Imputation-based Q-learning for optimizing dynamic treatment regimes with right-censored survival outcome.

Q-learning has been one of the most commonly used methods for optimizing dynamic treatment regimes (DTRs) in multistage decision-making. Right-censored survival outcome poses a significant challenge to Q-Learning due to its reliance on parametric models for counterfactual estimation which are subject to misspecification and sensitive to missing covariates. In this paper, we propose an imputation-based Q-learning (IQ-learning) where flexible nonparametric or semiparametric models are employed to estimate optimal treatment rules for each stage and then weighted hot-deck multiple imputation (MI) and direct-draw MI are used to predict optimal potential survival times. Missing data are handled using inverse probability weighting and MI, and the nonrandom treatment assignment among the observed is accounted for using a propensity-score approach. We investigate the performance of IQ-learning via extensive simulations and show that it is more robust to model misspecification than existing Q-Learning methods, imputes only plausible potential survival times contrary to parametric models and provides more flexibility in terms of baseline hazard shape. Using IQ-learning, we developed an optimal DTR for leukemia treatment based on a randomized trial with observational follow-up that motivated this study.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Immunostaining for hepatitis B viral antigens in liver: Association with clinical, biochemical, and virologic features of disease.

BACKGROUND AND AIM: Staining for hepatitis B viral antigens is often done in liver biopsies from patients with chronic hepatitis B, but its correlates with clinical phenotypes are not well described. METHODS: Biopsies were collected from a large cohort of adults and children with chronic hepatitis B viral infection through the Hepatitis B Research Network. Immunohistochemical staining of sections was done for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) and then centrally read by the pathology committee. The degree of liver injury and pattern of staining were then correlated with clinical characteristics, including the clinical phenotype of hepatitis B. RESULTS: Biopsies from 467 subjects were studied, including 46 from children. Immunostaining for HBsAg was positive in 417 (90%) with scattered hepatocyte staining being the most common pattern. HBsAg staining correlated best with serum levels of HBsAg and hepatitis B viral DNA; the absence of HBsAg staining was often a prelude to loss of HBsAg from serum. HBcAg staining was positive in 225 (49%), and, while cytoplasmic staining was more frequent than nuclear staining, both nuclear and cytoplasmic positivity were often seen in the same specimen. Staining for HBcAg correlated with both level of viremia and liver injury. No biopsies from inactive carriers had stainable HBcAg, while 91% of the biopsies from those with hepatitis B e antigen-positive chronic hepatitis B stained positively for HBcAg. CONCLUSION: Immunostaining for hepatitis B viral antigens may yield helpful insights into liver disease pathogenesis but appears to add little to commonly used serological and biochemical blood tests.

Withdrawal of Long-Term Nucleotide Analog Therapy in Chronic Hepatitis B: Outcomes From the Withdrawal Phase of the HBRN Immune Active Treatment Trial.

INTRODUCTION: Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn. METHODS: Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA <10 3 IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria. RESULTS: Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (>5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P < 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal. DISCUSSION: Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log 10 IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss.

Association between serum periostin levels and the severity of arsenic-induced skin lesions.

Arsenic is a potent environmental toxicant and human carcinogen. Skin lesions are the most common manifestations of chronic exposure to arsenic. Advanced-stage skin lesions, particularly hyperkeratosis have been recognized as precancerous diseases. However, the underlying mechanism of arsenic-induced skin lesions remains unknown. Periostin, a matricellular protein, is implicated in the pathogenesis of many forms of skin lesions. The objective of this study was to examine whether periostin is associated with arsenic-induced skin lesions. A total of 442 individuals from low- (n = 123) and high-arsenic exposure areas (n = 319) in rural Bangladesh were evaluated for the presence of arsenic-induced skin lesions (Yes/No). Participants with skin lesions were further categorized into two groups: early-stage skin lesions (melanosis and keratosis) and advanced-stage skin lesions (hyperkeratosis). Drinking water, hair, and nail arsenic concentrations were considered as the participants' exposure levels. The higher levels of arsenic and serum periostin were significantly associated with skin lesions. Causal mediation analysis revealed the significant effect of arsenic on skin lesions through the mediator, periostin, suggesting that periostin contributes to the development of skin lesions. When skin lesion was used as a three-category outcome (none, early-stage, and advanced-stage skin lesions), higher serum periostin levels were significantly associated with both early-stage and advanced-stage skin lesions. Median (IQR) periostin levels were progressively increased with the increasing severity of skin lesions. Furthermore, there were general trends in increasing serum type 2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and immunoglobulin E (IgE) levels with the progression of the disease. The median (IQR) of IL-4, IL-5, IL-13, eotaxin, and IgE levels were significantly higher in the early-and advanced-stage skin lesions compared to the group of participants without skin lesions. The results of this study suggest that periostin is implicated in the pathogenesis and progression of arsenic-induced skin lesions through the dysregulation of type 2 immune response.

