Results of a coastal measurement campaign called MediterraneAn Rfc and cLutter ENvironmental Experiment (MARLENE) are presented and studied. The campaign was held in spring 2014, on a DGA site in the ...Mediterranean Sea region of Toulon, France. Three coastal measurement radar systems, Millimeter wave Experimental Multifrequency Polarimetric High Resolution Interferometric System (Fraunhofer FHR), MARSIG (WTD 71), and MEDYCIS (ONERA), were deployed to simultaneously acquire sea clutter measurements. During the campaign, the in situ oceanic and meteorological conditions were characterized from the RV PLANET meteorological ship deployed by WTD 71 and by modeling from WAVEWATCH III and SWAN wave models. Radar measurements were performed at the C-, X-, Ku-, Ka-, and W-bands. The measurement results are presented in terms of reflectivity and mean Doppler spectrum according to low grazing angle and azimuth variations. Reflectivity variations are compared with the empirical GIT model and close results are obtained at the C- and Ka-bands. At the same frequency bands, mean Doppler Spectrum velocity is presented and analyzed according to grazing and azimuth angles. Physical interpretations of electromagnetic interaction with sea surface are discussed.
Summary
Quantitative hepatitis B core‐related antigen (qHBcrAg) has been proposed as an additional marker to quantitative HBsAg (qHBsAg), for management of chronic hepatitis B. Evaluate baseline ...combination of qHBsAg and qHBcrAg for identification of patients that could benefit from pegylated interferon‐alpha‐2a (PegIFN)‐based therapy. Sixty‐two HBeAg‐negative patients treated with PegIFN or PegIFN plus tenofovir disoproxil fumarate (PegIFN+TDF). HBsAg and HBcrAg titres were evaluated at baseline. Thirty patients received PegIFN and 32 PegIFN+TDF. SR was 10 of 30 and 17 of 32 in PegIFN and PegIFN+TDF patients, respectively. Cut‐offs determined by maximized Youden's index for identifying patients likely to respond to therapy were as follows: 3.141 log10 IU/mL and 3.450 log10 U/mL for HBsAg and HBcrAg, respectively. At the end of 3 years post‐treatment follow‐up, HBsAg loss was observed in 7 of 30 and 6 of 32 in PegIFN and PegIFN+TDF patients, respectively. The AUC was estimated to be 0.716 (95% CI 0.578, 0.855) for HBsAg and 0.668 (95% CI 0.524, 0.811) for HBcrAg (P=.5541). PPVs for AUCs(95%CI) were 0.762(0.590–0.947), 0.714(0.533–1.000) and 0.800(0.611–1.000), and NPVs for AUCs(95%CI) were 0.756(0.660–0.899), 0.718(0.630–0.857) and 0.765(0.675–0.889) for qHBsAg, qHBcrAg and the combination of both markers, respectively. Baseline qHBsAg 3.141 log10 IU/mL and qHBcrAg 3.450 log10U/mL thresholds used separately or in combination allow prediction of response, prior to PegIFN‐based therapy, with a PPV of 80.3% and NPV of 76.5%. Baseline qHBsAg is predictive of HBsAg loss. Both markers could be used, separately or in combination, for PegIFN‐based ‘precision therapy’. Our results emphasize that the combination of PegIFN alpha‐2a plus TDF with 53% of SR might be an alternative to finite therapy.
A novel controlled attenuation parameter (CAP) has been developed for Fibroscan® to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy ...in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan® and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S0: steatosis in <10% of hepatocytes, S1: 11–33%, S2: 34–66% and S3: 67–100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross‐validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis (P < 10−15) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75–0.84) for S ≥ S1, 0.86 (0.81–0.92) for S ≥ S2 and 0.88 (0.73–1) S = S3. CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan®, in patients with CHC.
Summary
A major hurdle in the long‐term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to ...tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS‐US‐174‐0102 (HBeAg−) and GS‐US‐174‐0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open‐label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF‐treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1‐2 to <4% over years 3‐8. Forty‐one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty‐nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance‐associated mutations. No accumulation of conserved site changes was detected. The long‐term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.
Hepatic steatosis is a common histological feature of chronic hepatitis C. Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, diabetes type II, and ...hyperlipidaemia. These factors may contribute to steatosis in patients with chronic hepatitis C. In humans, hepatitis C virus (HCV) genotype 3 is more commonly associated with steatosis. In vitro studies and the transgenic mouse model have suggested that the HCV core protein (genotype 1) can induce lipid accumulation within hepatocytes. However, what is the relevance of steatosis in chronic hepatitis C? It seems that in certain populations, steatosis may be associated with fibrosis progression and this may be genotype specific. The mechanisms underlying this association are unknown; neither is it clear whether this holds true for all patients or only a subgroup. Indeed, after antiviral treatment, virus related steatosis disappears whereas the host associated steatosis remains unaffected. This review describes and discusses the basic and clinical aspects of the relationship between steatosis and progression of fibrosis, and response to treatment in patients with chronic hepatitis C.
Summary
Background
In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG‐IFN) for 48‐weeks results in higher rates of hepatitis B surface antigen ...(HBsAg) loss than either monotherapy.
Aim
To identify baseline and on‐treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks.
Methods
A secondary analysis of data from an open‐label study where patients were randomised to TDF (300 mg/day, oral) plus PEG‐IFN (PI, 180 μg/week, subcutaneous) for 48 weeks (TDF/PI‐48w); TDF plus PEG‐IFN for 16 weeks, TDF for 32 weeks (TDF/PI‐16w+TDF‐32w); TDF for 120 weeks (TDF‐120w) or PEG‐IFN for 48 weeks (PI‐48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72.
