Antibiotic prescribing practices of medical doctors in a resource-limited setting and the influence of individual perceptions and stewardship support: a survey in three tertiary hospitals in Vietnam.

Objectives: To understand antibiotic prescribing and influencing factors to inform antimicrobial stewardship (AMS) interventions to reduce unwanted consequences of antibiotic use in hospitals in Vietnam, a lower-middle-income country in Asia. Methods: We conducted a cross-sectional study of doctors at three tertiary hospitals using non-probability convenience sampling, through a paper-based (Hospitals 1 and 2) or electronic (Hospital 3) survey. Questions included items on perceptions regarding antibiotic resistance and AMS, prescribing practices, knowledge, demographics and training. We used principal components analysis and mixed-effects models to examine practices and identify influencing factors. Results: Among 314 surveyed participants, 61%, 57% and 59% in Hospitals 1, 2 and 3, respectively, felt certain about the appropriateness of their antibiotic prescriptions. In total, 9% reported sometimes prescribing antibiotics when not needed to meet patients' expectations, and 13% reported doing so to avoid perceived complications. Higher prescribing confidence was found among those with positive perceptions about AMS (P < 0.0001), whereas negative perceptions about colleagues' practices reduced this confidence (P < 0.0001). Individual preference for branded antibiotics was associated with more unnecessary prescribing whereas having higher prescribing confidence decreased the habits of prescribing when not needed. Conclusions: This study provides important implications for design of hospital interventions to address influencing factors on antibiotic prescribing in Vietnam and similar resource-limited settings. Specific interventions should target improving knowledge through education and training for doctors, enhancing the support from the AMS team, and promoting guidelines and policies for appropriate antibiotic use in hospital.

Sex Differences in Clustering Unhealthy Lifestyles Among Survivors of COVID-19: Latent Class Analysis.

BACKGROUND: The COVID-19 pandemic has underscored the significance of adopting healthy lifestyles to mitigate the risk of severe outcomes and long-term consequences. OBJECTIVE: This study focuses on assessing the prevalence and clustering of 5 unhealthy lifestyle behaviors among Vietnamese adults after recovering from COVID-19, with a specific emphasis on sex differences. METHODS: The cross-sectional data of 5890 survivors of COVID-19 in Vietnam were analyzed from December 2021 to October 2022. To examine the sex differences in 5 unhealthy lifestyle behaviors (smoking, drinking, unhealthy diet, physical inactivity, and sedentary behavior), the percentages were plotted along with their corresponding 95% CI for each behavior. Latent class analysis was used to identify 2 distinct classes of individuals based on the clustering of these behaviors: the "less unhealthy" group and the "more unhealthy" group. We examined the sociodemographic characteristics associated with each identified class and used logistic regression to investigate the factors related to the "more unhealthy" group. RESULTS: The majority of individuals (male participants: 2432/2447, 99.4% and female participants: 3411/3443, 99.1%) exhibited at least 1 unhealthy behavior, with male participants being more susceptible to multiple unhealthy behaviors. The male-to-female ratio for having a single behavior was 1.003, but it escalated to 25 for individuals displaying all 5 behaviors. Male participants demonstrated a higher prevalence of combining alcohol intake with sedentary behavior (949/2447, 38.8%) or an unhealthy diet (861/2447, 35.2%), whereas female participants tended to exhibit physical inactivity combined with sedentary behavior (1305/3443, 37.9%) or an unhealthy diet (1260/3443, 36.6%). Married male participants had increased odds of falling into the "more unhealthy" group compared to their single counterparts (odds ratio [OR] 1.45, 95% CI 1.14-1.85), while female participants exhibited lower odds (OR 0.65, 95% CI 0.51-0.83). Female participants who are underweight showed a higher likelihood of belonging to the "more unhealthy" group (OR 1.11, 95% CI 0.89-1.39), but this was not observed among male participants (OR 0.6, 95% CI 0.41-0.89). In both sexes, older age, dependent employment, high education, and obesity were associated with higher odds of being in the "more unhealthy" group. CONCLUSIONS: The study identified notable sex differences in unhealthy lifestyle behaviors among survivors of COVID-19. Male survivors are more likely to engage in unhealthy behaviors compared to female survivors. These findings emphasize the importance of tailored public health interventions targeting sex-specific unhealthy behaviors. Specifically, addressing unhealthy habits is crucial for promoting post-COVID-19 health and well-being.

