| 1. |
- Bartlett, Sofia R., et al.
(författare)
-
Sequencing of Hepatitis C Virus for Detection of Resistance to Direct-Acting Antiviral Therapy : A Systematic Review
- 2017
-
Ingår i: HEPATOLOGY COMMUNICATIONS. - : JOHN WILEY & SONS LTD. - 2471-254X. ; 1:5, s. 379-390
-
Forskningsöversikt (refereegranskat)abstract
- The significance of the clinical impact of direct-acting antiviral (DAA) resistance-associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype- and subtype-specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority.
|
|
| 2. |
- Downey, Harriet, et al.
(författare)
-
Training future generations to deliver evidence-based conservation and ecosystem management
- 2021
-
Ingår i: Ecological Solutions and Evidence. - : Wiley. - 2688-8319. ; 2:1
-
Forskningsöversikt (refereegranskat)abstract
- 1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis.2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice.3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses.4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.
|
|
| 3. |
|
|
| 4. |
- Howe, Anita Y. M., et al.
(författare)
-
Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
- 2022
-
Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:5
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure.Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in >-1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing >-2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4.Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized.Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.
|
|
| 5. |
|
|
| 6. |
- Howe, John A., et al.
(författare)
-
Dinoflagellate cysts as proxies for palaeoceanographic conditions in Arctic fjords
- 2010
-
Ingår i: Geological Society, London, Special Publication. - 0305-8719. ; 344, s. 61-74
-
Tidskriftsartikel (refereegranskat)abstract
- The potential of using dinoflagellate cysts as proxies for palaeoceanographic conditions and as monitors of the dynamic marine environment of climatically sensitive Arctic fjords was investigated with sediment traps. Dinoflagellate cysts were analysed from three separate deployments in two high Arctic fjords in the Svalbard archipelago. Two deployments in Kongsfjorden on the west coast of Svalbard occurred during 2002 and 2006–2007 and a deployment in Rijpfjorden on the NE coast occurred during 2006–2007. The cyst production displayed peaks of abundance in the spring and late summer with distinct differences in cyst occurrence in different fjords and in different years. The recorded and identified cyst species were consistent both with the hydrography of the fjords and with changes in cyst composition that are comparable to the seasonal shifts in water mass characteristics. The presence of the heterotrophic species Protoperidinium conicum in Kongsfjorden during 2002 is of note and may reflect the availability of a particular food source possibly associated with the strong influx of Atlantic Water. Cysts recovered from Kongsfjorden during 2006–2007 were dominated by Islandinium minutum, an indicator of cold, polar to subpolar conditions. The temperature and salinity characteristics of the ambient hydrography in this period indicated less influence by Atlantic Water than in 2002, and the cyst production was consistent with regional cyst distribution patterns. In Rijpfjorden, cyst assemblages were dominated by Pentapharsodinium dalei, consistent with the fjord being dominated by full Arctic conditions during the mooring deployment and the possible occurrence of stratified water with high productivity during the spring phytoplankton bloom.
|
|
| 7. |
- Lawitz, Eric, et al.
(författare)
-
Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY) : a randomised, open-label phase 2 trial
- 2015
-
Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 385:9973, s. 1075-1086
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response.METHODS: The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326.FINDINGS: We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]).INTERPRETATION: Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.FUNDING: Merck & Co, Inc.
|
|
| 8. |
|
|
| 9. |
- Lontok, Erik, et al.
(författare)
-
Hepatitis C virus drug resistance-associated substitutions : State of the art summary
- 2015
-
Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 62:5, s. 1623-1632
-
Forskningsöversikt (refereegranskat)abstract
- Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon-free, all-oral combinations of direct-acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct-acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors' trials as a tool to inform the HCV drug development field.
|
|
| 10. |
|
|
