Interferon-based Therapy Research Articles

Relationships Between Vitamin D Status and Cytokine: Results from Interferon-Based Therapy in Non-Cirrhotic, Treatment-Naïve Patients with Chronic Hepatitis C Infection.

BackgroundVitamin D contributes to bone health and extra-skeletal effects. The mechanisms underlying vitamin D metabolism have not been extensively evaluated. The relationships between vitamin D and inflammatory cytokines are debated. Our objective was to investigate whether supplemental interferons are associated with longitudinal change of vitamin D status in humans.MethodsA total of 48 patients with 24 or 48 weeks of pegylated interferon-α plus ribavirin therapy were examined for serum 25-hydroxyvitamin D (25[OH]D) level before treatment, at the end of treatment, and 24 weeks after treatment. In addition, we analyzed publicly available RNA sequencing data from accession GSE42697 and GSE7123 in the Gene Expression Omnibus.FindingsThe overall sustained virologic response (SVR) rate was 62.5%. There was no statistically significant association between baseline 25(OH)D concentrations and liver fibrosis. In patients with SVR, serum 25(OH)D increased markedly at end-of-treatment and decreased markedly by the end of the 24-week follow-up period. In the non-SVR group, this treatment-dependent change was lost. In gene expression analysis, the vitamin D biosynthesis process was activated in subjects with SVR, but not in patients without SVR. Furthermore, vitamin D receptor (VDR) signaling in peripheral blood mononuclear cells (PBMCs) was triggered in marked responders but not in poor responders.ConclusionIn the aggregate, these data suggest that interferons have a regulatory influence on vitamin D status that can contribute to VDR signaling in PBMCs.

Interferon-Free Anti-HCV Therapy Has a Better Treatment Response Rate and Adherence Than Interferon-Based Therapy for Patients With HCV/HIV Coinfection: A Single-Center Retrospective Study

In the last decade, the standard treatment for hepatitis C virus (HCV)-infected patients has been pegylated interferon (IFN) and daily ribavirin from 24 to 48 weeks. Many patients are unable to tolerate the treatment, or have other contraindications, especially in difficult-to-treat populations such as HCV/human immunodeficiency virus (HIV) co-infected patients. The introduction of IFN-free anti-HCV therapy has resulted in a better therapeutic response with fewer side effects and is significantly beneficial to such patients. In the present study, we aimed to compare the clinical impact of IFN-free therapy in this difficult-to-treat patient population in real-world practice. We conducted a retrospective study from November 2007 to June 2019 involving 50 HCV- and HIV-infected patients who received anti-HCV therapy in our institution. Clinical features and treatment responses were analyzed. The mean patient age was 43.3 years, and 86% were male. Twenty percent of the patients had cirrhosis. The most prevalent HCV genotype was type 1 (54%), followed by type 6 (20%), type 3 (14%), and others (12%). The overall sustained virologic response (SVR) rate was 84% in this cohort. The patients in the direct-acting antiviral agent (DAA) treatment group were older on average, and a higher proportion had cirrhosis. The patients undergoing DAA-based treatment had a higher SVR rate than those receiving IFN-based therapy (96% vs. 68%, p = 0.016). Two patients in each group demonstrated virological non-response to treatment. A high discontinuation rate was noted in the IFN-based group (27% vs. 0%, p = 0.0035) as compared with the DAA group. IFN-free therapy is associated with a significantly higher treatment response rate and better adherence than IFN-based therapy.

Comparison of liver disease state progression in patients with eradication of versus persistent infection with hepatitis C virus: Markov chain analysis.