Impact of long COVID-19 on posttraumatic stress disorder as modified by health literacy: an observational study in Vietnam.

BACKGROUND: The prevalence of posttraumatic stress disorder (PTSD) has increased, particularly among individuals who have recovered from coronavirus disease 2019 (COVID-19) infection. Health literacy is considered a "social vaccine" that helps people respond effectively to the pandemic. We aimed to investigate the association between long COVID-19 and PTSD, and to examine the modifying role of health literacy in this association. METHODS: A cross-sectional study was conducted at 18 hospitals and health centers in Vietnam from December 2021 to October 2022. We recruited 4,463 individuals who had recovered from COVID-19 infection for at least 4 weeks. Participants provided information about their sociodemographics, clinical parameters, health-related behaviors, health literacy (using the 12-item short-form health literacy scale), long COVID-19 symptoms and PTSD (Impact Event Scale-Revised score of 33 or higher). Logistic regression models were used to examine associations and interactions. RESULTS: Out of the study sample, 55.9% had long COVID-19 symptoms, and 49.6% had PTSD. Individuals with long COVID-19 symptoms had a higher likelihood of PTSD (odds ratio [OR], 1.86; 95% confidence interval [CI], 1.63-2.12; p<0.001). Higher health literacy was associated with a lower likelihood of PTSD (OR, 0.98; 95% CI, 0.97-0.99; p=0.001). Compared to those without long COVID-19 symptoms and the lowest health literacy score, those with long COVID-19 symptoms and a 1-point health literacy increment had a 3% lower likelihood of PTSD (OR, 0.97; 95% CI, 0.96-0.99; p=0.001). CONCLUSION: Health literacy was found to be a protective factor against PTSD and modified the negative impact of long COVID-19 symptoms on PTSD.

Barriers and enablers to blood culture sampling in Indonesia, Thailand and Viet Nam: a Theoretical Domains Framework-based survey.

OBJECTIVE: Blood culture (BC) sampling is recommended for all suspected sepsis patients prior to antibiotic administration. We examine barriers and enablers to BC sampling in three Southeast Asian countries. DESIGN: A Theoretical Domains Framework (TDF)-based survey, comprising a case scenario of a patient presenting with community-acquired sepsis and all 14 TDF domains of barriers/enablers to BC sampling. SETTING: Hospitals in Indonesia, Thailand and Viet Nam, December 2021 to 30 April 2022. PARTICIPANTS: 1070 medical doctors and 238 final-year medical students were participated in this study. Half of the respondents were women (n=680, 52%) and most worked in governmental hospitals (n=980, 75.4%). OUTCOME MEASURES: Barriers and enablers to BC sampling. RESULTS: The proportion of respondents who answered that they would definitely take BC in the case scenario was highest at 89.8% (273/304) in Thailand, followed by 50.5% (252/499) in Viet Nam and 31.3% (157/501) in Indonesia (p<0.001). Barriers/enablers in nine TDF domains were considered key in influencing BC sampling, including 'priority of BC (TDF-goals)', 'perception about their role to order or initiate an order for BC (TDF-social professional role and identity)', 'perception that BC is helpful (TDF-beliefs about consequences)', 'intention to follow guidelines (TDF-intention)', 'awareness of guidelines (TDF-knowledge)', 'norms of BC sampling (TDF-social influence)', 'consequences that discourage BC sampling (TDF-reinforcement)', 'perceived cost-effectiveness of BC (TDF-environmental context and resources)' and 'regulation on cost reimbursement (TDF-behavioural regulation)'. There was substantial heterogeneity between the countries. In most domains, the lower (higher) proportion of Thai respondents experienced the barriers (enablers) compared with that of Indonesian and Vietnamese respondents. A range of suggested intervention types and policy options was identified. CONCLUSIONS: Barriers and enablers to BC sampling are varied and heterogenous. Cost-related barriers are more common in more resource-limited countries, while many barriers are not directly related to cost. Context-specific multifaceted interventions at both hospital and policy levels are required to improve diagnostic stewardship practices.

