Interferon Treatment In Patients Research Articles

Rechallenge Immunotherapy in Former Interferon-Treated Patients with Metastatic Renal Cell Carcinoma

Rechallenge Immunotherapy in Former Interferon-Treated Patients with Metastatic Renal Cell Carcinoma

Effect of Integrin α 4β 1 -VCAM-1 Interactions in JAK2V617F Myeloproliferative Neoplasm Pro-Thrombotic Interactions

Introduction: The JAK2 V617Fmutation, which occurs in up to 95% of polycythemia vera (PV) myeloproliferative neoplasm (MPN) patients, increases thrombosis risk 6-fold. A recent study in PV mice demonstrated that blocking JAK2 V617F+ leukocyte-mediated β1/β2 integrin interactions with anti-VCAM-1 antibodies decreases thrombosis. Interestingly, hydroxyurea (HU), a common PV treatment, reduces leukocyte and red cell α4β1 integrin expression. Overall, JAK2 V617F+ mouse models show inconsistent thrombosis and bleeding phenotype, hindering pre-clinical study reproducibility; therefore, we have developed an in vitro endothelialized microfluidic model to assess MPN-flow behavior. We hypothesized that in our microfluidic model, disrupting α4β1 integrin expression on JAK2 V617F+ leukocytes would reduce pro-adhesive interactions. We tested this hypothesis by assessing JAK2 V617F+ MPN blood flow in untreated and hydroxyurea treated subjects and through addition of a monoclonal antibody against α4β1 integrin, natalizumab. Methods: Primary human umbilical vein endothelial cells (HUVECs) were exposed to venous shear (15 dynes/cm 2) in microfluidics for a 4-day culture period. On day 4, endothelialized microfluidics were treated +/- 10 ng/mL TNFα for 4 hours. Blood samples were obtained from consented JAK2 V617F MPN individuals aged >18 years with ET, PV, or MF as diagnosed by the WHO 2016 Criteria identified in the M Health Fairview Masonic Cancer Center Clinics. Healthy age, race, and sex-matched blood samples served as controls. Clinical data on patients was collected and stored in REDCAP. Platelets and leukocytes were visualized using Calcein AM. Samples were treated +/- 0.25 μg/mL natalizumab for 30 minutes, then perfused through the microfluidic under a microscope to observe blood-endothelial interactions in real-time. Post-experiment, videos were analyzed to quantify velocity and adhesion of platelets and leukocytes for each treatment condition. Results: When perfused over TNF-α activated endothelium, both controls ( JAK2 negative, n=11) and JAK2 V617F MPN (n=20) had a significant reduction in cell velocity. Furthermore, compared to controls, JAK2 V617F MPN individuals exhibited significantly lower cell velocities. In multi-variate analysis, reduction in cell velocity was independent of white blood cell, hemoglobin, hematocrit or platelet counts. Hydroxyurea is a standard therapy in JAK2 V617F MPN and is known to reduce α4β1 expression. Therefore, we performed subgroup analysis in our JAK2 V617F MPN cohort based on treatment. When perfused over TNF-α activated endothelium, individuals with JAK2 V617F MPN (n=9) not on therapy (newly diagnosed) or on phlebotomy/aspirin only had a significant reduction in cell velocity. In the same conditions, HU-treated JAK2 V617F MPN patients (n=9) had no change in cell velocity. There was no difference in complete blood counts between these groups. In a separate subgroup analysis, compared to untreated JAK2 V617F MPN patients (n=9), interferon-treated JAK2 V617F MPN patients (n=5) had a greater reduction in cell velocity. Last, we specifically targeted α4β1 integrin by adding natalizumab to either control (n=7) or untreated JAK2 V617F MPN (n=3) samples. On inactivated endothelium, treatment of either control or JAK2 V617F MPN blood with natalizumab did not significantly change cell velocity. On a TNF-α activated endothelium, treatment of control (n=7) and JAK2 V617F MPN blood (n=3) with natalizumab led to a recovery in cell velocity. Conclusion: Our data suggests that the interaction between integrin α4β1 on JAK2 V617F cell surface and VCAM-1 on activated endothelium is important for initiation of pro-thrombotic interactions. JAK2 V617F MPN individuals treated with HU exhibit decreased adhesion to activated endothelium compared to control; JAK2 V617F MPN individuals treated with interferon exhibit increased adhesion. In the microfluidic system, based on current findings, blockage of integrin α4β1-VCAM-1 interactions using natalizumab is a potential therapeutic strategy. Further mechanistic studies evaluating interferon and cell populations changed by therapies as they pertain to integrin α4β1 are underway.

Early clinical efficacy of pegylated interferon treatment in patients with different phases of chronic HBV infection: A real-world analysis.