To investigate the long-term prognosis of liver disease in patients with hepatitis C virus (HCV) eradication after antiviral therapy versus those with persistent HCV infection. Four hundred and eighty patients (5259 person-years [PYs]) who received interferon-based therapy and achieved sustained virologic response and 848 patients (3853 PYs) with persistent HCV infection were included. In the analysis of 1-year liver disease state transition probability matrices using Markov chain models, progression to cirrhosis from the chronic hepatitis state was observed (0.00%-0.63%) in patients with HCV eradication. Among patients with chronic hepatitis or cirrhosis and HCV eradication, hepatocellular carcinoma (HCC) development was observed in males aged≥50years (0.97%-1.96%) and females aged≥60years (0.26%-5.00%). Additionally, in patients with cirrhosis and HCV eradication, improvement to chronic hepatitis was also observed (4.94%-10.64%). Conversely, in patients with chronic hepatitis and persistent HCV infection, progression to cirrhosis was observed in males aged≥30years and female aged≥40years (0.44%-1.99%). In males aged≥40years and female aged≥50years with cirrhosis, the transition probability for HCC was relatively high (4.17%-14.02%). Under the assumption of either chronic hepatitis or cirrhosis at age 40 or 60years as the starting condition for simulation over the next 30 or 40years, respectively, the probability of HCC was higher in patients with persistent HCV infection than those with HCV eradication. In conclusion, HCV eradication can reduce the risk of developing cirrhosis or HCC in patients with chronic HCV infection.

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.

Risk of Non-Hodgkin's Lymphoma in HCV Patients in the United States between 2013 and 2020: A Population-Based Study

Introduction Hepatitis C virus (HCV) is a major healthcare problem affecting ~ 1% of the United States population. HCV virus is known to have lymphotropic properties and metanalyses of epidemiological studies reported an association between HCV and non-Hodgkin's lymphoma (NHL) with a relative risk range (1.8 to 10.8). 1-4 Most studies included in these metanalyses were heterogenic with different control groups, and contained a relatively small number of patients that prevented the evaluation of racial differences or the association of HCV with distinct NHL subtypes. We conducted a population-based study to address these deficiencies and to explore if the prevalence of NHL has changed since older therapy of HCV based on interferon that shared both anti-viral and anti-lymphoma properties was replaced with the interferon-free direct-acting antivirals (DAA). Methods We reviewed data from a nationwide commercial database (Explorys, IBM) that aggregates records from 26 health-care-systems and includes 72 million patients. We identified adult patients aged ≥ 40 years with HCV between June 2013 and June 2020. The control population was HCV-negative matched for gender, race; Caucasian, and African-American, and two age groups; 40-64 years and ≥ 65 years. We excluded all patients who developed NHL before the study start date and patients with HIV. The association between NHL and HCV was evaluated using odds ratios (OR) with a 95% confidence interval. The differences were considered significant at a P value of less than 0.001. Results There were 940 cases of NHL among 129970 HCV individuals versus 107480 cases of NHL out of 37961970 persons in the control cohort [OR 2.6, 95% confidence interval (CI) 2.4-2.7]. A positive association was present in chronic lymphocytic leukemia (OR 1.4, 95% CI 1.2-1.6), follicular lymphoma (OR 2.7, 95% CI 2.2-3.4), marginal zone lymphoma (OR 5.2, 95% CI 3.8- 7.1), lymphoplasmacytic lymphoma (OR 2.6, 95% CI 1.8-3.8), diffuse large B-cell lymphoma (OR 4.4, 95% CI 3.4 - 5.6), Burkitt's lymphoma (OR 4.2, 95% CI 2.9-6.0), non-Hodgkin's T-cell lymphoma (OR 2.5, 95% CI 2.1-3.0) and primary cutaneous T-cell lymphoma (OR 2.8, 95% CI 1.9-3.3). There was no difference in Mantle cell lymphoma (see Figure 1, and Table 1). The increased risk of HCV-associated lymphoma was persistent when adjusted for gender, Caucasian and African-American races, and in age groups of 40-64 years and > 65 years (see Table 2). While in the control population, Caucasians had a higher risk of NHL compared to African-Americans (OR 1.8, 95% CI 1.75-1.84), there was no difference in HCV-associated lymphoma (see Tables 3 and 4). Discussion: Our study is the largest of population-based studies evaluating the risk of non-Hodgkin's lymphoma in patients with HCV. The Risk of HCV-associated NHL was higher with an OR of 2.6 compared to older studies in the US published before DAA therapy was available reporting an OR close to 1.5.5,6 The observation of increased risk of chronic lymphocytic leukemia, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, and diffuse large B-cell lymphoma was comparable with the prior meta-analysis. 1-4 However, we found an increased risk in Burkitt's lymphoma, non-Hodgkin's T-cell lymphoma and primary cutaneous T-cell lymphoma. Possible pathophysiology of HCV-associated lymphomagenesis is shown in Figure 2. Interestingly, while the risk of NHL lymphoma in HCV-negative Caucasians was higher than African-Americans in keeping with US-based epidemiologic studies.7 A novel finding of our study found was the lack of difference in HCV-associated lymphoma between Caucasians and African-Americans. Reason for possible increased oncogenicity of HCV in African-Americans is unclear. Limitations of the databased based project include inaccuracies and miscoding. Given the nature of the data it was not possible to study differences between patients who received interferon-based therapy versus DAA. In conclusion, despite recent advances in HCV treatment, the risk of NHL among HCV infected patients remains elevated and it was persistent in males and females. In contrast to non-HCV background population where Caucasians had a higher prevalence of NHL, there was no difference between Caucasians and African-Americans. An effort to early detect and treat HCV is needed along with establishing prospective studies to examine the impact of HCV therapy with DAA on NHL risk. Figure Disclosures No relevant conflicts of interest to declare.

Real-World Virological Efficacy and Safety of Ledipasvir and Sofosbuvir in Patients with Chronic Hepatitis C Virus Genotype 2 Infection: A Multicenter Study.

IntroductionThe real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2.MethodsA total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment.ResultsThe overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2–92.6) (110/126) and 97.3% (95% CI 92.4–99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5–96.9) (105/113), 99.1% (95% CI 95.2–100.0) (112/113), and 100.0% (95% CI 97.4–100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment.ConclusionThe LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection.Trial RegistrationUMIN registration no. 000038604.

Impact of direct-acting antiviral agents on liver function in patients with chronic hepatitis C virus infection.

Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan=99%, UK=78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.

Hepatocellular carcinoma risk with antivirals for chronic hepatitis B: no longer confounding

The risk of hepatocellular carcinoma associated with antiviral therapies has been a source of great controversy in clinical hepatology over the past few years. Initially an increased risk of hepatocellular carcinoma was proposed with direct-acting antiviral therapy for chronic hepatitis C virus (HCV) infection compared with interferon-based therapy. The original—epidemiologically flawed—study from Spain1 led to considerable concern among clinicians, and presumably patients, and was followed by a plethora of studies and meta-analyses.

The Economic Value of Improved Productivity from Treatment of Chronic Hepatitis C Virus Infection: A Retrospective Analysis of Earnings, Work Loss, and Health Insurance Data.

IntroductionPatients with chronic hepatitis C virus infection (HCV) may incur significant indirect costs due to health-related work loss. However, the impact of curative HCV therapy on work productivity is not well characterized. We estimated the economic value of improved productivity following HCV treatment.MethodsAdults diagnosed with HCV infection (Optum Healthcare Solutions data; Q1 1999 to Q1 2017) were stratified into two cohorts: (1) treated cohort, patients who received HCV therapy and (2) untreated cohort, therapy-naïve patients. For the treated cohort, the index date was set at the end of the post-treatment monitoring period, assumed to be 6 months after the end of treatment for patients with cirrhosis or for those treated with interferon-based therapy, and 3 months after the end of treatment for patients without cirrhosis who received interferon-free therapy. For the untreated cohort, an index date was randomly selected post-HCV diagnosis. Time from the index date to the first work-loss event was assessed using time to event analyses. An economic modeling approach was used to monetize the improved productivity from reduced risk of work-loss event in the 4 years post-index.ResultsPatients in the treated cohort had a lower risk of experiencing a work-loss event compared to untreated patients [unadjusted and adjusted hazard ratios and 95% CI 0.72 (0.61–0.86), and 0.68 (0.55–0.85), respectively; p < 0.001 for both]. The mean cumulative added productivity value associated with HCV treatment was US$4511 (CI $2778–$6278) at 1 year post-index and $21,429 (CI $12,733–$30,199) at 4 years post-index.ConclusionHCV treatment reduces the risk of work loss resulting in productivity gains for employers and employees. The monetary value associated with these productivity gains is substantial, and, after about 4 years, it is comparable to the wholesale acquisition cost of some direct-acting antiviral regimens in the United States. Employers may derive economic benefits from adopting HCV elimination strategies.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01492-x) contains supplementary material, which is available to authorized users.

The direct-medical costs associated with interferon-based treatment for Hepatitis C in Vietnam.