A computational study for understanding the impact of p120-catenin on the cis-dimerization of cadherin.

A prototype of cross-membrane signal transduction is that extracellular binding of cell surface receptors to their ligands induces intracellular signaling cascades. However, much less is known about the process in the opposite direction, called inside-out signaling. Recent studies show that it plays a more important role in regulating the functions of many cell surface receptors than we used to think. In particular, in cadherin-mediated cell adhesion, recent experiments indicate that intracellular binding of the scaffold protein p120-catenin can promote extracellular clustering of cadherin and alter its adhesive function. The underlying mechanism, however, is not well understood. To explore possible mechanisms, we designed a new multiscale simulation procedure. Using all-atom molecular dynamics simulations, we found that the conformational dynamics of the cadherin extracellular region can be altered by the intracellular binding of p120-catenin. More intriguingly, by integrating all-atom simulation results into coarse-grained random sampling, we showed that the altered conformational dynamics of cadherin caused by the binding of p120-catenin can increase the probability of lateral interactions between cadherins on the cell surface. These results suggest that p120-catenin could allosterically regulate the cis-dimerization of cadherin through two mechanisms. First, p120-catenin controls the extracellular conformational dynamics of cadherin. Second, p120-catenin oligomerization can further promote cadherin clustering. Our study, therefore, suggests a mechanistic foundation for the inside-out signaling in cadherin-mediated cell adhesion, while the computational framework can be generally applied to other cross-membrane signal transduction systems.

A community-based intervention to decrease the prevalence of HIV viremia among people who inject drugs in Vietnam.

Background: In most low-to-middle-income countries, HIV control at the population level among people who inject drugs (PWID) remains a major challenge. We aimed to demonstrate that an innovative intervention can identify HIV-positive PWID in the community who are not treated efficiently, and get them treated efficiently. Methods: Between 2016 and 2020, we implemented an intervention consisting of mass HIV screening of PWID using three annual respondent-driven sampling surveys (RDSS) and a post-intervention evaluation RDSS in community-based organisation (CBO) sites, coupled with peer support to facilitate/improve access to antiretroviral and methadone therapy in Haiphong, Vietnam. The primary outcome was the proportion of identified uncontrolled HIV-positive PWID who achieved viral control. We also estimated the potential effect of the intervention on the proportion of PWID with HIV RNA >1000 copies/mL among all PWID during the study period. Findings: Over the three RDSS, 3150 different PWID were screened, i.e. two-thirds of the estimated population size. They all injected heroin, their median age was of 39 years, 95% were male, 26.5% were HIV-infected, and 78.6% of the latter had HIV RNA ≤1000 copies/mL. Among the 177 PWID identified with an unsuppressed viral load, 73 (41.2%) achieved viral suppression at the final visit. HIV viremia decreased from 7.2% at baseline to 2.9% at the final RDSS (p<0.001). Up to 42% of this observed reduction may be explained by the intervention, in the absence of any external intervention targeting PWID during the study period. Interpretation: Mass community-based screening using RDSS coupled with CBO support is a powerful tool to rapidly identify untreated HIV-positive PWID and (re)link them to care. Funding: NIDA (USA) and ANRS (France).

Mechanical disruption of E-cadherin complexes with epidermal growth factor receptor actuates growth factor-dependent signaling.

Increased intercellular tension is associated with enhanced cell proliferation and tissue growth. Here, we present evidence for a force-transduction mechanism that links mechanical perturbations of epithelial (E)-cadherin (CDH1) receptors to the force-dependent activation of epidermal growth factor receptor (EGFR, ERBB1)-a key regulator of cell proliferation. Here, coimmunoprecipitation studies first show that E-cadherin and EGFR form complexes at the plasma membrane that are disrupted by either epidermal growth factor (EGF) or increased tension on homophilic E-cadherin bonds. Although force on E-cadherin bonds disrupts the complex in the absence of EGF, soluble EGF is required to mechanically activate EGFR at cadherin adhesions. Fully quantified spectral imaging fluorescence resonance energy transfer further revealed that E-cadherin and EGFR directly associate to form a heterotrimeric complex of two cadherins and one EGFR protein. Together, these results support a model in which the tugging forces on homophilic E-cadherin bonds trigger force-activated signaling by releasing EGFR monomers to dimerize, bind EGF ligand, and signal. These findings reveal the initial steps in E-cadherin-mediated force transduction that directly link intercellular force fluctuations to the activation of growth regulatory signaling cascades.

Developing a Reference Database for Typical Body and Organ Growth of the Artificially Reared Pig as a Biomedical Research Model.

Objectives: The pig is a common model utilized to support substantiation of novel bioactive components in infant formula. However, reference ranges for outcomes to determine safety are unclear. Our objective was to use historical data to objectively define typical body and organ growth metrics of the domesticated pig in research. Methods: Twenty-two studies were compiled to assess typical growth of body and organ weights in young pigs. Metadata were organized to include milk replacer sources, bioactive components, sex, breed, source of herd, feeding regimen, and rearing environment. A combination of statistical models including simple linear regression and linear mixed effect models were used to assess typical growth patterns. Results: Over 18,000 data points from 786 animals were available. In general, minimal differences in the growth of pigs who were male and female, artificially- or sow-reared, or fed ad libitum- or by scheduled-feeding, were observed in the first 30 days of life (P > 0.05). A weight-for-age chart from reference pigs was developed to compare body weights of pigs demonstrating growth characterized as accelerated, typical, reduced, and failure to thrive to illustrate effects of dietary interventions. Distributions of relative brain, liver, and intestine weights (as % of total body weight) were similar between rearing environments and sexes. An alternative bivariate level approach was utilized for the analysis of organ weights. This approach revealed significant biologically-relevant insights into how deficient diets can affect organ weight that a univariate level assessment of weight distribution was unable to detect. Conclusions: Ultimately, these data can be used to better interpret whether bioactive ingredients tested in the pig model affect growth and development within typical reference values for pigs in the first 30 days of life.

P120 catenin potentiates constitutive E-cadherin dimerization at the plasma membrane and regulates trans binding.

Cadherins are essential adhesion proteins that regulate tissue cohesion and paracellular permeability by assembling dense adhesion plaques at cell-to-cell contacts. Adherens junctions are central to a wide range of tissue functions; identifying protein interactions that potentiate their assembly and regulation has been the focus of research for over 2 decades. Here, we present evidence for a new, unexpected mechanism of cadherin oligomerization on cells. Fully quantified spectral imaging fluorescence resonance energy transfer (FSI-FRET) and fluorescence intensity fluctuation (FIF) measurements directly demonstrate that E-cadherin forms constitutive lateral (cis) dimers at the plasma membrane. Results further show that binding of the cytosolic protein p120ctn binding to the intracellular region is required for constitutive E-cadherin dimerization. This finding differs from a model that attributes lateral (cis) cadherin oligomerization solely to extracellular domain interactions. The present, novel findings are further supported by studies of E-cadherin mutants that uncouple p120ctn binding or with cells in which p120ctn was knocked out using CRISPR-Cas9. Quantitative affinity measurements further demonstrate that uncoupling p120ctn binding reduces the cadherin trans binding affinity and cell adhesion. These findings transform the current model of cadherin assembly at cell surfaces and identify the core building blocks of cadherin-mediated intercellular adhesions. They also identify a new role for p120ctn and reconcile findings that implicate both the extracellular and intracellular cadherin domains in cadherin clustering and intercellular cohesion.

Cadherin cis and trans interactions are mutually cooperative.

