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The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA.We conducted a randomized controlled trial of CHB patients on NA12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg)1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg200 IU/mL, qHBsAg100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT).A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P.0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P.001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P.0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy).ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

Background and Aims Recent case series and retrospective studies have raised concerns that patients who receive direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection are at increased risk of developing varicella-zoster virus infection (VZV reactivation). We investigated the relationship between DAA treatment and VZV reactivation by analyzing pooled participant-level data from 37 clinical trials of DAA agents. Methods We obtained demographic, adverse event, and laboratory data from 13,816 participants in 37 clinical trials submitted to the Food and Drug Administration for approval of DAA agents for treatment of HCV infection. Participants received DAAs (n = 12,249), placebo (n = 997), pegylated interferon (n = 243), or a combination of DAAs and pegylated interferon (n = 327). Occurrence of VZV reactivation was identified using systematically reported adverse event data. HCV virologic response was evaluated by measurement of HCV RNA. Results VZV reactivation occurred in 9.9 cases per 1000 person-years of DAA treatment (95% CI, 6.8–14.0 per 1000 person years) and 13.8 cases per 1000 person-years of placebo (95% CI, 3.5–37.5 per 1000 person years). No participants in the pegylated interferon or combination DAA and pegylated interferon groups experienced VZV reactivation. Within the placebo-controlled trials there was no significant difference in VZV reactivation between DAA treatment and placebo. VZV reactivation was associated with age older than 40 years, female sex, and HIV coinfection. We did not find an association between time of virologic response and time to VZV reactivation. Conclusion In an analysis of data from 37 trials, we found no evidence for an association between DAA treatment for HCV infection and increased risk of VZV reactivation.

Interferon (IFN) is a multifaceted immunomodulator that is effective against many diseases, including chronic hepatitis B and chronic hepatitis C infection. IFN defends against viral infection, but may also cause various side effects, such as ulcerative colitis (UC). Herein, we present a case of UC triggered by pegylated interferon alpha-2b (PEG-IFN-α-2b) therapy in a patient with concurrent chronic hepatitis B (CHB) infection. The diagnosis was based on typical clinical symptoms, colonoscopy findings, colonic mucosal biopsy, and histopathology. Accordingly, treatment with mesalazine was initiated without stopping PEG-IFN-α-2b. Fortunately, UC relieved gradually without compromising the effects of treatment. Simultaneously, we conducted a literature review of previously published case reports on the side effect of UC in patients with underlying chronic hepatitis. Various reactions have been reported, including induction, exacerbation, and no change. This is the first report of UC triggered by PEG-IFN-α-2b in a CHB patient. We recommend that physicians pay attention to the rare side effect of UC during administration of PEG-IFN-α-2b. Mesalazine can relieve UC with sustained use of PEG-IFN-α-2b.

Background The progress of liver diseases may not stop after viral eradication. This study aimed to provide data on long-term prognosis of patients with hepatitis C virus (HCV) infection who underwent pegylated interferon plus ribavirin (PR) regimen and achieved a sustained virological response 24 weeks post-treatment (SVR24). Methods Responders to the PR regimen in our hospital from January 2011 to June 2014 were enrolled and prospectively followed up. Baseline characteristics were profiled. The incidence of hepatocellular carcinoma (HCC), progression of liver disease (increase in liver stiffness or occurrence of decompensated complication), and HCV recurrence was all monitored. The accumulative and annualized incidence rates (AIRs) of these adverse events were analyzed, and the risk factors were also examined. Results In total, 151 patients reached a median follow-up time of 103 weeks. Among them, two had an incidence of HCC during the surveillance with AIR of 0.68% (95% CI: 0.00-1.63%). Six patients showed progression of liver disease with AIR of 2.05% (95% CI: 0.42%-3.68%). Three patients who had risky behaviors encountered HCV reinfection. The cirrhotic patients faced higher risk of poor prognosis than non-cirrhotic patients, including HCC and progression of liver disease (AIR: 6.17% vs. 1.42%, P = 0.039). Conclusions The incidence of HCC and progression of liver disease was evident in PR responders during the long-term follow-up period, but the risk level was low. Cirrhotic responders were more vulnerable to develop HCC post SVR24 compared with non-cirrhotic ones. HCV recurrence was rare in responders with SVR24 who had corrected their risky behaviors.

Background Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to the 8 to 14 isomers of other on-market pegylated interferon products, allowing every-two-week injection with high tolerability. It received European Medicines Agency marketing authorization in 2019 and Taiwan Biologics License Applications Approval in 2020 for the treatment of polycythemia vera. This study aimed to evaluate the safety and efficacy of Ropeginterferon alfa-2b plus ribavirin in genotype 2 chronic hepatitis C (CHC) patients. Methods Eighty-six treatment naive patients with genotype 2 CHC were randomized to weekly peginterferon alfa-2a (Peg–IFN–α2a) at 180 μg (n = 22), or every-two-week Ropeginterferon alfa-2b at 270 μg (n = 23), 360 μg (n = 21), 450 μg (n = 20), plus daily oral ribavirin 1000 mg (≤75 kg) or 1200 mg (>75 kg). Patients with rapid virologic response received 16-week regimen while those without RVR received 24-week regimen. The primary endpoint was sustained virologic response at 24 weeks post-treatment (SVR24). Results SVR24 was achieved by 95.5%, 78.3%, 85.7%, and 60% of subjects in Peg–IFN–α2a 180 μg, Ropeginterferon alfa-2b 270 μg, 360 μg, and 450 μg groups, respectively. The safety profile was similar across 4 groups. The incidence rate of adverse event during the treatment period was 0.407, 0.252, 0.395, and 0.347 per patient-week, respectively. Conclusion Ropeginterferon alfa-2b, although at only half the number of injections, is as safe and effective as Peg–IFN–α2a for genotype 2 CHC. A phase 3 study to confirm safety and efficacy of Ropeginterferon alfa-2b in genotype 2 CHC is ongoing.

Background Recent studies report incongruent finds regarding the addition of pegylated interferon -alpha (Peg- IFNα) to nucleos(t)ide analogues. This study was designed to compare the efficacy of Peg- IFNα and tenofovir disoproxil fumarate (TDF) combination therapy with each of the treatments separately. Methods In this open-label, randomized clinical trial, treatment-naive hepatitis B e antigen (HBeAg)-negative patients were randomly assigned to three treatment groups: Group A: Peg- IFNα (180 mcg/week) with TDF (300 mg/day); Group B: TDF (300 mg/day); and Group C: Peg- IFNα (180 mcg/week). The intervention spanned 48 weeks and patients were followed up every 12 weeks. The primary end-point was HBV DNA load Results Groups A, B and C each comprised of 22, 23 and 22 patients, respectively. The number of patients with HBV DNA suppression in group A was significantly higher compared to groups B and C (P = 0.034). No significant difference was observed in the normalization trends of serum ALT levels between the three groups (P = 0.082). At week 48, combination therapy was significantly more effective in suppressing HBV DNA concentration to below the level of detection than TDF monotherapy (OR = 2.1, 95%CI: 1.18–4.15; P = 0.034). Furthermore, a comparison between monotherapy arms revealed that both interventions had similar effects on the overall outcome (OR = 1.24, 95%CI: 1.02–5.8; P = 0.062). Conclusion A Peg- IFNα and TDF combination therapy resulted in improved virologic response and was safe in HBeAg negative patients. Monotherapy with Peg-IFNα or TDF procured limited benefits in comparison. Trial registration This study was registered in the Iranian Registry of Clinical Trials (IRCT20181113041635N1).

Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.

Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated prevalence worldwide. Hepatitis delta virus infection follows a challenging clinical course and is responsible for significant liver-related morbidity. Although the only currently available treatment (pegylated interferon) does not provide consistent results, emerging therapeutic options are promising. This article explores the epidemiology, natural history, as well as current and potential therapeutic options for hepatitis delta virus infection.

