HBsAg clearance by Peg-interferon addition to a long-term nucleos(t)ide analogues therapy

The ideal endpoint of hepatitis B virus(HBV)antiviral therapy is HBsAg loss,a difficult goal to obtain,especially in HBeAg negative patients.Herein,we report the results obtained by the addition of peg-interferonα-2a to a long-lasting nucleos(t)ide analogues therapy in a HBeAg negative,genotype D patient with steadily HBV-DNA negative/HBsAg positive values.In 2002,our Caucasian 44-year-old male patient received lamivudine and,4 years later,added adefovir because of a virological breakthrough.In 2011,considering his young age,liver stiffness(4.3 kPa)and HBsAg levels(3533IU/mL),we added Peg-interferonα-2a for six months(3in combination with nucleos(t)ide analogues followed by 3 mo of Peg-interferonα-2a monotherapy).A decrease of HBsAg levels was observed after 1 mo(1.21log)of Peg-interferon and 3 mo(1.88 log)after the discontinuation of all drugs.Later,a complete clearance of HBsAg was obtained with steadily undetectable HBVDNA serum levels(<9 IU/mL).HBsAg clearance by the addition of a short course of Peg-interferonα-2a represents an important result with clinical and pharmacoeconomic implications,considering that nucleos(t)ide analogues therapy in HBeAg negative chronic hepatitis B patients is considered a long-lasting/life-long treatment.

Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection:A prospective,real-life,observational study

AIM： To evaluate the impact of therapeutic education on adherence to antiviral treatment and sustained virological response （SVR） in a real-life setting in genotype 2/3 hepatitis C, as there are few adherence data in genotype 2/3 infection, even from randomized trials. METHODS： This prospective survey included genotype 2/3 patients who received peg-interferon alfa-2b and ribavirin. There was no intervention. Adherence wasself-reported over the past 4 wk （peg-interferon） or 7 d （ribavirin）. Adherence to bitherapy was defined as adherence to the two drugs for ≥ 20 wk. SVR was defined as undetectable RNA ≥ 12 wk after the end of treatment. RESULTS： 370/674 patients received education during the first 3 mo of treatment. After 6 too, adherence to bitherapy was higher in educated patients （61% vs 47%, P = 0.01）. Adherence to peg-interferon was 78% vs 69% （P=0.06）. Adherence to ribavirin was 70% vs 56% （P = 0.006）. The SVR （77% vs 70%, P = 0.05） and relapse （10% vs 16%, P = 0.09） rates tended to be improved. After adjustment for baseline differences, education improved adherence [Odds ratio （OR） 1.58, P = 0.04] but not the SVR （OR 1.54, P = 0.06）. CONCLUSION： In genotype 2/3 patients, therapeutic education helped maintain real-life adherence to bitherapy.

Treatment of chronic hepatitis delta virus with peg-interferon and factors that predict sustained viral response

AIM： To observe the efficacy of peg-interferon in the treatment of hepatitis delta virus （HDV） and to identify the factors that would be predictive of the sustained viral response （SVR）. METHODS： This prospective study was conducted in Medical Unit IV of the Liaquat University of Medi- cal and Health Sciences Hospital Jamshoro from June 2008 to September 2011. This study cohort included all patients of either sex who presented during this time with hepatitis B surface antigen positivity, hepa- titis B virus DNA 〉 20 000 IU/ml, serum glutamic py- ruvic transaminase （SGPT） 〉 2（upper limit of normal）, HDV-RNA positivity with fibrosis stage ≥ 2. Informed consent was obtained from each of these individuals. Patients were diagnosed with hepatitis D on the ba- sis of detectable viral antibodies and the presence of HDV-RNA in their serum. A liver biopsy was performed in all cases and fibrosis staging was performed in ac- cordance with the METAVIR scoring system. All eligible patients were administered peg-interferon at a weekly dosage of 1.5 μg/kg body weight for 48 wk. HDV-RNA was assayed at the end of this treatment period and again at 24 wk later. A biochemical response was de- termined by a normalization of SGPT at the end of the treatment or during follow up. The end of treatment response was defined by a HDV-RNA negative status. A sustained virological response was defined by unde- tectable serum HDV-RNA at six months after the end of treatment. RESULTS： Among the 277 patients enrolled in our present study, 238 completed a course of peg-interfer- on therapy of which 180 （75.6%） were male and 58 （24.4%） female. Biochemical responses were achieved in 122/238 （51.3%） patients. End of treatment re- sponses were achieved in 71/238 （29.8%） cases. A SVR was achieved in 70 of these patients （29.4%）. A strong association was found between the SVR and the end of treatment responses （P = 0.001）, biochemical responses （P = 0.001） and the degree of fibrosis （P = 0.002）. CONCLUSION： Peg-interferon therapy can induce re- mission in nearly one third of patients harboring HDV.

