Recurrence and influencing factors of hepatitis B surface antigen seroclearance induced by peginterferon alpha-based regimens

BACKGROUND The long-term stability of hepatitis B surface antigen(HBsAg)seroclearance following peginterferon alpha(peg-IFN-α)-based therapy has not been extensively studied,leaving the full potential and limitations of this strategy unclear.AIM To assess HBsAg recurrence after seroclearance achieved by peg-IFN-αregimens.METHODS This prospective,multicenter,observational study was conducted from November 2015 to June 2021 at three Chinese hospitals:The Second Affiliated Hospital of Xi’an Jiaotong University,Ankang Central Hospital,and The Affiliated Hospital of Yan’an University.Participants who achieved HBsAg seroclearance following peg-IFN-α-based treatments were monitored every 4-12 weeks post-treatment for hepatitis B virus(HBV)markers,HBV DNA,and liver function.The primary outcome was HBV recurrence,defined as the reemergence of HBsAg,HBV DNA,or both,at least twice within 4-8 weeks of follow-up.RESULTS In total,121 patients who achieved HBsAg seroclearance were enrolled.After a median follow-up of 84.0(48.0,132.0)weeks,four subjects were lost to follow-up.HBsAg recurrence was detected in 16 patients.The cumulative HBsAg recurrence rate in the intention-to-treat population was 15.2%.Multivariate logistic regression analysis demonstrated that consolidation time<12 weeks[odds ratio(OR)=28.044,95%CI:4.525-173.791]and hepatitis B surface antibody disappearance during follow-up(OR=46.445,95%CI:2.571-838.957)were strong predictors of HBsAg recurrence.HBV DNA positivity and decompensation of liver cirrhosis and hepatocellular carcinoma were not observed.CONCLUSION HBsAg seroclearance following peg-IFN-αtreatment was durable over 84 weeks of follow-up with a cumulative recurrence rate of 15.2%.

Peginterferon alfa-2a for the treatment of chronic hepatitis C in the era of direct-acting antivirals

BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE: Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.

Serum proteins in chronic hepatitis B patients treated with peginterferon alfa-2b

AIM: To study the differential protein profile in serum of hepatitis B patients.METHODS: Serum samples were obtained from patients with chronic hepatitis B who were receiving peginterferon alfa-2b.The serum samples were subjected to albumin depletion and analyzed by two-dimensional gel electrophoresis(2-DE).Differentially expressed protein spots were identified by electrospray ionizationquadrupole time-of-flight mass spectrometry.Alpha2-HS-glycoprotein,complement component C3c and CD5 antigen were further analyzed by an enzymelinked immunosorbent assay and immunonephelometry.RESULTS: Nineteen patients with HBeAg-positive chronic hepatitis B(CHB) were studied.These patients were followed for at least 1 year after treatment and were classified according to their treatment response: responders(n = 9) and non-responders(n = 10).2-DE and MS/MS analysis were performed to compare the serum proteins before initiating peginterferon alfa2b.From the quantitative analysis of the 2-D gel,7 proteins were detected between the two groups at different levels before treatment.Among these potential candidates,serum levels of alpha-2-HS-glycoprotein,complement component C3c and CD5 antigen-like precursor were further analyzed.In the validation phase,23 subjects,9 sustained responders and 14 nonresponders,were recruited.Interestingly,the levels of alpha-2-HS-glycoprotein and complement component C3c were elevated in the serum of the non-responders compared to the responders.CONCLUSION: Serum alpha-2-HS-glycoprotein and complement component C3c may be potential serum biomarkers in predicting the treatment response of peginterferon alfa-2b in patients with CHB prior to treatment.

Efficacy of low dose peginterferon alpha-2b with ribavirin on chronic hepatitis C

AIM: To assess the effi cacy of peginterferon alpha 2b at doses of 50 μg weekly and 80 μg weekly (based on body weight) plus ribavirin in HCV genotype 2 and genotype 3 chronic hepatitis C patients. METHODS: During the study period of Jan 2002 to Dec 2003, all patients diagnosed as chronic hepatitis C or HCV related compensated cirrhosis were treated with peginterferon alpha 2b 50 μg S/C weekly (body weight < 60 kg) or 80 μg S/C weekly (body weight > 60 kg) plus ribavirin 800 mg/d for 24 wk. RESULTS: Overall 28 patients, 14 patients in each group (based on body weight) were treated during the period. Out of 28 patients, 75% were genotype 3, 18% were genotype 2 and 7% were genotype 1. The mean dose of peginterferon alpha 2b was 0.91 μg/kg in group 1 and 1.23 μg/kg in group 2 respectively. The end of treatment and sustained virologic response rates were 82% and 78% respectively. Serious adverse effects were seen in 3.5% patients. CONCLUSION: Low dose peginterferon alpha 2b in combination with ribavirin for 24 wk is effective in HCV genotype 2 and 3 chronic hepatitis C patients.

