A two-center pilot study on the effects of clinical ethics support on coercive measures in psychiatry.

BACKGROUND: The use of formal coercion such as seclusion, mechanical restraint, and forced medication is one of the most challenging and complex issues in mental health care, on the clinical, the legal, and the ethical level. Clinical ethics support aims at assisting healthcare practitioners in determining the morally most justifiable course of action in these situations. However, the effectiveness of clinical ethics support has hardly been studied so far. METHODS: Monthly moral case deliberation (MCD) was implemented in two acute wards of two different psychiatric hospitals in Switzerland. Frequency and intensity of coercion was measured on ward level (npatients = 405), and the Moral Attentiveness Scale, Knowledge on Coercion Scale, and Staff Attitudes towards Coercion Scale were applied on healthcare practitioner level (nHP = 46). Pre-post-comparisons were conducted using multi-level modeling where appropriate. RESULTS: After implementation of MCD, formal coercion was less frequent (particularly seclusion, small effect size; 9.6 vs. 16.7%, p = .034, Cramér's V = .105) and less intense (particularly mechanical restraint, large effect size; 86.8 ± 45.3 vs. 14.5 ± 12.1 h, exact p = .019, r = -.74), and approval for coercive measures among healthcare practitioners was lower when controlling for the number of MCD sessions attended. CONCLUSIONS: Clinical ethics support such as MCD may be a hitherto underutilized service for the reduction of coercion, complementing existing strategies and programs. Implementing clinical ethics support may help improve quality of care for persons suffering from severe mental illness.

Attitudinal variance among patients, next of kin and health care professionals towards the use of containment measures in three psychiatric hospitals in Switzerland.

BACKGROUND: In psychiatric treatment containment measures are used to de-escalate high-risk situations. These measures can be characterized by their immanent amount of coercion. Previous research could show that the attitudes towards different containment measures vary throughout countries. The aim of this study was to compare the attitudes towards containment measures between three study sites in Switzerland which differ in their clinic traditions and policies and their actual usage of these measures. METHODS: We used the Attitude to Containment Measures Questionnaire (ACMQ) in three psychiatric hospitals in Switzerland (Zurich, Muensingen and Monthey) in patients, their next of kin (NOK) and health care professionals (HCP). Furthermore, we assessed the cultural specifics and rates of coercive measures for these three hospitals. RESULTS: We found substantial differences in the usage of and the attitudes towards some containment measures between the three study sites. The study site accounted for a variance of nearly zero in as needed medication to 15% in seclusion. The differences between study sites were bigger in the HCPs' attitudes (up to 50% of the variance), compared to NOK and patients. In the latter the study site accounted for up to 6% of the variance. The usage/personal experience of containment measures in general was associated with higher agreement. CONCLUSIONS: Although being situated in the same country, there are substantial differences in the rates of containment measures between the three study sites. We showed that the HCP's attitudes are more associated with the clinic traditions and policies compared to patients' and their NOKs' attitudes. One can conclude that patients' preferences depend less on clinic traditions and policies. Therefore, it is important to adapt treatment to the individual patients' attitudes. TRIAL REGISTRATION: The study was reviewed and approved by the Cantonal Ethics Commission of Zurich, Switzerland (Ref.-No. EK: 2016-01526, decision on 28.09.2016) and the Cantonal Ethics Commission of Bern, Switzerland (Ref.-Nr. KEK-BE: 2015-00074). This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The permission for conduction of the study was granted by the medical directors at the three study sites. The authors informed the respondents (patients, NOK, HCP) of their rights in the study in an oral presentation and/or a cover letter. They assured the participants of the confidentiality and anonymity of the data, and the voluntariness of participation. Patients were given an information sheet with the possibility to consent in the conduction of the study. Return of the completed questionnaires from HCP and NOK was constituted as confirmation of their consent. No identifying factors were collected to ensure privacy. This article does not contain any studies with animals performed by any of the authors.

Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials.

Over 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BPs) in NS3 at amino acid position 155 or 168 was low (<3%) in patients infected with GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid position 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients infected with GT1 to GT6, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates of ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% of patients and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when the recommended durations are used, allows for a pan-genotypic treatment option without the need for baseline resistance testing.

Integrated Resistance Analysis of CERTAIN-1 and CERTAIN-2 Studies in Hepatitis C Virus-Infected Patients Receiving Glecaprevir and Pibrentasvir in Japan.

Glecaprevir and pibrentasvir are hepatitis C virus (HCV) pangenotypic inhibitors targeting NS3/4A protease and NS5A, respectively. This once-daily, fixed-dose combination regimen demonstrated high sustained virologic response 12 weeks postdosing (SVR12) rates in CERTAIN-1 and CERTAIN-2 studies in Japanese HCV-infected patients, with a low virologic failure rate (1.2%). There were no virologic failures among direct-acting antiviral (DAA)-treatment-naive genotype 1a (GT1a) (n = 4)-, GT1b (n = 128)-, and GT2 (n = 97)-infected noncirrhotic patients treated for 8 weeks or among GT1b (n = 38)- or GT2 (n = 20)-infected patients with compensated cirrhosis treated for 12 weeks. Two of 33 DAA-experienced and 2 of 12 GT3-infected patients treated for 12 weeks experienced virologic failure. Pooled resistance analysis, grouped by HCV subtype, treatment duration, prior treatment experience, and cirrhosis status, was conducted. Among DAA-naive GT1b-infected patients, the baseline prevalence of NS3-D168E was 1.2%, that of NS5A-L31M was 3.6%, and that of NS5A-Y93H was 17.6%. Baseline polymorphisms in NS3 or NS5A were less prevalent in GT2, with the exception of the common L/M31 polymorphism in NS5A. Among DAA-experienced GT1b-infected patients (30/32 daclatasvir plus asunaprevir-experienced patients), the baseline prevalence of NS3-D168E/T/V was 48.4%, that of NS5A-L31F/I/M/V was 81.3%, that of the NS5A P32deletion was 6.3%, and that of NS5A-Y93H was 59.4%. Common baseline polymorphisms in NS3 and/or NS5A had no impact on treatment outcomes in GT1- and GT2-infected patients; the impact on GT3-infected patients could not be assessed due to the enrollment of patients infected with diverse subtypes and the limited number of patients. The glecaprevir-pibrentasvir combination regimen allows a simplified treatment option without the need for HCV subtyping or baseline resistance testing for DAA-naive GT1- or GT2-infected patients. (The CERTAIN-1 and CERTAIN-2 studies have been registered at ClinicalTrials.gov under identifiers NCT02707952 and NCT02723084, respectively.).

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir.

Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pangenotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 to 6 in vitro (half-maximal [50%] inhibitory concentration = 3.5 to 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 to 6 (50% effective concentration [EC50] = 0.21 to 4.6 nM). Glecaprevir had a median EC50 of 0.30 nM (range, 0.05 to 3.8 nM) for HCV replicons containing proteases from 40 samples from patients infected with HCV genotypes 1 to 5. Importantly, glecaprevir was active against the protease from genotype 3, the most-difficult-to-treat HCV genotype, in both enzymatic and replicon assays demonstrating comparable activity against the other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a, and 6a. Although the substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, replicons with these substitutions demonstrated a low replication efficiency in vitro Glecaprevir is active against HCV with most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to other currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pangenotypic activity and a high barrier to the development of resistance.

Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir.

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.

Reasons for living and dying in suicide attempters: a two-year prospective study.

BACKGROUND: The internal suicide debate hypothesis assumes that in a suicidal crisis, individuals are involved in an internal struggle over whether to live or die. Reasons for living (RFL) and Reasons for dying (RFD) are important individual reasons for staying alive (e.g. family) or wanting to die (e.g. hopelessness) and reflect this internal motivational conflict of the suicidal mind. The aim of this study was to explore the association between RFL and RFD of suicide attempters and current and future suicide ideation and behavior. METHOD: The sample consisted of 60 patients who were admitted at a psychiatric emergency unit in Switzerland following an attempted suicide. They received treatment as usual, participated in an assessment interview and completed self-report questionnaires. Additionally, they were instructed to write down up to five individual RFL and RFD. The number of RFL and RFD responses, depressive symptoms, and suicide ideation were assessed at baseline and 6, 12, and 24 months follow-up. Outcome measures were suicide ideation and repeated suicide attempts. Multiple imputations were used in order to address missing data. RESULTS: The number of RFD responses was the strongest predictor for increased suicide ideation at baseline. The number of RFL responses was not associated with suicide ideation and reattempts. RFD, depressive symptoms, and baseline suicide ideation predicted subsequent suicide reattempt up to 12 months later in simple regression analyses. Mediation analyses suggested that RFD mediated the effect of depressive symptoms at baseline on suicide ideation at 12-months follow-up. CONCLUSION: RFL were unrelated to the mental health of study participants and did not function as protective factor against suicide risk. RFD may be an important motivational driver in the suicidal process. Clinical interventions should focus more on the reduction of RFD than on RFL in suicidal individuals.

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.

Analysis of Hepatitis C Virus Genotype 1b Resistance Variants in Japanese Patients Treated with Paritaprevir-Ritonavir and Ombitasvir.

Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance-conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR24) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients.

Discovery of fluorobenzimidazole HCV NS5A inhibitors.

Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.

Hepatitis C virus genotype 4 resistance and subtype demographic characterization of patients treated with ombitasvir plus paritaprevir/ritonavir.

Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse, with 17 confirmed subtypes, and comprises approximately 13% of infections worldwide. In this study, we identified GT4 subtypes by phylogenetic analysis, assessed differences in patient demographics across GT4 subtypes, examined baseline sequence variability among subtypes and the potential impact on treatment outcome, and analyzed the development of viral resistance in patients who received a regimen of ombitasvir (nonstructural protein 5A [NS5A] inhibitor) plus ritonavir-boosted paritaprevir (NS3/4A inhibitor) with or without ribavirin (RBV) for the treatment of HCV GT4 infection. Phylogenetic analysis of HCV NS3/4A, NS5A, and NS5B nucleotide sequences identified 7 subtypes (4a, 4b, 4c, 4d, 4f, 4g/4k, and 4o) among 132 patient samples. Subtype prevalence varied by country, and the distributions of patient birth cohort and race were significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. Baseline amino acid variability was detected in NS5A across GT4 subtypes but had no impact on treatment outcome. Three patients experienced virologic failure and were infected with subtype 4d, and the predominant resistance-associated variants at the time of failure were D168V in NS3 and L28V in NS5A. Overall, high response rates were observed among patients infected with 7 HCV GT4 subtypes, with no impact of baseline variants on treatment outcome. GT4 subtype distribution in this study differed based on patient demographics and geography.

Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir.

AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.).

In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor.

Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.

In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450.

The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.).

In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A.

Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.).

Suicide tourism: a pilot study on the Swiss phenomenon.

While assisted suicide (AS) is strictly restricted in many countries, it is not clearly regulated by law in Switzerland. This imbalance leads to an influx of people-'suicide tourists'-coming to Switzerland, mainly to the Canton of Zurich, for the sole purpose of committing suicide. Political debate regarding 'suicide tourism' is taking place in many countries. Swiss medicolegal experts are confronted with these cases almost daily, which prompted our scientific investigation of the phenomenon. The present study has three aims: (1) to determine selected details about AS in the study group (age, gender and country of residence of the suicide tourists, the organisation involved, the ingested substance leading to death and any diseases that were the main reason for AS); (2) to find out the countries from which suicide tourists come and to review existing laws in the top three in order to test the hypothesis that suicide tourism leads to the amendment of existing regulations in foreign countries; and (3) to compare our results with those of earlier studies in Zurich. We did a retrospective data analysis of the Zurich Institute of Legal Medicine database on AS of non-Swiss residents in the last 5 years (2008-2012), and internet research for current legislation and political debate in the three foreign countries most concerned. We analysed 611 cases from 31 countries all over the world. Non-terminal conditions such as neurological and rheumatic diseases are increasing among suicide tourists. The unique phenomenon of suicide tourism in Switzerland may indeed result in the amendment or supplementary guidelines to existing regulations in foreign countries.

Serious suicidal behaviors: socio-demographic and clinical features in a multinational, multicenter sample.

BACKGROUND: Declared suicidal intent and physical danger are both considered important components in defining suicidal behaviors (SB). AIMS: 1) To investigate characteristics of serious suicidal behaviors (SSB), defined by either suicidal intent or lethality; 2) To determine any difference in terms of socio-demographic, clinical and/or service usage variables between SSB and non-serious suicidal behaviors (NSSB). METHODS: A total of 2631 contacts for SB were registered in the context of the MONSUE (Monitoring Suicidal Behavior in Europe) study project. Demographic and clinical information were registered. ICD-10 was used for classifying data about psychiatric diagnoses, methods used for SB and injuries reported. Clear intentionality, high-case fatality methods and serious injuries all defined SSB (n = 1169; 44.4%) RESULTS: SSB were more often preceded by a contact with an inpatient (either psychiatric or somatic) rather than an outpatient service. Among those having a previous history of SB, SSB subjects had fewer contacts with health services before the previous attempt. The strongest predictors for SSB appeared to be older age and not professing a religion. CONCLUSION: Many of the known factors contributing to the risk of completed suicide were also present for SSB. Our findings on service usage by suicide attempters show which aspects of mental health services should be strengthened in order to improve suicide prevention.

Euthanasia and assisted suicide in selected European countries and US states: systematic literature review.

BACKGROUND: Legal in some European countries and US states, physician-assisted suicide and voluntary active euthanasia remain under debate in these and other countries. OBJECTIVES: The aim of the study was to examine numbers, characteristics, and trends over time for assisted dying in regions where these practices are legal: Belgium, Luxembourg, the Netherlands, Switzerland, Oregon, Washington, and Montana. DESIGN: This was a systematic review of journal articles and official reports. Medline and Embase databases were searched for relevant studies, from inception to end of 2012. We searched the websites of the health authorities of all eligible countries and states for reports on physician-assisted suicide or euthanasia and included publications that reported on cases of physician-assisted suicide or euthanasia. We extracted information on the total number of assisted deaths, its proportion in relation to all deaths, and socio-demographic and clinical characteristics of individuals assisted to die. RESULTS: A total of 1043 publications were identified; 25 articles and reports were retained, including series of reported cases, physician surveys, and reviews of death certificates. The percentage of physician-assisted deaths among all deaths ranged from 0.1%-0.2% in the US states and Luxembourg to 1.8%-2.9% in the Netherlands. Percentages of cases reported to the authorities increased in most countries over time. The typical person who died with assistance was a well-educated male cancer patient, aged 60-85 years. CONCLUSIONS: Despite some common characteristics between countries, we found wide variation in the extent and specific characteristics of those who died an assisted death.

Gender differences in methods of suicide attempts and prevalence of previous suicide attempts.

OBJECTIVE: Suicide attempts are important predictors of completed suicide. Adolescents admitted to the emergency room of a large university hospital in Bern after a suicide attempt during the years 2004-2010 were prospectively assessed for methods of suicide attempt. METHOD: Adolescents (N = 257; 66.5% female; age 14-21 years), presenting after a suicide attempt, were assessed with the WHO/EURO Multicentre Study on Parasuicide assessment tool. RESULTS: Males more often used jumping from a high place (14% vs. 4.6% in females, p < .05) and less often intoxication (36% vs. 71.3%, p < .01). At least one previous suicide attempt was reported in 100 patients (44.4%; more females than males: Cramer-V = 0.21; p = .002). Of these, 35 adolescents did not present to this hospital or not at all for a previous suicide attempt. CONCLUSIONS: The present study is the first to examine methods of suicide attempts according to the ICD-10 X codes in this age group. Gender differences were observed. Because a relevant number of patients did not present to the same hospital or not at all for a previous suicide attempt, studies on pathways to care of adolescents after their first suicide attempt are important for early detection and intervention strategies.

Suicide in breast cancer patients: an individual-centered approach provides insight beyond epidemiology.

BACKGROUND: Epidemiologic studies have identified increased suicide rates among breast cancer (BC) patients. The population-based approach, however, has considerable methodic shortcomings. None of the studies have been carried out in a prospective manner and none reported suicide rates from a country in which physician-assisted suicide (PAS) is legal. PATIENTS AND METHODS: All cases recorded by a prospective Swiss BC database during a 17-year period (1990-2006; n = 1165) were analyzed. Using an individual-centered approach, the cases of women who committed suicide are reported according to the psychological autopsy method. RESULTS: In six patients (0.5%; 5.1/1.000 patients), suicidal death was identified. In four patients, suicide was committed during late stages of metastatic BC. In two cases, comorbid conditions were associated with suicide. Three women chose PAS. CONCLUSION: The individual-centered approach is a well-suited innovative concept to increase the knowledge regarding the relationship between cancer and suicide. We found a two to seven times higher suicide rate than those reported in epidemiologic studies. The population-based approach can barely elucidate the immense variety of one of the most personal decisions: the act of intentionally ending one's own life. These studies suffer from systematic failure of analysis since they did not a) consider the potential confounding role of comorbid medical and/or psychiatric conditions, and b) report in which disease stage suicide was committed, since the decisive disease-related event whether and when metastatic disease occurred was not recorded. Furthermore, epidemiologic data stems from countries in which PAS is prohibited and therefore not included in official statistics. This grey area of medicine accounts for a greater scope of underreporting than had previously been assumed.