Virological Remission Research Articles

Economic evaluation of hepatocellular carcinoma surveillance in chronic hepatitis B patients with virological remission

BackgroundSubsequent risk of hepatocellular carcinoma (HCC) persists in chronic hepatitis B (CHB) patients with virological remission. We aimed to assess the cost-effectiveness of HCC surveillance in those patients and determine appropriate age to commence or discontinue surveillance.MethodsWe developed an individual-based state transition model, simulating the advancement of HCC in CHB patients with virological remission. We used this model to compare the incremental cost-effectiveness ratio (ICER) and long-term health outcomes of biannual or annual HCC surveillance for varying durations with no surveillance.ResultsFor compensated cirrhosis patients with CHB, biannual surveillance was not cost-effective for all age groups, while annual surveillance was cost-effective for patients aged 55 to 70 (ICER USD 28,076 / quality-adjusted life years [QALY] gained), which detected 176 additional early HCC cases in a 100,000-person cohort compared to no surveillance. In CHB patients with advanced fibrosis, annual surveillance for patients aged 40 to 75 was the most cost-effective strategy (ICER USD 4,984/QALY gained), which detected 289 additional early HCC per 100,000 patients.ConclusionsAnnual surveillance for patients with compensated cirrhosis or advanced fibrosis was a more cost-effective option that demonstrated substantial economic benefits, being slightly less effective than biannual surveillance at a significantly lower cost, providing insights for professionals in evaluating HCC surveillance among high-risk patients in China.

Peripheral Neuropathy in Patients with Hepatitis C Infection-Reversibility after HCV Eradication: A Single Center Study.

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement.

Evaluation of chronic hepatitis B patients who voluntarily discontinued oral antiviral therapy: is there an answer to the controversial topic?

The uncertain treatment duration for nucleos(t)ide analogues (NA) used in the treatment of chronic hepatitis B (CHB) is an important problem for both patients and physicians. The aim of this study was to evaluate the determinants of virologic relapse (VR) and the optimum time of treatment discontinuation in the follow-up of CHB patients who voluntarily discontinued treatment after virological suppression was achieved under NA use. Data from 138 patients from 11 centers were included in this registry-based study. Factors associated with VR were investigated using multivariate Cox regression analysis. Ninety-nine (71.7%) of the patients were HBeAg (Hepatitis B e antigen) negative. During the 24-month follow-up period after treatment discontinuation, VR occurred in 58.7% (n = 81) of all patients and 57.6% (n = 57) of HBeAg-negative patients. The duration of NA treatment was significantly shorter (cutoff 60 months) in HBeAg-negative patients who later developed VR. In addition, the duration of virologic remission achieved under NA treatment was significantly shorter (cutoff 52 months) in those who later developed VR. In the Cox multivariate regression model of HBeAg-negative patients, having less than 60 months of NA treatment (HR = 2.568; CI:1.280-5.148; P = 0.008) and the levels of alanine aminotransferase being equal to or higher than twice the upper level of normal at the beginning of treatment (HR = 3.753; CI:1.551-9.081; P = 0.003) were found to be statistically significant and independently associated with VR. The findings of this study may provide clinical guidance in terms of determining the most appropriate discontinuation time for NA.

Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes.

Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs. The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays. NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ. NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.

Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

Higher HBeAg-reversion virological relapse and lower sustained remission after treatment cessation in tenofovir-treated HBeAg-positive patients.

