Activation of the type I interferon (IFN) signaling pathway is essential for the eradication of hepatitis C virus (HCV). Metformin can activate adenosine monophosphate-activated protein kinase (AMPK) ...to reduce insulin resistance. Cross talks between AMPK and IFN signaling remain unclear. To understand the influence of metformin on the type I IFN signaling pathway and HCV infection, the full-length HCV replicon OR6 cells and the infectious HCV clones JFH1 were used to assess the anti-HCV effect of the insulin sensitizers, metformin and pioglitazone. Immunofluorescence staining and the immunoblotting of HCV viral protein demonstrated that metformin, but not pioglitazone, inhibited HCV replication in OR-6 and JFH-1-infected Huh 7.5.1 cells. Immunoblotting data showed that metformin activated the phosphorylation of STAT-1 and STAT-2 in OR-6 and JFH-1 infected Huh 7.5.1 cells. Metformin enhanced the phosphorylation of AMPK, and the metformin-activated IFN signaling was down-regulated by AMPK inhibitor. After treatment of AMPK inhibitor, the level of HCV core protein decreased by metformin can be rescued. In conclusion, metformin activates type I interferon signaling and inhibits the replication of HCV via activation of AMPK.
Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) ...with/without ribavirin (RBV) in an open-label multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection.
All patients received coformulated OBV/ PTV/r daily + DSV twice daily (3-DAA). GTIa-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/ RBV nonresponders with cirrhosis who were treated for 24 weeks. GTIb-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR
).
The study enrolled 222 patients, 214 achieved an SVR
(96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR
was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event.
The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).
당뇨병과 바이러스 질환 김성민; Sungmin Kim
당뇨병(JKD),
06/2020, Letnik:
21, Številka:
2
Journal Article
Patients with diabetes are more susceptible to viral diseases, which are more likely to progress to severe cases in such patients. Diabetes and hyperglycemia have been reported to be major risk ...factors and poor prognostic factors for 2019 flu, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the currently ongoing coronavirus disease-2019 (COVID-19). However, it is not clear yet whether diabetes itself leads to higher risk and becomes a poor prognostic factor for viral diseases or if the real main factors are actually cardiovascular and renal complications that often accompany diabetes. On the other hand, viral diseases have frequently been suggested to be one cause or a contributing factor to develop diabetes. Two typical examples are the association between enteroviruses such as Coxsackie B virus and type 1 diabetes and the relationship between hepatitis C virus and type 2 diabetes. Recently, there has been research on the potentiality of changes in the intestinal microflora being a cause for diabetes, and there is evidence to suggest that intestinal virome affects intestinal microbiota. There has also been a claim that extracellular vesicles secreted by gut microbiota, rather than the microbiota itself, get absorbed into the body and come to cause diabetes.
Abstract
Hepatitis C virus (HCV; genus Hepacivirus) represents a major public health problem, infecting about three per cent of the human population. Because no animal reservoir carrying closely ...related hepaciviruses has been identified, the zoonotic origins of HCV still remain unresolved. Motivated by recent findings of divergent hepaciviruses in rodents and a plausible African origin of HCV genotypes, we have screened a large collection of small mammals samples from seven sub-Saharan African countries. Out of 4,303 samples screened, eighty were found positive for the presence of hepaciviruses in twenty-nine different host species. We, here, report fifty-six novel genomes that considerably increase the diversity of three divergent rodent hepacivirus lineages. Furthermore, we provide strong evidence for hepacivirus co-infections in rodents, which were exclusively found in four sampled species of brush-furred mice. We also detect evidence of recombination within specific host lineages. Our study expands the available hepacivirus genomic data and contributes insights into the relatively deep evolutionary history of these pathogens in rodents. Overall, our results emphasize the importance of rodents as a potential hepacivirus reservoir and as models for investigating HCV infection dynamics.
Limited data exist with regard to treatment outcomes in Asian Americans with chronic hepatitis C (CHC). We evaluated sofosbuvir (SOF)-based regimens in a national cohort of Asian Americans.
Eligible ...Asian Americans patients with CHC who had posttreatment follow-up of 24 weeks for SOF -based therapies from December 2013 to June 2017 were enrolled from 11 sites across the United States. The primary endpoint was sustained virologic response (SVR) rates at posttreatment weeks 12 and 24. Secondary endpoints were to evaluate safety by tolerability and adverse events (AEs).