Although there are therapeutic advantages for hepatitis B virus (HBV) withpegylated interferon alpha (peg-IFNα) treatment compared with nucleos(t)ide analog (NAs) therapy, the effect difference in infected population at different phases has not been well established. We studied the clinical efficacy of peg-IFNα in two populations with HBV infection, including inactive HBsAg carrier (IHC) and chronic hepatitis B (CHB). A total of 328 HBV-infected patients were included in this real-world analysis. Patients were divided into two groups according to the infected stages. Peg-IFNα monotherapy or combination therapy with NAs were used in IHCs, and peg-IFNα added-on NAs therapy was applied to patients with CHB. The primary efficacy endpoint was HBsAg loss at Week 24. Results: The Kaplan-Meier cumulative rates of HBsAg loss were 39.50% (n=47/119) in IHC group and 28.71% (n=60/209) in CHB group at Week 24 (p < .05). After Propensity Score Matching (PSM), the HBsAg loss rates were 36.84% (n=35/95) and 32.63% (n=31/95), respectively (p > .05). Patients with baseline HBsAg level < 100 IU/ml achieved higher rates of HBsAg clearance in IHC and CHB group (before PSM: 47.44% vs. 42.86%, after PSM: 49.12% vs. 45.83%, all p values > .05). Baseline HBsAg level and its level decline from baseline to Week 12 can be as the predictors for HBsAg loss at Week 24 in both groups. Hence, the efficacy of HBsAg clearance was broadly similar between IHCs and NA-treated CHB patients during the early peg-IFNα therapy. A significant downward trend of HBsAg level was observed in both groups during peg-IFNα therapy.

A prospective follow-up on thyroid function, thyroid autoimmunity and long COVID among 250 COVID-19 survivors.

We evaluated the evolution of thyroid function and autoimmunity among COVID-19 survivors over 6 months in relation to interferon beta-1b treatment and long COVID. We included COVID-19 survivors managed in a major COVID-19 centre between July 2020 and May 2021 who were reassessed three and/or six months after acute COVID-19. Thyroid function tests (TFTs) and anti-thyroid antibody titres were measured at acute COVID-19, 3-month and 6-month. 250 COVID-19 survivors were included (mean age 52.7 years, 50.4% men). Persistent thyroid function abnormalities were more likely in those with abnormal TFTs in acute COVID-19 (P < 0.001). Among 51 patients with abnormal TFTs in acute COVID-19, 82.4% resolved upon follow-up. Of 199 patients with normal TFTs in acute COVID-19, only 4.5% had incident abnormal TFTs, more likely in interferon-treated patients (P = 0.044) and none clinically overt. Among 129 patients with complete 6-month follow-up for anti-thyroid antibody titres, there was no significant change overall, except for modest increase in anti-thyroid antibody titres among the 84 interferon-treated patients (P < 0.05 at both 3 months and 6 months). Long COVID occurred in 19.5% and 10.4% at 3 and 6 months respectively, where TFTs and anti-thyroid antibody titres were not predictive of its occurrence. Over 6 months, most abnormal TFTs in acute COVID-19 resolved, with no significant incident thyroid dysfunction. SARS-CoV-2 infection did not lead to change in thyroid autoimmunity, while interferon treatment was associated with modest increase in anti-thyroid antibody titres. Thyroid function and anti-thyroid antibodies did not play a significant role in long COVID.

Incidence and risk factors of hepatocellular carcinoma in patients with hepatitis C who achieved a sustained virological response through direct-acting antiviral agents among the working population in Japan.

Background and AimThe development of hepatocarcinogenesis after a sustained virological response (SVR) remains an important issue affecting the balance between treatment and occupational life of workers with chronic hepatitis C virus (HCV) infection in Japan. Here, we aimed to evaluate the hepatocellular carcinoma (HCC) reducing effect and risk factors for developing HCC after SVR in patients treated with direct‐acting antiviral agents (DAAs) among the working population.MethodsWe studied 2579 working patients with chronic HCV infection who achieved SVR after antiviral treatment. We compared the difference in the cumulative incidence of post‐SVR HCC between the interferon (IFN)‐based n = 1615 and DAA (n = 964) groups. The risk factors for post‐SVR HCC development were determined in the DAA group.ResultsAfter propensity score matching (n = 644 in each group), the HCC development rates were not significantly different between the groups (P = 0.186). Multivariate Cox regression and the cutoff values determined by the receiver operating characteristic curve analyses revealed that age ≥61 years, diabetes, lower serum albumin levels <4.0 g/dL at 24 weeks after the end of treatment (EOT), and higher serum α‐fetoprotein levels ≥4.1 ng/mL at 24 weeks after the EOT were associated with the development of HCC.ConclusionThe HCC suppressing effect after SVR through DAA treatment is equivalent to that of IFN treatment in patients in the working population. Intensive follow‐up is required after SVR with DAA treatment in Japanese workers with these risk factors to ensure the promotion of health and employment support.