Background and aim Recently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients. Methods The ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naive to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks. Results ALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response. Conclusions ALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.

Summary Objectives The advent of direct-acting antivirals (DAAs) has revealed high rates of sustained virological response at 12 weeks (SVR 12) in Hepatitis C (HCV) treatment. Since the introduction of DAAs, in our centre, 42% of patients treated for HCV are HIV co-infected. Our study aimed to identify the SVR 12 rates between this group and HCV mono-infected patients. Methods Retrospective data analysis of HCV mono-infection and HIV-HCV co-infection patients between 1st July 2015 and 30th November 2018, who had a SVR at 12 weeks post treatment. Co-infected patients were only referred for HCV treatment if they had well controlled HIV. Patients treated with Pegylated Interferon and Ribavirin were excluded. Results During this period, 724 patients were treated for HCV and had data on SVR 12. Of those, 303 (41.8%) were co-infected with HIV. The SVR 12 was achieved in 386 (91.6%) of the HIV negative patients and 288 (95%) of the HIV positive patients (χ²= 3.10 p = 0.078). Cirrhotic patients had poorer SVR 12 in both groups (90% in co-infection and 88.4% in HCV mono-infection). Conclusions Our results demonstrate a higher SVR 12 in co-infected patients compared to patients with HCV mono-infection. We hypothesise that adherence to HIV treatment could increase compliance and success of HCV treatment.

Background In the era of direct-acting antivirals (DAA) for the treatment of hepatitis C virus (HCV) infection, HCV treatment uptake remains insufficiently documented in key populations such as people with opioid dependence. Access to opioid agonist therapy (OAT) is facilitated in France through delivery in primary care, and individuals with opioid dependence can be identified as those receiving OAT. Women with opioid dependence are especially vulnerable because of associated sex-related stigma, discrimination, and marginalization, all of which negatively interfere with access to HCV prevention and care. This study, based on data collected between 2012 and 2016 in France, aimed to assess whether (i) chronically HCV-infected women with opioid dependence had lower rates of HCV treatment uptake than their male counterparts during the same period (i.e., study period), and (ii) the advent of DAA resulted in increased treatment uptake rates in these women. Methods Individuals with opioid dependence were identified as those receiving OAT at least once during the study period. Analyses were based on exhaustive anonymous care delivery data from the French national healthcare reimbursement database. We used multinomial logistic regression to estimate sex-based disparities in HCV treatment uptake (DAA or pegylated-interferon (Peg-IFN)-based treatment versus no treatment) while accounting for potential confounders. Results The study sample comprised 27,127 individuals, including 5640 (20.8%) women. Median [interquartile range] age was 45 [40–49] years. Between 2012 and 2016, 70.9 (women: 77.2; men: 69.3), 17.3 (14.2; 18.2) and 11.7% (8.6%; 12.5%) of the study sample received, respectively, no HCV treatment, DAA and Peg-IFN-based treatment only. After multiple adjustment for potential confounders, women were 41% (adjusted odds-ratio (AOR) [95% confidence interval (CI]): 0.59[0.53−0.65]) and 28% (0.72[0.66−0.78]) less likely than men to have had Peg-IFN-based and DAA treatment, respectively. Conclusion Despite increased HCV treatment uptake in women with opioid dependence in the DAA era, rates remain lower than for men. In the coming years, access to DAA treatment will continue to increase in France thanks to a forthcoming simplified model of HCV care which includes primary care as an entry point. Nevertheless, a greater understanding of sex-specific barriers to HCV care and the implementation of appropriate sex-specific measures remain a priority.

Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics.

Background/Purpose: While direct-acting antiviral regimens have been approved for chronic hepatitis C (CHC) patients in Taiwan, reimbursement is limited to certain populations. Thus, pegylated interferon plus ribavirin (PEG-IFN/RBV) remains the standard of care for many patients. The aim of this study was to investigate the percentage of CHC patients who were recommended and willing to receive PEG-IFN/RBV, and to identify reasons why patients were not recommended or unwilling to receive treatment. Methods: 822 Taiwanese CHC patients were enrolled from May–August 2016 in this cross-sectional study. PEG-IFN/RBV recommendation and patient willingness to receive treatment were evaluated through surveys. Patient characteristics associated with treatment recommendation and willingness were assessed. Results: 311 (37.8%) patients were recommended PEG-IFN/RBV while 102 (12.4%) were willing to follow treatment recommendation. Rates of recommendation and willingness were lower in treatment-experienced, hepatitis C virus genotype 1 (GT1) and cirrhotic patients, and those treated in Northern Taiwan. Multivariate analyses found factors such as prior treatment experience, GT1, cirrhosis and low hemoglobin levels to be associated with lower recommendation rates while advanced age, GT1 and low baseline viral loads were associated with lower willingness rates. Physicians' top reasons for not recommending PEG-IFN/RBV included the wish to wait for better treatment options (60.3%), prior treatment failure (21.3%) and patients’ advanced age (20.9%). Patients were unwilling to receive treatment mainly due to concerns about side effects (91.4%), the wish to wait for better treatment options (71.3%) and inconvenience (25.4%). Conclusion: A minority of Taiwanese CHC patients were recommended PEG-IFN/RBV, of which few were willing to receive treatment. Keywords: Hepatitis C, Pegylated interferon, Ribavirin, Direct acting antiviral, Taiwan

Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.

Objective To investigate the efficacy and safety of sofosbuvir (SOF) plus daclatasvir (DCV) or simeprevir (SMV) in a randomized, open-label, noninferiority trial of patients infected with hepatitis C virus genotype 1, who were previously unresponsive to pegylated interferon and ribavirin or were treatment naive. Methods Patients were randomly assigned to receive SOF (400 mg once daily) plus DCV (60 mg once daily) or SMV (150 mg once daily) for 12 weeks. The analysis included all participants who received at least one dose of the study drugs. The primary endpoint was sustained virologic response 12 weeks after ending treatment (SVR12; hepatitis C virus RNA measured using COBAS TaqMan RT-PCR (lower limit of detection and quantification of 12 UI/mL)). This study was registered at ClinicalTrials.gov (NCT02624063). Results A total of 125 of 127 enrolled and randomized patients started treatment (n = 65 SOF + DCV; n = 60 SOF + SMV). SVR12 was attained in 121 patients (96.8%): 65 (100%) receiving SOF + DCV (95% confidence interval (CI), 94.5 to 100) and 56 (93.3%) receiving SOF + SMV (95% CI, 83.8 to 98.2; absolute difference, 6.6%; 95% CI, −15.0 to 0). The most common adverse events were fatigue (n = 32, 25.6%), headache (n = 27, 21.6%), and mood swings (n = 24, 19.2%). No patients discontinued therapy. Conclusions The overall SVR rate was 96.9%; SOF + DCV (100%) was higher than that of SOF + SMV (93.3%). Despite no statistically significant intergroup difference in SVR12 rates, the noninferiority of SOF + SMV to SOF + DCV could not be established because the difference in efficacy was clinically relevant.

Background: Hepatitis B surface antigen (HBsAg) seroconversion is considered the best outcome in the treatment of chronic hepatitis B virus (HBV) infection. In this study, we aimed to determine the cellular and molecular mechanisms by which pegylated interferon alpha (PEG-IFN-α) improves the seroconversion rate of patients with chronic hepatitis B (CHB). Methods: We first examined the significance of circulating T follicular helper (TFH) cells in the therapeutic response to PEG-IFN-α in patients with CHB. Flow cytometry was used to analyze the circulating TFH cells from 15 healthy individuals and 42 patients with CHB who exhibited different treatment responses [complete response group (CRG), incomplete response group (ICRG), and nonresponse group (NRG)] to the standard 48-week regimen of PEG-IFN-α monotherapy. In addition, the capacity of different TFH subsets to activate B cells and stimulate IgG production was examined using co-culture experiments. Findings: Longitudinal analysis revealed specific and significant increases in CD40L+CD4+ CXCR5+ TFH cells in CRG patients compared with NRG and ICRG patients given PEG-IFN-α monotherapy. In vitro co-culture experiments demonstrated that blocking CD40-CD40L signaling, but not ICOS-ICOSL signaling, specifically inhibited B cell activation and IgG production. In addition, HBV may impair the TFH function by boosting inhibitory regulatory T cells. Transcriptome analysis further revealed the upregulation of CD40L, but not ICOS, in TFH cells isolated from CRG patients. Interpretation: TFH cells, particularly those associated with CD40L expression, stimulate B cell differentiation and improve HBsAg seroconversion in patients with CHB following PEG-IFN-α treatment. Funding Statement: This research was funded by the National Natural Science Foundation of China (nos. 30972610, 81273240, 91742107, 81570002), National Key Research and Development Program (nos. 2017YFC0910000, 2017YFD0501300), Jilin Province Science and Technology Agency (nos. 20190101022JH, 2019J026, 20170622009JC, 2017C021, 2017J039, SXGJXX2017-8, JJKH20180197KJ, DBXM154-2018, 2018SCZWSZX-015), and the Fund of the State Key Laboratory of Kidney Diseases in PLA General Hospital (nos.KF-01-147). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The design of this study followed the guidelines of the Declaration of Helsinki and was approved by the Human Ethics Committee of the First Hospital of Jilin University (Changchun, Jilin, China). Written informed consent was obtained from all participants.

Objectives Hepatitis B virus infection is an important public health problem. We analysed the cost-effectiveness of the first-line therapies, including nucleotide analogues (namely tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir) and pegylated interferon (Peg-IFN) for patients with chronic hepatitis B (CHB) in China. Methods A Markov model describing CHB disease progression was constructed to compare the cost-effectiveness of the first-line therapies, considering both satisfactory (HBeAg seroconversion) and optimal (HBsAg seroclearance) treatment goals. We examined the main outcomes, including cumulative lifetime cost per patient, incremental quality-adjusted life years (QALYs), incremental cost-effectiveness ratio and net monetary benefit. Uncertainty analysis was conducted to identify key influential parameters. Results Compared with the baseline strategy, Peg-IFN had the highest QALY gain for HBeAg-positive (HBeAg+) CHB patients achieving a satisfactory goal and an optimal goal (3.19 and 6.32 respectively), and TDF was the most cost-effective therapy for HBeAg-negative CHB patients ($1418/QALY) achieving a satisfactory goal. Among nucleotide analogues, TAF was the most-effective strategy and had higher acceptability to achieve an optimal goal in the Eastern region of China (under 1 x GDP per capita threshold). Conclusions Among nucleotide analogues, TDF was the most cost-effective treatment in China for CHB patients to achieve satisfactory and optimal treatment goals, whereas TAF was cost-effective and more effective in the wealthier region. Peg-IFN was most cost-effective among HBeAg+ CHB patients to achieve both goals, with better clinical outcomes. Our findings also indicate the importance of regular monitoring during and after CHB treatment, and could inform treatment strategies in China and other countries.

Background Hepatitis C virus (HCV) infection is a major public health challenge in Cameroon with over three million people infected. Government efforts to improve care and treatment are unsatisfactory and need to be assessed. We aimed at studying the several steps along the HCV continuum of care in one of two hepatitis treatment centers in Cameroon. Methods We undertook a retrospective chart review of anti-HCV positive individuals, who attended the Douala general hospital between 2008 and 2015. We defined the HCV treatment cascade as follows: step 1—HCV RNA testing, step 2—complete pre-therapeutic evaluation (genotyping and liver fibrosis markers), step 3—initiation of treatment, step 4—treatment completion, and step 5—sustained virological response (SRV). Each successive step in the HCV care continuum was dependent on passing through the previous step. Results The mean age of the 669 anti-HCV antibody positive individuals was 57 (sd: ±13) years. Females were 52.8% of the study population. 410 (61.3%) were tested for HCV RNA. Three hundred and sixty-six (54.7%) were confirmed to have viral replication (HCV RNA positive). One hundred and eighty (26.9%) did a complete pre-therapeutic evaluation (both HCV genotyping and liver fibrosis assessment included). Eighty-one (12.1%) initiated treatment with pegylated interferon/ribavirin. Seventy-two (10.8%) completed treatment and 44 (6.6%) had SVR. Sociodemographic characteristics including age, gender, marital status, having medical insurance, and profession were associated with attaining later steps in the care cascade. Conclusion This study shows that HCV continuum of care and treatment is less optimal at the Douala general hospital and is highly impacted by socio-economic factors. Continued efforts are needed to improve HCV care.

Pegylated interferon alfa-2a (PEG-IFN alfa-2a), which was developed to overcome the disadvantages of conventional formulations, is widely prescribed for hepatitis B or C virus infection. It is characterized by pharmacokinetic (PK) and pharmacodynamic (PD) properties much different from those of conventional forms. The present study developed a population PK-PD model of subcutaneous PEG-IFN alfa-2a in a Korean population. For PK, IFN alfa-2a concentrations were described by a 1-compartment model with first-order absorption, preceded by skin-to-depot first-order input. For PD, serum 2'-5' oligoadenylsynthetase activity was described by an effect compartment model incorporating a tolerance compartment. The baseline serum 2'-5' oligoadenylsynthetase level was found to have an inverse relationship with sensitivity to tolerance, leading to high tolerance at low baseline. The model revealed that subjects with low baselines experienced time delay, while those with high baselines showed tolerance in their concentration-effect relationships. The developed models matched well with data and simulation results, and the model showed that the optimal dose decreases with the baseline, with no dose effective for a baseline >250 pmol/dL. Our results can serve as a basis for improving dosing regimens of PEG-IFN alfa-2a in adult patients with chronic hepatitis B or C infection.

Background People who inject drugs (PWID) are often excluded from HCV treatment programs due to concerns about their ability to adhere to care. Georgia has a high prevalence of HCV infection (5.4% of chronic cases in general population) with an epidemic concentrated among PWID. We evaluated adherence to care and sustained virologic response (SVR) among PWID in Georgia. Methods In this observational study, participants with recent injecting drug use (previous 6 months) and chronic HCV attending a needle- and syringe-program were included. Participants received sofosbuvir and ribavirin +/- pegylated interferon, with peer-based support during treatment. The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (SVR12). Factors associated with SVR were assessed using logistic regression. Results Among 244 participants [HCV genotype (GT) 3, 52%; GT2, 25%; GT1, 19%; mixed GT, 4%]; 55% had cirrhosis. Overall, 24% were receiving OST and 50% injected drugs in the previous month. 98% (239 of 244) completed treatment, with 88% (210 of 239) having never delayed a medical appointment and 79% (189 of 239) never missing a dose of medication. Overall, SVR was 84.8% (207 of 244). SVR was 88.5% (207 of 234) among participants who attended 12-week follow up appointment for HCV RNA testing. In multivariate analyses, SVR was significantly associated with adherence (no missed doses) to treatment [vs. missed doses; adjusted OR (aOR) 2.77; 95% confidence interval (95%CI), 1.01–7.51), and genotype (vs. GT1; GT2, aOR 0.27; 95%CI 0.06–1.21; GT3, aOR 1.09; 95%CI 0.27–4.50; and mixed GT, aOR 0.14; 95%CI 0.02-0.97). Conclusion In this real-life study in a middle-income country, PWID treated for HCV and receiving a simple peer-support intervention demonstrated an excellent treatment response and good adherence, not associated with injecting drug use during treatment and OST at treatment initiation.

We aim to detect the mostdifferentially expressed miRNAs in serum of Egyptian patients with chronic HCV infection before and after treatment using new treatment protocol of Sofosbuvir; pegylated interferon and ribavirin. The current study conducted on 50patientswith chronic HCV infection who received the treatment and 20 healthy controls. Array analysis revealed that, over-expression of 80 miRNAs and down-regulation of only 4miRNAs with significant different among HCV patients before treatment (over 2-fold changes). Both miR-122 and miR-221 were found to be significantly up-regulated among patients before treatment compared with control group (P = 0.04 & 0.003 respectively) and significantly down regulated in response to treatment (P = 0.02 & 0.008 respectively).In conclusion, aberrantmiRNA array especially miR-122 and miR-221could potentially extract data for HCV patients in response to combined new therapy. These findings empathizes the importance of contributing the role of miRNAsduring presence and clearance of HCV.

Background: Direct acting antivirals (DAAs) are highly effective for treatment of hepatitis C (HCV) but brand products are priced beyond the means of most low and middle income countries (LMICs). Although a few DAAs are offered at reduced prices in access programs, they are still beyond affordability in limited resource settings with a large HCV infected population. Cheap generics might fill this economic need, but studies comparing their clinical efficacy to that of original products are limited. Aim: To compare efficacy of brand and generic DAAs used in the national treatment program in Egypt. Methods: HCV treatment eligible patients (n = 971) were enrolled. They were treated with 12 weeks of either sofosbuvir-daclatasvir (SOF-DCV) or SOF-ledipasvir (SOF-LDV). Ribavirin (RBV) was added to patients with cirrhosis and to SOF experienced patients. Patients with cirrhosis who were RBV intolerant were treated for 24 weeks without RBV. Results: Most patients were males (61.4%), treatment naïve (88.6%), without cirrhosis (61.7%), and the mean age was 51.3 ± 11.31 years. Baseline characteristics were not different in patients treated with brand or generic medications regarding age, liver tests, creatinine, platelets, MELD score, baseline HCV-RNA and transient elastography. Overall sustained virologic response (SVR) rate was 98.1%, which was similar for generic and brand drugs (98.2% vs. 98.1%; p = 1), and similar with both regimens used (SOF-DCV ± RBV: brand: 98.1%, generic 97.8%; p = 0.729, SOF-LDV ± RBV: brand 98.2%, generic 100%; p = 0.729). AST and ALT decreased significantly with initiation of therapy with both generic and original drugs. Conclusion: Generic and brand DAAs are equally effective for achieving SVR and improving aminotransferases. Keywords: HCV, Direct acting antivirals, Generic, Brand, Sofosbuvir, Ledipasvir, Daclatasvir, Sustained virological response

Because PEGylated molecules exhibit different physicochemical properties from those of the parent molecules, PEGylated interferonβ-1a (pegIFNβ-1a) may be able to be used with retained bioactivity in Multiple Sclerosis (MS) patients who have previously developed neutralizing antibodies (NABs) to recombinant interferonβ (rIFNβ). Hence, the objective of the present study was to test whether pegIFNβ-1a is less antigenic for NABs in vitro than rIFNβ. Two in vitro assays were used to quantitate NABs in 115 sera obtained from MS patients included in the INSIGHT study: the cytopathic effect (CPE) assay, and the MxA protein induction assay. NABs cross-reactivity was assessed by comparing dilutions of serum with fixed doses of rIFNβ-1a Avonex® and pegIFNβ-1a Plegridy®. NABs were shown to cross-react in both assays. The y-intercept (c), the slope of the line of agreement (b), the Pearson coefficients as well as the Bland-Altman analysis, indicated that there is good level of agreement between NAB titers against the two IFNβ-1a formulations, with both the CPE (c = 0.1044 ± 0.1305; b = 0.8438 ± 0.06654; r2 = 0.587; bias index ± SD = −0.01702 ± 0.6334), and the MxA protein induction (c = 0.08246 ± 0.1229; b = 0.8878 ± 0.06613; r2 = 0.615; bias index ± SD = −0.09965 ± 0.6467) assays. Until further in vivo evidence is established, clinicians should consider the current in vitro data demonstrating NAB cross-reactivity between pegIFNβ-1a and rIFNβ when discussing new treatment options with MS patients.

Summary Limited clinical trial data has shown high efficacy of co-formulated ledipasvir/sofosbuvir (LDV/SOF) in the treatment of hepatitis C virus (HCV) genotype (GT)-4 infected cirrhotic patients. We assessed real-world safety and efficacy of LDV/SOF with or without ribavirin (RBV) in GT4-infected patients with compensated and decompensated cirrhosis. Patients & Methods This observational cohort (n = 213) included GT4 treatment-naive (59.6%) and -experienced (40.4%) patients with advanced fibrosis (F3, Metavir; n = 30), compensated (F4, n = 135) and decompensated cirrhosis (n = 48) treated for 12 (n = 202) or 24 weeks (n = 11) with LDV/SOF. RBV was dosed by physician discretion between 600–1200 mg daily. Patients with prior DAA failure were excluded from the analysis. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12) on an intention-to-treat analysis, and occurrence of serious adverse events (SAEs). Results The mean age of the overall cohort was 59.6 ± 12.1 years and 125 (58.7) were female. Overall, 197 (92.5%) of the patients achieved SVR12, including 93.3% of F3 fibrosis, 93.3% of compensated cirrhotics and 89.6% of the decompensated cirrhotics ( P = 0.686). Addition of RBV (68.5%) did not enhance efficacy (91.8% vs. 94.0% without RBV, P = 0.563), including in F3 fibrosis, compensated and decompensated cirrhosis ( P > 0.05, for all). There was no difference in SVR12 rates with 24 and 12 weeks therapy (90.9% and 92.6%, respectively; P = 0.586). Treatment failure (n = 16) was mostly related to relapse (n = 11), while on-treatment death (n = 3) and breakthrough (n = 2) comprised a minority. SAEs occurred in 9 (4.2%) patients requiring early treatment discontinuation in 4 (3 on-treatment deaths and 1 pregnancy). Conclusion LDV/SOF therapy yielded high SVR12 rates in both compensated and decompensated cirrhotic GT4 patients. The addition of RBV to this regimen did not improve efficacy. The safety profile of this regimen was comparable with that reported for other HCV genotypes.

Background Egypt is one of the largest epidemic areas of hepatitis C virus (HCV) in the world. Its prevalent genotype is 4 with a majority of subtype 4a. In 2013, the Food and Drug Administration approved a new direct-acting antiviral drug (sofosbuvir) to treat patients with chronic HCV infection. In Egypt, the patients are already being treated with sofosbuvir in conjunction with ribavirin and pegylated interferon alfa-2a (PEG-IFNα-2a) for 12 weeks since 2015. The present study was planned to explain the efficacy of this treatment regimen against the HCV genotype 4a in Egyptian patients and its pretreatment predictive factors of virological response. Methods In this population-based study, serum samples were biochemically analyzed and the HCV RNA levels were quantified. The direct sequencing and bioinformatics analysis were utilized to investigate the mutation of the core protein. Results The sustained virological response (SVR) and non-SVR were 72% and 16% respectively, but the nonvirological response was only 12% following the treatment regimen. The multivariable analysis recognized viral (level of viremia and substitution of aa70) and host-related factors (age, alanine aminotransferase and aspartate aminotransferase levels) affecting the virological response in patients infected with high viral load of HCV 4a. Conclusions Overall, these results concluded that sofosbuvir with ribavirin and PEG-IFNα-2a are highly efficient in HCV-4a Egyptian patients where a high SVR was achieved (72%). In addition to this, there is a significant association between core protein mutations and treatment outcome predominantly at amino acid position 70 (Arg or Gln).

Therapeutic proteins can facilitate the targeting and treatment of lymphatic diseases (such as cancer metastases, infections and inflammatory diseases) since they are cleared via the lymphatics following interstitial (SC or IM) administration. However, therapeutic proteins are often administered intravenously (IV). Recently therapeutic proteins have been found to access the thoracic lymph in surprisingly high quantities after IV administration. The aim of this study was to determine, for the first time, the major sites of thoracic lymph access of therapeutic proteins, and the protein properties that enhance lymph access, after IV administration. In order to achieve this, novel methods were developed or optimized to collect hepatic, mesenteric or thoracic lymph from male SD rats. Four different sized PEGylated or non-PEGylated therapeutic proteins (native interferon α2b (IFN, 19kDa), PEGylated interferon α2b (IFN-PEG12, 31kDa), PEGylated interferon α2a (IFN-PEG40, 60kDa) or trastuzumab (150kDa)) were then administered via short IV infusion, and plasma and lymph concentrations of the proteins determined via ELISA. The recovery of the therapeutic proteins in the thoracic lymph duct, which collects lymph from most of the body, was significantly greater for trastuzumab, IFN-PEG40 and IFN-PEG12 (all >3% dose over 8h) when compared to native IFN (0.9% dose). Conversely, the thoracic lymph/plasma (L/P) concentration ratio and thus efficiency of extravasation and transport through the interstitium to lymph was highest for the smaller proteins IFN and IFN-PEG12 (at 90-100% vs 15-30% for trastuzumab and IFN-PEG40). The lower total recovery of IFN and IFN-PEG12 in thoracic lymph reflected more rapid systemic clearance and thus lower systemic exposure. For all therapeutic proteins, the majority (>80%) of lymph access occurred via the hepatic and mesenteric lymphatics. This lymphatic distribution pattern was supported by quantitative imaging of the lymph node distribution of IV administered Cy5 labelled trastuzumab. Optimizing the properties of IV administered therapeutic proteins represents a viable approach to better target and treat pathological states involving the lymphatics, particularly in the liver and mesentery. This includes cancer metastases, infections and inflammatory diseases. Successful development of the novel technique to collect hepatic lymph will also enable future work to evaluate tissue-specific lymph transport in health and disease.

Background/Purpose Pegylated interferon (PegIFN) plus ribavirin (RBV) combination therapy has been the standard of care since 2002. Although a better viral response has been achieved among chronic hepatitis C (CHC) patients in Taiwan, approximately 25% of hepatitis C virus (HCV) genotype 1 (G1) patients and 15% of G2 patients failed to achieve a sustained virological response (SVR) at the first therapy. The actual cost-effectiveness of the retreatment remains elusive. The present study conducted a real-world cost-effectiveness analysis of a large cohort among different pre-specified subgroups of treatment-experienced CHC patients. Methods A total of 117 patients with CHC who failed to achieve SVR at the first IFN-based therapy and received a second IFN-based therapy were enrolled. The inpatient and outpatient costs were acquired from National Health Insurance Research Database of Taiwan. The related medical care costs per treatment and per SVR were calculated. Results We demonstrated that the average cost per SVR achieved was $13,722 in treatment-experienced CHC patients. Especially, patients with HCV G1 infection, baseline viral loads > 400,000 IU/mL, advanced hepatic fibrosis, not achieving a rapid viral response at week 4 or complete early viral response at week 12, had poorer cost-effectiveness for PegIFN/RBV retherapy, ranging from around $15,520 to as high as $72,546 per SVR achieved. Conclusion In the current study, we explored the real-world cost-effectiveness data of PegIFN/RBV for different subgroups of treatment-experienced HCV patients. These findings provide information for policy-makers for making decisions on treatment strategies of costly direct-acting antiviral agents for retreating CHC patients.

Introduction and Objectives: Covalently closed circular (ccc)DNA acts as a viral reservoir in the liver of patients with a chronic hepatitis B (CHB) infection and can only be quantified in liver biopsies. Hepatitis B core-related antigen (HBcrAg) levels in plasma/serum have been proposed to reflect intrahepatic cccDNA-levels and may therefore monitor treatment efficacy. This study aimed to validate the relationship between HBcrAg and other intrahepatic and circulating viral markers in CHB patients with high viral load, before and after combination treatment. Materials and methods: Plasma/serum levels of HBcrAg, HBsAg, HBV-DNA, and HBV pregenomic RNA (HBV-pgRNA), and intrahepatic cccDNA and HBV-DNA levels and fibrosis scores were measured in 89 CHB patients with HBV-DNA levels of >100,000 copies/mL (17,182 IU/mL). Measurements were done before and after a 48-week treatment with pegylated interferon alfa-2a and adefovir in a prospective study (ISRCTN77073364). Results: Baseline HBcrAg-values correlated strongly with intrahepatic cccDNA (ρ 0.77, p

Ruxolitinib is approved for the treatment of patients with polycythemia vera (PV) who are intolerant or resistant to hydroxyurea. While ruxolitinib discontinuation in myelofibrosis is associated with dismal outcomes, the analogous experience in PV has not been reported. Using a large, multi-institutional database of PV patients, we identified 93 patients with PV who were treated with ruxolitinib, of whom 22 discontinued therapy. Adverse events were the primary reason for discontinuation. After a median follow-up of 18.2 months following ruxolitinib discontinuation, no patients experienced a thrombotic event. One patient died 20.8 months after discontinuation. As compared with the 71 patients who were still receiving treatment with ruxolitinib at last follow up, patients who discontinued ruxolitinib were older at time of treatment initiation (67.5 versus 64.8 years, p = 0.0058), but had similar patient and disease characteristics. After discontinuation, only 4 patients (18 %) received subsequent cytoreductive therapy, including hydroxyurea in one patient and pegylated interferon α-2a in three patients. In stark contrast to the experience in myelofibrosis, discontinuation of ruxolitinib in PV was associated with generally favorable outcomes. However, there is a lack of available salvage therapies, highlighting the need for further therapeutic development in PV.

Aims: Pegylated-interferon has now replaced interferon-alfa 2a, which is no longer available in the UK, for patients with cutaneous T-cell lymphoma (CTCL) refractory to skin directed therapy. We present our experience of treating 12 CTCL patients with pegylated-interferon. Methods: A retrospective review of patients with CTCL from November 2019 to June 2021 treated with pegylated-interferon at a cancer centre in the UK. Results: Twelve patients were included in the review, eight males and four females. Patients were between 48 and 84 years old with Stage IIA-IIB mycosis fungoides. Patients received a selection of prior treatments; PUVA, UV-B, gemcitabine, bexarotene, total skin electron beam therapy, localised radiotherapy, topical steroids and retinoids. All patients were started on a weekly dose of 135 μg pegylated interferon. Nine patients demonstrated a significant improvement in skin appearance and symptoms. Four patients were subsequently escalated to 180 μg due to a diminished response and one patient was dose reduced to 90 μg due to weight loss. The duration of Pegylated-interferon ranged from 1 to 17 months with six patients currently still on treatment. One patient developed progressive disease over the first month and required intravenous chemotherapy to establish control. The median time to response was 42 days. Pegylated interferon was well tolerated and no patients discontinued treatment due to toxicity. Three patients reported no significant side effects. Four patients reported mild coryzal or flu-like symptoms. Two patients reported mild gastrointestinal symptoms. One patient suffered hot flushes, shedding and thinning of the hair that was initially troublesome but subsequently settled. One patient required a 20-week interruption due to stomach pains, bowel disturbance, dizziness and breathlessness all of which resolved. Similar symptoms were previously reported in the same patient on interferon alpha-2a. One patient suffered a pulmonary embolism 13 weeks into treatment which was successfully managed. One patient died following a stroke after 36 weeks of treatment and was confirmed COVID positive. Seven patients received interferon alpha 2a prior to pegylated-interferon. Two patients were converted directly and demonstrated an improved response. One patient reported new unilateral hearing loss that resolved with ear drops, and one patient reported tinnitus and poor appetite that also resolved. Otherwise, there were no significant differences in side effects and response was maintained. Conclusion: The substitution of Pegylated-interferon for alpha interferon was associated with a high response rate with no evidence of additional toxicity.

Background Previous studies suggested, variations in the IL28B gene can serve as predictors of sustained and rapid virological responses (SVR and RVR) in the treatment of HCV with pegylated interferon and ribavirin (pegINF-RBV) among HCV-HIV co-infected patients. Here, we explored the correlation between IL28B variants (rs12979860, rs8099917 and rs12980275) and treatment response for HCV among co-infected individuals using meta-analysis. Methods Relevant studies were retrieved from PubMed, EBSCO, ISI Web of Knowledge, Cochrane databases, and the role of IL28B variants on SVR and RVR in co-infected patients treated with pegINF-RBV was evaluated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by fixed- and random-effects models. Results Forty-three studies consisting 3499 patients who achieved SVR/RVR and 4308 non-responders were included in our study. The CC, TT and AA genotypes of IL28B rs12979860, rs8099917 and rs12980275, respectively, were associated with SVR in the recessive model for all HCV genotypes: rs12979860, OR = 3.18 [95% CI (2.66, 3.79)]; P Conclusions Our meta-analysis suggests that the CC, TT and AA genotypes of IL28B rs12979860, rs8099917 and rs12980275, respectively, are strong predictors for SVR, and the rs12979860 CC genotype has significant RVR predictive value in HCV-HIV co-infected patients treated with pegINF-RBV.

Hepatitis C virus infection affects 71 million people worldwide. It is at the origin of a multi-organ disease associating hepatic manifestations, cryoglobulinemic vasculitis and general manifestations linked to chronic inflammation (diabetes, cardio-, reno- or cerebrovascular manifestations, extra-hepatic cancers including non-Hodgkin’s lymphoma). The significant morbidity and mortality linked to the hepatitis C virus therefore justify its screening and access to treatments which have increased considerably over the past two decades. Understanding the replicative cycle of the hepatitis C virus has enabled the development of direct HCV-specific antivirals targeting viral proteins (NS3/4A protease, NS5B polymerase and the multifunctional NS5A replication complex). The combination of two to three specific inhibitors often co-formulated in a capsule, without pegylated interferon and most often without ribavirin, allows high antiviral efficacy (more than 97% cure) for a treatment duration of 8–12 weeks with satisfactory tolerance. HCV infection is the only chronic viral infection that can be cured and the hepatic or extrahepatic manifestations are mainly reversible. This underlines the importance of strengthening screening and access to care policies in order to achieve the elimination of viral infection C in the short term, in 2030, as expected from the program of the World Health Organization. If this elimination is possible in some countries (Iceland, France, Germany …), it seems compromised in others where prevention (USA), screening and/or access to care are still insufficient (Sub-Saharan Africa, Russia…).

Background and Aims Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment. Methods A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis. Results Propensity score-matched analysis showed no significant difference in HCC occurrence ( p =0.49) and recurrence rates ( p =0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment α-fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA + M2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFA + M2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFA + M2BP levels was greater than that for AFP levels in ROC analysis. Conclusion The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA + M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFA + M2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA + M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy.

Introduction and aim There is almost no data regarding the efficacy of direct acting antivirals (DAAs) therapy in Brazil. The aim of this historical cohort study is to describe the sustained virologic response (SVR) rate among real-world compensated chronic hepatitis C patients in three hepatology centers from Southern Brazil. Materials and methods Patients were included if they had at least 12 weeks follow-up after the end of therapy. Patients that were lost to follow-up or had treatment prematurely interrupted for any reason were considered treatment failure in this intention to treat analysis. Results 219 patients were analyzed. Mean age was 57.4 ± 10.9 years and 142/219 (64.8%) were male. Genotype 1 was present in 166 patients (75.8%; 1a 29.2%, 1b 46.6%); Genotypes 2, 3 and 4 in 8 (3.7%), 43 (19.6%) and 2 (0.9%), respectively. 96 (43.8%) were cirrhotic. 134 (59.5%) were treatment experienced. DAA therapies were: sofosbuvir (SOF) + ribavirin (RBV) in 10 patients; SOF + simeprevir (SMV) ± RBV in 73; SOF + pegylated interferon (PEG-IFN) + RBV in 6; SOF + daclatasvir (DCV) ± RBV in 51, SOF + ledipasvir (LDV) ± RBV in 61, and par-itaprevir/ritonavir + ombitasvir + dasabuvir (PTVr/OBV/DSV) ± RBV in 18 patients. SVR-12 was achieved in 208/219 (95%). Ten patients had virologic failure: 6 cirrhotic, 7 treatment experienced, and 6 either genotype 3 or 1a. No adverse event was attributed to the DAA therapy. Conclusions Real world experience with DAA therapy in Southern Brazil showed a high rate of SVR and excellent tolerability. Failure to achieve SVR was mainly observed among patients with at least one negative predictor of response: cirrhosis and/or genotypes 1a or 3.

Background and study aims Hepatitis C virus (HCV)-related cirrhosis is the leading cause of liver transplantation (LT). All patients who undergo LT with detectable serum HCV-RNA experience graft reinfection, which is the most frequent cause of graft loss and death in these patients. We estimated the rate of HCV recurrence and evaluated the current therapeutic regimens. Patients and methods The records of consecutive 325 living donor LT (LDLT) surgeries performed between May 2004 and August 2014 were retrospectively analysed; 207 of them were followed-up throughout the study. Clinical, laboratory, radiological and histopathological examinations were performed thoroughly. Patients received treatment in the form of either pegylated interferon (PEG-IFN) or sofosbuvir , both in combination with ribavirin . Results In total, 90.3% of recipients who were transplanted because of HCV-related end-stage liver disease experienced recurrence due to the virus. The donor age was older in the HCV recurrent group versus the non-recurrence group (28.7 ± 7.1 versus 22.6 ± 2.6 years: p ≤ 0.001 ), warm ischaemia time was prolonged (46.1 ± 18.1 versus 28.6 ± 4.1 min: p ≤ 0.001), median cold ischaemia time was 40.0 (10–175) versus 22.5 (15–38) min (p ≤ 0.001) and basal PCR was 414000 (546-116000000) versus 10766 (1230-40000) (p ≤ 0.001). Sustained virological response was achieved in 95.4% of patients treated with a combination of a fixed daily dose of 400 mg sofosbuvir with ribavirin and in 65.1% of those who were treated with PEG-IFN with ribavirin. Conclusions Older donor age and prolonged warm ischaemia time are independent predictors of HCV recurrence after LDLT, and early treatment with the direct-acting sofosbuvir is helpful in resolving the problem of post-LT HCV recurrence.

Background There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. Methods ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). Results Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. Conclusion This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response.

Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP-competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity because siRNA for SRC mRNA did not impair the HBV infection/replication. The anti-HBV activity of KX2-391 depended on the inhibitory effect of tubulin polymerization similar to other tubulin polymerization inhibitors, some of which were shown to inhibit HBV replication. KX2-391 inhibited HBV transcription driven by a HBV precore promoter in an HBV X protein-independent manner but did not inhibit the activity of HBV-S1, -S2, -X or cytomegalovirus promoters. Treatment with KX2-391 reduced the expression of several various factors including hepatocyte nuclear factor-4a.

In this prospective study, we examined new-onset major depressive disorder (MDD) and the differential expression of depressive symptoms in a sample of 132 HCV mono-infected and 40 HIV/HCV co-infected patients initiating pegylated interferon-based treatment, including protease inhibitor therapy. The semi-structured clinical interview (SCID-I) was used to assess MDD. Severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Of the total sample, 60 patients (34.9%) developed SCID-I defined MDD during antiviral treatment. The proportion of HCV mono- and HIV/HCV patients developing MDD during treatment was not significantly different (37.9% vs. 25%; p=0.185). In both groups, there was a significant increase in HAMD total score from baseline to week 4, and a significant decrease between week 24 and 6 months post-treatment cessation. The greatest increase was observed in the symptoms of the neurovegetative syndrome. HCV mono-infected patients reported higher scores than co-infected patients, particularly impaired activity and somatic symptoms, but the differences were only significant at week 12. The finding that co-infected patients appear less vulnerable to the development of depressive symptoms during HCV treatment than HCV mono-infected patients warrants further exploration, including a thorough analysis of the biological and psychosocial factors associated with this emergence.

Background & Aims Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have strongly improved treatment options since 2014, but it is unclear if treatment numbers have increased. We aimed to estimate the number of treatment regimens per month from 2010–2015 and the number of patients treated and cured with DAAs since 2014, as well as the associated costs. Methods Drug prescription data of hepatitis C virus (HCV) antivirals for patients with statutory health insurance in Germany (∼85% of population) from January 2010–December 2015 were evaluated. Standard 28-day prescriptions of pegylated interferon (PegIFN) and 1st/2nd generation DAAs were combined according to treatment guidelines and analysed. Drug costs were calculated from pharmacy sales prices. Mean treatment durations/regimen from real-world data were used to calculate drug costs/regimen and numbers of DAA-treated persons in 2014/15. Results From January 2010–December 2015 PegIFN/ribavirin-treatments/month decreased from ∼6500 to ∼650. Monthly HCV-prescriptions rose with the approval of 1st generation DAAs (2011), and decreased at the end of 2013. With the approval of 2nd generation DAAs, prescriptions/month increased (peak: ∼6600; March 2015), and subsequently decreased (∼4000; December 2015). In 2014, ∼7000 patients were treated with DAAs, and ∼20,100 in 2015. Treatment costs/month were stable at 12 million EUR (2010–2011), increased to ∼38 million EUR (March 2012), and peaked to 150 million EUR (March 2015). DAA-drug costs/year added up to ∼664million EUR (2014) and ∼1.3billion EUR (2015). Conclusions Despite an increase in DAA prescriptions, in December 2015 less persons/month were under treatment compared to January 2010, even though access to DAAs is not limited. However, yearly treatment numbers increased from 2014–2015. Under observed conditions, ∼18,000 patients/year can be cured, making substantial reduction of the estimated 160,000 diagnosed patients realizable. Political commitment to achieve further reduce DAA-prices and increase treatment numbers is recommended. Lay summary New treatment options with all-oral second generation direct-acting antivirals (DAAs) have resulted in the potential to cure chronic hepatitis C infection, but at high costs. Analyses from HCV drug prescription data of patients with statutory health insurance in Germany from 2010–2015, showed that DAAs replaced treatments with pegylated interferon and ribavirin, but accompanied by a disproportionate rise in costs. Although the monthly number of patients under treatment did not increase over time, the total number of patients yearly treated with DAAs increased from ∼7000 patients in 2014 to ∼20,100 in 2015, with a trend to shorter treatment regimens. Under observed conditions ∼18,000 patients can be cured yearly, making a substantial reduction of the estimated 160,000 diagnosed patients in Germany achievable.

Provide a brief summary of your article (100 to 150 words; no references or figures/tables). The synopsis appears only in the table of contents and is often used by indexing services such as PubMed Chronic viral hepatitis continues to be a global health threat and a financial burden. Hepatitis B and C viruses (HBV and HCV) are the most common causes of chronic viral hepatitis in the United States. The majority of cases are asymptomatic during childhood and young adulthood. Cirrhosis and hepatocellular carcinoma are rare during childhood but commonly expected in adulthood. Efforts from worldwide health organizations, pharmaceutical industries, and clinical and research institutions have resulted in much new knowledge, very effective therapy for HCV-infected children and the promise of new effective therapies for HBV-infected children. For HCV-infected children the current standard of care is pegylated interferon and ribavirin but clinical trials with highly effective direct acting antiviral agents are currently underway in the pediatric age group. There are currently 5 FDA-approved agents for HBV-infected children: alpha-interferon, lamivudine, adefovir, tenofovir, and entecavir. However treatment with these agents seldom results in a functional cure and more effective therapies are urgently needed

Immunocompromised patients are at risk of acquiring acute hepatitis E virus infection (HEV), leading to chronicity. Chronic HEV infection is associated with persistent viraemia, raised transaminase activity, histological features associated with chronic hepatitis and evidence of rapid development of cirrhosis. Extrahepatic manifestations have been associated with HEV. Most frequently reported are neurological disorders with predominantly involvement of the peripheral nervous system. In patients using immunosuppressive drugs antibody production is often delayed and HEV RNA detection is superior to serology to detect infection. Therapeutic options for chronic HEV includes tapering immunosuppressive and secondly ribavirin, pegylated interferon alpha (PEG-IFN). Present recommendation is to treat chronic HEV patients for 3 months, asses serum HEV RNA and stool HEV RNA and stop therapy if both are undetectable. Studies are required to determine which other antiviral agents than ribavirin and (PEG-)IFN are of clinical utility in treating HEV in the minority of patients who do not respond to ribavirin.

Summary Background Pegylated interferon alfa-2a is an immunomodulatory agent used to treat polycythemia vera. The durability of responses and long-term safety of this drug in patients with polycythaemia vera and essential thrombocythaemia have not been reported. Here, we present long-term efficacy and safety data from a single-centre, open-label, phase 2 trial, after a median of 83 months follow up. Methods Patients older than 18 years who were diagnosed with essential thrombocythaemia or polycythaemia vera according to 2001 WHO criteria were eligible to enrol in our study. The initial starting dose of pegylated interferon alfa-2a was 450 μg subcutaneously once per week, but was decreased in a stepwise manner due to toxic effects to a final starting dose of 90 μg per week: three patients were started at a dose of 450 μg per week, three at 360 μg per week, 19 at 270 μg per week, 26 at 180 μg per week, and 32 at 90 μg per week. Treatment was continued for as long as the patients derived clinical benefit with reductions in dose and frequency of administration allowed at the discretion of the treating physician. Haematological responses were assessed every 3–6 months on the basis of blood counts as defined by the European LeukemiaNet critieria. The primary endpoint of the initial study was the proportion of patients with a haematological response. Complete haematological response was defined as normalisation of blood counts (for patients with essential thrombocythaemia, platelets ≤440 × 10 9 per L; for patients with polycythaemia vera, haemoglobin Findings Between May 21, 2005, and Dec 1, 2015, patients were followed up for a median of 83 months (IQR 69–94 months). Pegylated interferon alfa-2a induced haematological (66 [80%] of 83 patients) and molecular responses (35 [63%] of 55 patients) in 40 patients with essential thrombocythaemia and 43 patients with polycythaemia vera, with median durations of 66 months (IQR 35–83) and 53 months (24–70), respectively. 26 (39%) of 66 haematological responders and 25 (71%) of 35 molecular responders (with the JAK2 Val617Phe mutation) have maintained some response during follow-up: 49% maintained their best molecular response (nine of ten patients who had a complete response, five of 20 who had a partial response, and three of five who had a minor response). The incidence of major venous-thrombotic events during the study was 1·22 per 100 person-years. Overall, 18 (22%) of 83 patients discontinued therapy due to treatment-related toxicity. Although toxicity rates decreased over time, five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy. 32 patients are still enrolled on the study. Interpretation Pegylated interferon alfa-2a can induce durable haematological and molecular responses in patients with essential thrombocythaemia and polycythaemia vera. This drug alone and in combination with other drugs could be explored further in clinical trials. Funding US National Cancer Institute.