A complete investigation of the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss is limited. We retrospectively recruited 242 HBeAg-positive patients with HBeAg loss after a median duration of 37.2 months with tenofovir (TDF, n = 77) or entecavir (ETV, n = 165) treatment. There were 77 (31.8%) patients with sustained virological remission (SVR), 85 (35.1%) with HBeAg-reversion virological relapse, 80 (33.1%) with HBeAg-negative virological relapse after treatment cessation, and 23 (9.5%) with HBsAg loss. Clinical data at baseline, on-treatment and during off-treatment follow-up were analyzed. The 3-year cumulative incidences of overall, HBeAg-reversion and HBeAg-negative virological relapse were 70.2%, 54%, and 53.5%, respectively. The common factors associated with HBeAg-reversion and HBeAg-negative virological relapse were tenofovir treatment (hazard ratio [HR] = 5.411, p < 0.001; HR = 2.066, p = 0.006, respectively) and HBsAg at end of treatment (EOT) (HR = 1.461, p = 0.001; HR = 1.303, p = 0.019, respectively). The 5-year cumulative incidence of HBsAg loss in SVR patients was 13.7% and EOT HBsAg was the only associated factor (HR = 0.524, p = 0.024). Compared to that of ETV-treated patients, TDF-treated patients had a significantly higher 3-year cumulative incidence of virological relapse (87.3% vs. 62.8%, p < 0.001), earlier HBeAg-reversion virological relapse (2.9 vs. 7.8 months, p < 0.001), a higher rate of HBeAg-reversion virological relapse (53.2% vs. 26.7%) and a lower SVR rate (15.6% vs. 39.4%) (p < 0.001). In summary, the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss were composed of HBeAg-reversion virological relapse, HBeAg-negative virological relapse and SVR. TDF was significantly associated with off-treatment virological relapse. EOT HBsAg plays an important role in HBsAg loss among SVR patients and posttreatment virological relapse.

Significance of Circulating Cell-Free DNA Biomarkers in HBeAg-Negative Chronic Hepatitis B Virus Infection and Their Changes after Treatment Initiation

Chronic hepatitis B virus (HBV) infection is a common chronic liver disease that is closely associated with increased morbidity and mortality. Circulating cell-free DNA (cf-DNA) and global DNA methylation, expressed as circulating levels of 5-methyl-2'-deoxycytidine, are increasingly used to monitor chronic inflammatory diseases of several etiologies. This study attempts to investigate the serum levels of circulating cf-DNA and 5-methyl-2'-deoxycytidine in HBeAg-negative patients with chronic infection (carriers) and chronic hepatitis B (CHB), as well as their changes after treatment initiation in CHB. Serum samples from a total of 61 HBeAg-negative patients (30 carriers and 31 CHB patients) were included in order to quantify the levels of circulating cf-DNA and 5-methyl-2'-deoxycytidine. In addition, serum samples from 17 CHB patients in complete virological and biochemical remission after initiation of treatment with a nucleos(t)ide analogue were included. Circulating cf-DNA concentration was significantly increased after the initiation of treatment (15 vs. 10 ng/mL, p = 0.022). There was a trend in higher mean levels of circulating 5-methyl-2'-deoxycytidine in carriers compared to CHB patients (211.02 vs. 175.66 ng/mL, p = 0.089), as well as a trend in increasing 5-methyl-2'-deoxycytidine levels after treatment initiation in CHB patients compared to pre-treatment levels (215 vs. 173 ng/mL, p = 0.079). Both circulating levels of cf-DNA and 5-methyl-2'-deoxycytidine might be useful biomarkers in order to monitor liver disease activity and response to antiviral treatment in HBeAg-negative chronic HBV patients, but further studies are essential in order to validate these intriguing findings.

Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19.