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level < 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level(< 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable(< 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.

Factors associated with early virological response to peginterferon-α-2a/ribavirin in chronic hepatitis C

AIM: To evaluate the impact of sociodemographic/clinical factors on early virological response (EVR) to pegin-terferon/ribavirin for chronic hepatitis C (CHC) in clinical practice. METHODS: We conducted a multicenter, cross-sectional, observational study in Hepatology Units of 91 Spanish hospitals. CHC patients treated with peginterferon α-2a plus ribavirin were included. EVR was defined as undetectable hepatitis C virus (HCV)-ribonucleic acid (RNA) or ≥ 2 log HCV-RNA decrease after 12 wk of treatment. A bivariate analysis of sociodemographic and clinical variables associated with EVR was carried out. Independent factors associated with an EVR were analyzed using a multiple regression analysis that included the following baseline demographic and clinical variables: age (≤ 40 years vs > 40 years), gender, race, educational level, marital status and family status, weight, alcohol and tobacco consumption, source of HCV infection, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and gamma glutamyl transpeptidase (GGT) (≤ 85 IU/mL vs > 85 IU/mL), serum ferritin, serum HCV-RNA concentration (< 400 000 vs ≥ 400 000), genotype (1/4 vs 3/4), cirrhotic status and ribavirin dose (800/1000/1200 mg/d).RESULTS: A total of 1014 patients were included in the study. Mean age of the patients was 44.3 ± 9.8 years, 70% were male, and 97% were Caucasian. The main sources of HCV infection were intravenous drug abuse (25%) and blood transfusion (23%). Seventyeight percent were infected with HCV genotype 1/4 (68% had genotype 1) and 22% with genotypes 2/3. The HCV-RNA level was > 400 000 IU/mL in 74% of patients. The mean ALT and AST levels were 88.4 ± 69.7 IU/mL and 73.9 ± 64.4 IU/mL, respectively, and mean GGT level was 82 ± 91.6 IU/mL. The mean ferritin level was 266 ± 284.8 μg/L. Only 6.2% of patients presented with cirrhosis. All patients received 180 mg of peginterferon α-2a. The most frequently used ribavirin doses were 1000 mg/d (41%) and 1200 mg/d (41%). The planned treatment duration was 48 wk for 92% of patients with genotype 2/3 and 24 wk for 97% of those with genotype 1/4 (P < 0.001). Seven percent of patients experienced at least one reduction in ribavirin or peginterferon α-2a dose, respectively. Only 2% of patients required a dose reduction of both drugs. Treatment was continued until week 12 in 99% of patients. Treatment compliance was ≥ 80% in 98% of patients. EVR was achieved in 87% of cases (96% vs 83% of patients with genotype 2/3 and 1/4, respectively; P < 0.001). The bivariate analysis showed that patients who failed to achieve EVR were older (P < 0.005), had higher ALT (P < 0.05), AST (P < 0.05), GGT (P < 0.001) and ferritin levels (P < 0.001), a diagnosis of cirrhosis (P < 0.001), and a higher baseline viral load (P < 0.05) than patients reaching an EVR. Age < 40 years [odds ratios (OR): 0.543, 95%CI: 0.373-0.790, P < 0.01], GGT < 85 IU/mL (OR: 3.301, 95%CI: 0.192-0.471, P < 0.001), low ferritin levels (OR: 0.999, 95%CI: 0.998-0.999, P < 0.01) and genotype other than 1/4 (OR: 4.716, 95%CI: 2.010-11.063, P < 0.001) were identified as independent predictors for EVR in the multivariate analysis. CONCLUSION: CHC patients treated with peginterferon-α-2a/ribavirin in clinical practice show high EVR. Older age, genotype 1/4, and high GGT were associated with lack of EVR.