Background: Injectable interferon-based therapies have been used to treat hepatitis C virus (HCV) infection since 1991. International guidelines have now moved away from interferon-based therapy towards direct-acting antiviral (DAA) tablet regimens, because of their superior efficacy, excellent side-effect profiles, and ease of administration. Initially DAA drugs were prohibitively expensive for most healthcare systems. Access is now improving through the procurement of low-cost, generic DAAs acquired through voluntary licenses. However, HCV treatment costs vary widely, and many countries are struggling with DAA treatment scale-up. This is not helped by the limited cost data and economic evaluations from low- and middle-income countries to support HCV policy decisions. We conducted a detailed analysis of the costs of treating chronic HCV infection with interferon-based therapy in Vietnam. Understanding these costs is important for performing necessary economic evaluations of novel treatment strategies. Methods: We conducted an analysis of the direct medical costs of treating HCV infection with interferon alpha (IFN) and pegylated-interferon alpha (Peg-IFN), in combination with ribavirin, from the health sector perspective at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, in 2017. Results: The total cost of the IFN treatment regimen was estimated to range between US$1,120 and US$1,962. The total cost of the Peg-IFN treatment regimen was between US$2,156 and US$5,887. Drug expenses were the biggest contributor to the total treatment cost (54-89%) and were much higher for the Peg-IFN regimen. Conclusions: We found that treating HCV with IFN or Peg-IFN resulted in significant direct medical costs. Of concern, we found that all patients incurred substantial out-of-pocket costs, including those receiving the maximum level of support from the national health insurance programme. This cost data highlights the potential savings and importance of increased access to generic DAAs in low- and middle-income countries and will be useful within future economic evaluations.

Supportive Interventions During Treatment of Chronic Hepatitis C: A Review of the Literature.

There are an estimated 3 million people living with chronic hepatitis C, yet many have limited access to healthcare and treatment due to a variety of behavioral/lifestyle determinants of health. The aim of this literature review was to examine care models and innovations for people successfully treated from 2011 to 2018. We searched PubMed, PsycINFO, and CINAHL to identify care models for people undergoing treatment of chronic hepatitis C. Ten articles met criteria for inclusion and included multiple types of care models, including nurse initiated (n = 2), telemedicine care (n = 3), group visit (n = 1), concurrent treatment (n = 1), community health center care (n = 1), and integrated care (n = 2). Eight of the studies focused on people with mental health challenges and/or substance use disorder. Sustained virological response was the primary outcome of all studies; adherence was a secondary outcome measured in 8 studies.This search occurred during a period where treatment moved from interferon-based therapy to all-oral direct-acting antiviral medications, representing a paradigm shift in treatment of chronic hepatitis C. As new treatments offer cure for up to 95% of patients, these studies provided strong evidence of benefit for innovative care models for patients with mental health and substance use disorder to complete treatment.

The direct-medical costs associated with interferon-based treatment for Hepatitis C in Vietnam

Background: Injectable interferon-based therapies have been used to treat hepatitis C virus (HCV) infection since 1991. International guidelines have now moved away from interferon-based therapy towards direct-acting antiviral (DAA) tablet regimens, because of their superior efficacy, excellent side-effect profiles, and ease of administration. Initially DAA drugs were prohibitively expensive for most healthcare systems. Access is now improving through the procurement of low-cost, generic DAAs acquired through voluntary licenses. However, HCV treatment costs vary widely, and many countries are struggling with DAA treatment scale-up. This is not helped by the limited cost data and economic evaluations from low- and middle-income countries to support HCV policy decisions. We conducted a detailed analysis of the costs of treating chronic HCV infection with interferon-based therapy in Vietnam. Understanding these costs is important for performing necessary economic evaluations of novel treatment strategies. Methods: We conducted an analysis of the direct medical costs of treating HCV infection with interferon alpha (IFN) and pegylated-interferon alpha (Peg-IFN), in combination with ribavirin, from the health sector perspective at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, in 2017. Results: The total cost of the IFN treatment regimen was estimated to range between US$1,120 and US$1,962. The total cost of the Peg-IFN treatment regimen was between US$2,156 and US$5,887. Drug expenses were the biggest contributor to the total treatment cost (54-89%) and were much higher for the Peg-IFN regimen. Conclusions: We found that treating HCV with IFN or Peg-IFN resulted in significant direct medical costs. Of concern, we found that all patients incurred substantial out-of-pocket costs, including those receiving the maximum level of support from the national health insurance programme. This cost data highlights the potential savings and importance of increased access to generic DAAs in low- and middle-income countries and will be useful within future economic evaluations.

Screening for Hepatitis C Virus Infection in Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Importance A 2013 review for the US Preventive Services Task Force (USPSTF) of hepatitis C virus (HCV) screening found interferon-based antiviral therapy associated with increased likelihood of sustained virologic response (SVR) and an association between achieving an SVR and improved clinical outcomes. New direct-acting antiviral (DAA) regimens are available. Objective To update the 2013 review on HCV screening to inform the USPSTF. Data Sources Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews through February 2019, with surveillance through September 2019. Study Selection Randomized clinical trials (RCTs) and nonrandomized treatment studies of HCV screening and DAA therapy; cohort studies on screening, antiviral therapy, and the association between an SVR after antiviral therapy and clinical outcomes. Data Extraction and Synthesis One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Main Outcomes and Measures Mortality, morbidity, quality of life, screening and treatment harms, and screening diagnostic yield. Results Eight RCTs of DAA therapy vs placebo or an outdated antiviral regimen, 48 other treatment studies, and 33 cohort studies, with a total of 179 230 participants, were included. No study evaluated effects of HCV screening vs no screening. One new study since the 2013 review (n = 5917) found similar diagnostic yield of risk-based screening (sensitivity, 82%; number needed to screen to identify 1 HCV case, 15) and birth cohort screening (sensitivity, 76%; number needed to screen, 29), assuming perfect implementation. Ten open-label studies (n = 3292) reported small improvements in some quality-of-life and functional outcomes (eg, less than 3 points on the 0 to 100 36-Item Short Form Health Survey physical and mental component summary scales) after DAA treatment compared with before treatment. Two cohort studies (n = 24 686) found inconsistent associations of antiviral therapy vs no therapy with risk of hepatocellular carcinoma. Forty-nine treatment studies (n = 10 181) found DAA regimens associated with pooled SVR rates greater than 95% across genotypes, and low short-term rates of serious adverse events (1.9%) and withdrawal due to adverse events (0.4%). An SVR after antiviral therapy was associated with decreased adjusted risk of all-cause mortality (13 studies, n = 36 986; pooled hazard ratio [HR], 0.40 [95% CI, 0.28-0.56) and hepatocellular carcinoma (20 studies, n = 84 491; pooled HR, 0.29 [95% CI, 0.23 to 0.38]) vs no SVR. Conclusions and Relevance Direct evidence on the effects of HCV screening on clinical outcomes remains unavailable, but DAA regimens were associated with SVR rates greater than 95% and few short-term harms relative to older antiviral therapies. An SVR after antiviral therapy was associated with improved clinical outcomes compared with no SVR.

Long-term prognosis of liver disease in patients with eradicated chronic hepatitis C virus: An analysis using a Markov chain model.

The long-term prognosis of patients with chronic hepatitis C virus (HCV) infection who have received antiviral therapy and who demonstrate HCV eradication remains incompletely characterized. In this study, we investigated the long-term prognosis of liver disease in patients with eradication of HCV. A total of 552 patients with chronic HCV infection (6815 person-years) who were treated with interferon-based therapy and who achieved sustained virologic response were included. Yearly transition probabilities for each liver state (chronic hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]) were calculated using a Markov chain model. In the analysis of 1-year liver disease state transition probabilities, progression to cirrhosis occurred in 0.5-2.1% of male patients with chronic hepatitis across all age groups. In male patients with cirrhosis, HCC developed in 0.6-1.9% of patients over the age of 50years. In female patients with chronic hepatitis, progression to cirrhosis occurred in 0.4-2.1% of patients across all age groups. In addition, in female patients with cirrhosis, HCC developed in those aged 60-69 (0.4%) and 70-79 (0.4%) years. Under the assumption of either a chronic hepatitis or cirrhosis state at age 40 or 60years as the starting condition for simulation over the next 40 or 20years, respectively, the probability of HCC gradually increased with age and was higher in male patients. The development or progression of cirrhosis and the development of HCC are risks in HCV patients despite HCV eradication, not only in those with cirrhosis but also in those with chronic hepatitis.

Interactions between Immunosuppressive Therapy and Direct-Acting Antivirals in Kidney Transplant Recipient with Hepatitis C Infection

Hepatitis C virus (HCV) causes increased mortality and morbidity in kidney transplant patients. Interferon-based therapies are poorly tolerated and involve the risk of rejection. The new direct-acting antiviral drugs (DAAs) have revolutionized the treatment of HCV infection in transplant patients. This observational study evaluates changes in immunosuppressive therapy during treatment with DAA in renal transplant recipients.In our transplant center, we selected seven HCV-positive patients at the time of transplantation , four men and three women, with an average age of 61 ± 7 years, in therapy with DAA. The dose and the blood levels of the immunosuppressive drugs were evaluated at the beginning and end of antiviral therapy, together with creatinine and proteinuria.Viremia was negativized in all patients within the initial 8 weeks of therapy. Currently, the number of patients is too limited to perform a sta-tistical analysis and obtain significant results. In one patient, the dose of Cyclosporine was lowered to 10 mg, while for the remaining patients it was not necessary to change the dose of immunosuppressive drugs.DAAs give encouraging results in the eradication of HCV in renal transplant recipients, although they are associated with potential adverse drug interactions. The preliminary data of our study suggest that it is not necessary to change the dose of immunosuppressive drugs during therapy and that creatinine and proteinuria remain stationary. We will achieve more significant results in the future, adding more patients to our study. However, further randomized trials are necessary to confirm the safety of DAAs.

Comparison of Recommendations for Treatment of Chronic Hepatitis C Virus Infection in Children and Adolescents: A Position Paper of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition.

This position paper written by the Hepatitis Expert Team of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition aimed to systematically evaluate clinical practice guidelines (CPGs), medical consensus, and position papers on the use of direct-acting antivirals (DAA) to treat chronic hepatitis C virus (HCV) infection in adolescents and children in order to compare recommendations and provide the basis for developing a unified position statement. MEDLINE, Cochrane-Library, National Guideline Clearinghouse and select websites of relevant societies/organizations were used to identify CPGs, medical consensus and position papers between 2011-2019. A total of 5 documents were analysed: 3 CPGs, 1 medical consensus, and 1 position paper. All publications were consistent in recommending DAA treatment for adolescents (12-17 years old) with chronic HCV infection. Similarly, all of these publications consistently recommended deferring therapy for children between 3 and 11 years of age until DAA became available as standard of care. Finally, none of the included publications recommended treating children younger than 3 years old. By contrast, there was significant discrepancy across the retrieved documents regarding specific DAA regimens and treatment strategies. There is strong consensus on treating all adolescents with chronic HCV infection with DAA and on delaying therapy in younger children until these agents are approved for them. Interferon-based therapies should be avoided. Specific recommendations regarding which DAA regimen to use and treatment duration varied significantly. Key stakeholders need to convene to standardize therapeutic strategies at a global level if we are to eradicate HCV in children.

HIV antibodies level as a marker of HIV persistence: the role of hepatitis C virus coinfection.

Human immunodeficiency virus (HIV) antibodies have been proposed as a measure of the size of the HIV reservoir. The aim of our study is to quantify the anti-HIV antibodies level in a cohort of people living with HIV (PLWH), stratified based on the presence of continuous undetectable HIV viral load and the co-existence of hepatitis C virus infection. A sample of 229 HIV-monoinfected (n = 114) or HIV/HCV-coinfected [either with resolved HCV infection (n = 75) or active HCV coinfection (n = 40)] patients, followed up a median of 34 (IQR 20-44) months, was studied. Anti-HIV index was obtained as the 1:800 dilution of HIV antibodies. CD4+ T cell count, time with undetectable HIV viral load, annual increase of CD4+ T cell count, anti-HCV therapy, and diagnosis of cirrhosis were analyzed. Patients with a continued suppressed HIV viral load had significant lower anti-HIV index compared with those with virologic failure during the follow-up. Significant higher CD4+ T cell increase was observed in those with a lower anti-HIV index. HIV-monoinfected patients showed an anti-HIV index significantly lower than patients with HCV coinfection. Resolved HCV infection after interferon-based therapy, but not with direct acting antivirals, was associated with a lower anti-HIV index. HIV/HCV-coinfected patients showed higher HIV antibodies level when compared with HIV-monoinfected individuals. A decrease in anti-HIV index in HIV/HCV-coinfected patients was detected when a sustained virological HCV response was obtained after interferon-based therapy, in possible relation with the direct or indirect effect of interferon on PLWH CD4 T cells.