Results
Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI‐48w group (6.5%) than in the TDF/PI‐16w+TDF‐32w (0.5%), TDF‐120w (0%) and PI‐48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI‐48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72.
Conclusions
HBsAg decline at Week 24 of TDF plus PEG‐IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.
Treatment of chronic hepatitis B Marcellin, P.; Asselah, T.; Boyer, N.
Journal of viral hepatitis,
July 2005, Letnik:
12, Številka:
4
Journal Article
Recenzirano
In the last years, marked progress has been made in the treatment of chronic hepatitis B. The efficacy of lamivudine, the first nucleoside analogue available, is limited by the high incidence of ...resistance. Adefovir, which was recently approved has a comparable efficacy with a very low frequency of resistance. However, adefovir needs to be indefinitely administered as withdrawal of therapy is generally associated with reactivation and sustained response is uncommon.
Recent large randomized controlled trials showed that PEG IFNs induce relatively high sustained response rates both in HBeAg positive and HBeAg negative chronic hepatitis B. So far, the combination of PEG IFN with lamivudine, used simultaneously, is disappointing in terms of short‐term efficacy. However, long‐term efficacy needs to be assessed and different schedules of combination (for example sequential) need to be evaluated.
A number of nucleoside analogues, with favourable toxicity profiles and a promise of increased effectiveness against HBV, are at various stages of clinical development. Results of phase III trials of entecavir and emtricitabine confirmed their efficacy. However, while entecavir is associated with a low incidences of resistance, emtricitabine is associated with a relatively high incidence of resistance which limits its use as a monotherapy. The efficacy and safety of new and more potent drugs like telbivudine and clevudine need to be confirmed.
The future of chronic hepatitis B therapy seems to be in the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should have different sites of action on HBV DNA replication, a potent antiviral effect, an excellent safety profile and they should induce a sustained response with a limited duration of therapy. Indeed, the concept of combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far few combinations have been evaluated. No combination therapy demonstrated a benefit as compared with monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are important challenges to improve the efficacy of treatment and decrease in the future the global burden related to chronic hepatitis B.
The gold standard treatment of chronic hepatitis C (CHC) is combined pegylated interferon and ribavirin. Considering side effects and treatment cost, prediction of treatment response before therapy ...is important. The aim of this study was to identify a liver gene signature to predict sustained virological response in patients with CHC.
Group A (training set) comprised 40 patients with CHC including 14 non-responders (NRs) and 26 sustained virological responders (SVRs). Group B (validation set) comprised 29 patients including 9 NRs and 20 SVRs. Eleven responder-relapsers were also included. A total of 58 genes associated with liver gene expression dysregulation during CHC were selected from the literature. Real-time quantitative RT-PCR assays were used to analyse the mRNA expression of these 58 selected genes in liver biopsy specimens taken from the patients before treatment.
From the Group A data, three genes whose expression was significantly increased in NRs compared with SVRs were identified: IFI-6-16/G1P3, IFI27 and ISG15/G1P2. These three genes also showed significant differences in their expression profiles between NRs and SVRs in the independent sample (Group B). Supervised class prediction analysis identified a two-gene (IFI27 and CXCL9) signature, which accurately predicted treatment response in 79.3% (23/29) of patients from the validation set (Group B), with a predictive accuracy of 100% (9/9) and of 70% (14/20) in NRs and SVRs, respectively. The expression profiles of responder-relapsers did not differ significantly from those of NRs and SVRs, and 73% (8/11) of them were predicted as SVRs with the two-gene classifier.
NRs and SVRs have different liver gene expression profiles before treatment. The most notable changes occurred mainly in interferon-stimulated genes. Treatment response could be predicted with a two-gene signature (IFI27 and CXCL9).
In a trial of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B, 24 week post-treatment biochemical and virological response rates with peginterferon alpha-2a with or without ...lamivudine were significantly higher than with lamivudine alone. The effect of pre-treatment factors on post-treatment responses was investigated.
Multivariate analyses were performed using available data from 518 patients treated with peginterferon alpha-2a with or without lamivudine, or with lamivudine alone. A post-treatment response was defined as alanine aminotransferase (ALT) normalisation and hepatitis B virus (HBV) DNA level of <20,000 copies/ml.
In logistic regression analyses across all treatment arms, peginterferon alpha-2a (with or without lamivudine) therapy, younger age, female gender, high baseline ALT, low baseline HBV DNA and HBV genotype were identified as significant predictors of combined response at 24 weeks post-treatment. In the peginterferon alpha-2a and lamivudine monotherapy arms, patients with genotypes B or C had a higher chance of response than genotype D infected patients (p<0.001), the latter responding better to the combination than to peginterferon alpha-2a monotherapy (p = 0.015). At 1 year post-treatment, response rates by intention-to-treat analysis were 19.2% for the peginterferon alpha-2a, 19.0% for the combination, and 10.0% for the lamivudine groups, with genotypes B or C associated with a sustained combined response to peginterferon alpha-2a with or without lamivudine therapy.
Baseline ALT and HBV DNA levels, patient age, gender, and infecting HBV genotype significantly influenced combined response at 24 weeks post-treatment, in patients treated with peginterferon alpha-2a and/or lamivudine. At 1 year post-treatment HBV genotype was significantly predictive of efficacy for patients treated with peginterferon alpha-2a with or without lamivudine.
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