SARS-CoV-2 infection is clinically heterogeneous, ranging from asymptomatic to deadly. A few patients with COVID-19 appear to recover from acute viral infection but nevertheless progress in their disease and eventually die, despite persistent negativity at molecular tests for SARS-CoV-2 RNA. Here, we performed post-mortem analyses in 27 consecutive patients who had apparently recovered from COVID-19 but had progressively worsened in their clinical conditions despite repeated viral negativity in nasopharyngeal swabs or bronchioalveolar lavage for 11-300 consecutive days (average: 105.5 days). Three of these patients remained PCR-negative for over 9months. Post-mortem analysis revealed evidence of diffuse or focal interstitial pneumonia in 23/27 (81%) patients, accompanied by extensive fibrotic substitution in 13 cases (47%). Despite apparent virological remission, lung pathology was similar to that observed in acute COVID-19 individuals, including micro- and macro-vascular thrombosis (67% of cases), vasculitis (24%), squamous metaplasia of the respiratory epithelium (30%), frequent cytological abnormalities and syncytia (67%), and the presence of dysmorphic features in the bronchial cartilage (44%). Consistent with molecular test negativity, SARS-CoV-2 antigens were not detected in the respiratory epithelium. In contrast, antibodies against both spike and nucleocapsid revealed the frequent (70%) infection of bronchial cartilage chondrocytes and para-bronchial gland epithelial cells. In a few patients (19%), we also detected positivity in vascular pericytes and endothelial cells. Quantitative RT-PCR amplification in tissue lysates confirmed the presence of viral RNA. Together, these findings indicate that SARS-CoV-2 infection can persist significantly longer than suggested by standard PCR-negative tests, with specific infection of specific cell types in the lung. Whether these persistently infected cells also play a pathogenic role in long COVID remains to be addressed. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth

Early antiretroviral therapy (ART) in HIV-infected infants generally fails to achieve a sustained state of ART-free virologic remission, even after years of treatment. Our studies show that viral reservoir seeding is different in neonatal macaques intravenously exposed to SIV at birth, in contrast to adults. Furthermore, one month of ART including an integrase inhibitor, initiated at day 3, but not day 4 or 5 post infection, efficiently and rapidly suppresses viremia to undetectable levels. Intervention initiated at day 3 post infection and continued for 9 months achieves a sustained virologic remission in 4 of 5 infants. Collectively, an early intervention strategy within a key timeframe and regimen may result in viral remission or successful post-exposure prophylaxis for neonatal SIV infection, which may be clinically relevant for optimizing treatment strategies for HIV-infected or exposed infants.

Towards a molecular profile of antiretroviral therapy-free HIV remission.

To summarize the current status and highlight recent findings on predictive biomarkers for posttreatment HIV control (PTC) and virological remission. While historically, many studies focused on virological markers, there is an increasing tendency to enter immune and metabolic factors into the equation. On the virological side, several groups reported that cell-associated HIV RNA could predict time to viral rebound. Recent data hints at the possible importance of the genic location and chromatin context of the integrated provirus, although these factors still need to be assessed in relation to PTC and virological remission. Evidence from immunological studies highlighted innate and humoral immunity as important factors for prolonged HIV remission. Interestingly, novel metabolic markers have emerged, which offer additional angles to our understanding of latency and viral rebound. Facilitating PTC and virological remission remain top priorities for the HIV cure research. We advocate for clear and precise definitions for both phenomena in order to avoid misconceptions and to strengthen the conclusions that can be drawn. As no one-size-fits-all marker has emerged yet, more biomarkers are on the horizon, and viral rebound is a complex and heterogeneous process, it is likely that a combination of various biomarkers in cohesion will be necessary for a more accurate prediction of antiretroviral therapy-free HIV remission.

Post-transplant Diabetes Mellitus: What Physicians Need to Know.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

Перекрестный синдром хронического гепатита С и аутоиммунного гепатита 1-го типа с последующей трансформацией в аутоиммунный гепатит 2-го типа: клиническое наблюдение

We present clinical case of patient with initially diagnosed chronic hepatitis C with an autoimmune component corresponding to type 1 autoimmune hepatitis. Considering that at the time of diagnosis, the therapeutic possibilities of hepatitis C were limited to the use of standard or pegylated interferon α in combination with ribavirin, in order to avoid the adverse immunomodulatory effect of interferon, we previously suppressed the autoimmune component with immunosuppressors. After 6-month course of prednisolone and azathioprine, antiviral therapy with interferon α and ribavirin was carried out with the achievement of sustained virological and biochemical response. After 7 years of complete virological, immunological and biochemical remission, the patient manifested autoimmune hepatitis type 2. The appointment of prednisolone and azathioprine led to a stable drug-induced remission.

An exploration of how broadly neutralizing antibodies might induce HIV remission: the 'vaccinal' effect.