Long-term outcome of chronic hepatitis C patients with sustained virological response to peginterferon plus ribavirin

AIM: To assess the clinical, biochemical and virological long-term outcome in chronic hepatitis C (CHC) patients with a sustained virological response (SVR) after peginterferon (PEG-IFN) plus ribavirin combination therapy. METHODS: One hundred and fifty three patients with a SVR after treatment with PEG-IFN plus ribavirin were included in a 5-year follow-up study in a single Spanish center, based on standard clinical practice. Clinical anamnesis, biochemical analysis, hepatitis C virus RNA and alpha-fetoprotein measurement, ultrasonography and transient elastography were performed annually. RESULTS: The mean follow-up period of the 153 patients was 76 ± 13 mo after they obtained a SVR. Five patients (3.26%) presented with cirrhosis before treatment and 116 (75.8%) had genotype 1. No patient showed evidence of hepatic decompensation. One patient (0.65%) developed a hepatocellular carcinoma at month 30 after achieving SVR. There were no virological relapses during this follow-up period. Persistently elevated alanine aminotransferase was found in only one patient (0.65%). At the end of the 5-year follow-up, the mean value of transient elastography was 7 ± 4.3 kPa (F1). There were no deaths and no other tumors. CONCLUSION: The long-term outcome of 153 CHC patients with SVR to PEG-IFN plus ribavirin was good. No evidence of a virological relapse was seen. One patient (0.65%) developed a hepatocellular carcinoma.

Twenty four-week peginterferon plus ribavirin after interferon-β induction for genotype 1b chronic hepatitis C

AIM:To investigate the possibility of shortening the duration of peginterferon(Peg-IFN)plus ribavirin(RBV) combination therapy by incorporating interferon-β (IFN-β)induction therapy. METHODS:A one treatment arm,cohort prospective study was conducted on seventy one patients.The patients were Japanese adults with genotype 1b chronic hepatitis C,HCV-RNA levels of≥5.0 Log IU/mL or 100 KIU/mL,and platelet counts of≥90 000/μL.The treatment regimen consisted of a 2 wk course of twicedaily administration of IFN-βfollowed by 24 wk PegIFN plus RBV combination therapy.We prolonged the duration of the Peg-IFN plus RBV therapy to 48 wk if the patient requested it. RESULTS:The patients,including 44%males,were characterized by an median age of 63 years(range: 32-78 years),an median platelet count of 13.9(range: 9.1-30.6)×10 4 /μL,62%IFN-na?ve,and median HCV- RNA of 6.1(range:5.1-7.2)Log IU/mL.The sustained virologic response(SVR)rates were 34%(Peg-IFN:1-24 wk,n=61,95%confidence interval(CI): 24%-47%)and 55%(Peg-IFN:20-24 wk,n=31,95% CI:38%-71%,P<0.001;vs Peg-IFN:1-19 wk).TheSVR rate when the administration was discontinued early was 13%(Peg-IFN:1-19 wk,n=30,95%CI: 5%-30%),and that when the administration was prolonged was 50%(Peg-IFN:25-48 wk,n=10,95% CI:24%-76%,P<0.05;vs Peg-IFN:1-19 wk).In the patients who received 20-24 wk of Peg-IFN plus RBV,only the higher platelet count(≥130 000/μL) was significantly correlated with the SVR(odds ratio: 11.680,95%CI:2.3064-79.474,P=0.0024).In 45% (14/31)of the patients with a higher platelet count (≥130000/μL)before therapy,the HCV-RNA level decreased to below 3.3 Log IU/mL at the completion of IFN-β,and their SVR rate was 93%(13/14)after 20-24 wk administration of Peg-IFN plus RBV. CONCLUSION:These results suggest the possibilities of shortening the duration of Peg-IFN plus RBV combination therapy by actively reducing HCV-RNA levels using the IFN-βinduction regimen.