A series of two-sample non-parametric tests for quantile residual life time.

Quantile residual lifetime (QRL) is of significant interest in many clinical studies as an easily interpretable quantity compared to other summary measures of survival distributions. In cancer or other chronic diseases, treatments are often compared based on the distributions or quantiles of the residual lifetime. Thus a common problem of interest is to test the equality of the QRL between two populations. In this paper, we propose two classes of tests to compare two QRLs; one class is based on the difference between two estimated QRLs, and the other is based on the estimating function of the QRL, where the estimated QRL from one sample is plugged into the QRL-estimating-function of the other sample. We outline the asymptotic properties of these test statistics. Simulation studies demonstrate that the proposed tests produced Type I errors closer to the nominal level and are superior to some existing tests based on both Type I error and power. Our proposed test statistics are also computationally less intensive and more straightforward compared to tests based on the confidence intervals. We applied the proposed methods to a randomized multicenter phase III trial for breast cancer patients.

Acute Hepatitis B Virus Infection in North American Adults.

BACKGROUND & AIMS: Acute hepatitis B virus (aHBV) is thought to be self-limited with clearance of hepatitis B surface antigen (HBsAg) within 6 months. There are limited reports of the presenting features and outcomes of adults with symptomatic aHBV in the United States. METHODS: Demographics, clinical features, and 12-month outcomes of patients with adjudicated aHBV were captured prospectively and compared with a contemporaneous cohort of chronic HBV (cHBV) patients enrolled in the Hepatitis B Research Network. RESULTS: Between 2011 and 2018, 60 adjudicated patients with aHBV were compared with 1534 cHBV untreated controls. Although similar in age, other features were dissimilar: aHBV patients were more often male (72% vs 51%), single (72% vs 30%), and non-Hispanic whites or blacks (75% vs 24%). They also were frequently genotype A2 (65% vs 9%), having different risk factors: sexual exposure (75% vs 16%) or injection drug use (10% vs 2%), compared with the cHBV controls. In addition to higher serum aminotransferase and bilirubin levels, acute patients had higher HBV DNA levels (4.8 vs 3.6 log10 IU/mL), whereas quantitative hepatitis B e antigen (HBeAg) levels were lower (1.4 vs 3.0 log10 IU/mL), despite higher rates of HBeAg (73% vs 25%). The median time to HBsAg clearance was 27 weeks and to anti-HBs appearance, 41 weeks. CONCLUSIONS: In the current era, caucasian men infected with genotype A2 as a result of sexual exposure or injection drug use were the predominant group in aHBV, suggesting a potential strategy for adult vaccination in North America. Strikingly, only an estimated 36% of subjects cleared HBsAg by month 6; the definition of resolution in acute hepatitis B may need to be modified. ClinicalTirals.gov number NCT01263587.

Weighted Bayesian Poisson Regression for The Number of Children Ever Born per Woman in Bangladesh.

Number of children ever born to women of reproductive age forms a core component of fertility and is vital to the population dynamics in any country. Using Bangladesh Multiple Indicator Cluster Survey 2019 data, we fitted a novel weighted Bayesian Poisson regression model to identify multi-level individual, household, regional and societal factors of the number of children ever born among married women of reproductive age in Bangladesh. We explored the robustness of our results using multiple prior distributions, and presented the Metropolis algorithm for posterior realizations. The method is compared with regular Bayesian Poisson regression model using a Weighted Bayesian Information Criterion. Factors identified emphasize the need to revisit and strengthen the existing fertility-reduction programs and policies in Bangladesh. Supplementary Information: The online version contains supplementary material available at 10.1007/s44199-022-00044-2.

Effect of HCV or HIV infection on mortality among hospitalized persons who used opioids, 2000-2010.