Broadly neutralizing antibodies (bNAbs) are a potential new therapeutic strategy to treat HIV infection. This review explores possible mechanisms of action of bNAbs and summarizes the current evidence supporting their immunomodulatory properties, which might lead to sustained virological remission - the 'vaccinal effect'. Antiretroviral therapy (ART) is required to confer lasting HIV suppression; stopping ART almost invariably leads to HIV recrudescence from a persistent pool of virally infected cells - the HIV reservoir. HIV-specific broadly neutralizing antibodies (bNAbs) may confer viral control after ART cessation predominantly through blockade of viral entry into uninfected target cells. In some human and animal studies, HIV bNAbs also conferred lasting viral suppression after therapeutic bNAb plasma levels had declined. Immune-modulatory mechanisms have been postulated to underlie this observation - the 'vaccinal effect'. Hypothesized mechanisms include the formation of immune complexes between bNAbs and HIV envelope protein, thereby enhancing antigen presentation and uptake by immune cells, with boosted adaptive immune responses subsequently controlling the HIV reservoir. There is emerging evidence for potent antiviral efficacy of bNAb therapy. Whether bNAbs can induce sustained viral suppression after dropping below therapeutic levels remains controversial. Mechanistic data from on-going and future clinical trials will help answer these questions.

Factors associated with prolonged viral detection in asymptomatic and mildly symptomatic patients with SARS-CoV-2 infection.

Data on the clinical course and duration of viral RNA detection in patients with mild or asymptomatic coronavirus disease 2019 are limited. In this retrospective analysis, clinical characteristics and serial real-time reverse transcriptase-polymerase chain reaction (RT-PCR) results were reviewed in a cohort of 1186 asymptomatic and mildly symptomatic coronavirus disease 2019 patients in South Korea. Factors associated with prolonged duration of RT-PCR positivity for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) were also evaluated. Patients with two consecutive negative RT-PCR tests ≥ 24 hours apart were considered to be in virologic remission and discharged. The average virologic remission period, defined as the number of days from diagnosis to virologic remission, was 22.0 ± 9.7 days; patients with longer than 30 days accounted for 21.2% (251/1186) of the population. Patients who took longer than 30 days to achieve virologic remission had a higher frequency of overall symptoms (p < 0.001) and respiratory symptoms (p < 0.001). In multivariate analysis using Cox-proportional hazard regression, it was confirmed that respiratory symptoms (hazard ratio [HR], 0.7372; 95% confidence interval [CI], 0.6540-0.8311) and gastrointestinal symptoms (HR, 0.8213; 95% CI, 0.6970-0.9679) were independent factors associated with prolonged virologic remission. Age and co-morbidity such as diabetes and hypertension were not associated with the prolonged RT-PCR positivity. A considerable percentage of asymptomatic and mildly symptomatic patients with coronavirus disease 2019 showed prolonged RT-PCR positivity for SARS-CoV-2; which was independently associated with the presence of symptoms, but not with age and co-morbidity.

Long-term efficacy and safety of oral nucleoside/tide analogues in maintaining biochemical and virological remission in renal transplant recipients with hepatitis B virus (HBV) infection.

Background and Aim: Hepatitis B virus (HBV) is a common infection in end stage renal disease (ESRD) patients on renal replacement therapy and may impact post-transplant outcome. We aimed to assess the long-term effect of antiviral drugs on chronic hepatitis B infection in ESRD patients after renal transplant.

Chronic hepatitis B virus (HBV) infection presenting as crescentic membranoproliferative glomerulonephritis: A distinctly rare occurrence

Abstract&#x0D; Hepatitis B virus (HBV) is a highly prevalent infection worldwide. It primarily infects liver and presents with features of chronic liver disease. Rarely, it presents with extra-hepatic manifestations. Kidney involvement in HBV infection is not uncommon. However, presentation with rapidly progressive glomerulonephritis is distinctly rare. A 40-year-old man with undiscovered HBV infection presented with fever-triggered body swelling for one month. Serum creatinine was 2.3 mg/dl on admission, which increased during hospitalization to 4.5 mg/dl. Renal biopsy demonstrated crescentic membranoproliferative glomerulonephritis, immune complex-mediated. Clinical, laboratory and imaging studies revealed mild chronic liver damage. Complete renal, hepatic and virological remission was achieved with steroids, plasmapheresis and antiviral therapy. This case emphasizes on early diagnosis and institution of multimodal therapy for better outcomes.