Serum cytokine levels in chronic hepatitis B patients receiving peginterferon alpha-2a therapy

BACKGROUND: The relationship between cytokines and responses to peginterferon α-2a treatment in chronic hepatitis B patients has not yet been fully elucidated. We analyzed the serum levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor, interferon-γ, tumor necrosis factor-α, monocyte chemotactic protein-1 (MCP1) and epidermal growth factor during the treatment with peginterferon α-2a. METHODS: Ninety-three serum samples from 20 chronic hepatitis B patients were collected before, during and after 48 weeks of peginterferon therapy and were assayed for 12 cytokines. The patients were categorized as either virologic responders (VRs) or non-responders (NRs) according to their HBV DNA levels taken at 6th month during treatment. The Evidence Investigator (Randox, Antrim, UK), a protein chip analyzer, was used to quantify cytokines. RESULTS: Among the 12 cytokines, the levels of MCP1 were increased and the levels of IL-4 were decreased during the treatment in VRs. However these cytokines were not significantly changed in NRs in the treatment phases. Area under the receiver operating characteristic curve (AUROC) value of HBV DNA measured before the treatment was 0.81 in predicting VRs, and that of the baseline MCP1 was 0.76. IL-6 levels at 3rd and 6th months during the treatment also showed AUROC values 0.85 and 0.78 respectively in predicting sustained VRs. CONCLUSION: Serum cytokine levels reflect the pathological differences of individual treatment phases and could also be useful in monitoring responses to peginterferon treatment in chronic hepatitis B patients.

Cytokine Profiles and Virological Marker Monitoring during 48 Weeks Peginterferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B

Objective This study aimed to investigate whether cytokine profiles and virological markers might add value in monitoring the effects of peginterferon(PEG-IFN)therapy for hepatitis B e-antigen(HBeAg)positive chronic hepatitis B(CHB).Methods HBeAg positive patients with CHB were treated with PEG-IFN for 48 weeks.Clinical biochemical,and HBV serological indexes,as well as cytokines,were detected at baseline and every12 weeks.Results A total of 116 patients with CHB were enrolled in this study;100 patients completed the 48-week treatment and follow-up,of whom 38 achieved serum HBeAg disappearance,25 achieved HBeAg seroconversion,37 showed HBsAg decreases≥1 log10 IU/mL,9 showed HBsAg disappearance,and 8became HBsAb positive.The cytokine levels at baseline and during treatment were similar between the HBeAg disappearance group and non-disappearance group.The disappearance of HBeAg was independently associated with HBeAg levels at weeks 12 and 24,and with the HBeAg decline at week 24(P<0.05).The HBsAg response was independently associated with HBsAg,the HBsAg decline,HBeAg,the HBeAg decline at week 12,and HBsAg at week 24(P<0.05).Conclusion There was no significant correlation between the response to interferon(IFN)and cytokines during PEG-IFN treatment.The changes in virological markers predicted the response to IFN after 48 weeks.

Acute sensorineural hearing loss associated with peginterferon and ribavirin combination therapy during hepatitis C treatment: Outcome after resumption of therapy

Peginterferon and ribavirin combination therapy for the treatment of hepatitis C virus （HCV） is well known to be associated with significant adverse effects. Sensorineural hearing loss, that in most cases is unilateral, has been reported as a consequence of therapy with both non-pegylabed and pegylated interferon （pegIFN） but is not a well-known adverse effect. We report a 45-year-old Caucasian woman who developed acute sensorineural hearing loss 2 mo after starting therapy with pegIFN-α 2b and ribavirin for the treatment of chronic HCV, genotype la. She did not report the hearing loss to the hepatitis clinic until 1 mo, later whereupon therapy was promptly discontinued. Although her serum alanine aminotransferase （ALT） normalized and her HCV-RNA became undetectable after 12 wk of pegIFN and dbavirin therapy, after discontinuation, her HCV-RNA became detectable with significant elevations of serum ALT. Four months after initial discontinuation, the patient re-commenced pegIFN and ribavirin combination therapy. After 44 of 48 wk of therapy, the patient＇s liver biochemistry has normalized and the HCV-RNA is undetectable. She has not developed worsening of her hearing loss and hearing on the left-side is unaffected. Both patients and physicians should be aware that sensorineural hearing loss may occur with pegIFN therapy. Our experience suggests that re-institution of therapy is not always associated with further hearing impairment.