HBsAg Loss with Peg-interferon Alfa-2a in Hepatitis B Patients with Partial Response to Nucleos(t)ide Analog:New Switch Study

Background and Aims:Hepatitis B surface antigen(HBsAg)loss is seldom achieved with nucleos(t)ide analog(NA)therapy in chronic hepatitis B patients but may be enhanced by switching to finite pegylated-interferon(Peg-IFN)alfa-2a.We assessed HBsAg loss with 48-and 96-week Peg-IFN alfa-2a in chronic hepatitis B patients with partial response to a previous NA.Methods:Hepatitis B e antigen(HBeAg)-positive patients who achieved HBeAg loss and hepatitis B virus DNA<200 IU/mL with previous adefovir,lamivudine or entecavir treatment were randomized 1:1 to receive Peg-IFN alfa-2a for 48(n=153)or 96 weeks(n=150).The primary endpoint of this study was HBsAg loss at end of treatment.The ClinicalTrials.gov identifier is NCT01464281.Results:At the end of 48 and 96 weeks'treatment,14.4%(22/153)and 20.7%(31/150)of patients,respectively,who switched from NA to Peg-IFN alfa-2a cleared HBsAg.Rates were similar irrespective of prior NA or baseline HBeAg seroconversion.Among those who cleared HBsAg by the end of 48 and 96 weeks'treatment,77.8%(14/18)and 71.4%(20/28),respectively,sustained HBsAg loss for a further 48 weeks.Baseline HBsAg<1500 IU/mL and week 24 HBsAg<200 IU/mL were associated with the highest rates of HBsAg loss at the end of both 48-and 96-week treatment(51.4%and 58.7%,respectively).Importantly,extending treatment from 48 to 96 weeks enabled 48.3%(14/29)more patients to achieve HBsAg loss.Conclusions:Patients on long-term NA who are unlikely to meet therapeutic goals can achieve high rates of HBsAg loss by switching to Peg-IFN alfa-2a.HBsAg loss rates may be improved for some patients by extending treatment from 48 to 96 weeks,although the differences in our study cohort were not statistically significant.Baseline and on-treatment HBsAg may predict HBsAg loss with Peg-IFN alfa-2a.

Vitamin D improves viral response in hepatitis C genotype 2-3 nave patients

AIM: To examine whether vitamin D improved viral response and predicted treatment outcome in patients with hepatitis C virus (HCV) genotype 2-3. METHODS: Fifty patients with chronic HCV genotype 2-3 were randomized consecutively into two groups: Treatment group [20 subjects, age 48 ± 14 years, body mass index (BMI) 30 ± 6, 65% male], who received 180 μg pegylated α-interferon-2a plus oral ribavirin 800 mg/d (Peg/RBV), together with oral vitamin D3 (Vitamidyne D drops; 2000 IU/d, 10 drops/d, normal serum level > 32 ng/mL) for 24 wk; and control group (30 subjects, age 45 ± 10 years, BMI 26 ± 3, 60% male), who received identical therapy without vitamin D. HCV RNA was assessed by reverse transcription polymerase chain reaction. Undetectable HCV RNA at 4, 12 and 24 wk after treatment was considered as rapid virological response, complete early virological response, and sustained virological response (SVR), respectively. Biomarkers of in? ammation were measured. RESULTS: The treatment group with vitamin D hadhigher BMI (30 ± 6 vs 26 ± 3, P < 0.02), and high viral load (> 400 000 IU/mL, 65% vs 40%, P < 0.01) than controls. Ninety-fi ve percent of treated patients were HCV RNA negative at week 4 and 12. At 24 wk after treatment (SVR), 19/20 (95%) treated patients and 23/30 (77%) controls were HCV RNA negative (P < 0.001). Baseline serum vitamin D levels were lower at baseline (20 ± 8 ng/mL) and increased after 12 wk vitamin D treatment, to a mean level of (34 ± 11 ng/ mL). Logistic regression analysis identifi ed vitamin D supplement [odds ratio (OR) 3.0, 95% CI 2.0-4.9, P < 0.001], serum vitamin D levels (< 15 or > 15 ng/mL, OR 2.2, P < 0.01), and BMI (< 30 or > 30, OR 2.6, P < 0.01) as independent predictors of viral response. Adverse events were mild and typical of Peg/RBV. CONCLUSION: Low vitamin D levels predicts negative treatment outcome, and adding vitamin D to conventional Peg/RBV therapy for patients with HCV genotype 2-3 signifi cantly improves viral response.

IL28B polymorphism as a predictor of antiviral response in chronic hepatitis C

AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean age, 44 ＋ 12 years） with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was per- formed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, ami- notransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. RESULTS： A sustained virological response （SVR） was significantly associated with IL28B polymorphism （CC vs -l-r allele： odds ratio （OR）, 25; CC vs CT allele： OR, 5.4）, inflammation activity （G 〈 1 vs G 〉 1： OR, 3.9）, fibrosis （F 〈 1 vs F 〉 1： OR, 5.9）, platelet count （〉 200 × 109/L vs 〈 200 ×109/L： OR, 4.7; OR in patients with genotype CT： 12.8）, fatty liver （absence vs presence of steatosis： OR, 4.8）, insulin resistance index （〈 2.5 vs 〉 2.5： OR, 3.9）, and baseline HCV viral load （〈 106 IU/mL vs 〉 106 IU/mL： OR, 3.0）. There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance （P = 0.064） of increased fibrosis in patients with the I-I allele, and no differences in the insulin resistance index between groups of patients with CC, CT and -IF alleles （P = 0.12）. Spearman＇s rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively （P 〈 0.001）. Significant dif- ferences were found in the insulin resistance index （P = 0.01） between patients with and without steatosis. Patients with the C-I- allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon （P = 0.07）. CONCLUSION： IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.

Antiviral therapy in hepatitis C virus cirrhotic patients in compensated and decompensated condition

The main goals of treating cirrhotic patients with antiviral therapy are to attain sustained viral clearance(SVR),halt disease progression,and prevent re-infection of the liver graft.However,while the medical need is great,the use of interferon and ribavirin might expose these patients to severe treated-related side effects as a large proportion of them have pre-existing hematological cytopenias.We have reviewed potential benefits and risks associated with antiviral drugs in patients with liver cirrhosis,due to hepatitis C virus(HCV) infection.In cases presenting with bridging fibrosis or cirrhosis,current regimens of antiviral therapy have attained a 44%-48% rate of SVR.In cirrhotic patients with portal hypertension,the SVR rate was 22% overall,12.5% in patients with genotype 1,and 66.7% in those with genotypes 2 and 3 following therapy with low doses of either Peg-IFN alpha-2b and of ribavirin.In patients with decompensated cirrhosis,full dosages of Peg-IFN alpha-2b and of ribavirin produced a SVR rate of 35% overall,16% in patients with genotype 1 and 4,and 59% in those with genotype 2 and 3.Use of hematological cytokines will either ensure full course of treatment to be accomplished with and prevent development of treatment-associated side effects.Major benefits after HCV eradication were partial recovery of liver metabolic activity,prevention of hepatitis C recurrence after transplantation,and removal of some patients from the waiting list for liver transplant.Several observations highlighted that therapy is inadvisable for individuals with poor hepatic reserve(Child-Pugh-Turcotte score ≥ 10).Although SVR rates are low indecompensated cirrhotics due to hepatitis C,these patients have the most to gain as successful antiviral therapy is potentially lifesaving.

Analysis of peripheral blood dendritic cells as a non-invasivetool in the follow-up of patients with chronic hepatitis C

Hepatitis C virus(HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells(DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs(pb DCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the noninvasive accessibility of pb DCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pb DCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pb DCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.

Hepatitis C in injection drug users: It is time to treat

Injection drug users(IDUs)are at risk of hepatitis C virus(HCV)infection,due to needle and syringe sharing.Chronic HCV infection is a major cause of liver-related morbidity and mortality but can be cured with antiviral treatment leading to sustained viral response(SVR).It is well demonstrated that,when close cooperation between specialists in drug addiction and psychiatrists is assured,patients on maintenance treatment with methadone/buprenorphine can be treated for HCV with response rate,tolerability and side effects similar to those reported in non-IDUs.Current guidelines recommend that active injection drug use should not exclude patients from HCV treatment,but many services remain reluctant to treat IDUs.No significant pharmacodynamic interactions were reported between approved direct anti-viral agents(DAAs)and buprenorphine or methadone.Dose adjustments are not recommended;therefore DAAs appear to be the"perfect"therapy for patients taking opiate substitutive therapy.These suggestions have been recently recognized by the European Association for the Study of the Liver(EASL)and included in EASL Recommendations on Treatment of Hepatitis C 2016.Guidelines confirm that HCV treatment for IDUs should be considered on an individualized basis and delivered within a multidisciplinary team setting;a history of intravenous drug use and recent drug use at treatment initiation are not associated with reduced SVR and decisions to treat must be made on a case-by-case basis.

Boceprevir or telaprevir in hepatitis C virus chronic infection:The Italian real life experience

AIM: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus(HCV) genotype 1 in the real-world settings. METHODS: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-Taq Man2.0(Roche, LLQ 25 IU/m L). RESULTS: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57(range 18-78), of whom 18.3% were over 65; mean body mass index 25.6(range 16-39); genotype 1b(79.4%); diagnosis of cirrhosis(38.2%); and fibrosis F3/4(71.2%). The following drugs were used: Telaprevir(66.2%) and PEG-IFN-alpha2a(67.6%). Patients were na?ve(24.4%), relapsers(30.5%), partial responders(14.8%) and null responders(30.3%). Overall, adverse events(AEs) occurred in 617 patients(73.9%) during the treatment. Anemia was the most frequent AE(52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure(15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, nonresponders to peginterferon + ribavirin.

Entecavir add-on Peg-interferon therapy plays a positive role in reversing hepatic fibrosis in treatment-naive chronic hepatitis B patients: a prospective and randomized controlled trial

Background:The efficacy of entecavir(ETV)add-on peg-interferon therapy compared with ETV monotherapy in treatment-naive hepatitis B virus(HBV)patients remains controversial.We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not.Methods:All patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital(China).Eligible HBV patients(n=144)were randomly divided(1:1)to receive either ETV monotherapy(n=70)or peg-interferon add-on therapy from week 26 to 52(«=74).Patients were followed-up for at least 2 years.Indexes including hepatitis B surface antigen(HBsAg)and hepatitis B e antigen(HBeAg)seroconversion rate,sustained virologic response,transient elastography value,and histological scores were evaluated every 3 months until the end of the study.The rate of patients with HBsAg loss was defined as the primary endpoint criteria.Results:At week 26,no patient achieved HBsAg seroconversion in either group.At week 52,one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group.The monotherapy group showed significantly better liver function recovery results than the combination therapy group.At week 78,one patient in the combination group had HBsAg seroconverted.At week 104,only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy.The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline.Both groups showed a favorable decrease in alpha-fetoprotein(monotherapy:4.5[2.8,7.1]vs.2.2[1.8,3.1]ng/mL,P<0.001;combination therapy:5.7[3.0,18.8]vs.3.2[2.0,4.3]ng/mL,P<0.001)and an improved result of liver biopsy examination scores.The combination group showed a better improvement in histology compared with the monotherapy group(mean transient elastography value 6.6[4.9,9.8]vs.7.8[5.4,11.1]kPa,P=0.028).But there was no significant difference in HBsAg conversion rate(1.8%[1/56]i^s.4.1%[3/73],P=0.809)and HBeAg conversion rate(12.5%[7/56]i/s.11.0%[8/73],P=0.787),as well as HBV-DNA,sustained virologic response(93.2%vs.98.5%,P=0.150)between the two groups.Conclusions:Both therapies supported liver function recovery and histology improvement.Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy.However,combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy.Trial registration:ClinicalTrials.gov:NCT02849132;https://clinicaltrials.gov/ct2/show/NCT02849132.