55 research outputs found

    Real-world effectiveness of voxilaprevir/velpatasvir/sofosbuvir in patients following DAA failure

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    Hepatitis C virus; VoxilaprevirVirus de l'hepatitis C; VoxilaprevirVirus de la hepatitis C; VoxilaprevirBackground & Aims Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection. In the present study, predictors of virologic treatment response were analyzed in an integrative analysis of three large real-world cohorts. Methods Consecutive patients re-treated with VOX/VEL/SOF after DAA failure were enrolled between 2016 and 2021 in Austria, Belgium, Germany, Italy, Spain and Switzerland. Results A total of 746 patients were included: median age was 56 (16-88) years and 77% were male. Most patients were infected with HCV genotype 1 (56%) and 3 (32%). 86% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Overall, 95.4% (683/716) of patients achieved a sustained virologic response. Treatment effectiveness was significantly affected by advanced liver disease (p <0.001), hepatocellular carcinoma (p <0.001), higher baseline ALT levels (p = 0.02), HCV genotype 3 (p <0.001), and prior VEL/SOF treatment (p = 0.01). In a multivariate analysis, only HCV genotype 3, hepatocellular carcinoma and cirrhosis turned out to be independent predictors of treatment failure. Resistance-associated substitutions, as well as the presence of rare genotypes, did not impact treatment outcome. The effectiveness of rescue therapy with glecaprevir/pibrentasvir and SOF, with or without ribavirin, for 12 to 24 weeks was found to be high (100%). Conclusions Infection with HCV genotype 3, the presence of liver cancer and cirrhosis are independently associated with failure of VOX/VEL/SOF re-treatment. It is unclear whether the addition of ribavirin and/or extension of treatment duration may be effective to avoid virologic relapse on VOX/VEL/SOF. However, rescue treatment with glecaprevir/pibrentasvir+SOF seems to be effective. Impact and implications Representative data on the effectiveness of voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given. Thus, we aimed to analyze treatment effectiveness and predictors of virologic response to VOX/VEL/SOF in an integrative analysis of three large real-word cohorts. The study results, derived from a multicenter cohort consisting of 746 patients, demonstrated that re-treatment with VOX/VEL/SOF is an effective salvage therapy associated with an overall per protocol sustained virologic response rate of 95%. Hepatocellular carcinoma onset, cirrhosis and HCV genotype 3 were identified as independent negative predictors of treatment response, whereas resistance-associated substitutions, as well as rare genotypes and chimera, did not impact sustained virologic response rates following re-treatment with VOX/VEL/SOF.This study was supported by a DZIF (German Center for Infection Research) grant entitled ‘HCV Treatment Optimization’ to CS and JD (TTU 05.809)

    Clinical Study Cirrhosis and Rapid Virological Response to Peginterferon Plus Ribavirin Determine Treatment Outcome in HCV-1 IL28B rs12979860 CC Patients

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    Background. The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. Aim. To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. Methods. Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. Results. 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI &gt;25, 69 with &gt;600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07-6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics ( = 0.03). HCV RNA undetectability (&lt;50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (−) ( = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (−) (10/13 (77%) versus 6/17 (35%) = 0.03). Conclusions. In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy

    Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients

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    Background/Aims The utility of Baveno-VII criteria of clinically significant portal hypertension (CSPH) to predict decompensation in compensated advanced chronic liver disease (cACLD) patient needs validation. We aim to validate the performance of CSPH criteria to predict the risk of decompensation in an international real-world cohort of cACLD patients. Methods cACLD patients were stratified into three categories (CSPH excluded, grey zone, and CSPH). The risks of decompensation across different CSPH categories were estimated using competing risk regression for clustered data, with death and hepatocellular carcinoma as competing events. The performance of “treating definite CSPH” strategy to prevent decompensation using non-selective beta-blocker (NSBB) was compared against other strategies in decision curve analysis. Results One thousand one hundred fifty-nine cACLD patients (36.8% had CSPH) were included; 7.2% experienced decompensation over a median follow-up of 40 months. Non-invasive assessment of CSPH predicts a 5-fold higher risk of liver decompensation in cACLD patients (subdistribution hazard ratio, 5.5; 95% confidence interval, 4.0–7.4). “Probable CSPH” is suboptimal to predict decompensation risk in cACLD patients. CSPH exclusion criteria reliably exclude cACLD patients at risk of decompensation, regardless of etiology. Among the grey zone, the decompensation risk was negligible among viral-related cACLD, but was substantially higher among the non-viral cACLD group. Decision curve analysis showed that “treating definite CSPH” strategy is superior to “treating all varices” or “treating probable CSPH” strategy to prevent decompensation using NSBB. Conclusions Non-invasive assessment of CSPH may stratify decompensation risk and the need for NSBB in cACLD patients

    Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis

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    Objective: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration. Design: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson. Results: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I2=74.6%) and 5.7 (2.5 to 15.3, I2=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1). Conclusion: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified

    DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

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    Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p&lt;0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

    The beginning of the Neolithic in the Po Plain (northern Italy): Problems and perspectives

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    The Po Valley is one of the major physiographic units of northern Italy. It can be considered as a key area for the interpretation of long-term historical events and processes because of its location midway between the Mediterranean world and continental Europe. This paper is an updated summary of our knowledge of the Early Neolithic farming communities of the region. In particular it discusses data derived from radiocarbon dated sites. Its aim is to provide the international audience with an updated view of the topic, based on the discussion of a new series of AMS radiocarbon results, to frame the earliest producing communities of the Po Valley into the more general picture of the Neolithization of Italy. To achieve the goal, apart from radiocarbon assays, we have taken into consideration material culture remains, subsistence economy, environmental resources, and data gathered from archaeometric analyses and technology

    HDV RNA and liver disease progression: What do we know?