Mortality due to opioid misuse and overdose has increased substantially in the United States over the past two decades. The study objective was to describe the causes of death among persons with opioid-related hospitalizations and examine survival by Hepatitis C virus (HCV) or HIV. Opioid-related hospitalization records in Pennsylvania from 2000 to 2010 were linked to death registry files to assess cause of death, and survival from first hospital discharge date to death date, or December 31, 2010. Accelerated failure time models were used to compare survival between persons with and without HCV or HIV diagnoses. Among the 136,416 individuals with an opioid-related hospitalization, 13.0% died over a median of 56 months of follow-up; the most common causes of death were circulatory diseases (26.4%) and drug overdose (23.5%). There were 27,122 (19.9%) and 3662 (2.7%) persons who had an HCV and HIV diagnosis, respectively. Among patients aged ≥20 years, those with HCV had shorter survival time compared to those without HCV, with discrepancies more pronounced at older ages. Patients with HIV also had shorter survival time (time ratio: 0.29 [95% CI: 0.26, 0.34]) compared to without HIV. These findings show that in a cohort of patients with opioid-related hospitalizations, those with HCV or HIV diagnoses have shorter survival. This has public health implications, providing further evidence that medical providers should educate patients who use opioids about the risks of HCV and HIV infection and focus prevention and treatment to decrease mortality among patients hospitalized for opioid use.

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).

HBV transcription and translation persist despite viral suppression in HBV-HIV co-infected patients on antiretroviral therapy.

BACKGROUND AND AIMS: Liver injury may persist in patients with HBV receiving antiviral therapy who have ongoing transcription and translation. We sought to assess ongoing HBV transcription by serum HBV RNA, translation by serum hepatitis B core related antigen (HBcrAg), and their associations with hepatic HBsAg and HBcAg staining in patients coinfected with HBV and HIV. METHODS: This is a cross-sectional study of 110 adults coinfected with HBV and HIV who underwent clinical assessment and liver biopsy. Immunohistochemistry (IHC) was performed for HBsAg and HBcAg. Viral biomarkers included quantitative HBsAg, HBV RNA, and HBcrAg. RESULTS: Participants' median age was 49 years (male, 93%; Black, 51%; HBeAg+, 65%), with suppressed HBV DNA (79%) and undetectable HIV RNA (77%) on dually active antiretroviral therapy. Overall, HBV RNA and HBcrAg were quantifiable in 81% and 83%, respectively (96% and 100% in HBeAg+, respectively). HBcAg staining was detected in 60% and HBsAg in 79%. Higher HBV RNA was associated with higher HBcAg and HBsAg IHC grades (both p < 0.0001). The HBsAg membranous staining pattern was significantly associated with higher HBV-RNA and HBcrAg levels. CONCLUSION: HBcAg and HBsAg IHC staining persisted despite viral suppression, and IHC grades and staining patterns correlated with markers of transcription (HBV RNA) and translation (HBcrAg). These data indicate that apparent HBV suppression is associated with residual transcription and translation that could contribute to liver pathology. Additional antiviral strategies directed to HBV protein expression may be useful to ameliorate liver injury.

Change in C-reactive protein after Roux-en-Y gastric bypass through 7 years of follow-up.

BACKGROUND: Long-term change in CRP is not well characterized in the context of RYGB. OBJECTIVE: To report C-reactive protein (CRP) after Roux-en-Y gastric bypass surgery (RYGB). SETTING: Between 2006 and 2009 1770 adults enrolled in a prospective cohort study underwent Roux-en-Y gastric bypass (RYGB) at 1 of 10 U.S. hospitals. METHODS: Research assessments were conducted before surgery and annually postoperatively for up to 7 years. This study included those with high-sensitivity CRP assessed before surgery and 1 or more follow-up assessments (n = 1180). RESULTS: Before surgery, participants' median age was 46 years, and the median body mass index (BMI) was 46 kg/m2; 80% were female. Before surgery, mean (95% confidence interval [CI]) CRP was the highest of all time points (1.01 [.95-1.08] mg/L); it then decreased to a nadir of .18 (.15-.22) mg/L at 2 years postoperatively (P < .001). CRP was higher at 7 years (.26 [.22, .29] mg/L) than at 2 years postoperatively (P < .001) but remained lower at 7 years than preoperatively (P < .001). Additionally, only 3.2% (95% CI: 1.6%-4.8%) of participants had elevated CRP (>1 mg/dL) 7 years postoperatively versus 32.9% (95% CI: 30.2%-35.3%) preoperatively (P < .001). Several preoperative factors were associated with following a less favorable CRP trajectory over time, including higher preoperative CRP level, higher BMI, current smoking, and diabetes. CONCLUSION: The vast majority of adults who underwent RYGB experienced a sustained improvement in CRP throughout 7 years of follow-up with nonelevated values. However, those with higher preoperative CRP and BMI levels and diabetes and who smoke may benefit from additional testing and monitoring to ensure nonelevated inflammation after surgery.