Among 231 patients screened, 186 were enrolled. At baseline, 31% (57/186) patients were cirrhotic, 34% (63/186) were treatment experienced. Most of the subjects (42%, 79/186) received ledispavir/SOF therapy. The overall SVR12 was 95%, ranging from 86% in genotype (GT) 1b on SOF+ribavirin to 100% in GT 1b patients on ledipasvir/SOF at subgroup analyses. SVR12 was significantly lower in cirrhotic than in noncirrhotic patients 88% (50/57) vs. 98% (126/129), P<0.01. Stratified by GT, SVR12 were: 96% (43/45) in GT 1a; 93% (67/72) in GT 1b; 100% (23/23) in GT 2; 90% (19/21) in GT 3; 100% (1/1) in GT 4; 83% (5/6) in GT 5; and 100% (16/16) in GT 6. Cirrhotic patients with treatment failure were primarily GT 1, (GT 1a, n=2; GT 1b, n=4) with 1 GT 5 (n=1). Patients tolerated the treatment without serious AEs. Late relapse occurred in 1 patient after achieving SVR12.
In Asian Americans with CHC, SOF-based regimens were well tolerated without serious AEs and could achieve high SVR12 regardless of hepatitis C viral infection GT.
Fatigue is a common symptom of chronic hepatitis C virus (cHCV) infection and a common side effect of interferon-based treatment for cHCV. This study provides confirmatory evidence of the reliability ...and validity of the Fatigue Severity Scale (FSS) to document fatigue in cHCV research and identifies values that indicate clinically important differences in FSS to aid in interpreting fatigue in cHCV clinical trials.
The study used data from two double-blind, randomized, placebo-controlled, Phase IIb trials evaluating the efficacy and safety of simeprevir plus peginterferon-α/ribavirin in treatment-naïve (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) with cHCV infection. Patients completed the FSS and EuroQoL 5 dimension questionnaire (EQ-5D) at baseline and at regular intervals throughout both trials. Reliability was assessed using Cronbach's coefficient α at Week 24 (internal consistency reliability) and intraclass correlation (ICC) between FSS at Weeks 12 and 24 in stable patients (<0.5 g/dL hemoglobin Hb change between Weeks 12/24). Correlation with the EQ-5D visual analog scale (VAS) and "Usual Activity" domain score was used to assess concurrent validity. Clinical validity was evaluated using a case-control method to link spontaneously reported fatigue and anemia adverse events (AEs) during the study to FSS scores.
FSS total scores demonstrated good reliability (Cronbach's α: 0.95, 0.96; ICC: 0.74, 0.86 for PILLAR and ASPIRE, respectively) and concurrent validity (correlation with EQ-5D VAS: -0.63, -0.66) with a monotonic relationship between the EQ-5D "Usual Activities" item response and FSS. Clinical validity was confirmed by a significant difference between cases and controls for fatigue AEs (p < 0.05); however, anemia defined by AE or Hb abnormalities was only weakly related to FSS score. Analyses indicate that a change of 0.33-0.82 in mean FSS scores represents a meaningful improvement in fatigue, and a one-point change is a conservative indicator of an important change in individual FSS scores.
A difference of ≥0.7 in mean FSS scores can be considered a clinically important difference within groups over time or between groups. A one-point change or less in individual FSS scores indicates a clinically relevant change in fatigue.
Chronic hepatitis C virus infection and its sequela are major health problems facing the Egyptian community. The high prevalence and spread rates of the disease require serious actions to stop or ...decrease these rates. Determination of HCV genotypes and subgenotypes adds significant knowledge about the epidemiology of the disease, and provides an added value in the decision making process of what strategy to follow and what therapy response to expect. The molecular epidemiology and genetic variability of HCV variants circulating in Egypt still need further analysis.
The study was held to evaluate the genotype and subgenotype of the hepatitis c virus circulating in Sharkia as one of the large governorates of Egypt, which was not included in any study for genotyping of the virus before.
The HCV molecular epidemiology in Sharkia governorate was studied using direct sequencing and further phylogenetic analysis of a partial NS5B region of the HCV genome from 63 patients. HCV genotype and subtype were successfully determined in 62 out of 63 patients.
