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Background & Aims: We evaluated the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) in difficult-to-treat PWIDs with presumed high risk for non-adherence to antiviral therapy using an innovative concept involving their opioid agonist therapy (OAT) facility., Methods: N = 221 patients (m/f: 168/53; median age: 44.7 years (IQR 16.9); HCV-genotype 3: 45.2%; cirrhosis: 33.9%) treated with SOF/VEL were included. PWIDs at high risk for non-adherence to DAA therapy (n = 122) received HCV treatment alongside OAT under the supervision of medical staff ("directly observed therapy", DOT). These patients were compared to patients with presumed excellent drug compliance, who were treated in a "standard setting" (SS) of SOF/VEL prescription at a tertiary care center (n = 99)., Results: DOT-patients (n = 122/221; 55.2%) were younger than SS-patients (median age: 41.3 vs. 53.0 years), all had psychiatric comorbidities and most had a poor socioeconomic status. 83/122 (68.0%) reported ongoing intravenous drug use. Within the DOT-group, SVR12 was achieved in 99.1% (95% CI: 95.0-100; n = 109/110) with one patient experiencing treatment failure, while n = 12/122 (9.8%) patients were excluded due to loss of follow-up (FU). 5 patients showed HCV reinfection after achieving SVR12. SS-patients achieved SVR in 96.6% (95% CI: 90.3-99.3%; n = 84/87) after exclusion of 10/99 (10.1%) patients who were lost to FU and 2 patients who died prior to SVR12 due to reasons not related to DAA therapy., Conclusions: SOF/VEL given as DOT along with OAT in PWIDs at high risk of non-adherence to antiviral therapy including those with ongoing intravenous drug use resulted in excellent SVR rates similar to patients with presumed "excellent compliance" under standard drug intake., Competing Interests: C. Schmidbauer (schmidbauer.c@gmail.com): received travel support from Gilead, Abbvie and Gebro; and speaking honoraria from Abbvie. M. Schwarz (michael.schwarz@wienkav.at): received travel support from MSD, Sandoz, BMS and Abbvie; and speaking honoraria from BMS. A. Schütz (angelika.schuetz@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. R. Schubert (raphael.schubert@outlook.at): is employed by Suchthilfe Wien gGmbH and received travel support from Gilead. C. Schwanke (cornelia.schwanke@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. E. Gutic (enisa.gutic@extern.wienkav.at): received travel support from Gilead and Abbvie. R. Pirker (roxana.pirker@aon.at): no conflicts of interest. T. Lang (tobiaslang1904@gmail.com): no conflicts of interest. T. Reiberger (thomas.reiberger@meduniwien.ac.at): received grant support from Abbvie, Boehringer- Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fees from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. H. Haltmayer (hans.haltmayer@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. M. Gschwantler (michael.gschwantler@wienkav.at): received grants from Abbvie, Gilead, MSD; speaking honoraria from Abbvie, Gilead, MSD, Janssen, Roche, Intercept; consulting/advisory board fees from Abbvie, Gilead, MSD, Janssen, Roche, Intercept. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Directly acting antivirals (DAA) against hepatitis C virus (HCV) infection have facilitated sustained virologic response (SVR) rates >90% in clinical studies. Yet, real life data regarding DAA treatment in people who inject drugs (PWIDs) are scarce. We evaluated the effectiveness of glecaprevir/pibrentasvir (G/P) in difficult-to-treat PWIDs with presumed high risk of non-adherence to DAA therapy using the concept of directly observed therapy involving their opioid substitution therapy (OST) facility., Methods: N = 145 patients (m/f: 91/54; median age: 41.1 (IQR 19.5) years; HCV-genotype (GT) 1/2/3/4: 82/1/56/5, GT3: 38.6%; cirrhosis: n = 6; 4.1%) treated with G/P were included. PWIDs at high risk for non-adherence to DAA therapy received HCV treatment together with their OST under the supervision of medical staff ("directly observed therapy", DOT). The effectiveness of G/P given as DOT in PWIDs with presumed high risk of non-adherence to DAA therapy was compared to patients with suspected "excellent compliance" in the "standard setting" (SS) of G/P prescription at a tertiary care center and self-managed G/P intake at home. Treatment duration was 8-16 weeks according to the G/P drug label., Results: DOT-patients (n = 74/145; 51.0%) were younger than SS-patients (median 38.7, IQR 12.5 vs. median 50.6, IQR 20.3 years), all had psychiatric co-morbidities and most had a poor socioeconomic status. 