Purpose To report a case of a temporal artery biopsy negative anterior ischemic optic neuropathy associated with a recently completed course of pegylated interferon 2 α with ribavirin for chronic hepatitis C. Observations Despite the early presentation with symptoms and prompt treatment with systemic intravenous steroids the patient experienced deterioration of their optic neuropathy over the following few days. Although nonarteritic anterior ischemic optic neuropathy is a common disorder with known risk factors, the timing of onset of symptoms in our patient was suggestive of a possible etiology related to treatment with ribavirin and interferon 2 α, as found in the previously reported cases. Conclusions and importance There have been a few reported cases of the association between the use of interferon/ribavirin for treatment of chronic hepatitis with nonarteritic anterior ischemic optic neuropathy. In these cases stopping the drug caused some improvement of symptoms or halting the progression of optic neuropathy. Having reviewed the literature on previous cases, we postulate that there may be a dose related reaction to explain the delay and deterioration of vision in some cases despite stopping the drugs. We also advise that any person who is started on this treatment for chronic hepatitis are appropriately counselled as to the potential optic nerve side effect of the drug, based on the evidence reported in the literature.

Polycythemia vera, essential thrombocytosis, and myelofibrosis are chronic Philadelphia-negative myeloproliferative neoplasms that are characterized by clonal hematopoiesis, splenomegaly, risk of hemorrhagic and thrombotic sequelae, and profound symptom burden. We review the outcomes of 75 myeloproliferative neoplasm patients treated with pegylated interferon alpha 2a off study at an academic medical center. In the 56 treated polycythemia vera and essential thrombocytosis patients, a complete or partial response was obtained in 78.6% of patients per ELN/IWG-MRT revised criteria, with >80% of polycythemia vera patients becoming phlebotomy independent and 60% of essential thrombocytosis patients having platelet normalization with therapy. In the 19 treated myelofibrosis patients, stable disease was seen in 63.2% of patients. Vascular events occurred in 2/75 (2.6%) of treated patients while on therapy. Grade 3 toxicity was uncommon with leukopenia noted in 1 patient (1.3%). The most common adverse event overall was grade 1 fatigue in 18.7%. This retrospective single center analysis demonstrates pegylated interferon alpha 2a is active and well-tolerated therapy outside the support of a clinical trial. These results substantiate the previously reported efficacy of pegylated interferon alpha 2a in myeloproliferative neoplasms. Further prospective and randomized clinical trial data is required to better delineate pegylated interferon alpha 2a's use in myeloproliferative disease, with emphasis placed on comprehensive molecular characterization, allelic burden quantification, and measurement of histologic response.

Acute severe recurrence of hepatitis C virus (HCV) after solid organ transplant is associated with high mortality. Pegylated interferon and ribavirin are suboptimal in treatment of this severe form of recurrence. We report 4 cases of acute severe HCV recurrence (within 6 months after transplant), including 3 cases with fibrosing cholestatic hepatitis treated with sofosbuvir and ribavirin. All four patients achieved a rapid suppression of HCV RNA with a normalization of liver function tests within 4 weeks of starting therapy. All patients were HCV RNA negative at 12 weeks after stopping therapy. The combination was found to be safe as anemia was the only adverse effect, which developed in 2 patients (1 patient required blood transfusion, while another managed with erythropoietin). Sofosbuvir and ribavirin appear to be safe and efficacious in treatment of acute severe HCV recurrence after organ transplant.

It is suggested that interleukin 10 (IL-10), as a modulator of immune response, is likely to influence the elimination of hepatitis C virus (HCV), the progression of chronic hepatitis C (CHC) and the response to interferon-based therapy in CHC patients. The aim of the study was to analyze the association of single nucleotide polymorphisms (SNPs) of IL-10 gene with severity of liver disease (degree of inflammation and stage of fibrosis) and outcome of pegylated interferon alpha and ribavirin combined therapy (sustained virological response (SVR) and relapse) in 196 Polish CHC patients infected with HCV genotype 1. The analysis included IL-10 promoter SNPs: -1082(A/G) rs1800896, -819(C/T) rs1800871, -592(C/A) rs1800872 and SNP in the 3' UTR of IL-10 gene: +4529(A/G) rs3024498. Genotyping was performed using PCR-RFLP and HRM analysis. It was demonstrated that the -592C allele is associated with mild hepatic inflammation. Moreover, it was found that the -819C allele might be associated with SVR and that the ACCA haplotype and intermediate IL-10 producer ACC haplotype are associated with SVR and non-relapse. It can be concluded that IL-10 SNPs are associated with severity of disease and response to therapy and may be considered as potential prognostic and predictive markers in CHC.

In the past 10years, there has been a lot of enthusiasm surrounding the use of serum hepatitis B surface antigen (HBsAg) quantification to predict disease activity and monitor treatment response in chronic hepatitis B. The measurement of HBsAg levels have been standardized in IU/ml, and nowadays it is almost a mandatory measurement due to the development of new antiviral treatments aiming at HBsAg seroclearance, i.e., functional cure of hepatitis B. Recently, there has been an improved understanding of the molecular virology of HBsAg, and particularly the relative roles of covalently closed circular DNA and integrated hepatitis B virus (HBV) DNA. This has shed new light on the interpretation of HBsAg levels in different phases of chronic hepatitis B. HBsAg level can assist the differentiation of immune tolerance and immune clearance in hepatitis B e antigen (HBeAg)-positive patients, and it can predict inactive disease and spontaneous HBsAg seroclearance in HBeAg-negative patients. The determination of HBsAg level is pivotal to individualize pegylated interferon (PegIFN) treatment; it is the key investigation to decide early termination of PegIFN among non-responders. Among patients treated by nucleos(t)ide analogues, responders tend to have dramatic reduction of HBsAg to low levels, which may be followed by HBsAg seroclearance. With newer data on combination treatment of PegIFN and nucleos(t)ide analogues as well as emerging new antiviral agents, HBsAg quantification is expected to become increasingly important to monitor and guide antiviral therapy for chronic hepatitis B.

Background and aims: Pegylated interferon (Peg-INF) and ribavirin (RBV) based therapy is suboptimal and poorly tolerated. We evaluated the safety, tolerability and efficacy of a 24-week course of sofosbuvir plus daclatasvir without ribavirin for the treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) in both HCV-monoinfected and human immunodeficiency virus (HIV)-HCV coinfected patients. Material and Methods: We retrospectively evaluated 22 consecutive adult LT recipients (16 mo-noinfected and 6 coinfected with HIV) who received a 24-week course of sofosbuvir plus daclatasvir treatment under an international compassionate access program. Results: Most patients were male (86%), with a median age of 58 years (r:58-81y). Median time from LT to treatment onset was 70 months (r: 20-116 m). HCV genotype 1b was the most frequent (45%), 55% had not responded to previous treatment with Peg-INF and RBV and 14% to regiments including first generation protease inhibitors. Fifty-six percent of the patients had histologically proven cirrhosis and 6 had ascites at baseline. All patients completed the 24-week treatment course without significant side effects except for one episode of severe bradicardya, with only minor adjustments in immunosuppressive treatment in some cases. Viral suppression was very rapid with undetectable HCV-RNA in all patients at 12 weeks. All 22 patients achieved a sustained virological response 12 weeks after treatment completion. Conclusion: The combination of sofosbuvir plus daclatasvir without ribavirin is a safe and effective treatment of HCV recurrence after LT in both monoinfected and HIV-coinfected patients, including those with decompensated cirrhosis.