S2796 Warm Autoimmune Hemolytic Anemia Secondary to Acute Hepatitis B Virus Infection

Introduction: Autoimmune hemolytic anemia (AIHA) is a rare extrahepatic manifestation, typically associated with HIV, hepatitis C, E, and Epstein Barr virus (EBV) infections. Hepatitis B virus (HBV) induced AIHA is an unusual association, not previously described in the literature. We report the first case of HBV-induced warm-AIHA, successfully treated with corticosteroids and anti-viral therapy. Case Description/Methods: A 67-year-old man presented to our hospital with one month of myalgias, arthralgias, and fatigue. He had no known history of the lymphoproliferative disorder, autoimmune disease, immunodeficiency, malignancy, or alcohol abuse. He lived in the woods and reported previous tick exposure and recent unprotected sexual encounters with multiple intravenous drug users. His physical examination revealed mild scleral icterus. Laboratory workup was notable for hemoglobin (Hb) 12.5 gm/dL, reticulocyte count 4.1%, elevated aspartate aminotransferase 493 units/L, alanine aminotransferase 693 units/L, total bilirubin 5.3mg/dL with indirect bilirubinemia 2.4 mg/dL, lactate dehydrogenase 1,158 units/L, and undetectable haptoglobin. Immunohematologic studies showed a direct antiglobulin test positive for IgG and C3 with isolation of warm autoantibodies by elution, consistent with a diagnosis of warm AIHA. Workup to elucidate the cause of AIHA including ANA, anti-proteinase-3, myeloperoxidase antibodies, peripheral blood smear, malaria smear, northeast tick panel, serum protein electrophoresis, and immunofixation were unrevealing. HIV, hepatitis A, C, E, and EBV infections were ruled out. HBV serologies revealed positive HBs-antigen, anti-HBc IgM, and PCR quantification HBV DNA 824,000,000 IU/ml, consistent with acute HBV infection. A diagnosis of warm AIHA secondary to acute HBV infection was made. 1mg/kg/day of prednisone and Tenofovir 25 mg/day were started. During the hospitalization, his anemia worsened, reaching a Hb nadir of 5.2 gm/dl and requiring ten units of packed red blood cell transfusions. He eventually stabilized at day 18, followed by a sustained virological response, clinical and laboratory remission of AIHA. Discussion: This case highlights AIHA as an unusual manifestation of acute HBV infection. An association between AIHA and hepatic viruses, including HIV, HCV, and EBV, has been well recognized. Acute HBV infection induced AIHA has not been reported in the literature yet. Therefore, clinicians should consider HBV infection in any patient presenting with new-onset AIHA of unclear etiology.Figure 1.: The patient's jaundice on physical exam.

Serum PIVKA-II and alpha-fetoprotein at virological remission predicts hepatocellular carcinoma in chronic hepatitis B related cirrhosis

The risk of hepatocellular carcinoma (HCC) is reduced but not eliminated after nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB). We aimed to investigate the role of serum Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) and alpha-fetoprotein in predicting HCC and mortality in cirrhotic CHB patients at virological remission (VR) following NA therapy. Patients with CHB-related cirrhosis undergoing NA therapy from two medical centers in Taiwan were retrospectively included. Serum PIVKA-II were quantified by an automated chemiluminescence assay. Multivariable Cox proportional hazards regression models were used to identify predictors for HCC and death. Serial on-treatment PIVKA-II levels after VR were investigated. Overall, 293 CHB-related cirrhosis patients were included. At VR, the mean age was 55, and the mean PIVKA-II level was 35 mAU/mL. After a mean follow-up of 78 months, 76 patients developed HCC and 19 died. After adjustment for confounding factors, alpha-fetoprotein >7ng/mL (hazard ratio [HR]: 2.84, 95% confidence interval [CI]: 1.73-4.67) and PIVKA-II >50 mAU/mL (HR: 2.46, 95%CI: 1.35-4.49) at VR significantly predicted HCC development. In patients with alpha-fetoprotein ≤10ng/mL or ≤20ng/mL at VR, PIVKA-II >50 mAU/mL increased 2.45 or 3.16-fold risk of HCC, respectively. PIVKA-II levels after VR increased serially in patients who developed HCC afterwards. In patients with CHB-related cirrhosis, serum alpha-fetoprotein >7ng/mL and PIVKA-II >50 mAU/mL at the time of antiviral therapy-induced VR is associated with a greater risk of HCC. PIVKA-II is a predictive marker for HCC in patients with low normal alpha-fetoprotein level.

Predictive Nomograms for Clinical Outcomes in Hepatitis B-Related Cirrhosis Patients Receiving Antiviral Therapy.

ObjectiveMany scores have been constructed to predict liver-related events in chronic hepatitis B, while most of them are based on baseline clinical parameters. The objective of this study was to develop nomograms based on on-treatment improvement in established scores to predict clinical outcomes in patients with hepatitis B virus (HBV)-related cirrhosis who are receiving antiviral therapy.MethodsThe Cox proportional hazards regression model was used. Nomograms were constructed for the prediction of liver-related events, hepatocellular carcinoma (HCC), and liver-related mortality risk during long-term antiviral therapy.ResultsA total of 277 treatment-naive patients with HBV-associated cirrhosis were enrolled from January 2010 to December 2013. After a median follow-up of 63.3 months, 95 patients developed liver-related events, including 59 patients with liver-related death. Multivariate Cox analysis showed that the albumin-bilirubin score at year 1 was an independent predictor of liver-related events, liver-related mortality, and HCC. Age, decompensation, and delayed virological remission were independent factors for liver-related mortality. Age was also a risk factor for liver-related events. The concordance index values of event-nomogram, mortality-nomogram, and HCC-nomogram were 0.742 (95% confidence interval [CI], 0.691~0.793), 0.799 (95% CI, 0.748~0.850), and 0.613 (95% CI, 0.540~0.686), respectively. The calibration plots showed an agreement between the predicted and observed incidences, which indicates good calibration of the model of event-nomogram and mortality-nomogram.ConclusionThe nomograms achieved an optimal preoperative prediction of liver-related events, mortality, and HCC development in patients with HBV-related cirrhosis receiving antiviral therapy. These findings may help to identify high-risk patients for further optimal surveillance and intervention strategies.

IL-21 Is Associated With Virological Relapse of HBeAg Positive Chronic Hepatitis B After Discontinuance of Entecavir.

To investigate the association between interleukin-21 (IL-21) expression level and virological relapse (VR) of HBeAg positive chronic hepatitis B (CHB) after discontinuance of entecavir (ETV). The serum IL-21 level of 112 CHB patients was measured at 0, 12, 24, 52, and 104 weeks after ETV discontinuance. ELISA was used for the measurement of serum IL-21 level. VR was defined as two continuous examinations with an interval of 1 month with both showing HBV DNA >10 000 copies/mL after drug discontinuance. The serum IL-21 levels at 0, 12, 24, 52, and 104 weeks after discontinuance of ETV were significantly higher in the durable virological remission (DVR) group than in the VR group (all P < .01). The area under the ROC curve (AUC) was 0.728 (95% CI: 0.630-0.827, P < .001), while the best cut-off value was 49.8 pg/mL. Multivariate Cox model showed that the factors affecting the relapse included age, followed by HBsAg level at the serological conversion of HBeAg and serum IL-21 level (all P < .05). Serum IL-21 level at ETV discontinuance is an independent risk factor for CHB relapse. IL-21 acts as an immunomodulatory factor in maintaining DVR in HBeAg positive CHB patients after ETV discontinuance.