Hepcidin expression levels involve efficacy of pegylated interferon-α treatment in hepatitis B-infected liver

BackgroundHepcidin is the master iron regulator hormone produced by the liver. The association of serum hepcidin with pegylated interferon therapy in patients with chronic hepatitis C infection has been studied. However, the role of serum hepcidin level in predicting the effect of pegylated interferon treatment in patients with chronic hepatitis B (CHB) infection is yet to be elucidated. Our study aims to investigate the correlation between hepcidin expression levels and the curative effect of interferon-alpha therapy in patients with CHB. MethodsA total of 47 patients with CHB who accepted pegylated interferon-α (PEG-IFN- α) treatment were recruited. The serum level of hepcidin was estimated by ELISA. The alternation in the gene expression level of hepcidin was detected by RT-PCR, and immunofluorescence cell staining was performed to detect hepcidin peptide. The induction of antiviral proteins was analyzed by Western blotting. The predictive value of early on-treatment variation in serum hepcidin during treatment progress was assessed by receiver operating characteristic analysis. ResultsHigh levels of early on-treatment serum hepcidin were observed in patients who achieved a decline in HBsAg > 1 log10 IU/mL or HBV DNA > 1 log10 IU/mL. In vitro, an elevation of the hepcidin expression in HepG2.2.15 cells induced by PEG-IFN-α treatment was noted. Furthermore, combined treatment with hepcidin and PEG-IFN-α increased the levels of antiviral proteins. The predictive cut-off value of hepcidin for HBsAg decline > 1 log10 IU/mL was 239 pg/mL, and the sensitivity and specificity were 72.73% and 70.97%, respectively. The predictive cut-off value of hepcidin for the decline in HBV DNA > 1 log10 IU/mL was 190.4 pg/mL, and the sensitivity and specificity were 72.73% and 61.11%, respectively. Early-on treatment changes in the hepcidin level signified the predictive value of the PEG-IFN-α curative effect. ConclusionsA higher early-on treatment hepcidin level indicates a higher possibility of HBsAg and HBV DNA decline in patients with CHB during PEG-IFN-α treatment. A high early-on treatment serum hepcidin level is significant in predicting the PEG-IFN-α therapeutic effect in patients with CHB.

Single-Arm Salvage Therapy with Pegylated Interferon Alfa-2a for Patients with High-Risk Polycythemia Vera or High-Risk Essential Thrombocythemia Who Are Either Hydroxyurea-Resistant or Intolerant: Final Results of the Myeloproliferative Disorders-Research Consortium (MPD-RC) Protocol 111 Global Phase II Trial

Abstract Background: Several phase 2 trials have independently reported high response rates with recombinant interferon treatment in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further clarify the role of interferon therapy, we carried out a large trial to investigate pegylated-rIFN-α2a (PEG) as therapy in ET/PV patients. Methods: MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 trial evaluating complete and partial response rates (ELN Criteria) toPEG in patients with high-risk ET/PV who were either refractory or intolerant to hydroxyurea (HU) (Modified ELN Criteria). The study was designed to accrue 74 patients with ET and 74 with PV, but it was closed after accrual of 115 patients for administrative reasons. The starting PEG dose was 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Results Patients : The study enrolled 65 patients with ET and 50 patients with PV from 02/2012 to 12/2015. The median age was 64.0 years (range 20-85) (Table 1). Median time from diagnosis was 37.3 months (0.4-290.9) for ET and 54.8 months (0.5-393.7) for PV, entire cohort 42.3 months (0.5-394). Prior thrombosis was present in 32.3% of ET and 22% of PV patients. Palpable splenomegaly was present in 18.5% of ET patients and 56% of PV patients. Response CR / PR (ORR=CR+PR) at 12 months were observed in 43.1% / 26.2% (69.2%) in ET, and 22% / 38% (60%) in PV. The intention-to-treat (ITT) best ORR was 70.8% for ET and 64% for PV. In 77 patients (42 ET and 35 PV) who completed 24 months on-study, the ITT ORR (CR) was 73.8% (47.6%) for ET and 74.3% (42.9%) for PV. Patients with disease duration 42.3 months with 57% ORR (p=0.115). Higher treatment doses of PEG were not associated with increase in response rate (mean 118.2 vs 106.2 mcg, p: 0.225). Age Mutational analysis at baseline was available for 107 patients. JAK2V617F, CALR and MPL mutations are listed in table 1. Additional mutations included ASXL1 in 10, and TP53 in 5 patients. CR rate was higher in CALR mutated patients (56.3% vs. 28.6%, p= 0.02). None of 5 patients with TP53 mutation, and only 3/10 of ASXL1 mutated patients achieved CR. Safety Seventy-two % of patients remained on therapy for over 12 months with a median (range) duration of 78.5 (1-245) weeks in ET and 82 (4-209) weeks in PV. The mean (SD) weekly dose of PEG was 102.7 (52.3) mcg for ET and 128.7 (46.4) for PV. The causes for discontinuation of therapy are listed in Table 2. Grade 3 AEs regardless of attribution occurred in 38% of patients. Five grade 4 AEs were reported (AML, depression, hyperuricemia, and 2 subjects with neutropenia). Four non-myeloid malignancies developed in study patients. There were 3 off-trial deaths to date: drug abuse, lung adenocarcinoma, and patient decision unknown. Conclusions PEG is an effective agent to treat patients with ET/PV, capable of achieving 12 month ORR in 69% and 60% of ET and PV patients, respectively. The presence of CALR at baseline was associated with superior CR rates in ET. Treatment was associated with significant numbers of AEs which can limit tolerability. Thrombotic events and evolution to MF or AML continued to occur during the treatment period. The effects of PEG on the mutational burdens will be available at the time of presentation. QOL data will be presented separately. Download : Download high-res image (294KB) Download : Download full-size image Disclosures Yacoub: Novartis: Speakers Bureau; Sandoz: Consultancy; CTI: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Mascarenhas: Janssen: Research Funding; Merck: Research Funding; Novartis: Other: DSMB member , Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding. Berenzon: Incyte Corporation: Research Funding. Ritchie: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau; Bristol-Myers Squibb: Other: Research funding to my institution; Celgene: Consultancy, Other: Travel, Speakers Bureau; Astellas Pharma: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Pfizer: Consultancy, Other: Research funding to my institution. Rambaldi: Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses; Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy. Vannucchi: Novartis: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Hexner: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: Promedico: Research Funding; Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; Ariad: Consultancy; CTI BioPharma Corp.: Research Funding; Galena Biopharma, Inc.: Consultancy; Gilead Sciences, Inc.: Research Funding.

Evolution of ferritin levels in hepatitis C patients treated with antivirals

The evolution of ferritin levels in hepatitis C virus (HCV)-infected patients with sustained virological responses (SVRs) following various therapy regimens remains elusive. An 8-year prospective cohort study of 1194 HCV-infected patients [interferon-based therapy (n = 620), direct-acting antiviral agent (DAA) therapy (n = 355)] was conducted. At baseline, sex, alanine aminotransferase (ALT), triglycerides, homeostatic model assessment of insulin resistance (HOMA-IR), estimated glomerular filtration rate (eGFR), hemoglobin, iron/total iron-binding capacity (Fe/TIBC) and IFNL3-rs12979860 genotypes were associated with ferritin levels. At 24 weeks posttherapy, ALT, triglycerides, total cholesterol, eGFR, Fe/TIBC and the therapy regimen were associated with ferritin levels in SVR patients. Among interferon-treated patients, ferritin levels increased at 24 weeks posttherapy, regardless of SVR, and 24-week posttherapy ferritin levels were higher in non-SVR patients (n = 111) than in SVR patients (n = 509); ferritin levels began decreasing at 3 years posttherapy and were lower than pretherapy levels since 4 years posttherapy in SVR patients. Among DAA-treated SVR patients (n = 350), ferritin levels decreased and remained stable since 24 weeks posttherapy. ALT, triglycerides, eGFR, and Fe/TIBC were HCV-unrelated factors associated with ferritin levels; sex, HOMA-IR, total cholesterol, hemoglobin and IFNL3-rs12979860 genotype were HCV-related factors associated with ferritin levels. In interferon-treated SVR patients, the increased trend of posttherapy ferritin levels was not reversed until 4 years posttherapy. In DAA-treated SVR patients, ferritin levels decreased since 24 weeks posttherapy.

Association of serum autotaxin levels with liver fibrosis in patients pretreatment and posttreatment with chronic hepatitis C.

The evaluation of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection is important as it is a risk factor for hepatocellular carcinoma. In the recent years, autotaxin (ATX) has been established as a new noninvasive biomarker to predict liver fibrosis. However, antiviral treatment has been reported to decrease serum ATX, but it is unclear whether posttreatment ATX levels reflect liver fibrosis. In the present study, the correlation between ATX and liver fibrosis in pretreatment and posttreatment patients with HCV infection was analyzed. A total of 199 samples from 136 patients with HCV infection who had undergone hepatic biopsy before and/or after antiviral treatment at Osaka City University Hospital were used. Posttreatment patients included 38 interferon-treated patients and 80 interferon-free direct-acting antiviral-treated patients; all patients achieved a sustained virological response (SVR). Serum ATX levels were determined by enzyme immunoassay with an AIA-2000 analyzer. Serum ATX levels were largely correlated with liver fibrosis stage in patients with HCV infection before and after antiviral treatment. The measured values decreased even in similar liver fibrosis stages after treatment. The area under the receiver operating characteristic curve for the ability of ATX to diagnose above F2 stage before treatment was 0.81 (both male and female) and that after achieving SVR, it was 0.71 (male) and 0.72 (female). Serum ATX levels were correlated with histological liver fibrosis stage after achieving SVR. However, separate cutoff values before and after antiviral therapy should be established.

High rates of cirrhosis and severe clinical events in patients with HBV/HDV co-infection: longitudinal analysis of a German cohort

BackgroundChronic hepatitis delta virus (HDV) infection causes severe liver disease which often leads to cirrhosis and hepatocellular carcinoma (HCC). Aim of this study was to establish the disease severity and prognostic factors for disease outcome by analysing frequencies of clinical events and their correlation with baseline virological and biochemical parameters as well as interferon and nucleos(t)ide analogue treatment choice.MethodsWe studied a single-centre cohort of 49 anti-HDAg-positive patients with HBsAg persistence for at least 6 months. Virological and biochemical parameters, interferon and nucleos(t)ide analogue treatment choice as well as clinical events during follow-up were analysed by retrospective chart review (mean follow-up time 3 years, range 0.25–7.67 years).ResultsSevere clinical events occurred in 11/49 hepatitis D patients, including HCC (8/49), death (8/49) or liver transplantation (2/49). HCCs only occurred secondary to liver cirrhosis and their event rates in this cohort of hepatitis D patients did not differ from a matched HBV mono-infected cohort with comparable frequency of liver cirrhosis. A stepwise multivariate logistic regression revealed low platelet count (p = 0. 0290) and older age (p = 0.0337) correlating most strongly with overall clinical events, while serum HDV RNA positivity at baseline did not correlate with any clinical outcome. Interferon-free but not nucleos(t)ide analogue-free patient care correlated with the occurrence of HCC at logistic regression, although only 3/18 interferon-treated patients demonstrated repeatedly negative HDV PCR results post therapy.ConclusionsOur data indicate that progressive liver disease at baseline plays a major role as predictive factor for overall clinical outcome of hepatitis D patients. In particular, HCC risk may not be underestimated in hepatitis D virus RNA negative hepatitis D patients with advanced liver fibrosis.

Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia.

Chronic hepatitis delta is a severe liver disease with rapid progression to cirrhosis. The impact of hepatitis delta virus (HDV)-RNA on disease progression and interferon treatment in a real-world cohort has been barely explored. To assess the development of clinical events in a cohort of chronic hepatitis delta patients according to the presence or absence of HDV-RNA METHODS: Multicentre study at four academic hospitals in Spain included anti-HDV-positive patients with compensated liver disease with a follow-up ≥12months. Among 2888 HBsAg-positive subjects, 151 (5.2%) tested positive for anti-HDV, and 118 were included (58% men; median age, 49years; 73% detectable HDV-RNA and 30% cirrhosis, most often in subjects with HDV-RNA). After a median follow-up of 8years, subjects with initially detectable HDV-RNA were more prone to developing cirrhosis (31% vs 0%, P=.002) and/or liver decompensation (28% vs 3%, P=.019). Mortality rate was 0.44 per 1000 person-months. The probability of a clinical event was 6%, 25%, and 80% according to initial baseline-event-anticipation score. HDV-RNA became undetectable in 21 (24%) subjects either due to interferon or spontaneously (48% vs 52%, P=.29). Liver decompensation was reduced in interferon-treated patients (13% vs 38%, P=.026). Subjects with persistently positive HDV-RNA had a worse prognosis in terms of clinical events. Baseline-event-anticipation score is useful in predicting the risk of developing liver decompensation and hepatocellular carcinoma. Interferon was beneficial in reducing liver decompensation, even in the absence of virological response.

Increased Risk for Hepatocellular Carcinoma Persists Up to 10 Years After HCV Eradication in Patients With Baseline Cirrhosis or High FIB-4 Scores

It is unclear if hepatocellular carcinoma (HCC) risk declines over time after hepatitis C virus (HCV) eradication. We analyzed changes in HCC annual incidence over time following HCV eradication and identified dynamic markers of HCC risk. We identified 48,135 patients who initiated HCV antiviral treatment from 2000 through 2015 and achieved a sustained virologic response (SVR) in the Veterans Health Administration (29,033 treated with direct-acting antiviral [DAA] agents and 19,102 treated with interferon-based regimens). Patients were followed after treatment until February 14, 2019 (average 5.4 years), during which 1509 incident HCCs were identified. Among patients with cirrhosis before treatment with DAAs (n= 9784), those with pre-SVR fibrosis-4 (FIB-4) scores ≥3.25 had a higher annual incidence of HCC (3.66%/year) than those with FIB-4 scores <3.25 (1.16%/year) (adjusted hazard ratio 2.14; 95% confidence interval 1.66-2.75). In DAA-treated patients with cirrhosis and FIB-4 scores ≥3.25, annual HCC risk decreased from 3.8%/year in the first year after SVR to 2.4%/year by the fourth year (P=.01). In interferon-treated patients with FIB-4 scores ≥3.25, annual HCC risk remained above 2%/year, even 10 years after SVR. A decrease in FIB-4 scores from ≥3.25 pre-SVR to <3.25 post-SVR was associated with an approximately 50% lower risk of HCC, but the absolute annual risk remained above 2%/year. Patients without cirrhosis before treatment (n= 38,351) had a low risk of HCC, except for those with pre-SVR FIB-4 scores ≥3.25 (HCC risk 1.22%/year) and post-SVR FIB-4 scores ≥3.25 (HCC risk 2.39%/year); risk remained high for many years after SVR. Patients with cirrhosis before an SVR to treatment for HCV infection continue to have a high risk for HCC (>2%/year) for many years, even if their FIB-4 score decreases, and should continue surveillance. Patients without cirrhosis but with FIB-4 scores ≥3.25 have a high enough risk to merit HCC surveillance, especially if FIB-4 remains ≥3.25 post-SVR.

Durability of Spontaneous and Treatment-Related Loss of Hepatitis B s Antigen

Clearance of hepatitis B surface antigen (HBsAg) from serum is the most desirable end point and a proposed definition of functional cure for hepatitis B virus (HBV) infection. However, little is known about the long-term durability of HBsAg loss, and there is controversy over whether the development of antibodies against HBsAg (anti-HBs) is required for maintenance. We aimed to assess the durability of spontaneous or treatment-related (interferon or nucleos(t)ide analogue [NA]) loss of HBsAg. We performed a retrospective study of patients with chronic HBV infection followed up at the National Institutes of Health from February 1980 through November 2017. We identified those with HBsAg loss, confirmed on 2 visits at least 24 weeks apart. Patients with hepatitis C virus, hepatitis D virus, human immunodeficiency virus, or human T lymphocyte virus co-infection or HBsAg loss after liver transplantation were excluded. Patients were assigned to the following groups: spontaneous clearance (cleared HBsAg without ever receiving treatment or those who received treatment with a NA or interferon and discontinued therapy >5 years before HBsAg loss), interferon-treated (cleared HBsAg either during treatment or ≤5 years after stopping interferon), and NA-treated (cleared HBsAg either during treatment or ≤5 years after stopping NA). Among the 787 HBsAg-positive patients, 89 achieved HBsAg loss; 65 of 89 had confirmed HBsAg loss, which was spontaneous in 19 of the patients (29%), after interferon in 22 (34%), and after NA in 24 (37%). Of the 65 patients with confirmed loss of HBsAg, 62 patients (95%) remained HBsAg negative after a mean time of 9.6 years from the first negative HBsAg test result. HBsAg seroreversion occurred in 3 of the 46 treated patients (7%) (1 interferon and 2 NA), 1 of whom was positive for anti-HBs. At the time of HBsAg loss, 33 of 65 (51%) were anti-HBs positive. At the last follow-up evaluation, anti-HBs was detectable in 50 of the 62 patients (81%) assessed. The rate of development of anti-HBs was proportionally higher among interferon-treated patients (19 of 21; 90%) than NA-treated patients (17 of 22; 77%) or patients with spontaneous loss of HBsAg (14 of 19; 74%). In a retrospective study of 787 HBsAg-positive patients, loss of HBsAg (either spontaneous or after treatment) was confirmed in 8% and was durable. Seroconversion to anti-HBs increased over time and appeared to be more frequent after interferon treatment. HBsAg loss is therefore a robust end point for functional cure.

Sustained virological response to hepatitis C treatment decreases the incidence of complications associated with type 2 diabetes.

The role of hepatitis C (HCV) eradication on the long-term complications of type 2 diabetes mellitus remains incompletely studied. To investigate whether antiviral treatment impacted risk of acute coronary syndrome, end-stage renal disease, ischaemic stroke, and retinopathy among diabetic patients from the four US health systems comprising the Chronic Hepatitis Cohort Study (CHeCS). We included CHeCS HCV patients with diagnosis codes for type 2 diabetes who were on antidiabetic medications. Patients were followed until an outcome of interest, death, or last health system encounter. The effect of treatment on outcomes was estimated using the competing risk analysis (Fine-Gray subdistribution hazard ratio [sHR]), with death as a competing event. Among 1395 HCV-infected patients with type 2 diabetes, 723 (52%) were treated with either interferon-based or direct-acting antivirals (DAAs); 539 (75% of treated) achieved sustained virological response (SVR). After propensity score adjustment to address treatment selection bias, patients with SVR demonstrated significantly decreased risk of acute coronary syndrome (sHR=0.36; P<0.001), end-stage renal disease (sHR=0.46; P<0.001), stroke (sHR=0.34; P<0.001), and retinopathy (sHR=0.24; P<0.001) compared to untreated patients. Results were consistent in subgroup analyses of DAA-treated patients and interferon-treated patients, an analysis of cirrhotic patients, as well as in sensitivity analyses considering cause-specific hazards, exclusion of patients with on-treatment retinopathy, and treatment status as a time-varying covariate. Successful HCV treatment among patients with type 2 diabetes significantly reduces incidence of acute coronary syndrome, end-stage renal disease, ischaemic stroke, and retinopathy, regardless of cirrhosis. Our findings support the importance of HCV antiviral therapy among patients with type 2 diabetes to reduce the risk of these extrahepatic outcomes.

The impact of interferon therapy on the sexual function of hepatitis C male patients

Objective To evaluate the impact of interferon therapy on male sexual function. Patients and methods One hundred hepatitis C patients were included in the study. Fifty two patients were receiving interferon and 48 patients were not receiving interferon. All participants underwent history taking including International Index of Erectile Function (IIEF-5) score, general and local examination, assessment of hormonal profile, and pharmacopenile duplex Doppler ultrasonography. Results The IIEF-5 score of the noninterferon-treated group (18 ± 6.5) was significantly higher than the interferon-treated group (12 ± 4.5) (P = 0.022). Forty (76.9%) patients on interferon reported low sexual desire compared with 22 (45.8%) patients of noninterferon-treated group (P = 0.001). Total testosterone among interferon-treated patients (188 ± 0.32 ng/dl) was significantly lower than noninterferon-treated patients (270 ± 0.52 ng/dl) (P = 0.001). Similarly, free testosterone level among interferon-treated patients (3 ± 0.22 ng/dl) was significantly lower than noninterferon-treated group (7 ± 2.3 ng/dl) (P = 0.05). Estradiol levels among interferon-treated patients (80 ± 3.3 pg/ml) were significantly higher than noninterferon-treated patients (58 ± 2.3 pg/ml) (P = 0.01). However, prolactin level showed no significant difference between the interferon-treated (13 ± 1.3 ng/ml) and the noninterferon-treated groups (12 ± 1.5 ng/ml) (P = 0.59). Thirty eight (73%) patients on interferon showed vasculogenic erectile dysfunction compared with 32 (66.7%) patients not receiving interferon (P = 0.11). Twenty two (42.2%) patients on interferon showed veno-occlusive dysfunction which was significantly higher than noninterferon group (16.6%) (P = 0.03). Eighteen (37.5%) patients of the noninterferon group showed mixed vasculogenic erectile dysfunction compared with eight (15.4%) patients on interferon (P = 0.05). Conclusion Interferon had negative impact on libido, IIEF-5 score, and hormonal profile but did not affect penile hemodynamics.

Prevalence of thyroid stimulating hormone dysfunction among sofosbuvir-treated HCV-infected patients: A real-world clinical experience.

Thyroid dysfunctions occur frequently among hepatitis C virus (HCV)-infected patients. Accumulating evidence has shown the higher incidence of thyroid dysfunctions in interferon-treated patients that was previously the standard of care therapy. However, the prevalence of thyroid disorders has not been studied in the recently developed interferon-free regimens or direct-acting antiviral (DAA) drugs-treated patients. We recruited 37 patients who had just completed 6 months long sofosbuvir-based treatment, and 26 interferon-treated patients were also included in the study. Serum thyrotropin level of all participants was measured using VIDAS. We observed thyroid dysfunctions in both pegylated interferon-experienced and DAA drug-experienced patients but the prevalence of hyperthyroidism was found significantly higher in patients treated with interferon-based regimen as compared with interferon-free regimens. This high prevalence of hypothyroidism in patients with HCV posttreatment highlights the need for regular periodic screening of patients during the treatment.

Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo

Polycythemia vera is characterized by the acquisition of the JAK2V617F mutation. Recommended treatments include hydroxyurea and interferon-alpha. Several groups have reported a reduction in the JAK2 mutant allele burden in interferon-treated patients, but significance of this observation is questioned. We characterized the activity of ropeginterferon alpha-2b, a novel form of interferon-alpha recently shown to be safe and efficacious in polycythemia vera. Ropeginterferon was able to inhibit the proliferation of the HEL, UKE-1, and UT-7 JAK2-mutant cell lines while sparing JAK2-wild-type UT-7 and normal CD34+ cells growth. In vitro treatment of erythroid progenitors derived from PV patients showed that ropeginterferon could considerably inhibit the growth of endogenous erythroid colonies, a hallmark of polycythemia vera. Finally, we could study in sequential samples the clonal architecture of erythroid progenitors derived from patients included in a randomized study comparing hydroxyurea to ropeginterferon. After 1 year of treatment with ropeginterferon, the ratio of JAK2-mutated to wild-type colonies grown from bone marrow progenitors was reduced by 64%, compared to 25% in patients receiving hydroxyurea. This study shows that ropeginterferon has a potent targeted activity against JAK2-mutant cells and is able to drastically reduce the proportion of malignant progenitors in patients treated with this drug.

Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies.

To evaluate the immunogenicity and safety of a seasonal influenza vaccine in a cohort of multiple sclerosis (MS) patients receiving different immunomodulating/immunosuppressive therapies and assess predictors of immune response. A prospective, multicenter, non-randomized observational study including 108 patients receiving a trivalent seasonal influenza vaccination was conducted. Influenza-specific antibody titers (H1N1, H3N2, and influenza B) were measured to evaluate rates of seroprotection and seroconversion/significant titer increase. Univariable and multivariable analyses were performed to identify prognostic factors of vaccination outcomes. Regarding the whole cohort, seroprotection rates >70% were achieved for each influenza strain. Interferon-treated patients reached high seroprotection rates (>84%). Good seroprotection rates were seen in patients treated with glatiramer acetate. In particular for H3N2, response rates were low in natalizumab-treated patients and in the small subgroup of fingolimod-treated patients. Patients with a previous disease-modifying therapy and a longer disease duration were less likely to respond sufficiently. No severe adverse events were reported. MS disease activity was not increased after a one-year follow-up period. Vaccination led to good immunogenicity, especially in MS patients treated with interferons and glatiramer acetate. At least for the H1N1 strain, rates of seroprotection and seroconversion/significant titer increase were high (>70% and >60%, respectively) for all therapeutic subgroups. Patients with a longer duration of the disease are exposed to an increased risk of insufficient immune response to vaccination.

The long-term impact of hepatitis C infection in kidney transplantation in the pre-direct acting antiviral era.

Hepatitis C virus (HCV) infection in kidney transplantation is an important issue with effects on patient and graft survival. The current standard of care involves using oral Direct Acting Antiviral drugs. Till recently, pre-transplant treatment with interferon was the only option for treatment. We studied 677 consecutive kidney transplant recipients with HCV infection. 5.2% patients had evidence of HCV infection. 2.0% were newly detected to have HCV infection after transplant (de novo HCV group). Nearly 28.6% had negative antibody tests but positive Nucleic Acid Test at the time of diagnosis. Eighty-five percent of pre-transplant HCV-positive patients were treated with interferon-based regimens. Early virologic response was seen in 66.6%. End of treatment response was achieved by 94.1%. Sustained virologic response was seen in 81.2%. Overall, patient and graft survival were not different between HCV and control groups (log-rank P = 0.154). Comparing HCV and control groups, there was a tendency toward increased fungal (11.4% vs. 5.6%, P = 0.144) and CMV infections (25.7% vs. 17.1%, P = 0.191) in the HCV group, though it did not reach statistical significance. Eighty-percent of the interferon-treated patients suffered side effects. On comparing, the pre-transplant HCV-positive group (85% treated) with the de novo HCV group (none treated), the de novo group had significantly reduced patient survival (P = 0.020) and NODAT (35.7 vs 4.8%, P = 0.028), and a tendency toward higher CMV infections (35.7% vs 19%, P = 0.432). In addition, death and hepatic complications (decompensated liver disease, fibrosing cholestatic hepatitis) occurred only in de novo HCV group. These results highlight the need for continued post-transplant treatment of HCV positive patients. The newer anti-HCV drugs are expected to fulfill this felt-need in kidney transplantation but long-term results are awaited. This study can serve as a benchmark for future studies to compare the long-term effect of Direct Acting Antiviral drugs.

Depression and anxiety disorders during pegylated interferon treatment in patients with chronic hepatitis B

ABSTRACTObjectives: Interferon (IFN) treatment has many neuropsychiatric side effects such as depression and anxiety disorder. Although untreated depression is a major contributor to dosage reduction or premature discontinuation of the IFN treatment, it is found that depressive symptoms among patients undergoing hepatitis C virus (HCV) treatment are commonly overlooked during routine clinical interviews. Besides depression, anxiety disorders are shown to affect adherence to pegylated IFN (Peg-IFN) treatment in patients with hepatitis C. Despite the occurrence of neuropsychiatric side effects of IFN treatment being widely reported in patients with hepatitis C, there are few studies studying patients infected with hepatitis B virus (HBV). The aim of this prospective study was to evaluate the incidence and risk factors of depressive and anxiety disorders that occur during Peg-IFN treatment of patients with HBV.Methods: The sample consisted of volunteer patients who were diagnosed with HBV infection and who w...