two-thirds of middle school students do not read proficiently. Research has shown that targeted interventions using explicit instruction methods can improve reading outcomes for struggling readers. A central feature of explicit instruction is the systematic implementation of instructional interactions, but it is not clear what specific instructional interaction practices lead to stronger outcomes for middle school readers. This study used a regression discontinuity design to compare the frequency and impact of instructional interactions experienced by eighth-grade students who received a targeted reading intervention (n = 1,461) with those who did not (n = 4,292). Results indicated that students who received intervention experienced far more instructional interactions with their teachers than did students who did not. However, the association between rates of interaction and student need in the intervention group was minimal, and the relationship between the rate of instructional interactions and reading growth was mixed. Implications for intervening with struggling students in the middle grades are discussed.

Proteome-wide base editor screens to assess phosphorylation site functionality in high-throughput.

Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here, we describe "signaling-to-transcription network" mapping through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally-resolved phosphoproteomics. Using T cell activation as a model, we observe hundreds of unstudied phosphorylation sites that modulate NFAT transcriptional activity. We identify the phosphorylation-mediated nuclear localization of the phosphatase PHLPP1 which promotes NFAT but inhibits NFκB activity. We also find that specific phosphosite mutants can alter gene expression in subtle yet distinct patterns, demonstrating the potential for fine-tuning transcriptional responses. Overall, base editor screening of PTM sites provides a powerful platform to dissect PTM function within signaling pathways.

Evaluation of the HBV liver reservoir with fine needle aspirates.

Background & Aims: Finite duration of treatment associated with HBsAg loss is the current goal for improved therapeutic approaches against chronic HBV infection, as it indicates elimination or durable inactivation of intrahepatic covalently closed circular DNA (cccDNA). To assist drug development, the definition of early predictive markers of HBsAg loss by assessing their value in reflecting intrahepatic cccDNA levels and transcriptional activity is essential. Fine needle aspirates (FNAs) have recently emerged as a less invasive alternative to core liver biopsy (CLB) and showed to be useful for investigating intrahepatic immune responses. The aim of this study was to optimise and validate the use of FNA vs. CLB to evaluate the intrahepatic viral reservoir. Methods: Paired FNA/CLB samples were obtained from patients with HBeAg+ chronic hepatitis (n = 4), HBeAg- chronic hepatitis (n = 4), and HBeAg- chronic infection (n = 1). One HBeAg+ patient was undergoing tenofovir treatment. HBV 3.5-kb RNA and cccDNA were quantified by droplet digital PCR. Results: cccDNA was quantifiable in all but one FNA/CLB pair, showing the highest levels in untreated HBeAg+ patients, except for the tenofovir-treated patient. Similarly, 3.5-kb RNA was detectable in all but one FNA sample and showed higher levels in HBeAg+ patients. When comparing cccDNA and 3.5-kb RNA quantification in FNA vs. CLB samples, no statistically significant differences were identified. Conclusions: These results demonstrate the possibility to quantify cccDNA and assess its transcriptional activity in patients with chronic hepatitis B by combining FNA and droplet digital PCR. This supports the use of FNA in clinical trials to evaluate the intrahepatic viral reservoir during the development of new antivirals and immunomodulatory agents. Impact and implications: Chronic hepatitis B infection is characterised by a complex interplay between immune responses and viral replication in the liver, which determines the long-term outcome of the disease. In this study, we show that fine needle aspiration of the liver, a less-invasive alternative to core biopsies, allows the assessment of the hepatic viral reservoir.

Utility of novel viral and immune markers in predicting HBV treatment endpoints: A systematic review of treatment discontinuation studies.

Background & Aims: Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term therapy. Treatment discontinuation has emerged as a strategy to maintain partial cure and achieve functional cure in select patient groups. We aimed to evaluate how data from treatment discontinuation studies exploring novel viral and/or immune markers could be applied to the functional cure program. Methods: Treatment discontinuation studies evaluating novel viral and/or immune markers were identified by a systematic search of the PubMed database through to October 30, 2022. Data extraction focused on information regarding novel markers, including identified cut-off levels, timing of measurement, and associated effect on study outcomes of virological relapse, clinical relapse, and HBsAg seroclearance. Results: From a search of 4,492 citations, 33 studies comprising a minimum of 2,986 unique patients met the inclusion criteria. Novel viral markers, HBcrAg and HBV RNA, were demonstrated across most studies to be helpful in predicting off-therapy partial cure, with emerging evidence to support a link with functional cure. From novel immune marker studies, we observed that treatment discontinuation has the potential to trigger immune restoration, which may be associated with a transient virological relapse. To this end, these studies support the combination of virus-directing agents with immunomodulator therapies to induce two key steps underlying functional cure: viral antigen load reduction and restoration of the host immune response. Conclusions: Patients with a favourable profile of novel viral and immune markers stand to benefit from a trial of antiviral treatment discontinuation alongside novel virus-directing agents with the aim of achieving functional cure without excessive risk of severe clinical relapse. Impact and implications: Select patients with chronic hepatitis B undergoing nucleoside analogue therapy may benefit from a trial of treatment discontinuation, aiming to maintain partial cure and/or achieve functional cure. We propose a profile of novel viral and immune markers to identify patients who are likely to achieve these goals without excessive risk of hepatic decompensation. Furthermore, treatment discontinuation may also be considered as a therapeutic strategy to trigger immune restoration, which may increase the chance of functional cure when used in conjunction with novel virus-directing agents.

Evidence for Benefits of Early Treatment Initiation for Chronic Hepatitis B.

Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Antiviral treatment reduces the risk of HCC and mortality; nonetheless, globally in 2019, only 2.2% of CHB patients received treatment. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage. This contrasts with hepatitis C or HIV where early treatment is recommended in all infected patients, regardless of end-organ damage. This narrative review aims to provide an overview of data on the early initiation of antiviral treatment and its related potential economic impact. Literature searches were performed using PubMed and abstracts from international liver congresses (2019-2021). Data on risk of disease progression and HCC and the impact of antiviral treatment in currently ineligible patients were summarized. Cost-effectiveness data on early antiviral treatment initiation were also collated. Accumulating molecular, clinical, and economic data suggest that early initiation of antiviral treatment could save many lives through HCC prevention in a highly cost-effective manner. In light of these data, we consider several alternative expanded treatment strategies that might further a simplified 'treatment as prevention' approach.