Cadherin transmembrane proteins are responsible for intercellular adhesion in all biological tissues and modulate tissue morphogenesis, cell motility, force transduction, and macromolecular transport. The protein-mediated adhesions consist of adhesive trans interactions and lateral cis interactions. Although theory suggests cooperativity between cis and trans bonds, direct experimental evidence of such cooperativity has not been demonstrated. Here, the use of superresolution microscopy, in conjunction with intermolecular single-molecule Förster resonance energy transfer, demonstrated the mutual cooperativity of cis and trans interactions. Results further demonstrate the consequent assembly of large intermembrane junctions, using a biomimetic lipid bilayer cell adhesion model. Notably, the presence of cis interactions resulted in a nearly 30-fold increase in trans-binding lifetimes between epithelial-cadherin extracellular domains. In turn, the presence of trans interactions increased the lifetime of cis bonds. Importantly, comparison of trans-binding lifetimes of small and large cadherin clusters suggests that this cooperativity is primarily due to allostery. The direct quantitative demonstration of strong mutual cooperativity between cis and trans interactions at intermembrane adhesions provides insights into the long-standing controversy of how weak cis and trans interactions act in concert to create strong macroscopic cell adhesions.

Cadherin clusters stabilized by a combination of specific and nonspecific cis-interactions.

We demonstrate a combined experimental and computational approach for the quantitative characterization of lateral interactions between membrane-associated proteins. In particular, weak, lateral (cis) interactions between E-cadherin extracellular domains tethered to supported lipid bilayers, were studied using a combination of dynamic single-molecule Förster Resonance Energy Transfer (FRET) and kinetic Monte Carlo (kMC) simulations. Cadherins are intercellular adhesion proteins that assemble into clusters at cell-cell contacts through cis- and trans- (adhesive) interactions. A detailed and quantitative understanding of cis-clustering has been hindered by a lack of experimental approaches capable of detecting and quantifying lateral interactions between proteins on membranes. Here single-molecule intermolecular FRET measurements of wild-type E-cadherin and cis-interaction mutants combined with simulations demonstrate that both nonspecific and specific cis-interactions contribute to lateral clustering on lipid bilayers. Moreover, the intermolecular binding and dissociation rate constants are quantitatively and independently determined, demonstrating an approach that is generalizable for other interacting proteins.

Comparative effects of N-cadherin protein and peptide fragments on mesenchymal stem cell mechanotransduction and paracrine function.

The recent interest in exploiting cadherin-derived fragments to mimic intercellular adhesion in engineered hybrid biomaterials raises questions about which cadherin constructs effectively mimic cadherin interactions. This study compared the biophysical properties of and signaling initiated by three different, immobilized N-cadherin-derived fragments, in order to identify a minimal construct that mimics intercellular adhesion in biomaterials. Specifically, we compared: i) the full N-cadherin extracellular region with all five ectodomains (EC1-5), ii) the first two ectodomains (EC1-2) of N-cadherin, and iii) a peptide containing the histidine-alanine-valine-aspartic acid-valine (HAVDI) sequence in the first extracellular domain. Comparisons of the binding kinetics and affinities between each of these ligands and N-cadherin expressed on mesenchymal stem cells (MSCs) revealed quantitative differences. Nevertheless, MSCs exhibited similar, rigidity-dependent spreading and traction forces when cultured on gels displaying any of these N-cadherin ligands. There were, however, differences in cell signaling and secretory activities. MSCs cultured on the full N-cadherin extracellular domain (EC1-5) exhibited stiffness-dependent changes in nuclear YAP/TAZ localization and significantly higher secretion of vascular endothelial growth factor and insulin growth factor 1, compared to cells cultured on hydrogels displaying either EC1-2 or the HAVDI peptide. The increased paracrine secretion also enhanced myogenic differentiation. These findings reveal functional differences between N-cadherin derived ligands important for the design of biomaterials that mimic intercellular adhesion.

Cadherin Extracellular Domain Clustering in the Absence of Trans-Interactions.