Elevated serum periostin levels among arsenic-exposed individuals and their associations with the features of asthma.

Chronic exposure to arsenic via drinking water is a serious public health issue in many countries. Arsenic causes not only cancers but also non-malignant diseases, including asthma. We have previously reported that arsenic exposure increases the risk of Th2-mediated allergic asthma. The serum level of periostin, an extracellular matrix protein activated by Th2 cytokines, is recognized as a biomarker for Th2-mediated eosinophilic asthma and contributes to enhanced airway inflammation and remodeling. However, the role of periostin in arsenic-related asthma is unknown. Therefore, this study was designed to explore the associations of serum periostin levels with arsenic exposure and the features of asthma in 442 individuals in Bangladesh who participated in our previous study. Exposure levels of the participants were determined by measuring the arsenic concentrations in drinking water, hair, and nails through inductively coupled plasma mass spectroscopy. Periostin levels in serum were assessed by immunoassay. In this study, we found that serum periostin levels of the participants were increased with increasing exposure to arsenic. Notably, even the participants with 10.1-50 µg/L arsenic in drinking water had significantly higher levels of periostin than participants with <10 µg/L of water arsenic. Elevated serum periostin levels were positively associated with serum levels of Th2 mediators, such as interleukin (IL)-4, IL-5, IL-13, and eotaxin. Each log increase in periostin levels was associated with approximately eight- and three-fold increases in the odds ratios (ORs) for reversible airway obstruction (RAO) and asthma symptoms, respectively. Additionally, causal mediation analyses revealed that arsenic exposure metrics had both direct and indirect (periostin-mediated) effects on the risk of RAO and asthma symptoms. Thus, the results suggested that periostin may be involved in the arsenic-related pathogenesis of Th2-mediated asthma. The elevated serum periostin levels may predict the greater risk of asthma among the people living in arsenic-endemic areas.

Adaptive randomization in a two-stage sequential multiple assignment randomized trial.

Sequential multiple assignment randomized trials (SMARTs) are systematic and efficient media for comparing dynamic treatment regimes (DTRs), where each patient is involved in multiple stages of treatment with the randomization at each stage depending on the patient's previous treatment history and interim outcomes. Generally, patients enrolled in SMARTs are randomized equally to ethically acceptable treatment options regardless of how effective those treatments were during the previous stages, which results in some undesirable consequences in practice, such as low recruitment, less retention, and lower treatment adherence. In this article, we propose a response-adaptive SMART (RA-SMART) design where the allocation probabilities are imbalanced in favor of more promising treatments based on the accumulated information on treatment efficacy from previous patients and stages. The operating characteristics of the RA-SMART design relative to SMART design, including the consistency and efficiency of estimated response rate under each DTR, the power of identifying the optimal DTR, and the number of patients treated with the optimal and the worst DTRs, are assessed through extensive simulation studies. Some practical suggestions are discussed in the conclusion.

Incidence and prediction of HBsAg seroclearance in a prospective multi-ethnic HBeAg-negative chronic hepatitis B cohort.

BACKGROUND AND AIMS: Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics. METHODS: The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated. RESULTS: Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253 HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively. CONCLUSION: HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling.

Prognostic accuracy for predicting ordinal competing risk outcomes using ROC surfaces.

Many medical conditions are marked by a sequence of events in association with continuous changes in biomarkers. Few works have evaluated the overall accuracy of a biomarker in predicting disease progression. We thus extend the concept of receiver operating characteristic (ROC) surface and the volume under the surface (VUS) from multi-category outcomes to ordinal competing-risk outcomes that are also subject to noninformative censoring. Two VUS estimators are considered. One is based on the definition of the ROC surface and obtained by integrating the estimated ROC surface. The other is an inverse probability weighted U estimator that is built upon the equivalence of the VUS to the concordance probability between the marker and sequential outcomes. Both estimators have nice asymptotic results that can be derived using counting process techniques and U-statistics theory. We illustrate their good practical performances through simulations and applications to two studies of cognition and a transplant dataset.