Protracted anaphylaxis developed after peginterferon α-2a administration for chronic hepatitis C

Peginterferon is a key drug used to treat chronic viral hepatitis that is known for causing various side effects.Side effects occurring immediately after administration include headache, nausea, and influenza-like symptoms, such as fever and joint pain.However, reports of anaphylactic shock are extremely rare.Here we report a patient with protracted anaphylaxis who suffered shock symptoms after peginterferon α-2a administration for chronic hepatitis C.Although the patient improved temporarily with shock treatment, symptoms of anaphylaxis recurred.As peginterferon is often administered on an outpatient basis, it is important to recognize life-threatening side effects that may develop in a protracted manner.

Association of ITPA polymorphism with outcomes of peginterferon-α plus ribavirin combination therapy

AIM:To analyzed the association between inosine triphosphatase(ITPA)(rs1127354) genotypes and sustained virological response(SVR) rates in peginterferon(Peg-IFN)α + ribavirin(RBV) treatment.METHODS:Patients who underwent Peg-IFNα + RBV combination therapy were enrolled(n = 120) and they had no history of other IFN-based treatments.Variation in hemoglobin levels during therapy,cumulative reduction of RBV dose,frequency of treatment withdrawal,and SVR rates were investigated in each ITPA genotype.RESULTS:In patients with ITPA CC genotype,hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype.However,SVR rates were equivalent between CC and CA/AA genotypes,and within a subset of patients with Interleukin 28B(IL28B)(rs8099917) TT genotype,SVR rates tended to be higher in patients with ITPA CC genotype,although the difference was not significant.CONCLUSION:ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose.However,CC genotype was not inferior to CA/AA genotype for SVR rates.When full-length treatment is accomplished,it is plausible that more SVR is achieved in patients with ITPA CC variant,especially in a background of IL28B TT genotype.

Boceprevir plus peginterferon/ribavirin for treatment ofchronic hepatitis C in Russia

AIM: to evaluate addition of boceprevir to peginterferon/ribavirin(PR) in Russian patients with chronic hepatitis C virus(HCV).METHODS: treatment-naive(t N) and treatmentexperienced(t E) patients(who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebocontrolled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. t N patients randomized to triple therapy received boceprevir(800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8(t W8) HCV RNA levels. t E patients received boceprevir plus PR for 32 wk and then further therapy according to t W8 HCV RNA levels. treatment was discontinued for t N patients with detectable HCV RNA at t W24 and t E patients with detectable HCV RNA at t W12 because of futility. the primary efficacy end point was sustained virologic response(SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy.RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2%(95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both t N and t E patient groups(t N 78.4% vs 56.3%; t E 69.4% vs 30.0%). Within t E patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type(null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both t N(86%) and t E(71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone(47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia(< 10 g/d L) and those without anemia(71.2% vs 77.4%).CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients

Hepatitis B virus(HBV)infection plays an important role in the occurrence and development of hepatocellular carcinoma(HCC),and the rate of HBV infection in liver cancer patients in China is as high as 92.05%.Due to long-term exposure to chronic antigens from the gut,the liver needs to maintain a certain level of immune tolerance,both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors.Therefore,HBV infection interacts with the tumor microenvironment(TME)through a highly complex and intertwined signaling pathway,which results in a special TME in HCC.Due to changes in the TME,tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4(CTLA-4)and programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1).Interferons,as a class of immune factors with strong biological activity,can improve the TME of HBV-HCC through various pathways.In recent years,the systematic treatment of HCC has gradually come out of the dilemma.In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs,immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC.At present,immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC,and the disease charac-teristics of patients included in global clinical studies are different from those of Chinese patients.Therefore,whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern.This review aims to elucidate the advances of immuno-therapy for HBV related HCC patients with regard to:(1)Immunotherapy based on interferons;(2)Immunotherapy based on PD-1/L1 inhibitors;(3)Immunotherapy based on CTLA4 inhibitors;(4)Adoptive cell transfer;(5)Combination immunotherapy strategy;and(6)Shortcomings of immunotherapy.