While both cis and trans (adhesive)-interactions cooperate in the assembly of intercellular adhesions, computational simulations have predicted that two-dimensional confinement may promote cis-oligomerization, in the absence of trans-interactions. Here, single-molecule tracking of cadherin extracellular domains on supported lipid bilayers revealed the density-dependent formation of oligomers and cis-clusters in the absence of trans-interactions. Lateral oligomers were virtually eliminated by mutating a putative cis (lateral) binding interface. At low cadherin surface coverage, wild-type and mutant cadherin diffused rapidly, consistent with the motion of a lipid molecule within a cadherin-free supported bilayer and with cadherins diffusing as monomers. Although the diffusion of mutant cadherin did not change appreciably with increasing surface coverage, the average short-time diffusion coefficient of wild-type cadherin slowed significantly above a fractional surface coverage of ∼0.01 (∼1100 molecules/µm2). A detailed analysis of molecular trajectories suggested the presence of a broad size distribution of cis-cadherin oligomers. These findings verify predictions that two-dimensional confinement promotes cis-oligomerization, in the absence of trans-interactions.

VE-PTP stabilizes VE-cadherin junctions and the endothelial barrier via a phosphatase-independent mechanism.

Vascular endothelial (VE) protein tyrosine phosphatase (PTP) is an endothelial-specific phosphatase that stabilizes VE-cadherin junctions. Although studies have focused on the role of VE-PTP in dephosphorylating VE-cadherin in the activated endothelium, little is known of VE-PTP's role in the quiescent endothelial monolayer. Here, we used the photoconvertible fluorescent protein VE-cadherin-Dendra2 to monitor VE-cadherin dynamics at adherens junctions (AJs) in confluent endothelial monolayers. We discovered that VE-PTP stabilizes VE-cadherin junctions by reducing the rate of VE-cadherin internalization independently of its phosphatase activity. VE-PTP serves as an adaptor protein that through binding and inhibiting the RhoGEF GEF-H1 modulates RhoA activity and tension across VE-cadherin junctions. Overexpression of the VE-PTP cytosolic domain mutant interacting with GEF-H1 in VE-PTP-depleted endothelial cells reduced GEF-H1 activity and restored VE-cadherin dynamics at AJs. Thus, VE-PTP stabilizes VE-cadherin junctions and restricts endothelial permeability by inhibiting GEF-H1, thereby limiting RhoA signaling at AJs and reducing the VE-cadherin internalization rate.

Hepatitis B and renal function: A matched study comparing non-hepatitis B, untreated, treated and cirrhotic hepatitis patients.

BACKGROUND & AIM: Renal impairment is associated with chronic hepatitis B (CHB). To overcome prior study design differences, we used propensity score matching to balance the non-CHB and CHB cohorts and generalized linear modelling (GLM, models using probit and logit linking functions for complex models) to evaluate the effect of CHB, treatment and cirrhosis on renal function. METHODS: A retrospective cohort (1996-2017) from one U.S. university medical centre. Included patients had ≥12 months of serial creatinine laboratories and a baseline estimated glomerular filtration rate (eGFR, by the Modification of Diet in Renal Disease Study equation) ≥60 mL/min/1.73 m2 . Propensity score matching was performed using age, sex, ethnicity, diabetes, hypertension and baseline eGFR. GLM was performed to generate adjusted mean eGFR over time. RESULTS: Adjusted mean eGFR was significantly higher for non-CHB vs. untreated CHB patients (eGFR 87.4 vs. 85.6, P= 0.004, n = 580, median follow-up = 82 months). A significant difference in adjusted mean eGFR between untreated vs. entecavir (ETV)-treated CHB patients (eGFR 85.1 vs. 83.5, P= 0.02, n = 340, median follow-up = 70 months) was found among non-cirrhotic CHB. Among treated CHB, there was no difference in adjusted mean eGFR between non-cirrhotic vs. cirrhotic patients (eGFR 77.0 vs. 76.5; P= 0.66, n = 112, median follow-up = 58 months). CONCLUSION: After PSM and GLM, the significant predictors for worsening renal function were age, hypertension and diabetes mellitus but not CHB, ETV or cirrhosis. However, given small sample size, data regarding the use of ETV in patients with cirrhosis should be interpreted with caution and requires additional investigation.

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients.

Despite recent evidence of improved graft outcomes and safety, the high incidence of early acute cellular rejection with belatacept, a high-affinity CTLA4-Ig, has limited its use in clinical transplantation. Here we define how the incomplete control of endogenous donor-reactive memory T cells results in belatacept-resistant rejection in an experimental model of BALB/c.2W-OVA donor heart transplantation into C57BL/6 recipients presensitized to donor splenocytes. These sensitized mice harbored modestly elevated numbers of endogenous donor-specific memory T cells and alloantibodies compared with naive recipients. Continuous CTLA4-Ig treatment was unexpectedly efficacious at inhibiting endogenous graft-reactive T cell expansion but was unable to inhibit late CD4+ and CD8+ T cell infiltration into the allografts, and rejection was observed in 50% of recipients by day 35 after transplantation. When CTLA4-Ig was combined with the sphingosine 1-phosphate receptor-1 (S1PR1) functional antagonist FTY720, alloantibody production was inhibited and donor-specific IFN-γ-producing T cells were reduced to levels approaching nonsensitized tolerant recipients. Late T cell recruitment into the graft was also restrained, and graft survival improved with this combination therapy. These observations suggest that a rational strategy consisting of inhibiting memory T cell expansion and trafficking into the allograft with CTLA4-Ig and FTY720 can promote allograft survival in allosensitized recipients.

HCV Genotype 6 Increased the Risk for Hepatocellular Carcinoma Among Asian Patients With Liver Cirrhosis.

OBJECTIVES: Hepatitis C virus (HCV) infection is a well-documented risk factor for hepatocellular carcinoma (HCC). Seven HCV genotypes have been classified, and the genotypes show a great variety of geographic distribution. HCV genotype 6 is prevalent in Southeast Asia and has been less studied than the other genotypes. METHODS: This follow-up study was designed to evaluate the natural history of HCV genotype 6. The cohort enrolled 851 Asian patients consisting of 222 with HCV genotype 6 and 629 with other genotypes. The incidence of HCC per 1,000 person-years of various HCV genotypes was estimated by dividing the new HCC cases to the person-years of follow-up. The adjusted hazards ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox's proportional hazards models. RESULTS: After 4072 person-years of follow-up, there were 96 newly-developed HCC cases, confirming an incidence of 23.6 per 1000 person-years. By stratifying cirrhosis at study entry, the cumulative risk of HCC among HCV genotype 6 vs. non-6 was 2.9 vs. 2.2% for those without cirrhosis (P=0.45) and 76.2% (95% CI: 55.6-96.8%) vs. 36.2% (95% CI: 28.7-39.1%) for those with cirrhosis (P<0.05), respectively. Among patients with cirrhosis, HCV genotype 6 was significantly associated with HCC compared to patients with non-6 genotypes, with the adjusted HR=2.12 (1.33-3.39), P<0.05. In a model treating patients with genotypes other than 1 or 6 as the reference, the adjusted HR for HCC for HCV genotypes 1 and 6 were 1.13 (0.56-2.27) and 2.34 (1.12-4.86), respectively. CONCLUSIONS: Among patients with cirrhosis, those with HCV genotype 6 infection should be given high priority for antiviral therapy to decrease HCC risk and for vigilant adherence to HCC surveillance.

Poor adherence and low persistency rates for hepatocellular carcinoma surveillance in patients with chronic hepatitis B.

Our goal was to examine rates and predictors for hepatocellular carcinoma (HCC) surveillance adherence and persistency, since studies of such adherence and persistency in patients with chronic hepatitis (CHB) are currently limited.Consecutive CHB patients (N = 1329) monitored for ≥1 year at 4 US clinics from January 1996 to July 2013 were retrospectively studied. Surveillance adherence was evaluated based on the American Association for the Study of Liver Diseases guidelines. Kaplan-Meier method was used to analyze surveillance persistency of 510 patients who had initially fair adherence (having at least annual surveillance imaging with further follow-up).Mean age was 48, with the majority being male (58%), Asian (92%), foreign-born (95%), and medically insured (97%). Patients with cirrhosis and those seen at university liver clinics were more likely to have optimal HCC surveillance than those without cirrhosis and those seen at community clinics (38.4% vs 21.6%, P <0.001 and 33.5% vs 14.4%, P < 0.001, respectively). HCC diagnosed in optimally adherent patients trended toward smaller tumor size (P < 0.08). On multivariate analysis also inclusive of age, sex, clinical visits, cirrhosis, clinic setting and antiviral therapy use, strong independent predictors for having at least annual imaging were a history of more frequent clinical visits (odds ratio [OR] = 2.5, P < 0.001) and university-based care (OR = 5.2, P < 0.001). Even for those with initially fair adherence, persistency dropped to 70% at 5 years.Adherence and persistency to HCC surveillance in CHB patients is generally poor. More frequent clinic visits and university-based settings were significant and strong predictors of at least annual HCC surveillance adherence.

