Medically Tailored Meals for Patients With Cirrhosis and Hepatic Encephalopathy: The BRAINFOOD Proof-of-concept Trial.

Background and aims: Guidelines recommend that patients with hepatic encephalopathy (HE) receive a high-protein diet (roughly 1 g/kg actual body weight). Concommitant sodium restriction, low health literacy, and food insecurity limit patients' ability to meet this goal. We aimed to determine the feasibility of home-delivered high-protein medically tailored meals (MTMs) for patients with a recent episode of overt HE. Methods: We enrolled patients with prior overt HE on active HE therapy in a 6-month trial of MTM. All received 21 home-delivered meals/week with protein snacks (mid-day and bedtime) for 12 weeks. Patients completed follow-up at week 24. The primary outcome was feasibility. Additional outcomes included change in protein and micronutrient intake (measured using 24 h dietary recalls performed by dieticians), cognitive function (Animal Naming Test [ANT]; EncephalApp Stroop), physical function (Liver Frailty Index [LFI]), and quality of life (Short Form-8 Health Survey [SF-8]). Healthcare utilization was also assessed. Results: Ten patients competed the study with >90% of MTM consumed. Protein intake rose from 74.6 ± 25.1 g at baseline to 93.8 ± 24.3 g on MTM (P = 0.04). Branched-chain amino acids also increased-valine 3.73 ± 1.26 g to 5.17 ± 1.28 g, isoleucine 3.32 ± 1.18 to 4.69 ± 1.55, leucine 5.83 ± 2.00 to 7.49 ± 2.07, all P < 0.001. The LFI score improved from 4.42 ± 0.32 to 3.96 ± 0.82 by the end of the MTM phase (P = 0.03). SF-8 quality-of-life scores improved from 55.5 ± 15.5 at baseline to 64.7 ± 18.3 after the MTM phase, to 64.4 ± 19.1 at the end of the study (P = 0.1). EncephalApp Stroop time improved from 227 ± 94 to 194 ± 58s by the end of the MTM phase (P = 0.08). ANT scores were similarly non-significantly improved. Conclusion: Home-delivered MTMs are feasible, increase protein consumption, and may improve patient wellbeing. A randomized trial is needed.

Toward a Functional Cure for Hepatitis B.

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Improving alcohol treatment engagement using integrated behavioral interventions in alcohol-associated liver disease: A randomized pilot trial.

INTRODUCTION: Alcohol cessation improves mortality in alcohol-associated liver disease (ALD), but few ALD patients will engage in treatment. We aimed to demonstrate the feasibility and acceptability of a mobile health intervention to increase alcohol use disorder (AUD) treatment among ALD patients. METHODS: We conducted a pilot randomized controlled trial (September 2020 to June 2022) at a single tertiary care center in adults with any stage of ALD, past 6-month drinking, and no past-month AUD treatment. Sixty participants were randomized 1:1 to a mobile health application designed to increase AUD treatment engagement through preference elicitation and matching to treatment and misconception correction. Controls received enhanced usual care. The primary outcomes were feasibility (recruitment and retention rates) and acceptability. Exploratory outcomes were AUD treatment engagement and alcohol use, measured by Timeline Followback. Outcomes were measured at 3 and 6 months. RESULTS: Baseline characteristics were balanced. The recruitment rate was 46%. Retention was 65% at 6 months. The intervention was highly acceptable to participants (91% were mostly/very satisfied; 95% felt that the intervention matched them well to AUD treatment). Secondary outcomes showed increased AUD treatment at 6 months in the intervention group (intent-to-treat: 27.3% vs. 13.3%, OR 2.3, 95% CI, 0.61-8.76). There was a trend toward a 1-level or greater reduction in World Health Organization (WHO) drinking risk levels in the intervention group (OR 2.25, 95% CI, 0.51-9.97). CONCLUSIONS: A mobile health intervention for AUD treatment engagement was highly feasible, acceptable, and produced promising early outcomes, with improved AUD treatment engagement and alcohol reduction in ALD patients.

What will it take to cure hepatitis B?

The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.

Hepatitis B.

Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.

Higher mortality among lean patients with non-alcoholic fatty liver disease despite fewer metabolic comorbidities.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can develop in individuals who are not overweight. Whether lean persons with NAFLD have lower mortality and lower incidence of cirrhosis, cardiovascular diseases (CVD), diabetes mellitus (DM) and cancer than overweight/obese persons with NAFLD remains inconclusive. We compared mortality and incidence of cirrhosis, CVD, DM and cancer between lean versus non-lean persons with NAFLD. METHODS: This is a retrospective study of adults with NAFLD in a single centre from 2012 to 2021. Primary outcomes were mortality and new diagnosis of cirrhosis, CVD, DM and cancer. Outcomes were modelled using competing risk analysis and Cox proportional hazards regression analysis. RESULTS: A total of 18,594 and 13,420 patients were identified for cross-sectional and longitudinal analysis respectively: approximately 11% lean, 25% overweight, 28% class 1 obesity and 35% class 2-3 obesity. The median age was 51.0 years, 54.6% were women. The median follow-up was 49.3 months. Lean patients had lower prevalence of metabolic diseases at baseline and lower incidence of cirrhosis and DM than non-lean patients and no difference in CVD, any cancer or obesity-related cancer during follow-up. However, lean patients had significantly higher mortality with incidence per 1000 person-years of 16.67, 10.11, 7.37 and 8.99, respectively, in lean, overweight, obesity class 1 and obesity class 2-3 groups respectively. CONCLUSIONS: Lean patients with NAFLD had higher mortality despite lower incidence of cirrhosis and DM, and similar incidence of CVD and cancer and merit similar if not more attention as non-lean patients with NAFLD.

Hepatitis B RNA and Core-Related Antigen Provide Value Beyond DNA in Evaluating e But Not Surface Antigen Clearance.

In chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) clearance are important milestones toward immune control.1 A drop in HBV DNA is an established correlate of both HBeAg and HBsAg clearance.2 We evaluated changes in HBV RNA and hepatitis B core-related antigen (HBcrAg) levels, markers of transcriptional activity of covalently closed circular DNA (cccDNA),3,4 with HBeAg and HBsAg clearance, and compared them with changes in HBV DNA level among adult participants in the Hepatitis B Research Network (HBRN).

How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?

Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.

A multivariate parametric empirical Bayes screening approach for early detection of hepatocellular carcinoma using multiple longitudinal biomarkers.

The early detection of hepatocellular carcinoma (HCC) is critical to improving outcomes since advanced HCC has limited treatment options. Current guidelines recommend HCC ultrasound surveillance every 6 months in high-risk patients however the sensitivity for detecting early stage HCC in clinical practice is poor. Blood-based biomarkers are a promising direction since they are more easily standardized and less resource intensive. Combining of multiple biomarkers is more likely to achieve the sensitivity required for a clinically useful screening algorithm and the longitudinal trajectory of biomarkers contains valuable information that should be utilized. We propose a multivariate parametric empirical Bayes (mPEB) screening approach that defines personalized thresholds for each patient at each screening visit to identify significant deviations that trigger additional testing with more sensitive imaging. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial provides a valuable source of data to study HCC screening algorithms. We study the performance of the mPEB algorithm applied to serum α -fetoprotein, a widely used HCC surveillance biomarker, and des- γ carboxy prothrombin, an HCC risk biomarker that is FDA approved but not used in practice in the United States. Using cross-validation, we found that the mPEB algorithm demonstrated moderate but improved sensitivity compared to alternative screening approaches. Future research will validate the clinical utility of the approach in larger cohort studies with additional biomarkers.

Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America.

BACKGROUND AND AIMS: The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear. APPROACH AND RESULTS: Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log10 IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg+ and 58% of HBeAg- participants; HBcrAg was quantifiable in 20% of HBeAg+ (above linear range in the other 80%) and 51% of HBeAg- participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg+ and HBeAg- immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg+ and HBeAg- phases (HBV RNA: e+ ρ = 0.84; e- ρ = 0.78; HBcrAg: e+ ρ = 0.66; e- ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg+ phases only (HBV RNA: e+ ρ = 0.71; P < 0.001; e- ρ = 0.18; P = 0.56; HBcrAg: e+ ρ = 0.51; P < 0.001; e- ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg- , but not HBeAg+ , phases. CONCLUSIONS: Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.

Feasibility and early experience of a novel multidisciplinary alcohol-associated liver disease clinic.

BACKGROUND: Alcohol cessation improves mortality in alcohol-associated liver disease (ALD), but access to treatment is limited. To address this gap, implementation and early feasibility and outcomes of a multidisciplinary ALD clinic are described. METHODS: The clinic comprised a hepatologist, psychiatrist, psychologist, nurse, and social worker. Patients included those with alcohol-associated cirrhosis or acute alcoholic hepatitis who were not in the transplant evaluation process, who had less than 6 months' sobriety and willingness to engage in alcohol use treatment. Psychosocial metrics in addition to routine hepatic function labs were collected. Treatment plans were tailored based on patient preferences and needs after multidisciplinary discussion. RESULTS: 89 patients were referred from both inpatient and outpatient settings, with 51 seen during the initial year. 38 remained active in clinic (4 died, 6 discharged, 3 moved to transplant clinic). 55% were women, 88% were white, 61% had private insurance. 49% had alcoholic hepatitis. 71% were decompensated. 80% had severe alcohol use disorder (AUD) and 84% had at least 1 comorbid psychiatric or substance use disorder. 63% chose one-on-one AUD treatment, 57% were prescribed relapse prevention medications. Mean MELD-Na score improved from baseline of 14 (SD 6.6) to 11.3 at 6 months (p=0.01). Hospital utilization significantly declined when comparing 6 months before to 6 months after initial visit (emergency department visits: 0.51 to 0.20 per person-month; inpatient admission: 0.34 to 0.14 per person-month; (ß= -0.89, 95% CI -1.18 to -0.60). CONCLUSIONS: A multidisciplinary ALD clinic was feasible with encouraging early outcomes. Further research should explore ways to expand this model and increase clinic capacity.

The 2020 Nobel Prize for Medicine or Physiology for the Discovery of Hepatitis C Virus: A Triumph of Curiosity and Persistence.

The 2020 Nobel Prize in Medicine or Physiology was awarded to Drs. Harvey Alter, Michael Houghton, and Charles Rice for their contributions to the discovery and characterization of the hepatitis C virus (HCV). Their achievements represent a remarkable triumph of biomedical science which allowed the development of curative therapy for HCV, that will save countless lives. This tribute provides a historical perspective of the laureates' seminal work leading to the discovery of the HCV and a synopsis of a forum hosted by the American Association for the Study of Liver Diseases to honor the laureates in which they offered their perspectives, advice for young investigators and what's left to accomplish in the field. Finally, others in the research community who have worked closely with one or more of the laureates, share some of their personal reflections and anecdotes.

Bariatric surgery and the risk of alcohol-related cirrhosis and alcohol misuse.

BACKGROUND & AIMS: Bariatric surgery is common, but alcohol misuse has been reported following these procedures. We aimed to determine if bariatric surgery is associated with increased risk of alcohol-related cirrhosis (AC) and alcohol misuse. METHODS: Retrospective observational analysis of obese adults with employer-sponsored insurance administrative claims from 2008 to 2016. Subjects with diagnosis codes for bariatric surgery were included. Primary outcome was risk of AC. Secondary outcome was risk of alcohol misuse. Bariatric surgery was divided into before 2008 and after 2008 to account for patients who had a procedure during the study period. Cox proportional hazard regression models using age as the time variable were used with interaction analyses for bariatric surgery and gender. RESULTS: A total of 194 130 had surgery from 2008 to 2016 while 209 090 patients had bariatric surgery prior to 2008. Age was 44.1 years, 61% women and enrolment was 3.7 years. A total of 4774 (0.07%) had AC. Overall risk of AC was lower for those who received sleeve gastrectomy and laparoscopic banding during the study period (HR 0.4, P <.001; HR 0.43, P =.02) and alcohol misuse increased for Roux-en-Y and sleeve gastrectomy recipients (HR 1.86 and 1.35, P <.001, respectively). In those who had surgery before 2008, women had increased risk of AC and alcohol misuse compared to women without bariatric surgery (HR 2.1 [95% CI: 1.79-2.41] for AC; HR 1.98 [95% CI 1.93-2.04]). CONCLUSIONS: Bariatric surgery is associated with a short-term decreased risk of AC but potential long-term increased risk of AC in women. Post-operative alcohol surveillance is necessary to reduce this risk.

Appropriate and Potentially Inappropriate Medication Use in Decompensated Cirrhosis.

