Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

Background: Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design: Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results: HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted \u3b4 and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted \u3bb, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions: Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of "cell-cure" by DAAs, leading to a fast improvement of liver homeostasis

Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation

Efficacy of 8 weeks elbasvir/grazoprevir regimen for naïve-genotype 1b, HCV infected patients with or without glucose abnormalities: Results of the EGG18 study

Background and aim: Direct Acting Antivirals(DAAs) achieve the highest rate of sustained viral re- sponse(SVR) in patients with genotype-1b(G1b) Hepatitis C virus(HCV) infection. Reducing treatment du- ration can simplify the management and improve adherence of therapy. Patients and methods: The study evaluates the efficacy of 8 weeks of elbasvir/grazoprevir regimen in 75 treatment-naïve(TN), G1b patients with mild-moderate fibrosis(Liver Stiffness by Fibroscan®< 9.0 kPa). Viral load(VL) has been evaluated by Roche TaqMan RT-PCR(LLOQ < 15 IU/ml). Results: Mean age was 61.0 ±14.2 years, 44% were male, mean LS by Fibroscan®was 6.1 ±1.8 kPa. Twenty-eight patients(37.3%) had an HOMA > 2.5. Two patients were excluded from analysis(one dropped out and the other one had diagnosed genotype 2c at genotyping by sequencing performed after relapse). At 8 weeks(EOT), 71 out of 73 patients(97.3%) had undetectable HCV-RNA, while in two cases HCV- RNA was detectable but with VL < 15 IU/ml. Both of them achieved SVR. Two G1b patients relapsed at 12 weeks of follow-up, both with baseline VL > 80 0,0 0 0 IU/ml and HOMA score 1.3 and 3.8 respectively. Both had undetectable HCV VL at 4th week and at the EOT. Modified intention-to-treat SVR12 for G1b patients was 71/73(97.3%). Conclusion: In naïve, genotype-1b HCV-infected patients with mild/moderate liver fibrosis, short course of 8 weeks of EBR/GZR appears to achieve high efficacy regardless of features of insulin resistance

Influenza viruses circulation in a tertiary care children hospital in Rome: a comparison between 2022 and the previous 5 years

Abstract Background Influenza surveillance aims to determine onset, duration and intensity of the seasonal Influence-like Illness (ILI); data collection begins in the week 42 of a year and ends in the week 17 of the following year. In this observational study, we report the experience of a tertiary care children hospital in Rome about Influenza viruses circulation during the calendar year 2022 (January-December) in comparison with the previous five years (2017–2021), with a special focus on the weeks 18–41, usually not under surveillance. Methods This retrospective study involved 36782 respiratory samples referred to 21354 patients (pts), median age 2.63 years, admitted with respiratory symptoms at Bambino Gesù Children’s Hospital in the years 2017–2022. Respiratory viruses were detected by molecular Allplex™ Respiratory Panel Assays (Seegene, Korea). Results Regarding the pre pandemic years, 2017–2019, distribution of Flu positive patients focused in the first weeks of the year (weeks 1–17). During the pandemic period, Flu was not detected. In 2022, 239 Flu viruses were identified: 37 FluA (weeks 1–17), 29 FluA (weeks 18–41) and 168 FluA and 5 FluB (weeks 42–52). For the year 2022, during the non-epidemic period, the number of Flu viruses detected corresponded to 12.1% of total Flu detected, respect to 0-1.7% for the previous five years (p < 0.001). Conclusions When compared with pre SARS-CoV-2 pandemic years, our data show a significant increase in Influenza cases during weeks 18–41/2022 and reveal an unexpected summer circulation of these viruses: just weeks 26–30 showed to be influenza virus free. A national year-round Flu surveillance could be useful to understand if changing in influenza epidemiology is transitional or likely to persist in the following years

Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning

Resistance-associated variants (RAVs) have been shown to influence treatment response to direct-acting antivirals (DAAs) and first generation NS3/4A protease inhibitors (PIs) in particular. Interpretation of hepatitis C virus (HCV) genotypic drug resistance remains a challenge, especially in patients who previously failed DAA therapy and need to be retreated with a second DAA based regimen. Bayesian network (BN) learning on HCV sequence data from patients treated with DAAs could provide insight in resistance pathways against PIs for HCV subtypes 1a and 1b, in a similar way as applied before for HIV. The publicly available ‘Rega-BN’ tool chain was developed to study associative analyses for various pathogens. Our first analysis, comparing sequences from PI-naïve and PI-experienced patients, determined that NS3 substitutions R155K and V36M arise with PI-exposure in HCV1a infected patients, and were defined as major and minor resistance-associated variants respectively. NS3 variant 174H was newly identified as potentially related to PI resistance. In a second analysis, NS3 sequences from PI-naïve patients who cleared the virus during PI therapy and from PI-naïve patients who failed PI therapy were compared, showing that NS3 baseline variant 67S predisposes to treatment-failure and variant 72I to treatment success. This approach has the potential to better characterize the role of more RAVs, if sufficient therapy annotated sequence data becomes available in curated public databases. In addition, polymorphisms present in baseline sequences that predispose patients to therapy failure can be identified using this approach.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy

BACKGROUND: In-depth phylogeographic analysis can reveal migration patterns relevant for public health planning. Here, as a model, we focused on the provenance, in the current Italian HCV subtype 1a epidemic, of the NS3 resistance-associated variant (RAV) Q80K, known to interfere with the action of NS3/4A protease inhibitor simeprevir. HCV1a migration patterns were analysed using Bayesian phylodynamic tools, capitalising on newly generated and publicly available time and geo-referenced NS3 encoding virus genetic sequence data. RESULTS: Our results showed that both immigration and local circulation fuel the current Italian HCV1a epidemic. The United States and European continental lineages dominate import into Italy, with the latter taking the lead from the 1970s onwards. Since similar migration patterns were found for Q80K and other lineages, no clear differentiation of the risk for failing simeprevir can be made between patients based on their migration and travel history. Importantly, since HCV only occasionally recombines, these results are readily transferable to the genetic sequencing policy concerning NS5A RAVs. CONCLUSIONS: The patient migration and travel history cannot be used to target only part of the HCV1a infected population for drug resistance testing before start of antiviral therapy. Consequently, it may be cost-effective to expand genotyping efforts to all HCV1a infected patients eligible for simeprevir-based therapies.status: publishe

Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy

Background: In-depth phylogeographic analysis can reveal migration patterns relevant for public health planning. Here, as a model, we focused on the provenance, in the current Italian HCV subtype 1a epidemic, of the NS3 resistance-associated variant (RAV) Q80K, known to interfere with the action of NS3/4A protease inhibitor simeprevir. HCV1a migration patterns were analysed using Bayesian phylodynamic tools, capitalising on newly generated and publicly available time and geo-referenced NS3 encoding virus genetic sequence data. Results: Our results showed that both immigration and local circulation fuel the current Italian HCV1a epidemic. The United States and European continental lineages dominate import into Italy, with the latter taking the lead from the 1970s onwards. Since similar migration patterns were found for Q80K and other lineages, no clear differentiation of the risk for failing simeprevir can be made between patients based on their migration and travel history. Importantly, since HCV only occasionally recombines, these results are readily transferable to the genetic sequencing policy concerning NS5A RAVs. Conclusions: The patient migration and travel history cannot be used to target only part of the HCV1a infected population for drug resistance testing before start of antiviral therapy. Consequently, it may be cost-effective to expand genotyping efforts to all HCV1a infected patients eligible for simeprevir-based therapies.publishersversionpublishe