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2.
Viruses ; 12(1)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963118

RESUMO

Mathematical modeling of Ebola virus (EBOV)-host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model's predictions. We also explored the model's predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV-host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment.

3.
Ann Surg Oncol ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925595

RESUMO

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC), with most clinical data stemming from single-institution series. The variability in the literature lends support for analysis using a large national dataset. In doing so, we sought to (1) define the characteristics and outcomes of patients with FLC; (2) determine factors associated with survival in patients undergoing resection; and (3) compare the overall survival (OS) of patients with FLC with a matched group of patients with HCC. METHODS: The National Cancer Database was queried for patients with FLC, and their clinicopathologic features were recorded. Univariate and multivariate analyses were performed to delineate factors associated with survival. RESULTS: Between 2004 and 2015, 496 patients were diagnosed with FLC, 229 of whom underwent a curative resection. The median OS for patients with FLC undergoing curative resection was 78.5 months. Factors associated with abbreviated OS in this surgical cohort include multiple tumors [hazard ratio (HR) 3.15, p = 0.025], positive regional lymph nodes (HR 2.83, p = 0.023), and elevated serum α-fetoprotein (AFP; HR 2.81, p = 0.034). When the OS of patients with FLC was compared with a matched group of patients with HCC, no difference was detected (p = 0.748); however, patients with FLC and elevated AFP had abbreviated OS compared with patients with HCC and elevated AFP (43 vs. 82 months, p ≤ 0.001). CONCLUSIONS: Elevations in serum AFP occur more frequently than previously documented for patients with FLC and are associated with abbreviated OS. AFP levels may help guide the decision for operative intervention in patients with FLC.

4.
Hepatology ; 71(1): 397-398, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31531987
5.
Am J Med Genet A ; 182(1): 229-249, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710777

RESUMO

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

6.
Hepatology ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31816111

RESUMO

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) initiated the hepatitis C guidance project (hereafter HCV guidance) in 2013. The AASLD-IDSA HCV guidance website (www.HCVGuidelines.org) disseminates up-to-date, peer-reviewed, unbiased, evidence-based recommendations to aid clinicians making decisions regarding the testing, management, and treatment of hepatitis C virus (HCV) infection. Utilizing a web-based system enables timely and nimble distribution of the HCV guidance, which is periodically updated in near real time as necessitated by emerging research data, recommendations from public health agencies, the availability of new therapeutic agents, or other significant developments affecting the rapidly evolving hepatitis C arena.

7.
Antiviral Res ; 174: 104691, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31837393

RESUMO

BACKGROUND: Chronic Hepatitis D virus (HDV) infection results in the most severe form of viral hepatitis with a rapid progression to cirrhosis. However, non-invasive fibrosis tests that can accurately predict cirrhosis have not been adequately validated. We aimed to develop a clinically useful non-invasive score that can accurately detect cirrhosis. MATERIAL AND METHODS: Patients with chronic HDV diagnosed by liver histology or serum PCR were evaluated. Data regarding demographics, laboratory, imaging, vibration-controlled transient elastography (VCTE), and liver biopsy were collected. The total cohort was randomized into a training and validation cohort. The training cohort was used to develop a novel score, the Delta-4 fibrosis score (D4FS) which was then compared to other non-invasive tests in the validation cohort by area under receiver operating characteristics (AUROC). RESULTS: 77 patients with chronic HDV were evaluated: mean age 42.6 (SD:11.1) years, 59.7% male, and 57.1% Asian. The total cohort was then separated into a training (n = 45) and validation (n = 32) cohort with no significant differences in terms of clinical characteristics between the two. From the training cohort, the D4FS was derived from variables of statistical and clinical interest (gamma-glutamyl transpeptidase (GGT), platelet count, alanine aminotransferase (ALT), and liver stiffness measurement (LSM)). The D4FS demonstrated the best AUROC in the validation cohort (0.94) followed by VCTE (0.90), FIB-4 (0.86), APRI (0.81), and AAR (0.71). DISCUSSION: The D4FS is a clinically useful non-invasive fibrosis score that can accurately detect cirrhosis in patients with chronic HDV infection. Further studies should be performed to further validate clinical utility.

8.
Hepatology ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31872446

RESUMO

Hepatitis D virus (HDV) is an RNA virus that requires the presence of Hepatitis B virus (HBV) to complete its life cycle. Worldwide, chronic HDV infection is believed to occur in ~5% of people chronically infected with HBV and is the most virulent of the chronic viral hepatitis infections1 . While acute hepatitis D has an increased risk of liver failure compared to acute hepatitis B, chronic hepatitis D may often be missed as elevations in aminotransferases can be attributed to concomitant hepatitis B infection1 .

9.
J Viral Hepat ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742822

RESUMO

Noninvasive detection of cirrhosis via vibration-controlled transient elastography (VCTE) has revolutionized the management of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, VCTE has not been studied in chronic hepatitis D virus (HDV) infection and accuracy remains in question due to the significant hepatic inflammation associated with this infection. Consecutive HBV, HCV and HDV patients who underwent VCTE (2006-2019) were evaluated. Diagnosis of cirrhosis was made via liver biopsy or clinical findings. VCTE was compared with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compared. We evaluated 319 patients (HBV-112; HCV-132; HDV-75), 278(87%) patients had histology for evaluation. HDV patients had evidence of higher hepatic inflammation as evidence by aspartate aminotransferase, alanine aminotransferase and histology activity index. Cirrhotic HDV patients had higher mean liver stiffness measurements compared with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE demonstrated excellent diagnostic accuracy for the detection of cirrhosis with an AUROC of 0.90 compared with APRI (0.83), FIB-4 (0.88), AAR (0.73) and RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) and HCV (0.94). At the optimized cut-off value of ≥14.0 kPa for determining cirrhosis in HDV, VCTE had a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 and PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for determining cirrhosis despite the presence of significant hepatic inflammation.

10.
ACG Case Rep J ; 6(6): e00098, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31616768

RESUMO

Granulocyte-colony-stimulating factors such as filgrastim are currently used for multiple indications, one of which is administration to healthy donors for allogeneic stem cell collection. So far, filgrastim has not been described as a cause of drug-induced liver injury. We report a case of drug-induced liver injury secondary to filgrastim use in a 54-year-old healthy donor. The patient presented with an upsurge of liver enzymes a week from the drug administration with a rapid downtrend over the next few weeks. We wish to highlight the possibility of a similar idiosyncratic adverse drug reaction in other healthy individuals.

11.
World J Gastroenterol ; 25(32): 4580-4597, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31528088

RESUMO

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.

12.
Hepatol Commun ; 3(9): 1271-1280, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31497747

RESUMO

With the success of hepatitis C virus (HCV) direct-acting antiviral therapies, there has been a shift in research focus to the other major chronic liver diseases (CLDs). The use of social media, specifically Twitter, has become a popular platform for understanding public health trends and for performing health care research. To evaluate this, we studied the areas of public interest and social media trends of the following three major CLDs: hepatitis B virus (HBV), HCV, and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). Twitter activity data from January 1, 2013, through January 1, 2019, for HBV, HCV, and NAFLD/NASH were collected using the social media analytic tool Symplur Signals (Symplur LLC) software. Content and regression analyses were performed to understand and predict Twitter activity for each of the CLDs. Over the study period, there were 810,980 tweets generating 4,452,939,516 impressions. HCV tweet activity peaked in 2015 at 243,261 tweets, followed by a decline of 52.4% from 2015 to 2016 with a subsequent plateau through 2018. Meanwhile, NAFLD/NASH and HBV tweet activity has continued to increase, with projections that these two CLDs will surpass HCV by the second half of 2023 and 2024, respectively. Treatment and Management was the most popular content category for HCV and NAFLD/NASH, while Prevention was the most popular content category for HBV. Conclusion: Twitter is a useful social media tool to gauge public interest in liver disease over time. The information provided by Twitter can be used to identify gaps in public knowledge or highlight areas of interest that may need further research. Future studies on the use of Twitter in liver disease are warranted.

13.
Dig Dis Sci ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407130

RESUMO

BACKGROUND: Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis. METHODS: Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point. RESULTS: Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point. CONCLUSION: In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).

14.
Open Forum Infect Dis ; 6(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363763

RESUMO

Hepatitis C virus (HCV) infects 71 million individuals, and barriers to treatment remain. Bacterial translocation is a complication of chronic HCV infection, and this study evaluated circulating microbial components including lipopolysaccharide, peptidoglycan, and ß-D-glucan in addition to their pattern recognition receptors and degree of hepatic macrophage uptake. The findings suggest that regulation of serum peptidoglycan and ß-D-glucan differs from that of lipopolysaccharide. Additionally, macrophage activation in the liver may be better reflected by the degree of macrophage uptake than by circulating levels of microbial markers. These findings allow for a greater understanding of bacterial translocation and host immune activation during HCV infection.