恩替卡韦联合聚乙二醇干扰素-α2b治疗代偿期乙型肝炎肝硬化患者疗效研究

目的探讨应用恩替卡韦(ETV)联合聚乙二醇干扰素-α2b(Peg-IFN-α2b)治疗乙型肝炎肝硬化患者的近期疗效。方法2019年3月~2021年3月安徽医科大学附属巢湖医院诊治的代偿期乙型肝炎肝硬化患者78例,被随机分为对照组40例和观察组38例,分别给予ETV或ETV联合Peg-IFN-α2b治疗24 w,然后两组均继续接受ETV治疗,随访至48 w。常规检测肝功能指标、血清肝纤维化指标、血清HBV标志物定量和HBV DNA载量。结果在随访24 w末,观察组血清白蛋白水平为(45.7±3.2)g/L,显著高于对照组【(38.5±4.3)g/L,P<0.05】;观察组血清IV-C、HA、PⅢP和LN水平分别为(154.3±11.7)μg/L、(130.9±17.5)μg/L、(110.6±16.2)μg/L和(152.7±14.3)μg/L,均显著低于对照组【分别为(200.7±12.4)μg/L、(161.8±18.7)μg/L、(157.4±17.3)μg/L和(200.9±16.3)μg/L,P<0.05】;观察组血清HBsAg水平为1363.8(623.1,2767.6)IU/ml,显著低于对照组【2119.6(1144.9,5094.3)IU/ml,P<0.05】,而血清HBsAg阴转率为15.8%,显著高于对照组的0.0%(P<0.05)。结论联合应用ETV和Peg-IFN-α2b治疗代偿期乙型肝炎肝硬化患者可改善血清肝纤维化指标,提高血清HBsAg阴转率,可能有助于病情恢复。

聚乙二醇干扰素α-2b联合恩替卡韦治疗HBeAg阳性慢性乙型肝炎患者疗效研究

目的观察比较聚乙二醇干扰素α-2b(Peg-IFN-α)联合恩替卡韦治疗血清HBeAg阳性的慢性乙型肝炎(CHB)患者的疗效。方法2019年1月~2022年1月我院收治的279例血清HBeAg阳性的CHB患者,被分为3组,每组93例,分别给予恩替卡韦口服治疗、Peg-IFN-α皮下注射治疗或恩替卡韦联合Peg-IFN-α治疗,均持续治疗48 w,评估疗效。常规检测血清生化学、血清学和病毒学指标。结果在治疗48 w末,联合组HBeAg转阴率和HBeAg血清转换率分别为32.3%和21.5%,Peg-IFN-α治疗组分别为22.6%和15.1%,而恩替卡韦治疗组则无血清HBeAg转阴或HBeAg血清转换者,联合组尚有一些零星的病例发生HBsAg转阴(3.2%)或HBsAg血清转换(2.2%);联合组血清HBsAg和HBeAg水平分别为(1.9±0.3)lg s/co和(0.5±0.1)lg s/co,Peg-IFN-α治疗组分别为(2.2±0.2)lg s/co和(0.6±0.1)lg s/co,均显著低于恩替卡韦治疗组【分别为(3.6±0.2)lg s/co和(1.3±0.2)lg s/co,P<0.05】,而联合组和恩替卡韦治疗组血清HBV DNA载量均显著低于Peg-IFN-α治疗组(P<0.05);联合组血清ALT和AST水平分别为(30.9±4.5)U/L和(28.4±5.3)U/L,恩替卡韦治疗组分别为(31.5±3.6)U/L和(32.3±4.7)U/L,均显著低于Peg-IFN-α治疗组【分别为(48.1±4.2)U/L和(42.7±5.0)U/L,P<0.05】。结论联合应用恩替卡韦和Peg-IFN-α治疗血清HBeAg阳性的CHB患者可能获得更好的血清学转换率,在优势人群可能获得功能性治愈,值得深入研究。

