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.

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.

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.

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.

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.

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 end point 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% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with 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. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance.

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.

Interim monitoring in sequential multiple assignment randomized trials.

A sequential multiple assignment randomized trial (SMART) facilitates the comparison of multiple adaptive treatment strategies (ATSs) simultaneously. Previous studies have established a framework to test the homogeneity of multiple ATSs by a global Wald test through inverse probability weighting. SMARTs are generally lengthier than classical clinical trials due to the sequential nature of treatment randomization in multiple stages. Thus, it would be beneficial to add interim analyses allowing for an early stop if overwhelming efficacy is observed. We introduce group sequential methods to SMARTs to facilitate interim monitoring based on the multivariate chi-square distribution. Simulation studies demonstrate that the proposed interim monitoring in SMART (IM-SMART) maintains the desired type I error and power with reduced expected sample size compared to the classical SMART. Finally, we illustrate our method by reanalyzing a SMART assessing the effects of cognitive behavioral and physical therapies in patients with knee osteoarthritis and comorbid subsyndromal depressive symptoms.

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.

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.

Symptoms of Liver Disease During Tenofovir Therapy With or Without Peginterferon: Results from the Hepatitis B Research Network Immune Active Trial.

AIMS: Evaluate patient-reported liver symptoms during treatment for chronic hepatitis B viral (HBV) infection and associations between changes in symptoms and levels of alanine aminotransferase (ALT) and viral markers. METHODS: Data from 200 participants in the Hepatitis B Research Network Immune Active Trial who completed symptom assessments were analyzed. Patients were treated with tenofovir, with or without peginterferon (TDF + PegIFN vs. TDF alone) for 192 weeks. Participants completed a Symptom Checklist at baseline and every 4-12 weeks. A total symptom score was created, ranging from 0 (none) to 40 (severe). The SF-36 was completed every 48 weeks. Associations of symptom scores with ALT and viral markers were evaluated at baseline and end of treatment. RESULTS: Participants were 65% male, 83% Asian, with a mean age of 42. Baseline symptoms were mild (median = 2, range 0-25) and associated with baseline ALT, HBV DNA levels and HBeAg + status. Patients on TDF alone experienced a more rapid and greater improvement in symptoms, but by week 192, symptom improvement was similar in both groups (54% vs 36%). Symptom improvements correlated with ALT and HBV DNA, most markedly among those with symptoms at baseline. Most patients (4 out of 6) who achieved HBsAg loss experienced symptom improvements. Overall, SF-36 scores did not change with treatment. CONCLUSIONS: Reduction in ALT and HBV DNA levels with therapy are associated with significant improvement in liver symptoms such as fatigue and pain over the liver, especially among those with higher ALT, HBV DNA, symptoms and HBeAg + status prior to treatment.

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.

Precore and Basal Core Promoter Hepatitis B Virus (HBV) Variants Are Present From a Young Age and Differ Across HBV Genotypes.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) precore (PC) and dual basal core promoter (BCP) mutations halt and down-regulate hepatitis B e antigen (HBeAg) production respectively. PC mutation is rarely associated with HBV genotype A. We sought to examine the association of these variants with HBV genotypes, age, and HBeAg status in a racially diverse population in North America. Prospective study included 1,036 (808 adults, 228 children) participants in the Hepatitis B Research Network. PC and BCP variants were determined by Sanger sequencing, and dominant HBV species (>50%) were reported. APPROACH AND RESULTS: Median age was 36.3 years (range, 2-80), 44.6% HBeAg(+), 74.2% Asians, 13.3% black, and 9.7% white. The dominant PC variant was present in 29.4% participants, including 20 with subgenotype A1 or A2. Seventeen of 20 participants with genotype A and PC had a compensatory C1858T mutation. In the HBeAg(+) cohort, the prevalence of PC and/or BCP variants increased from 14.4% in the first two decades to 51% after 40 years of age. Among those aged 2-18, 52% and 83% with dominant PC and BCP variants were HBeAg(+) compared to 3.8% and 29% in the >40 years age group. HBeAg clearance rates were significantly higher for those with dominant PC or BCP variants: 24.4 and 15.0 per 100 person-years compared to 6.0 in wild-type HBV (P < 0.0001). CONCLUSIONS: PC variants can be present in HBV genotype A and are usually associated with C1858T, which preserves the pregenome encapsidation sequence. Selection of PC and BCP variants occurred at a young age, with increasing prevalence across age groups. HBeAg(+) participants with dominant PC and BCP variants progressed to the HBeAg(-) phase of chronic HBV infection significantly faster. This finding has potential clinical and therapeutic implications.