16.
Sci Transl Med ; 11(495)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31167928

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

17.
Mol Pharmacol ; 96(2): 158-167, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31175181

RESUMO

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/ß) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas de Membrana Transportadoras/genética , Plicamicina/efeitos adversos , Neoplasias Torácicas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/genética , Ensaios Clínicos Fase II como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Neoplasias Torácicas/genética , Neoplasias Torácicas/metabolismo
18.
J Gastrointest Oncol ; 10(3): 407-411, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31183189

RESUMO

Background: Hereditary diffuse gastric cancer (HDGC) syndrome results most often from a mutation in the CDH1 tumor suppressor gene and confers a 56-70% lifetime risk of gastric cancer. In asymptomatic carriers HDGC is characterized by multiple foci of signet ring cancer cells (SRCC) throughout the gastric mucosa. Because SRCC foci are less than 1 mm in diameter, and often make up less than 2% of the gastric mucosa, they are undetectable on standard screening endoscopy. International consensus guidelines recommend thorough white light endoscopic gastric mapping with a systematic method for gastric biopsies. Despite a painstaking approach to gastric mapping, retrospective analyses have demonstrated a low rate of detection and poor sensitivity of standard white light endoscopy for detecting occult cancer cells. Therefore, a more sensitive cancer screening tool is needed for these high-risk patients. Confocal endoscopic microscopy (CEM) allows for real-time, in vivo histologic imaging of gastrointestinal mucosa during upper endoscopy. Clinical application has demonstrated the ability of CEM to differentiate normal mucosal cells and cancer cells. Methods: A phase II clinical trial is currently underway to compare CEM to standard endoscopic gastric mapping in an effort to reduce the false negative detection rate of SRCC in patients diagnosed with HDGC. After an upper endoscopy with gastric mapping is performed, patients will undergo probe-based CEM. The endoscopist will scan the anatomic zones of the stomach in a similar fashion to the systematic gastric mapping approach. Any abnormal areas visualized with the CEM probe will be biopsied and sent for permanent pathologic analysis. The primary endpoint is to determine if CEM affords a higher sensitivity for detection of SRCC in CDH1 germline mutation carriers compared to white light endoscopy with gastric mapping. Discussion: This novel screening technique is expected to provide greater sensitivity for detecting occult cancer in patients with HDGC, thereby improving cancer risk-assessment and overall cancer care. Trial registration: ClinicalTrials.gov NCT03648879 (registration date: August 28, 2018, clinicaltrials.gov).

19.
Br J Haematol ; 187(1): 117-123, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31218662

RESUMO

Vibration controlled transient elastography (VCTE) is validated for the evaluation of hepatic fibrosis in different liver diseases. Sickle cell liver disease (SCLD) results from a cumulative hepatic injury and its lifelong and progressive nature raises the need for a non-invasive tool for fibrosis evaluation. Fifty patients, aged between 23 and 59 years with sickle cell disease and suspected SCLD underwent a VCTE followed by a liver biopsy. Biopsies were evaluated for various scores of liver disease that were then correlated to VCTE score. 90% of our patients had an Ishak Fibrosis (IF) score between 0-2 (Group A-minimal to no fibrosis) and 10% of the patients had IF score between 3-6 (Group B-advanced fibrosis). The median Transient Elastography (TE) for patients in Groups A and B was 4·8 kilopascals (kPa) and 17·6 kPa, respectively. A positive correlation was shown between TE and IF score, R = 0·0·68 (P = <0·0001); a positive correlation was also shown with Histology Activity Index fibrosis score, R = 0·64 (P = <0·0001). This study emphasises the need for further studies of non-invasive tools and their utility in liver fibrosis evaluation of patients with SCLD.

20.
Antiviral Res ; 168: 61-67, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31125632

RESUMO

BACKGROUND: Fibrosis regression has been associated with nucleoside analogue (NA) treatment in chronic hepatitis B (CHB) patients. Although non-invasive fibrosis markers have been evaluated in CHB, their utility for monitoring on-treatment histologic regression has not been evaluated. AIMS: To characterize improvements in disease severity and the utility of non-invasive biomarkers in CHB NA treated patients. METHODS: Histology, labs, AST-to-platelet ratio index, and Fibrosis-4 (Fib-4) from treatment-naïve CHB patients were evaluated at baseline and longitudinally. Relative change from baseline to various time points during treatment were evaluated. Correlative analysis of APRI and Fib-4 with histology was performed longitudinally. RESULTS: 80 CHB patients (84% male, median age 45 (IQR 32, 54)) with histology up to 17 years (median 6(IQR 3.9, 8.0)) years were studied. Median baseline Ishak fibrosis was 3 (IQR 2, 4), histologic activity index (HAI) inflammation was 9 (IQR 7, 11), and AUROC of fibrosis markers for detecting cirrhosis (Ishak ≥ 5) was >0.64. HAI improved at a rate of 54% during year 1 and 37% in year 2, both greater than in the remaining follow-up periods. Within the first year, fibrosis improved by 35%, greater than all other time periods. Non-invasive biomarkers began to correlate with histology beyond 4 years (APRI: 4-6 years: r = 0.33, p = 0.03; ≥6 years: r = 0.41, p = 0.009; Fib-4: ≥6 years: r = 0.35, p = 0.03). CONCLUSION: Early dynamic changes in histology occur in CHB patients on NA followed by linear improvements. Non-invasive fibrosis biomarkers do not capture these dynamic changes and may demonstrate clinical utility beyond 4 years of treatment.

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