丙酚替诺福韦联合PEG-IFNα-2b治疗慢性乙型肝炎患者疗效研究

目的探讨丙酚替诺福韦(TAF)联合聚乙二醇干扰素α-2b(PEG-IFNα-2b)治疗慢性乙型肝炎(CHB)患者的疗效。方法2021年3月~2023年3月我院收治的CHB患者122例,被随机分为对照组61例和观察组61例,分别给予TAF或TAF联合PEG-IFNα-2b治疗48 w。采用实时荧光定量PCR法检测血清HBV DNA载量,采用电化学发光法定量检测血清HBeAg和HBsAg水平,采用ELISA法检测血清Toll样受体4(TLR4)和白细胞介素-35(IL-35)水平。结果在治疗24 w末和治疗48 w末,观察组血清HBeAg水平分别为(195.3±36.4)IU/ml和(180.6±25.9)IU/ml,显著低于对照组【分别为(236.1±42.5)IU/ml和(217.5±33.8)IU/ml,P<0.05】,血清HBsAg水平分别为(925.1±226.9)IU/ml和(816.2±175.3)IU/ml,显著低于对照组【分别为(1028.4±251.5)IU/ml和(921.7±226.8)IU/ml,P<0.05】;观察组HBeAg转阴率分别为21.3%和29.5%,显著高于对照组的3.3%和6.6%(P<0.05);观察组血清TLR4水平分别为(68.6±17.4)pg/mL和(41.4±15.9)pg/mL,显著低于对照组【分别为(90.1±20.5)pg/mL和(73.5±18.2)pg/mL,P<0.05】,血清IL-35水平分别为(127.9±25.5)pg/mL和(73.5±18.6)pg/mL,均显著低于对照组【分别为(191.4±30.6)pg/mL和(102.7±26.1)pg/mL,P<0.05】。结论应用TAF联合PEG-IFNα-2b治疗CHB患者具有良好的抗病毒疗效,能提高血清HBeAg转阴率,可能与降低了TLR4和IL-35表达有关,值得进一步研究。

艾司西酞普兰干预干扰素治疗慢性丙型病毒性肝炎引发的精神症状

目的旨在评估引起这些精神心理症状的易感因素并分析艾司西酞普兰干预这些症状的效果。方法 59例慢性丙型病毒性肝炎患者,经聚乙二醇干扰素联合利巴韦林的抗病毒治疗,12周时由精神科医师使用DSM-IV标准进行评估,并指导患者使用SCL-90量表自评。对于符合重度抑郁标准者进行艾司西酞普兰干预治疗,在用药后4周,8周时再次行SCL-90测评。结果中重度抑郁的易感因素有:男性,1b基因型,感染途径为静脉药瘾。干扰素相关中重度抑郁的发病率为32.2%。其他精神症状,如:敌对、焦虑、人际关系敏感各因子的发生率为分别为19.7%,9.2%,5.26%。使用艾司西酞普兰治疗后4周及8周,患者的SCL-90总分,敌对、焦虑、抑郁、人际关系敏感各因子得分显著下降。结论干扰素引发的精神症状在我国丙型肝炎的患者中发生率较高,应做常规的精神症状评估,特别注意对静脉药瘾感染人群的评估,及时使用艾司西酞普兰对于干扰素引发的精神症状有较好的疗效。

聚乙二醇干扰素α和其他抗乙肝病毒药物对中国HBeAg阳性慢性乙型肝炎患者的疗效对比(英文)

目的:通过Meta分析来评价聚乙二醇干扰素(peg interferon,PEG-IFN)α与IFNα、阿德福韦酯(adefovir dipivoxil,ADV)和恩替卡韦(entecavir,ETV)对中国HBeAg阳性慢性乙型肝炎患者的疗效。方法:计算机检索MEDLINE和3个主要的中文数据库(万方、维普和CNKI),检索年限为1966年到2012年。由两名评价员对纳入的有关PEG-IFNα治疗中国HBeAg阳性慢性乙型肝炎患者的随机对照试验独立进行评价。结果:14个随机对照试验符合最终的纳入条件。Meta分析结果显示:在中国HBeAg阳性慢性乙型肝炎患者中,PEG-IFNα组的ALT复常率、HBV DNA阴转率、HBeAg血清转换率、HBeAg血浆清除率和肝纤维化的改善率均高于IFNα组,差异有统计学意义(P<0.05)。PEG-IFNα对HBeAg血清转换率和HBeAg血浆清除率明显优于ETV组,差异有统计学意义(P<0.05),但总体的HBeAg血清转换率和HBeAg血浆清除率较低。PEG-IFNα与ADV的联合用药组ALT复常率、HBV DNA阴转率和HBeAg血清转换率高于ADV单药治疗组,差异有统计学意义(P<0.05)。PEG-IFNα对血浆HBsAg清除率和其他几种抗乙肝病毒药物相比无明显优势。结论:PEG-IFNα对中国HBeAg阳性慢性乙型肝炎患者疗效显著,可作为治疗中国HBeAg阳性慢性乙型肝炎的一线药物。而对PEG-IFNα的联合用药对中国HBeAg阳性慢性乙型肝炎患者的益处和危害尚缺乏足够的证据。