Twelve-month effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV from the Canadian cohort of the observational BICSTaR study.

The BICSTaR (BICtegravir Single Tablet Regimen) study is investigating the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with human immunodeficiency virus (HIV) treated in routine clinical practice. BICSTaR is an ongoing, prospective, observational cohort study across 14 countries. Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (≥18 years of age) are being followed for 24 months. We present an analysis of the primary endpoint (HIV-1 RNA < 50 copies/mL; missing-equals-excluded [M = E]) at month 12 in the BICSTaR Canada cohort, including secondary (CD4 count, CD4/CD8 ratio, safety/tolerability) and exploratory (persistence, treatment satisfaction) endpoints. In total, 201 participants were enrolled in the BICSTaR Canada cohort. The analysis population included 170 participants (TN, n = 10; TE, n = 160), with data collected between November 2018 and September 2020. Of the participants, 88% were male, 72% were White, and 90% had ≥ 1 comorbid condition(s). Median (quartile [Q]1-Q3) age was 50 (39-58) years and baseline CD4 count was 391.5 (109.0-581.0) cells/µL in TN participants and 586.0 (400.0-747.0) cells/µL in TE participants. After 12 months of B/F/TAF treatment, HIV-1 RNA was < 50 copies/mL in 100% (9/9) of TN-active participants and 97% (140/145) of TE-active participants (M = E analysis). Median (Q1-Q3) CD4 cell count increased by +195 (125-307) cells/µL in TN participants and by + 30 (-50 to 123) cells/µL in TE participants. Persistence on B/F/TAF was high through month 12 with 10% (1/10) of TN and 7 % (11/160) of TE participants discontinuing B/F/TAF within 12 months of initiation of treatment. No resistance to B/F/TAF emerged. Study drug-related adverse events occurred in 7% (12/169) of participants, leading to B/F/TAF discontinuation in 4 of 169 participants. Improvements in treatment satisfaction were observed in TE participants. B/F/TAF demonstrated high levels of effectiveness, persistence, and treatment satisfaction, and was well tolerated through month 12 in people with HIV treated in routine clinical practice in Canada.

Twelve-month effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV: Real-world insights from BICSTaR cohorts.

BACKGROUND: Real-world evidence is an essential component of evidence-based medicine. The aim of the BICSTaR (BICtegravir Single Tablet Regimen) study is to assess effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in antiretroviral treatment-naïve (TN) and treatment-experienced (TE) people with HIV. METHODS: BICSTaR is a prospective, observational cohort study. Participants (≥18 years) are being followed for 24 months. A pooled analysis is presented at 12 months, with the primary endpoint of effectiveness (HIV-1 RNA <50 copies/mL) and secondary endpoints of safety and tolerability (as per protocol). An exploration of patient-reported outcome measures using standardized questionnaires is included. RESULTS: Between June 2018 and May 2021, 1552 people with HIV were enrolled across 12 countries. The analysed population comprised 1509 individuals (279 TN, 1230 TE); most were white (76%), male (84%) and had one or more comorbid conditions (68%). Median age was 47 years. After 12 months of B/F/TAF treatment, HIV-1 RNA was <50 copies/mL in 94% (221/236) of TN participants and 97% (977/1008) of TE participants. Median CD4 cell count increased by 214 cells/µL (p < 0.001) in TN participants and 13 cells/µL (p = 0.014) in TE participants; median CD4/CD8 ratios increased by 0.30 and 0.03, respectively (both p < 0.001). Persistence was high at 12 months (TN, 97%; TE, 95%). No resistance to B/F/TAF emerged. Study drug-related adverse events occurred in 13% of participants through 12 months, leading to B/F/TAF discontinuation in 6%. CONCLUSIONS: The findings of this study provide robust real-world evidence to support the broad use of B/F/TAF in both TN and TE people with HIV.

Knowledge of Chronic Traumatic Encephalopathy and Concussion Cannot Support a Negligence Suit against Major Sporting Organisations by Athletes. Or Can It?

The settlement of the National Football League (NFL) Players Concussion Litigation was founded on a unique set of circumstances: in essence that the NFL investigated the risk of Chronic Traumatic Encephalopathy-like harm and then denied the risk. These circumstances are unlikely to be repeated in any of the thousands of lawsuits presently proposed by "non-NFL athletes" around the globe. These athletes face the far more difficult task of proving their overseeing sporting organisation had, or should have had, knowledge that repeated head trauma in playing contact sport can cause severe long-term cognitive harm, but to do so relying on "archived" reports dating back decades.

Concussion, Chronic Traumatic Encephalopathy, and the Legal Obligation of Sporting Organisations to be Informed of the Scientific Knowledge of the Day and to Warn of Material Risks.

Athletes, many comparatively young, are reported to have initiated legal action claiming their sporting organisation negligently failed to inform itself of the risk of chronic traumatic encephalopathy (CTE) and to warn its athletes of that risk when sufficient information to do so was available. This article considers the legal obligation of sporting organisations, perhaps through their medical staff, "to be informed" of the risk of CTE, to assess the risk, and to warn their athletes of that risk. The law pertaining to the "medical model", adjusted as to expertise, is proposed as the most suitable test of liability for failure to be informed and to warn. On the basis that CTE is a malady caused by repetitive head trauma, this article argues that delays in acquiring knowledge and warning of the risk of CTE deny athletes the opportunity to make a timely response to the risk of cognitive harm.

Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting.

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R).

The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino[4,5-b]indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound 19. Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that 19 activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9-36)NH2 of the potent endogenous ligand GLP-1(7-36)NH2. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.

Concussion, Chronic Traumatic Encephalopathy and Sport in a Legal Setting.