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.

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.

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.

Cumulative incidence regression for dynamic treatment regimens.

Recently dynamic treatment regimens (DTRs) have drawn considerable attention, as an effective tool for personalizing medicine. Sequential Multiple Assignment Randomized Trials (SMARTs) are often used to gather data for making inference on DTRs. In this article, we focus on regression analysis of DTRs from a two-stage SMART for competing risk outcomes based on cumulative incidence functions (CIFs). Even though there are extensive works on the regression problem for DTRs, no research has been done on modeling the CIF for SMART trials. We extend existing CIF regression models to handle covariate effects for DTRs. Asymptotic properties are established for our proposed estimators. The models can be implemented using existing software by an augmented-data approximation. We show the improvement provided by our proposed methods by simulation and illustrate its practical utility through an analysis of a SMART neuroblastoma study, where disease progression cannot be observed after death.

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.

Evaluating Noninvasive Markers to Identify Advanced Fibrosis by Liver Biopsy in HBV/HIV Co-infected Adults.

Noninvasive biomarkers are used increasingly to assess fibrosis in patients with chronic liver disease. We determined the utility of dual cutoffs for noninvasive biomarkers to exclude and confirm advanced fibrosis in hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infected patients receiving combined antiretroviral therapy. Participants were anti-HIV/hepatitis B surface antigen-positive adults from eight clinical sites in the United States and Canada of the Hepatitis B Research Network. Fibrosis was staged by a central pathology committee using the Ishak fibrosis score (F). Clinical, laboratory, and vibration-controlled transient elastography (VCTE) data were collected at each site. Dual cutoffs for three noninvasive biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 index [FIB-4], and liver stiffness by VCTE) with the best accuracy to exclude or confirm advanced fibrosis (F ≥ 3) were determined using established methodology. Of the 139 enrolled participants, 108 with a liver biopsy and having at least one noninvasive biomarker were included: 22% had advanced fibrosis and 54% had normal alanine aminotransferase. The median (interquartile range) of APRI (n = 106), FIB-4 (n = 106), and VCTE (n = 63) were 0.34 (0.26-0.56), 1.35 (0.99-1.89), and 4.9 (3.8-6.8) kPa, respectively. The area under the curve for advanced fibrosis was 0.69 for APRI, 0.66 for FIB-4, and 0.87 for VCTE. VCTE cutoffs of 5.0 kPa or less (to exclude) and 8.8 kPa or greater (to confirm) advanced fibrosis had a sensitivity of 92.3% and specificity of 96.0%, respectively, and accounted for 65.1% of participants. Among the 34.9% with values between the cutoffs, 26.1% had advanced fibrosis. Considering APRI or FIB-4 jointly with VCTE did not improve the discriminatory capacity. Conclusion: VCTE is a better biomarker of advanced fibrosis compared with APRI or FIB-4 in HBV/HIV co-infected adults on combined antiretroviral therapy. Using VCTE dual cutoffs, approximately two-thirds of patients could avoid biopsy to determine advanced fibrosis.

Alcohol, tobacco and coffee consumption and liver disease severity among individuals with Chronic Hepatitis B infection in North America.

INTRODUCTION AND OBJECTIVES: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described. MATERIALS AND METHODS: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1-2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values. RESULTS: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34-52). Median ALT was 33U/L (IQR: 22-50), 37% had HBV DNA <103IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and 'at-risk' alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics. CONCLUSIONS: In this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors.