Direct-acting antivirals in women of reproductive age infected with hepatitis C virus.

Eliminating hepatitis C virus (HCV) infection in the population of women of reproductive age is important not only for the health of women themselves but also for the health of newborns. This study aimed to evaluate the implementation of this goal by analysing the effectiveness of contemporary therapy in a large cohort from everyday clinical practice along with identifying factors reducing therapeutic success. The analysed population consisted of 7861 patients, including 3388 women aged 15-49, treated in 2015-2022 in 26 hepatology centres. Data were collected retrospectively using a nationwide EpiTer-2 database. Females were significantly less often infected with HCV genotype 3 compared to males (11.2% vs. 15.7%) and less frequently showed comorbidities (40.5% vs. 44.2%) and comedications (37.2% vs. 45.2%). Hepatocellular carcinoma, liver transplantation, HIV and HBV coinfections were reported significantly less frequently in women. Regardless of the treatment type, females significantly more often reached sustained virologic response (98.8%) compared to males (96.8%). Regardless of gender, genotype 3 and cirrhosis were independent factors increasing the risk of treatment failure. Women more commonly reported adverse events, but death occurred significantly more frequently in men (0.3% vs. 0.1%), usually related to underlying advanced liver disease. We have demonstrated excellent effectiveness and safety profiles for treating HCV infection in women. This gives hope for the micro-elimination of HCV infections in women, translating into a reduced risk of severe disease in both women and their children.

The burden of infectious diseases throughout and after the COVID-19 pandemic (2020-2023) and Russo-Ukrainian war migration.

Understanding how the infectious disease burden was affected throughout the COVID-19 pandemic is pivotal to identifying potential hot spots and guiding future mitigation measures. Therefore, our study aimed to analyze the changes in the rate of new cases of Poland's most frequent infectious diseases during the entire COVID-19 pandemic and after the influx of war refugees from Ukraine. We performed a registry-based population-wide study in Poland to analyze the changes in the rate of 24 infectious disease cases from 2020 to 2023 and compared them to the prepandemic period (2016-2019). Data were collected from publicly archived datasets of the Epimeld database published by national epidemiological authority institutions. The rate of most of the studied diseases (66.6%) revealed significantly negative correlations with the rate of SARS-CoV-2 infections. For the majority of infectious diseases, it substantially decreased in 2020 (in case of 83%) and 2021 (63%), following which it mostly rebounded to the prepandemic levels and, in some cases, exceeded them in 2023 when the exceptionally high annual rates of new cases of scarlet fever, Streptococcus pneumoniae infections, HIV infections, syphilis, gonococcal infections, and tick-borne encephalitis were noted. The rate of Clostridioides difficile enterocolitis was two-fold higher than before the pandemic from 2021 onward. The rate of Legionnaires' disease in 2023 also exceeded the prepandemic threshold, although this was due to a local outbreak unrelated to lifted COVID-19 pandemic restrictions or migration of war refugees. The influx of war migrants from Ukraine could impact the epidemiology of sexually transmitted diseases. The present analysis indicates that continued efforts are needed to prevent COVID-19 from overwhelming healthcare systems again and decreasing the control over the burden of other infectious diseases. It also identifies the potential tipping points that require additional mitigation measures, which are also discussed in the paper, to avoid escalation in the future.

Deep-sequencing of viral genomes from a large and diverse cohort of treatment-naive HIV-infected persons shows associations between intrahost genetic diversity and viral load.

BACKGROUND: Infection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment. METHODS: We analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure. RESULTS: We confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-value<2.0x10-5) and Shannon entropy at AA positions which in our association analysis explained 13% of the variance in VL. Finally, equivalent analysis based on variation in HIV consensus sequences explained only 2% of VL variance. CONCLUSIONS: Our results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes. TRIAL REGISTRATION: Samples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site.

Cardiovascular risk and the COVID-19 pandemic: a population-based and case‒control studies.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is associated with increases in morbidity and mortality worldwide. The mechanisms of how SARS-CoV-2 may cause cardiovascular (CV) complications are under investigation. The aim of the study was to assess the impact of the COVID-19 pandemic on CV risk. METHODS: These are single-centre Bialystok PLUS (Poland) population-based and case‒control studies. The survey was conducted between 2018 and 2022 on a sample of residents (n = 1507) of a large city in central Europe and patients 6-9 months post-COVID-19 infection (n = 126). The Systematic Coronary Risk Estimation 2 (SCORE2), the Systematic Coronary Risk Estimation 2-Older Persons (SCORE2-OP), the Cardiovascular Disease Framingham Heart Study and the LIFEtime-perspective model for individualizing CardioVascular Disease prevention strategies in apparently healthy people (LIFE-CVD) were used. Subsequently, the study populations were divided into CV risk classes according to the 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. RESULTS: The study population consisted of 4 groups: a general population examined before (I, n = 691) and during the COVID-19 pandemic (II, n = 816); a group of 126 patients post-COVID-19 infection (III); and a control group matched subjects chosen from the pre-COVID-19 pandemic (IV). Group II was characterized by lower blood pressure, low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) values than group I. Group III differed from the control group in terms of lower LDL-c level. There was no effect on CV risk in the general population, but in the population post-COVID-19 infection, CV risk was lower using FS-lipids, FS-BMI and LIFE-CVD 10-year risk scores compared to the prepandemic population. In all subgroups analysed, no statistically significant difference was found in the frequency of CV risk classes. CONCLUSIONS: The COVID-19 pandemic did not increase the CV risk calculated for primary prevention. Instead, it prompted people to pay attention to their health status, as evidenced by better control of some CV risk factors. As the COVID-19 pandemic has drawn people's attention to health, it is worth exploiting this opportunity to improve public health knowledge through the design of wide-ranging information campaigns.

Differential Inflammatory Responses in Adult and Pediatric COVID-19 Patients: Implications for Long-Term Consequences and Anti-Inflammatory Treatment.

BACKGROUND COVID-19 manifests with varying degrees of severity across different age groups; adults typically experience more severe symptoms than children. Matrix metalloproteinases (MMPs), known for their role in tissue remodeling and immune responses, may contribute to the pathophysiological disparities observed between these groups. We sought to delineate differences in serum MMP profiles between adult and pediatric COVID-19 patients, assess the influence of anti-inflammatory treatment on MMP levels, and examine potential implications for long-term consequences. MATERIAL AND METHODS Serum samples from adult and pediatric COVID-19 patients, alongside controls, were analyzed for MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, EMMPRIN, TNF-alpha, TIMP-1, TIMP-2, TIMP-3, and TIMP-4. A subset of adult patients received treatment with glucocorticoids, tocilizumab, and convalescent plasma, and MMP levels were compared with those of untreated patients. RESULTS Elevated levels of MMP-1, MMP-7, TIMP-1, and TIMP-2 were observed in adult and pediatric patients. Adult patients displayed higher concentrations of MMP-3, MMP-8, MMP-9, TNF-alpha, and TIMP-4 than children. Post-treatment reduction in MMP-1, MMP-8, MMP-9 levels was observed, with median decreases from 21% to 70%. MMP-3 and MMP-7 remained largely unchanged, and MMP-2 concentrations increased after treatment. Notably, anti-inflammatory treatment correlated with reduced post-treatment MMP levels, suggesting potential therapeutic benefit. CONCLUSIONS Distinctive inflammatory responses in COVID-19 were evident between adults and children. While certain MMPs exhibited post-treatment reduction, the persistence of elevated levels raises concerns about potential long-term consequences, including lung fibrosis. Our findings emphasize the need for personalized treatment strategies and further investigation into the dynamics of MMP regulation in COVID-19.

Overview of autoantibodies in COVID-19 convalescents.

Accumulating evidence shows that SARS-CoV-2 can potentially trigger autoimmune processes, which can be responsible for the long-term consequences of COVID-19. Therefore, this paper aims to review the autoantibodies reported in COVID-19 convalescents. Six main groups were distinguished: (i) autoantibodies against components of the immune system, (ii) autoantibodies against components of the cardiovascular system, (iii) thyroid autoantibodies, (iv) autoantibodies specific for rheumatoid diseases, (v) antibodies against G-protein coupled receptors, and (vi) other autoantibodies. The evidence reviewed here clearly highlights that SARS-CoV-2 infection may induce humoral autoimmune responses. However, the available studies share number of limitations, such as: (1) the sole presence of autoantibodies does not necessarily implicate the clinically-relevant risks, (2) functional investigations were rarely performed and it is often unknown whether observed autoantibodies are pathogenic, (3) the control seroprevalence, in healthy, noninfected individuals was often not reported; thus it is sometimes unknown whether the detected autoantibodies are the result of SARS-CoV-2 infection or the accidental post-COVID-19 detection, (4) the presence of autoantibodies was rarely correlated with symptoms of the post-COVID-19 syndrome, (5) the size of the studied groups were often small, (6) the studies focused predominantly on adult populations, (7) age- and sex-related differences in seroprevalence of autoantibodies were rarely explored, (8) genetic predispositions that may be involved in generation of autoantibodies during SARS-CoV-2 infections were not investigated, and (9) the autoimmune reactions following infection with SARS-CoV-2 variants that vary in the clinical course of infection remain unexplored. Further longitudinal studies are advocated to assess the link between identified autoantibodies and particular clinical outcomes in COVID-19 convalescents.

Short-term exposure to ambient air pollution and COVID-19 severity during SARS-CoV-2 Delta and Omicron waves: A multicenter study.

Air pollution may affect the clinical course of respiratory diseases, including COVID-19. This study aimed to evaluate the relationship between exposure of adult patients to mean 24 h levels of particulate matter sized <10 µm (PM10 ) and <2.5 µm (PM2.5 ) and benzo(a)pyrene (B(a)P) during a week before their hospitalization due to SARS-CoV-2 infection and symptomatology, hyperinflammation, coagulopathy, the clinical course of disease, and outcome. The analyses were conducted during two pandemic waves: (i) dominated by highly pathogenic Delta variant (n = 1440) and (ii) clinically less-severe Omicron (n = 785), while the analyzed associations were adjusted for patient's age, BMI, gender, and comorbidities. The exposure to mean 24 h B(a)P exceeding the limits was associated with increased odds of fever and fatigue as early COVID-19 symptoms, hyperinflammation due to serum C-reactive protein >200 mg/L and interleukin-6 >100 pg/mL, coagulopathy due to  d-dimer >2 mg/L and fatal outcome. Elevated PM10 and PM2. 5 levels were associated with higher odds of respiratory symptoms, procalcitonin >0.25 ng/mL and interleukin >100 pg/mL, lower oxygen saturation, need for oxygen support, and death. The significant relationships between exposure to air pollutants and the course and outcomes of COVID-19 were observed during both pandemic waves. Short-term exposure to elevated PM and B(a)P levels can be associated with a worse clinical course of COVID-19 in patients requiring hospitalization and, ultimately, contribute to the health burden caused by SARS-CoV-2 variants of higher and lower clinical significance.

Genotype Distribution and Characteristics of Chronic Hepatitis C Infection in Estonia, Latvia, Lithuania, and Ukraine: The RESPOND-C Study.

Background and objectives: Since 2013, highly effective direct-acting antiviral (DAA) treatment for chronic hepatitis C (CHC) has become available, with cure rates exceeding 95%. For the choice of optimal CHC treatment, an assessment of the hepatitis C virus (HCV) genotype (GT) and liver fibrosis stage is necessary. Information about the distribution of these parameters among CHC patients in Estonia, Latvia, and Lithuania (the Baltic states) and especially in Ukraine is scarce. This study was performed to obtain epidemiologic data regarding CHC GT and fibrosis stage distribution for better planning of resources and prioritization of patients for DAA drug treatment according to disease severity in high-income (the Baltic states) and lower-middle-income (Ukraine) countries. Materials and methods: The retrospective RESPOND-C study included 1451 CHC patients. Demographic and disease information was collected from medical charts for each patient. Results: The most common suspected mode of viral transmission was blood transfusions (17.8%), followed by intravenous substance use (15.7%); however, in 50.9% of patients, the exact mode of transmission was not clarified. In Ukraine (18.4%) and Estonia (26%), transmission by intravenous substance use was higher than in Lithuania (5%) and Latvia (5.3%). Distribution of HCV GT among patients with CHC was as follows: GT1-66.4%; GT3-28.1; and GT2-4.1%. The prevalence of GT1 was the highest in Latvia (84%) and the lowest in Ukraine (63%, p < 0.001). Liver fibrosis stages were distributed as follows: F0-12.2%, F1-26.3%, F2-23.5%, F3-17.1%, and F4-20.9%. Cirrhosis (F4) was more prevalent in Lithuanian patients (30.1%) than in Estonians (8.1%, p < 0.001). Conclusions: This study contributes to the knowledge of epidemiologic characteristics of HCV infection in the Baltic states and Ukraine. The data regarding the patterns of HCV GT and fibrosis stage distribution will be helpful for the development of national strategies to control HCV infection in the era of DAA therapy.

Safety analysis of glecaprevir/pibrentasvir in patients with markers of advanced liver disease in clinical and real-world cohorts.

Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct-acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV-infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease-inhibitor-containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on-label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥ 100 × 109 /L, and Child-Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real-world post-marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 × 109 /L (n = 800), platelet count <100 × 109 /L (n = 215), a Child-Pugh score of 5 (n = 915) and a Child-Pugh score of 6 (n = 95). In the clinical trial and real-world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short-duration G/P therapy may contribute to meeting HCV elimination targets.

Air pollution might affect the clinical course of COVID-19 in pediatric patients.

Air pollution, to which children are more susceptible than adults, can promote airway inflammation, potentially exaggerating the effects of respiratory viral infection. This study examined the association between the clinical manifestation of COVID-19 in unvaccinated pediatric patients hospitalized in Poland (n = 766) and levels of particulate matter 2.5 (PM2.5) and benzo(a)pyrene (B(a)P) within a week before hospitalization. Children aged ≤ 12 years exposed to mean and max 24 h B(a)P levels > 1 ng/m3 revealed higher odds of cough, dyspnea, fever, and increased concentrations of inflammatory markers (C-reactive protein, interleukin-6, procalcitonin, white blood cell count). In older patients (13-17 years), elevated mean 24 h B(a)P levels increased odds of dyspnea, fever, and diarrhea, and higher concentrations of C-reactive protein and procalcitonin. Exposure to max 24 h PM2.5 levels > 20 µg/m3 was associated with higher odds of cough, increased concentrations of C-reactive protein (group ≤12 years), and increased procalcitonin concentration (groups ≤12 years and 13-17 years). In both age groups, length of stay was extended in patients exposed to elevated levels of max 24 h PM2.5, mean and max 24 h B(a)P. This study suggests that worse air quality, particularly reflected in increased B(a)P levels, might affect the clinical course of COVID-19 in pediatric patients and adds to the disease burden during a pandemic.

Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection.

BACKGROUND: Glecaprevir and pibrentasvir are direct-acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8-week and 12-week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS: We conducted two phase 3, randomized, open-label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once-daily glecaprevir-pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir-pibrentasvir or sofosbuvir-daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir-pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS: In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1-infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8-week group and 99.7% (95% CI, 99 to 100) in the 12-week group. Genotype 3-infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir-pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir-daclatasvir; 8 weeks of treatment with glecaprevir-pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS: Once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE-1 and ENDURANCE-3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157 .).

Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study.

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-α2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%-67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (-0.1 log10  IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-α2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials.

Is elimination of HCV in 2030 realistic in Central Europe.