Extrahepatic Malignancy Among Patients With Chronic Hepatitis C After Antiviral Therapy: A Real-World Nationwide Study on Taiwanese Chronic Hepatitis C Cohort (T-COACH).

Chronic hepatitis C virus (HCV) infection is associated with nonhepatocellular carcinoma malignancies. We aimed to evaluate whether achieving a sustained virological response (SVR, defined as HCV RNA seronegativity throughout posttreatment 24-week follow-up) could reduce the risk of non-hepatocellular carcinoma malignancy in a real-world nationwide Taiwanese Chronic Hepatitis C Cohort (T-COACH). A total of 10,714 patients with chronic hepatitis C who had received interferon-based therapy (8,186 SVR and 2,528 non-SVR) enrolled in T-COACH and were linked to the National Cancer Registry database for the development of 12 extrahepatic malignancies, including those with potential associations with HCV and with the top-ranking incidence in Taiwan, over a median follow-up period was 3.79 years (range, 0-16.44 years). During the 44,354 person-years of follow-up, 324 (3.02%) patients developed extrahepatic malignancies, without a difference between patients with and without SVR (annual incidence: 0.69% vs 0.87%, respectively). Compared with patients with SVR, patients without SVR had a significantly higher risk of gastric cancer (0.10% vs 0.03% per person-year, P = 0.004) and non-Hodgkin lymphoma (NHL) (0.08% vs 0.03% per person-year, respectively, P = 0.03). When considering death as a competing risk, non-SVR was independently associated with gastric cancer (hazard ratio [HR]/95% confidence intervals [CIs]: 3.29/1.37-7.93, P = 0.008). When patients were stratified by age, the effect of SVR in reducing gastric cancer (HR/CI: 0.30/0.11-0.83) and NHL (HR/CI: 0.28/0.09-0.85) was noted only in patients aged <65 years but not those aged >65 years. HCV eradication reduced the risk of gastric cancer and NHL, in particular among younger patients, indicating that patients with chronic hepatitis C should be treated as early as possible.

Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy - data from theGerman hepatitis C registry (DHC-R).

Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective.

Impact of HCV eradication with direct-acting antiviral agents on serum gamma globulin levels in HCV and HCV/HIV coinfected patients

Backgroundchronic viral infections by both HCV and HIV may lead to polyclonal activation of B cells resulting in hypergammaglobulinemia. This study retrospectively analyzed the effect of HCV eradication with interferon-free direct-acting antiviral agents (DAAs) on the gamma globulin levels in HCV-infected patients with or without HIV coinfection to identify factors potentially associated with gamma globulins decrease. MethodsThe charts of patients treated with DAAs for HCV chronic infection between January 2015-June 2019 were retrospectively reviewed. Gamma globulin levels before treatment and 12 weeks after the end of anti-HCV therapy were evaluated along with liver tests, liver fibrosis stage by elastography, SVR achievement, HIV-coinfection. Multivariate analyses were carried out to assess the factors and the potential confounders related to the changes in gamma globulin levels. ResultsA significant decrease of gamma globulin concentration was found in both cirrhotic and non-cirrhotic HCV-infected patients after treatment (from mean ± SD of 1.5 ± 0.44 g/dL to 1.31 ± 0.37 g/dL; p = 0.0001). Adjusted linear regression analyses of serum gamma globulin changes from baseline to SVR12 showed a positive significant association with pre-treatment gamma-globulin levels (β-coefficient −0.23; p = 0.0001), Metavir fibrosis score (β-coefficient -0.74; p = 0.008), ALT values and baseline HCV-RNA levels > 800,000. No difference was found between HIV-infected and HIV-uninfected patients. ConclusionsOur study confirms previous preliminary observation of the decrease of serum gamma globulins after HCV eradication either achieved with interferon-based therapy or with DAAs, suggesting a leading role of the virus on the activation of B cell compartment and gamma globulins production.