BACKGROUND AND AIMS: Patients with decompensated cirrhosis are prescribed numerous medications. Data are limited as to whether patients are receiving medications they need and avoiding those they do not. We examined a large national claims database (2010-2015) to characterize the complete medication profile as well as the factors associated with appropriate and potentially inappropriate medication use in 12,621 patients with decompensated cirrhosis. APPROACH AND RESULTS: Clinical guidelines and existing literature were used to determine appropriate and potentially inappropriate medications in decompensated cirrhosis. The total medication days' supply was calculated from pharmacy data and divided by the follow-up period for each decompensation. Ascites was the most common (86.5%), followed by hepatic encephalopathy (HE; 37.8%), variceal bleeding (VB; 17.5%), hepatorenal syndrome (6.3%), and spontaneous bacterial peritonitis (SBP; 6.1%). For patients with ascites, 55.8% filled a diuretic. For patients with HE, 32.4% and 63.3% filled rifaximin and lactulose, respectively. After VB, 60.3% of patients filled a nonselective beta blocker, and after an episode of SBP, 48.0% of patients filled an antibiotic for prophylaxis. The minority (4.5%-17.3%) had enough medication to cover >50% follow-up days. Potentially inappropriate medication use was common: 53.2% filled an opiate, 46.0% proton pump inhibitors, 14.2% benzodiazepines, and 10.1% nonsteroidal anti-inflammatory drugs. Disease severity markers were associated with more appropriate mediation use but not consistently associated with less inappropriate medication use. CONCLUSIONS: Patients with decompensated cirrhosis are not filling indicated medications as often or as long as is recommended and are also filling medications that are potentially harmful. Future steps include integrating pharmacy records with medical records to obtain a complete medication list and counseling on medication use with patients at each visit.

Prevalence and clinical features of patients with concurrent HBsAg and anti-HBs: Evaluation of the hepatitis B research network cohort.

The prevalence of concurrent HBsAg and anti-HBs in plasma of persons with chronic hepatitis B virus (HBV) infection is variable and its clinical significance enigmatic. We examined the prevalence and clinical and virological features of concurrent HBsAg and anti-HBs in children and adults with chronic HBV infection living in North America. A total of 1462 HBsAg positive participants in the Hepatitis B Research Network paediatric and adult cohorts were included (median age 41 (range 4-80) years, 48% female, 11% white, 13% black, 73% Asians). Only 18 (1.2%) were found to be anti-HBs positive (≥10 mIU/mL) at initial study evaluation. Distributions of sex, race, HBV genotype and ALT were similar between participants with and without concurrent anti-HBs. Those who were anti-HBs positive appeared to be older (median age 50 vs 41 years, P = .06), have lower platelet counts (median 197 vs 222 × 103/mm3 , P = .07) and have higher prevalence of HBeAg (44% vs 26%, P = .10). They also had lower HBsAg levels (median 2.0 vs 3.5 log10 IU/mL, P = .02). Testing of follow-up samples after a median of 4 years (range 1-6) in 12 of the 18 participants with initial concurrent anti-HBs showed anti-HBs became undetectable in 6, decreased to <10 mIU/mL in 1 and remained positive in 5 participants. Two patients lost HBsAg during follow-up. In conclusion, prevalence of concurrent HBsAg and anti-HBs was low at 1.2%, with anti-HBs disappearing in some during follow-up, in this large cohort of racially diverse children and adults with chronic HBV infection living in North America. Presence of concurrent HBsAg and anti-HBs did not identify a specific phenotype of chronic hepatitis B, nor did it appear to affect clinical outcomes.

Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad.

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares might occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and might mark transitions to inactive disease or clearance of infection, but in certain scenarios they might also lead to hepatic decompensation or death. As such, understanding of the clinical significance of flares in different patient populations and different scenarios is important for optimal management. In this Review, we summarise what is known about flares in different stages of chronic HBV infection; describe flares in the context of the natural history of chronic infection; summarise the immunological mechanisms underlying flares, and describe flares in different clinical scenarios. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve the understanding of flares, hopefully providing insights into their pathogenesis that can be used to improve current clinical management and ideally to further develop new curative therapeutic approaches for HBV infection. We also propose a working definition of an ALT flare to facilitate future research.

Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B.

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.