This article highlights aspects of the medical condition Chronic Traumatic Encephalopathy (CTE) relevant to legal claims in negligence threatened by players of collision and contact sports in Australia against their sporting organisations. CTE is characterised by cognitive dysfunction, irritability, aggression, depression, short-term memory loss, heightened suicidality and ultimately death, which may, in advanced forms, be preceded by dementia and parkinsonism. It is neither the purpose nor intention of this article to consider each element of a negligence claim, but rather to provide a means to understand the foundational and factual basis for such a claim within a legal context. For the litigant the medical literature is foundational to establishing a legal connection between the playing of contact sport and cognitive dysfunction. As the High Court of Australia quoted with approval of a claim of negligent "failure to inform": "the non-disclosed risk must manifest itself into actual injury in order for a plaintiff to establish proximate causation".

Accounting for the increase of children in care in western Australia: What can a client information system tell us?

This paper analyses a fourteen-year period of Western Australian data from the client information system of the Department for Child Protection and Family Support. Western Australia saw a large increase in the number of children in state care similar to trends across Australia as a whole. The study shows the following trends: changes in response to 'referrals' with particular increases in the number of findings of neglect and increasing proportions of these followed swiftly by entry to care; changes in patterns of entry to care with more children under one-year-old entering; increased length of stay of children in care; and, the high incidence of Aboriginal children entering and remaining in care. The data demonstrate unequivocally that increased 'referrals' are not associated with increased substantiations of harm or 'acts of commission with dangerous intent', but that neglect assessed early in the lives of children was the major precipitant for entry to care and particularly so for Aboriginal infants.

Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment.

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.

Responding to information about children in adversity: ten years of a differential response model in Western Australia.

This article uses a comprehensive database about children in adversity collected over the 16-year period from 1990 to 2005 in the state of Western Australia. The focus of this interrogation is the effect of major changes in responses to information about children brought to the attention of the Western Australian statutory authority in a 10-year period during this 16 years. The initiative for these changes was termed New Directions, and its associated policy and practice changes were aimed at differentiating information expressing concerns about children and families from allegations of child maltreatment. They emphasized the provision of supportive and empowering services to families experiencing difficulties - a form of differential response to children in adversity. The article covers the period leading up to the policy and practice change and the 10 years during which these changes were implemented. It examines some effects of the new policy and comments on whether the changes resulted in missed opportunities to protect children from harm, which in turn, might have led to higher rates of re-reporting. The authors present an overall picture of the nature of the information accepted by the statutory authority and how the interpretation of that information might have affected subsequent outcomes for children. In doing so, it shows that the policy and consequential practice changes associated with a differential response mechanism had long lasting positive effects that, despite dire warnings, did not compromise the protection of the small group of children identified as requiring protective interventions.

Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis.

The once daily, single-tablet regimen (STR) combining rilpivirine (RPV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) provides a simplified treatment option for antiretroviral therapy (ART)-naïve patients with baseline HIV-1 RNA (BLVL) of ≤100,000 copies/mL. The aim of this analysis is to compare long-term efficacy, safety, and tolerability of RPV+FTC/TDF vs. efavirenz (EFV)+FTC/TDF as individual components in subjects with BLVL ≤100,000 copies/mL. Week 96 efficacy and safety data from subjects with BLVL ≤100,000 copies/mL, who received daily RPV 25 mg or EFV 600 mg with FTC/TDF in the phase 3, randomized, double-blind, double-dummy, active-controlled, registrational trials ECHO and THRIVE, were analyzed. Virologic response was evaluated by intent-to-treat, time to loss of virological response (ITT-TLOVR), and Snapshot algorithms. Through Week 96, RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF (84% vs. 81%, respectively; ITT-TLOVR) in 543 subjects with BLVL ≤100,000 copies/mL, and overall rates of virologic failure (VF) were 5.9% vs. 2.4%, respectively. Resistance development was lower in Year 2 than Year 1. Subjects in both arms with suboptimal adherence (≤95%) had lower virologic responses (63% vs. 62%, respectively). Treatment with RPV+FTC/TDF was associated with significantly fewer treatment-related adverse events (AEs), grade 2-4 AEs, neurological and psychiatric AEs (including dizziness and abnormal dreams/nightmares), and rash. Additionally, grade 2-4 treatment-emergent laboratory abnormalities and grade 1-3 lipid abnormalities were significantly less common with RPV+FTC/TDF than EFV+FTC/TDF. RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF in ART-naïve subjects with BLVL ≤100,000 copies/mL and was associated with a higher rate of VF but a more favorable safety and tolerability profile through Week 96.

Forward & reverse chemical genetics using SPOS-based combinatorial chemistry.

Combinatorial chemistry is being applied to diverse problems in the biological and pharmaceutical sciences. This review will describe an emerging application called "chemical genetics" or "chemical genomics" - genetics and genomics are often used interchangeably in this context. In forward chemical genomics, chemical libraries are tested in living systems to discover compounds that cause a desirable effect. Subsequently, the protein target is identified using various biochemical and molecular biological tools. By this method, we gain insights into the inner workings of life, and indeed, in some forms this has been the path by which most of the pharmacopoeia was discovered. In reverse chemical genetics, proteins of interest are used to probe compound collections, and those compounds that bind the proteins of interest are used to treat living systems and observed for interesting biological responses. Plausible biological roles of these proteins are inferred from the effects of the compounds because they are assumed to generally inhibit, or more rarely, stimulate, the protein's functions. Interestingly, the reverse genetic approach is emerging as the leading model for drug discovery today. Different methods and cases will be described to illustrate forward and reverse paradigms, including those developed in the author's laboratory.