Lower liver cancer risk with antiviral therapy in chronic hepatitis B patients with normal to minimally elevated ALT and no cirrhosis.

For chronic hepatitis B (CHB), alanine aminotransferase (ALT) ≥2 × upper limit of normal (ULN) is often used as a major criteria to initiate treatment in absence of cirrhosis, though patients with lower ALT may not be free from future risk of hepatocellular carcinoma (HCC). We aimed to examine the effect of antiviral therapy on HCC incidence based on ALT levels.We performed a retrospective study on 3665 patients consisting of United States and Taiwanese REVEAL-HBV cohort who were consecutive, treatment-naïve, noncirrhotic CHB patients aged ≥40 years. Patients were categorized by ALT cutoffs (≥2 × ULN vs <2 × ULN) and subgrouped by treatment status. Kaplan-Meier and Cox proportional hazards models were used to calculate cumulative incidence and hazard ratio (HR) of HCC adjusting for REACH-B scores.A total of 202 patients developed HCC. Antiviral treatment significantly reduced HCC risk: HR 0.24, 95% confidence interval 0.10-0.58; P = 0.001. HCC incidence per 100,000 person-years was significantly higher in untreated versus treated patients, even for those with ALT < 2 × ULN: 314.46 versus 0 per 100,000 person-years, P = 0.0042. For patients with Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) ≥ 2000 IU/mL, the number-needed-to-treat (NNT) were 15 and 14 to prevent 1 incident HCC at year 10 for patients with ALT < 2 × ULN and ≥2 × ULN, respectively.After adjustment by REACH-B score, antiviral treatment significantly decreased HCC incidence even in patients with ALT < 2 × ULN. NNT to prevent 1 incident HCC after 10 years of therapy was low (14-15) in patients with mildly elevated HBV DNA ≥ 2000 IU/mL regardless of ALT levels.

Long-term follow-up and suboptimal treatment rates of treatment-eligible chronic hepatitis B patients in diverse practice settings: a gap in linkage to care.

BACKGROUND AND AIMS: Despite available effective therapies, only a minority of patients with chronic hepatitis B (CHB) receive treatment. Our goal is to study treatment rates and time to treatment initiation in patients who meet treatment criteria on long-term follow-up. METHODS: We performed a retrospective cohort study of 608 consecutive treatment-eligible patients with CHB (by 2008 US Panel or 2009 American Association for the Study of Liver Disease (AASLD) criteria) at a US community gastroenterology clinic and a university liver clinic between 2007 and 2011. Patients were observed until they started treatment or last follow-up if untreated. RESULTS: Mean age was 44 and most were Asian (96%) with community patients being younger and having lower alanine aminotransferase (ALT) levels. A total of 62% started treatment, and 38% remained untreated after median follow-up of 17 months (IQR=1-40 months). Overall, treatment rate was significantly higher at university liver clinic than in the community (66.7% vs 59.9%, p=0.01). In multivariate analysis, older age (HR 1.02, p=0.002), male gender (HR 1.37, p=0.02), and baseline ALT >45 U/L for males and >29 U/L for females (HR 2.24, p<0.0001) were significant predictors of treatment initiation, but not practice setting. CONCLUSIONS: Approximately 40% of treatment-eligible patients still have not started treatment on longer follow-up. Treatment rates were higher at university clinics, but practice setting was not a predictor for treatment, but older age, male gender, and higher ALT levels were. Further studies are needed to determine the barriers for treatment initiation and to improve treatment rates in treatment-eligible patients.