Randomized Trial of Tenofovir With or Without Peginterferon Alfa Followed by Protocolized Treatment Withdrawal in Adults With Chronic Hepatitis B.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss. METHODS: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary endpoint was HBsAg loss at week 240. RESULTS: Of 201 participants (52% HBeAg-positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99) 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% compared to 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg-positive) compared to only 2 of 189 (1%) with other hepatitis B virus genotypes, and in 8 of 93 (8.6%) HBeAg-positive vs 1 of 87 (1.1%) HBeAg-negative. DISCUSSION: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pre-treatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

Liver disease symptoms are associated with higher risk of adverse clinical outcomes: A longitudinal study of North American adults with chronic Hepatitis B.

BACKGROUND: Symptoms of chronic hepatitis B (CHB) are not well characterized. AIMS: To evaluate CHB symptoms and associations with disease activity and clinical outcomes. METHODS: Longitudinal data from 1,576 participants in the Hepatitis B Research Network Cohort Study who completed symptom assessments were analyzed. A composite symptom score was calculated using a Symptom Checklist (0=none to 40=extreme). Multivariable mixed models assessed variables associated with symptom change over time. Latent class symptom trajectories were evaluated. The cumulative probability of long-term clinical outcomes (new onset cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, death) was examined by baseline symptom groups. RESULTS: Participants median age was 42 (range:18-80), 51% were male, 75% Asian, (68% of whom were born outside North America) with a median follow-up of 4.2 years. On average, symptoms did not significantly change over time. The multivariable model identified several variables associated with higher symptoms during follow-up: being female, non-Asian, born in the US/Canada, lower education, higher AST, lower platelets, and more comorbidities. Two patient subgroups were identified based on longitudinal symptom trajectories: a low symptom group (92%, n=1,451) with symptom scores averaging 2.4 over time and a moderate symptom group (8%, n=125) with symptom scores averaging 11.5. During follow-up, 7.3% in the moderate symptom group, but only 3.2% of the low symptom group, developed adverse outcomes (p=0.02). CONCLUSIONS: In this large cohort of CHB patients, symptoms were generally mild and stable over time. However, in some patients with moderate symptoms at baseline, deleterious clinical outcomes were more frequent in follow-up.

A Prospective Study Evaluating Changes in Histology, Clinical and Virologic Outcomes in HBV-HIV Co-infected Adults in North America.

BACKGROUND AND AIMS: Histological and clinical outcomes in HBV-HIV coinfection in the era of combination antiretroviral therapy (cART) are poorly defined. APPROACH AND RESULTS: Adult patients co-infected with HBV-HIV from eight North American sites were enrolled in this National Institutes of Health (NIH)-funded prospective observational study (n = 139). Demographic, clinical, serological, and virological data were collected at entry and every 24 weeks for ≤ 192 weeks. Paired liver biopsies were obtained at study entry and at ≥ 3 years of follow-up. Biopsies were assessed by a central pathology committee using the modified Ishak scoring system. Clinical outcome rate and changes in histology are reported. Among participants with follow-up data (n = 114), median age was 49 years, 91% were male, 51% were non-Hispanic Black, and 13% had at-risk alcohol use, with a median infection of 20 years. At entry, 95% were on anti-HBV cART. Median CD4 count was 562 cells/mm3 and 93% had HIV < 400 copies/mL. HBeAg was positive in 61%, and HBV DNA was below the limit of quantification (< 20 IU/mL) in 61% and < 1,000 IU/mL in 80%. Clinical events were uncommon across follow-up: one hepatic decompensation, two HCC, no liver transplants, and one HBV-related deaths, with a composite endpoint rate of 0.61/100 person-years. Incident cirrhosis (n = 1), alanine aminotransferase flare (n = 2), and HBeAg loss (n = 13) rates were 0.40, 0.65, and 6.86 per 100 person-years, respectively. No participants had HBsAg loss. Paired biopsy (n = 62; median 3.6 years apart) revealed minimal improvement in Histologic Activity Index (median [interquartile range]: 3 [2-4] to 3 [1-3]; P = 0.02) and no significant change in fibrosis score (1 [1-2] to 1 [0-3]; P = 0.58). CONCLUSIONS: In a North American cohort of adults with HBV-HIV on cART with virological suppression, clinical outcomes and worsening histological disease were uncommon.

Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver.

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.