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    New Evidence of Ancestral Landscape in Trentino in the Copper and Bronze Ages: the Ritual Sites of Cles-Campi Neri and La Vela di Trento

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    Recent investigations (1999-2007) carried out at the site of Cles-Campi Neri in the Valle di Non have brought to light a circular stone structure which can be attributed to a period between the Late Copper Age and the initial phase of the Early Bronze Age. Two structural phases have been identified. The earlier one saw the presence of a large enclosure made up of large blocks enclosing a smaller structure. The items found at the upper levels are made up of flint tools altered by heat. There are also small agglomerations of calcined human bones. In the subsequent phase the area inside the large enclosure was filled in with a platform made up of stones and pebbles, covered and surrounded by organic soil, in which hundreds of flint tools and flakes have been found, along with rarer fragments of pottery. The agglomerations of calcined human bones continue in this phase. Other circular stone structures are positioned along the external perimeter of the platform. Initial analysis of the structural context and the overall material culture, the presence of probable food offerings, suggested by palaeobotanical analysis, and of cremated human remains, make it possible to surmise that the site may have been linked to ritual practices or complex funeral rites. There are considerable similarities between the site of Cles-Campi Neri and the funeral and cult complex dating back to the Copper Age discovered in 2006 at La Vela di Trento (sector Vela IX) in the Adige valley. The cult area developed diachronically according to the principle of horizontal stratigraphy, illustrating the progressive extension of the structure from the centre towards the outside. It was made up of a series of stone rings delimiting the structured platforms. The placing of the remains of human skeletons and animal remains, mostly calcined, on these has been documented, along with archaeological material including flint tools, parts of copper and stone ornaments and occasional pottery sherds. It has also been ascertained that fires were lit. A baby was found buried in a jar (pithos burial) in the southern part of the area investigated. This can be attributed to the Early Bronze Age. The structure brought to light at La Vela very probably represents evidence of more extensive rites and funeral practices linked to the cult of ancestors, according to a practice also documented in other alpine areas.Endrizzi Lorenza, Mottes Elisabetta, Nicolis Franco, Degasperi Nicola. New Evidence of Ancestral Landscape in Trentino in the Copper and Bronze Ages: the Ritual Sites of Cles-Campi Neri and La Vela di Trento. In: Ancestral Landscape. Burial mounds in the Copper and Bronze Ages (Central and Eastern Europe – Balkans – Adriatic – Aegean, 4th-2nd millennium B.C.) Proceedings of the International Conference held in Udine, May 15th-18th 2008. Lyon : Maison de l'Orient et de la MĂ©diterranĂ©e Jean Pouilloux, 2012. pp. 511-522. (Travaux de la Maison de l'Orient et de la MĂ©diterranĂ©e. SĂ©rie recherches archĂ©ologiques, 58

    New Evidence of Ancestral Landscape in Trentino in the Copper and Bronze Ages: the Ritual Sites of Cles-Campi Neri and La Vela di Trento

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    Recent investigations (1999-2007) carried out at the site of Cles-Campi Neri in the Valle di Non have brought to light a circular stone structure which can be attributed to a period between the Late Copper Age and the initial phase of the Early Bronze Age. Two structural phases have been identified. The earlier one saw the presence of a large enclosure made up of large blocks enclosing a smaller structure. The items found at the upper levels are made up of flint tools altered by heat. There are also small agglomerations of calcined human bones. In the subsequent phase the area inside the large enclosure was filled in with a platform made up of stones and pebbles, covered and surrounded by organic soil, in which hundreds of flint tools and flakes have been found, along with rarer fragments of pottery. The agglomerations of calcined human bones continue in this phase. Other circular stone structures are positioned along the external perimeter of the platform. Initial analysis of the structural context and the overall material culture, the presence of probable food offerings, suggested by palaeobotanical analysis, and of cremated human remains, make it possible to surmise that the site may have been linked to ritual practices or complex funeral rites. There are considerable similarities between the site of Cles-Campi Neri and the funeral and cult complex dating back to the Copper Age discovered in 2006 at La Vela di Trento (sector Vela IX) in the Adige valley. The cult area developed diachronically according to the principle of horizontal stratigraphy, illustrating the progressive extension of the structure from the centre towards the outside. It was made up of a series of stone rings delimiting the structured platforms. The placing of the remains of human skeletons and animal remains, mostly calcined, on these has been documented, along with archaeological material including flint tools, parts of copper and stone ornaments and occasional pottery sherds. It has also been ascertained that fires were lit. A baby was found buried in a jar (pithos burial) in the southern part of the area investigated. This can be attributed to the Early Bronze Age. The structure brought to light at La Vela very probably represents evidence of more extensive rites and funeral practices linked to the cult of ancestors, according to a practice also documented in other alpine areas.Endrizzi Lorenza, Mottes Elisabetta, Nicolis Franco, Degasperi Nicola. New Evidence of Ancestral Landscape in Trentino in the Copper and Bronze Ages: the Ritual Sites of Cles-Campi Neri and La Vela di Trento. In: Ancestral Landscape. Burial mounds in the Copper and Bronze Ages (Central and Eastern Europe – Balkans – Adriatic – Aegean, 4th-2nd millennium B.C.) Proceedings of the International Conference held in Udine, May 15th-18th 2008. Lyon : Maison de l'Orient et de la MĂ©diterranĂ©e Jean Pouilloux, 2012. pp. 511-522. (Travaux de la Maison de l'Orient et de la MĂ©diterranĂ©e. SĂ©rie recherches archĂ©ologiques, 58
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