50/74 (67.6%) reported ongoing intravenous drug use (IDU). SVR was achieved in n = 70/74 (94.6%) patients with n = 3 being lost to follow-up (FU) and n = 1 showing nonresponse to therapy. SS-patients achieved SVR in 97.2% (69/71) with n = 1 patient being lost to FU and n = 1 patient with GT3 showing HCV relapse., Conclusion: G/P given as DOT along with OST in PWIDs with high risk of non-adherence to DAA therapy resulted in similarly high SVR rates (94.6%) as in patients with presumed "excellent compliance" under standard drug intake., Competing Interests: Competing Interests: C. Schmidbauer (schmidbauer.c@gmail.com): received travel support from Gilead, Abbvie and Gebro. R. Schubert (raphael.schubert@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and received travel support from Gilead. A. Schütz (angelika.schuetz@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. C. Schwanke (cornelia.schwanke@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. J. Luhn (julian.luhn@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. E. Gutic (enisa.gutic@extern.wienkav.at): received travel support from Gilead and Abbvie. R. Pirker (roxana.pirker@aon.at): no conflicts of interest. T. Lang (tobiaslang1904@gmail.com): no conflicts of interest. T. Reiberger (thomas.reiberger@meduniwien.ac.at): received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fees from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. H. Haltmayer (hans.haltmayer@suchthilfe.at): is employed by Suchthilfe Wien gGmbH and has no conflicts of interest. M. Gschwantler (michael.gschwantler@wienkav.at): received grants from Abbvie, Gilead, MSD; speaking honoraria from Abbvie, Gilead, MSD, Janssen, Roche, Intercept; consulting/advisory board fees from Abbvie, Gilead, MSD, Janssen, Roche, Intercept. Suchthilfe Wien gGmbH represents a governmental non-profit organization financed by the City of Vienna and the Austrian Ministry of Health. Suchthilfe Wien gGmbH did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors’ salaries. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Suchthilfe Wien gGmbH provided support in the form of salaries for authors [Raphael Schubert, Angelika Schütz, Cornelia Schwanke, Julian Luhn, Hans Haltmayer], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.“

We describe two new cynodonts from the early Late Triassic of southern Brazil. One taxon, Bonacynodon schultzi gen. et sp. nov., comes from the lower Carnian Dinodontosaurus AZ, being correlated with the faunal association at the upper half of the lower member of the Chañares Formation (Ischigualasto-Villa Unión Basin, Argentina). Phylogenetically, Bonacynodon is a closer relative to Probainognathus jenseni than to any other probainognathian, bearing conspicuous canines with a denticulate distal margin. The other new taxon is Santacruzgnathus abdalai gen. et sp. nov. from the Carnian Santacruzodon AZ. Although based exclusively on a partial lower jaw, it represents a probainognathian close to Prozostrodon from the Hyperodapedon AZ and to Brasilodon, Brasilitherium and Botucaraitherium from the Riograndia AZ. The two new cynodonts and the phylogenetic hypothesis presented herein indicate the degree to which our knowledge on probainognathian cynodonts is incomplete and also the relevance of the South American fossil record for understanding their evolutionary significance. The taxonomic diversity and abundance of probainognathians from Brazil and Argentina will form the basis of deep and complex studies to address the evolutionary transformations of cynodonts leading to mammals., Competing Interests: The authors have declared that no competing interests exist.