150 research outputs found

    Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure

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    BACKGROUND & AIMS: Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT). METHODS: We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated. RESULTS: A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H. CONCLUSIONS: We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. IMPACT AND IMPLICATIONS: There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment

    Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

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    Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1-3 Infections

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    An analysis and reconstruction of transitive nominalization in Ch’olan languages

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    This paper reconstructs the transitive nominalizing suffix *-yaj (IPA */-jax/) in the Ch’olan branch of Mayan languages. I consider data from modern Chol, Chontal, and Ch’orti’ as well as colonial Ch’olti’ to reconstruct the phonological form and syntactic function of this morpheme. This suffix has been called nominalizing antipassive (e.g., Robertson et al. 2010:186-7), although it does not eliminate the object in all cases. Rather, I analyze it as a more general valency-reducing suffix. Each of the languages has undergone small phonological changes, and all of them allow truncation of the suffix to -aj in certain phonological contexts and in fast speech. This paper argues that the glide is underlying, rather than epenthetic, and that the final consonant reconstructs to the velar fricative /x/ rather than the glottal /h/. It also considers the distribution of these nominalizations in each of the languages, and the additional morphology that can appear on them. In particular, there has been a shift between colonial Ch’olti’ and modern Ch’orti’ in the preferred method for marking the thematic roles of the nominalized verb. Ch’olti’ requires a prepositional phrase to reference the patient or stimulus of the verb if it has been derived into an agentive, while Ch’orti’ uses the Set A possessor for the same function. When there is no agentive prefix in Ch'olti', the Set A proclitic can appear before the nominalization, as in Ch’orti’. Chol and Chontal use the *-yaj suffix very similarly to each other. Although there is some debate about the role of nominalizations in split-ergative languages like these, these particular forms act as syntactic nouns, taking nominal morphology including possessors and being incorporated into verbs like any other noun. Further fieldwork on the distribution of the allomorphs in these languages would be particularly useful, as would a closer study focused on the syntactic distributionLinguistic

    Meteoric fluid‐rock interaction in Variscan shear zones

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    International audienceVariscan shear zones in the Armorican Massif represent sites of strong fluid‐rock interaction. The hydrogen isotope composition of muscovite (δDMs) from syntectonic leucogranite allows to determine the source of fluids that infiltrated the footwall of three detachment zones and the South Armorican Shear Zone. Using temperatures of hydrogen isotope exchange estimated from microstructural data, we calculate the hydrogen isotope ratios of water (δDwater) present within the shear zones during high‐temperature deformation. A ~40‰ difference in δDwater values from deep to shallow crustal level reveals a mixing relationship between deep crustal fluids with higher δD values that range from −34 to −33‰, and meteoric fluids with δD values as low as −74‰ in the upper part of detachment footwalls

    Real-Life Experiences with Telaprevir in the Treatment of Chronic Genotype 1 Hepatitis C — The TEPS Study

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    As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved

    Real-Life Experiences with Telaprevir in the Treatment of Chronic Genotype 1 Hepatitis C — The TEPS Study

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    As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved

    Organic carbon content and carbon isotope variations across the Permo-Triassic boundary in the Gartnerkofel-1 borehole, Carnic Alps, Austria

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    The Gartnerkofel borehole is one of the most thoroughly studied and described Permo-Triassic sections in the world. Detailed bulk organic carbon isotope studies show a negative base shift from − 24‰ to − 28‰ in the Latest Permian which latter value persists into the Earliest Triassic after which it decreases slightly to − 26‰. Two strongly negative peaks of > − 38‰ in the Latest Permian and a lesser peak of − 31‰ in the Early Triassic are too negative to be due to a greater proportion of more negative organic matter and must be due to very negative methane effects. The overall change to more negative values across the Bulla/Tesero boundary fits the relative rise in sea level for this transition based on the facies changes. A positive shift in organic carbon isotope values at the Late Permian Event Horizon may be due to an increase in land-derived organic detritus at this level—a feature shown by all Tethyan Permo-Triassic boundary sections though these other sections do not have the same values. Carbonate carbon isotope trends are similar in all sections dropping by 2–3 units across the Permo-Triassic boundary. Gartnerkofel carbonate oxygen values are surprisingly, considering the ubiquitous dolomitization, compatible with values elsewhere and indicate reasonable tropical temperatures of 60 °C in the Latest Permian sabkhas to 20–40 °C in the overlying marine transition beds. Increased land-derived input at the Late Permian Event Horizon may be due to offshore transport by tsunamis whose deposits have been recognized in India at this level

    Efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist, in primary biliary cholangitis: 52-week analysis of an ongoing international, randomized, dose ranging phase 2 study.

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    Background: Seladelpar is a potent, selective PPARdelta agonist and a candidate therapy for inflammatory liver diseases. We report the safety and efficacy of daily seladelpar treatment for up to 52 weeks from an ongoing open-label phase 2 study in primary biliary cholangitis (PBC). The 52-week time-point has been previously used for regulatory approval. Methods: This open-label study (NCT02955602) randomized PBC patients with either an inadequate response to ursodeoxycholic acid (UDCA) or an intolerance to UDCA and an alkaline phosphatase (AP) ≥1.67 x upper limit of normal (ULN) to seladelpar 5 or 10 mg. After 12 weeks, patients on 5 mg could escalate to 10 mg if AP treatment goal was not met (5/10 mg group). Follow-up to 52 weeks evaluated dose regimens of 5/10 and 10 mg/day. The primary efficacy outcome was the AP % change from baseline. Other outcomes included a responder analysis defined as a composite of AP\u3c1.67 x ULN, ≥15% decrease in AP, and total bilirubin ≤ULN, as well as changes in liver, metabolic, and inflammatory markers. Pruritus was evaluated with a visual analogue scale (VAS). Safety analyses included adverse events (AE) and laboratory markers. Results: As of 7/2018, 119 patients were exposed to at least one dose of seladelpar. In each group, 17 patients completed 52-week treatment. At baseline, mean (SD) AP were 351 (166) U/L and 279 (74) U/L in the 5/10 and 10 mg groups, respectively. At 52 weeks, the mean decreases in AP were-47% and-46% in the 5/10 and 10 mg groups, respectively. At 52 weeks, 59% and 71% of patients responded to the composite efficacy outcome in the 5/10 and 10 mg groups, respectively. AP normalization occurred in 24% and 29% of patients in the 5/10 and 10 mg groups, respectively. Median ALT decreases were-31% and-33% in the 5/10 and 10 mg groups, respectively. Baseline median VAS were 20 and 41 in the 5/10 and 10 mg groups, respectively. Median changes in VAS were-30% and-66% in the 5/10 and 10 mg groups, respectively. There was no transaminase safety signal. There were 11 serious AEs in the study, none considered related to seladelpar. One discontinuation for a grade 1 gastroesophageal reflux was deemed related to seladelpar. Conclusion: Seladelpar maintained a potent anti-cholestatic effect over 52 weeks. Seladelpar was generally safe, well tolerated and not associated with pruritus. A 52-week phase 3 PBC study has been initiated to confirm these results
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