The highest prevalent genotype was genotype 4a, which was found in 57 patients (92%) followed by 2 isolates (3%) with genotype 4o, 2 strains (3%) with genotype 1g and one isolate (2%) with genotype 4n.
This molecular epidemiology study revealed high prevalence of HCV genotype 4, subtype 4a among Egyptian patients residing in Sharkia governorate, Egypt.
The advent of triple therapy (TT) with first‐generation protease inhibitors boceprevir (BOC) and telaprevir (TVR) in addition to pegylated interferon and ribavirin (PEG‐IFN/RBV) has resulted in a ...significant improvement in the sustained virological response (SVR) rate and potentially in life years gained compared to dual therapy (DT), when treating naïve or treatment‐experienced patients with genotype 1 (G1) chronic hepatitis C (CHC). This benefit is partly offset by the increased complexity of treatment, and the increased costs and risks of therapy, making it necessary to optimize the indications for TT. Naïve patients with mild fibrosis and the IL28B CC polymorphism and/or with a rapid virological response (RVR) to DT can still benefit from DT, while TT is preferable in all others. Phase 3 trials have clearly shown that a 1 log10 decrease in HCVRNA after 4 weeks of DT associated with a favourable IL28B genotype and a low stage of fibrosis, and a pattern of previous response to DT in treatment‐experienced patients are the strongest predictors of an SVR to TT. Moreover, an extended rapid virological response (eRVR) is associated with an SVR rate >90%, so that the overall duration of treatment can be shortened in a high proportion of patients. Further efforts to optimize the current TT regimens both by increasing efficacy and improving tolerance are still needed. Most important, in the future, treatment can probably be personalized based on data from post‐marketing surveillance of TT providing information about patient groups that were underrepresented in phase 3 studies such as those with cirrhosis.
Abstract The intra-host evolutionary process of hepatitis C virus (HCV) was analyzed by phylogenetic and coalescent methodologies in a patient co-infected with HCV-1a, HCV-2a, HCV-3a and human ...immunodeficiency virus (HIV) along a 13-year period. Direct sequence analysis of the E2 and NS5A regions showed diverse evolutionary dynamics, in agreement with different relationships between these regions and the host factors. The Bayesian Skyline Plot analyses of the E2 sequences (cloned) yielded different intra-host evolutionary patterns for each genotype: a steady state of a “consensus” sequence for HCV-1a; a pattern of lineage splitting and extinction for HCV-2a; and a two-phase (drift/diversification) process for HCV-3a. Each genotype evolving in the same patient and at the same time presents a different pattern apparently modulated by the immune pressure of the host. This study provides useful information for the management of co-infected patients and provides insights into the mechanisms behind the intra-host evolution of HCV.
The classification of hepatitis C virus (HCV) genotypes is of clinical importance as it may help to predict drug therapy responses and estimate treatment duration. The classical method of HCV ...subgenotype classification is whole genome sequencing (WGS). However, the high cost and time-consuming nature of WGS limits its usage in clinical practice. A number of studies have been conducted to confirm whether specific regions of HCV could replace WGS in the classification of HCV subgenotypes. In the present study, we used the HCV database to select HCV sequences from different countries. The neighbor-joining method was used to construct phylogenetic trees based on different regions of HCV (core, E1, E2 and NS5B), to confirm which region could replace WGS in subgenotype classification. Our results indicated that the core, E1 and E2 regions could not be used to classify the HCV subgenotype correctly (core failed to recognize subgenotypes c and a, E1 failed to discriminate between subgenotypes a and b, and E2 failed to identify subgenotypes a and c). The NS5B region provided the correct subgenotype classification. The HCV samples (n=153) collected from patients in Sichuan province, (Southwest China) were sequenced and classified based on the NS5B region. The results indicated that the major subgenotype of HCV in patients from Sichuan was 1b (51.6%, n=79); other subgenotypes included 3b (30.1%, n=46), 3a (7.8%, n=12), 6a (8.5%, n=13), 2a (n=2) and 6n (n=1). The data from our analysis may prove to be helpful in future epidemiological investigations of HCV, and may aid in the prevention and clinical treatment of HCV.
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