According to the recent data presented by Central-European HCV experts, the estimated prevalence of HCV is between 0.2% and 1.7% in certain countries in this region. There are no financial limitations to access to treatment in most countries. Patients in these countries have access to at least one pangenotypic regimen. The most common barriers to the elimination of HCV in Central Europe are a lack of established national screening programmes and limited political commitment to the elimination of HCV. Covid-19 has significantly affected the number of patients who have been diagnosed and treated, thus, delaying the potential elimination of HCV. These data suggest that the elimination of HCV elimination projected by WHO before 2030 will not be possible in the Central Europe.

Real-world effectiveness and safety of direct-acting antivirals in patients with cirrhosis and history of hepatic decompensation: Epi-Ter2 Study.

BACKGROUND AND AIMS: The aim of this study was to assess the real-life effectiveness and safety of direct acting antivirals (DAAs) in patients with cirrhosis and history of hepatic decompensation compared to those with compensated cirrhosis. METHOD: Data of patients treated with DAAs and included in the EpiTer-2 database (N = 10 152) were collected retrospectively. The primary endpoint was sustained viral response (SVR) at 12 weeks posttreatment. Patients were also evaluated in terms of liver-related adverse events and treatment modification/discontinuation. RESULTS: The overall SVR rate was 91.4% in the intent to treat (ITT) analysis and 95.2% in the per-protocol (PP) analysis (P < .001). Patients with decompensated cirrhosis had lower SVR rates compared to those with compensated cirrhosis in ITT analysis (86.4% vs 92.0%, P < .001), while not in PP analysis (92.9% vs 95.5%, P > .05). Adverse events (AE) occurred 45.6% and 29.3% of patients with decompensated and compensated cirrhosis (P < .001). Patients with decompensated cirrhosis were at higher risk of death (5.4% vs 0.9%; P < .0001) or liver decompensation (21.5% vs 1.3%; P < .0001). Treatment with protease inhibitors was not associated with hepatic decompensation (P = .3). Only 82.6% of patients with decompensated cirrhosis completed DAA treatment (vs 92.8% in compensated cirrhotics; P < .0001). CONCLUSION: Despite higher frequency of AE and treatment modifications, once completed, DAAs yield comparable results for patients with decompensated and compensated cirrhosis. High rate of serious adverse events in patients with advanced liver disease treated with PI may not be related to the detrimental effect of the medications, but rather to the disease itself.

Is an 8-week regimen of glecaprevir/pibrentasvir sufficient for all hepatitis C virus infected patients in the real-world experience?

BACKGROUND AND AIMS: The revolution of the antiviral treatment of hepatitis C virus (HCV) infection resulting in higher effectiveness came with the introduction of direct-acting antivirals with pangenotypic regimens as a final touch. Among them, the combination of glecaprevir (GLE) and pibrentasvir (PIB) provides the opportunity for shortening therapy to 8 weeks in the majority of patients. Because of still insufficient evaluation of this regimen in the real-world experience, our study aimed to assess the efficacy and safety of 8-week GLE/PIB in chronic hepatitis C patients depending on liver fibrosis and genotype (GT). METHODS: The analysis included patients who received GLE/PIB for 8 weeks selected from the EpiTer-2 database, large retrospective national real-world study evaluating antiviral treatment in 12 584 individuals in 22 Polish hepatology centers. RESULTS: A total of 1034 patients with female predominance (52%) were enrolled in the analysis. The majority of them were treatment naïve (94%), presented liver fibrosis (F) of F0-F3 (92%), with the most common GT1b, followed by GT3. The overall sustained virologic response after exclusion of nonvirologic failures was achieved in 95.8% and 98%, respectively (P = 0.19). In multivariate logistic regression HCV GT-3 (beta = 0.07, P = 0.02) and HIV infection (beta = -0.14, P < 0.001) were independent predictors of nonresponse. CONCLUSIONS: We demonstrated high effectiveness of 8-week GLE/PIB treatment in a non-GT3 population irrespective of liver fibrosis stage. Comparable efficacy was achieved in non-cirrhotic patients regardless of the genotype, including GT3 HCV.

Efficacy and safety of glecaprevir/pibrentasvir in renally impaired patients with chronic HCV infection.

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection increases the risk of incident chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD). Previously available direct-acting antiviral regimens are not approved for patients with advanced CKD across all HCV genotypes. METHODS: EXPEDITION-5 is a phase 3 study to evaluate efficacy and safety of the fixed-dose combination of glecaprevir and pibrentasvir (G/P) for chronic HCV infection (genotype 1 through 6) in adults without cirrhosis or with compensated cirrhosis and with stage 3b, 4 or 5 CKD. Patients received approved duration of G/P according to HCV genotype, cirrhosis status and prior HCV treatment experience. The primary efficacy endpoint was percentage of patients with sustained virologic response at 12 weeks post-treatment (SVR12). RESULTS: Among the 101 patients enrolled in the study, 24% had predialysis CKD and 76% were on dialysis. Eighty-four patients were treated with G/P for 8 weeks, 13 patients for 12 weeks and four patients for 16 weeks. Fifty-five per cent of patients had genotype 1, 27% had genotype 2, 15% had genotype 3 and 4% had genotype 4, and none had genotype 5 or 6 infection. The SVR12 rate was 97% (98/101, 95% confidence interval, 91.6-99.0). No patients experienced virologic failure. Adverse events (AEs) reported in at least 5% of the patients were pruritus, bronchitis, hypertension and generalized pruritus. Serious AEs were reported in 12% of patients; none related to study drug. CONCLUSIONS: G/P treatment yielded high SVR12 rates irrespective of the presence of stage 3b, 4 or 5 CKD. No safety signals were detected. CLINICALTRIALS. GOV IDENTIFIER: This Phase 3 clinical trial was funded by AbbVie and registered with clinicaltrials.gov as NCT03069365 (EXPEDITION-5).

Real-world experience with Grazoprevir/Elbasvir in the treatment of previously "difficult to treat" patients infected with hepatitis C virus genotype 1 and 4.

BACKGROUND AND AIM: Grazoprevir/elbasvir (GZR/EBR) was approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infected patients with or without compensated liver cirrhosis. The aim of this study was to assess GZR/EBR regimen in the real-world experience, particularly in previously "difficult-to-treat" patients with chronic kidney diseases, human immunodeficiency virus-coinfected, cirrhotics, and treatment-experienced. METHODS: The analysis included patients treated with GZR/EBR selected from 10 152 individuals from the EpiTer-2 database, large national real-world study evaluating antiviral treatment in 22 Polish hepatology centers between 2015 and 2018. Data were completed retrospectively and submitted online. RESULTS: A total of 1615 patients who started GZR/EBR therapy in 2017 and 2018 with a female predominance (54%) and median age of 54 years were analyzed. The majority were infected with GT1b (89%) and treatment naïve (81%). Liver cirrhosis was diagnosed in 19%, and 70% of patients had comorbidities, of which chronic renal disease was present in 7% and HIV-coinfection in 4%. Overall, a sustained virologic response (SVR) was achieved by 95% according to intent-to-treat (ITT) and 98% after exclusion of lost to follow up (modified ITT). No differences were found in cure rate between all included patients and subpopulations previously considered as difficult-to-treat. Majority of patients completed the treatment course as scheduled, adverse events were mostly mild and did not lead to therapy discontinuation. CONCLUSIONS: GZR/EBR treatment carried-out in patients infected with HCV genotype 1 and 4 demonstrated good tolerability and an excellent SVR rate with no effectiveness reduction in so called difficult-to-treat populations.

Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.

Real-world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1- and 4-infected patients with diverse comorbidities and comedications: A pooled analysis of post-marketing observational studies from 13 countries.

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment-naïve or -experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post-treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off-label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow-up data at post-treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2-96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b-infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro-esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post-baseline Grade 3-4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real-world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real-world setting.

Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well-described cohort of CHB patients. METHODS: Hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients from two randomised, double-blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open-label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. RESULTS: Of 641 randomised and treated patients, 585 (91%) entered the open-label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg-negative patients and 78/80 (98%) of HBeAg-positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal- or bone-related adverse events. CONCLUSIONS: Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance.