Subsequent Switches Research Articles

Clinical efficacy and safety of new compound single tablet antiviral drugs in the treatment of HIV/AIDS

AimsGenvoya, Biktarvy and Dovato are novel single-tablet antiretroviral therapy(ART). The aim of this study is to explore the therapeutic effects of these novel drugs on HIV/AIDS. Main methodsThis retrospective cohort study, conducted at a single center, included a total of 200 HIV-treated patients who transitioned to these new antiretroviral drugs from July 2021 to August 2023. Data were extracted from electronic medical records at Ditan Hospital. The Genvoya group comprised 22 patients, and all subsequent switches in this group were to Biktarvy. The primary HAART group consisted of 178 patients initially treated with a first-line triple Highly Active Antiretroviral Therapy (HAART) regimen during the same period. This group was further subdivided into HAART+Dovato, HAART+Biktarvy, and HAART+Genvoya groups based on the switching regimen. The primary outcomes focused on changes in viral load and immune efficacy, while secondary safety indicators included blood/liver function, lipid parameters, renal function, blood glucose, blood uric acid, etc. Key findingsThe viral suppression rate was 100 % after the drug change treatment, and CD4+ T cell counts increased significantly across all four groups. Over the 6-month treatment period, there were increases in creatinine (Cr), low-density lipoprotein (LDL), high-density lipoprotein (HDL), erythrocyte count, and glomerular filtration rate (eGFR). Conversely, Alanine transaminase (ALT), Aspartate aminotransferase (AST), C-reactive protein (CRP), albumin (ALB), and blood glucose (Glu) levels decreased. SignificanceGenvoya, Biktarvy and Dovato are recommended for the treatment of HIV/AIDS and have a good safety profile.

The influence of reward and loss outcomes after free- and forced-tasks on voluntary task choice

In four experiments, we investigated the impact of outcomes and processing mode (free versus forced) on subsequent voluntary task-switching behavior. Participants freely chose between two tasks or were forced to perform one, and the feedback they received randomly varied after correct performance (reward or no-reward; loss or no-loss). In general, we reasoned that the most recently applied task goal is usually the most valued one, leading people to prefer task repetitions over switches. However, the task values might be additionally biased by previous outcomes and the previous processing mode. Indeed, negatively reinforcing tasks with no-reward or losses generally resulted in more subsequent switches. Additionally, participants demonstrated a stronger attachment to free- compared to forced-tasks, as indicated by more switches when the previous task was forced, suggesting that people generally value free over forced-choice task goals. Moreover, the reward manipulation had a greater influence on switching behavior following free- compared to forced-tasks in Exp. 1 and Exp. 3, suggesting a stronger emphasis on evaluating rewarding outcomes associated with free-task choices. However, this inflationary effect on task choice seemed to be limited to reward and situations where task choice and performance more strongly overlap. Specifically, there was no evidence that switching behavior was differentially influenced after free-and forced-task as a function of losses (Exp. 2) or reward when task choice and task performance were separated (Exp. 4). Overall, the results provide new insights into how the valuation of task goals based on choice freedom and outcome feedback can influence voluntary task choices.

SHORT- AND LONG-RUN EFFECTS OF DEVALUATIONS: EVIDENCE FROM ARGENTINA

ABSTRACTDevaluations were traditionally considered to be expansionary in the short run and have no real long-run effects. Alternatively, some observers in developing countries found that devaluations were contractionary on impact, and that they might foster long-term growth. Using Argentina as a case study, which is convenient due to its long series availability and its subsequent switches in exchange rate regimes, four structural shocks are identified in line with the traditional and alternative views. It is found that devaluations were mostly contractionary, and that real long-run effects were only possible when inflation was either low or moderate. In light of the estimates, a historical revision of Argentinean devaluation episodes from 1854 to 2018 has been carried out.

International cohort study on the effectiveness of dronedarone and other antiarrhythmic drugs for atrial fibrillation in real-world practice (EFFECT-AF)

AimsTo evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences.Methods and resultsAn international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85–1.42); adjusted HR 1.16 (0.87–1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone.ConclusionIn this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence.

Emergence of New ST301 Shiga Toxin-Producing Escherichia coli Clones Harboring Extra-Intestinal Virulence Traits in Europe.

O80:H2 enterohemorrhagic Escherichia coli (EHEC) of sequence type ST301 is one of the main serotypes causing European hemolytic and uremic syndrome, but also invasive infections, due to extra-intestinal virulence factors (VFs). Here, we determined whether other such heteropathotypes exist among ST301. EnteroBase was screened for ST301 strains that were included in a general SNP-phylogeny. French strains belonging to a new heteropathotype clone were sequenced. ST, hierarchical clusters (HC), serotype, resistome, and virulome were determined using EnteroBase, the CGE website, and local BLAST. The ST301 general phylogeny shows two groups. Group A (n = 25) is mainly composed of enteropathogenic E. coli, whereas group B (n = 55) includes mostly EHEC. Three serotypes, O186:H2, O45:H2 and O55:H9, share the same virulome as one of the O80:H2 sub-clones from which they derive subsequent O-antigen switches. The O55:H9 clone, mainly present in France (n = 29), as well as in the UK (n = 5) and Germany (n = 1), has a low background of genetic diversity (four HC20), although it has three Stx subtypes, an H-antigen switch, and genes encoding the major extra-intestinal VF yersiniabactin, and extended-spectrum beta-lactamases. Diverse heteropathotype clones genetically close to the O80:H2 clone are present among the ST301, requiring close European monitoring, especially the virulent O55:H9 clone.

Predictive factors for switching in patients with psoriatic arthritis undergoing anti-TNF\u03b1, anti-IL12/23, or anti-IL17 drugs: a 15-year monocentric real-life study

ObjectivesWe aimed to evaluate the (a) potential predictors of first biological disease-modifying anti-rheumatic drug (bDMARD) failure and (b) factors associated with failure of multiple therapies in psoriatic arthritis (PsA).Materials and methodsWe enrolled consecutive PsA patients attending our unit and undergoing bDMARDs during 2004–2020. Disease characteristics, previous/ongoing treatments, comorbidities, and follow-up duration were recorded. Disease activity and functional and clinimetric scores were recorded at baseline and yearly and were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Effectiveness was evaluated over time with descriptive statistics; multivariate Cox and logistic regression models were used to evaluate predictors of response and failure of multiple bDMARDs. Kaplan–Meier curves were used to assess differences in time-to-first bDMARD discontinuation. Infections and adverse events were recorded.ResultsTwo hundred sixty-four patients were included (117 (44.32%) females, mean age 56 years, mean PsA duration 15 years); 117 (44.32%) switched bDMARDs at least once. Switchers were mostly females, with higher Psoriasis Area and Severity Index and worse Health Assessment Questionnaire at baseline. Mean time-to-first bDMARD discontinuation was 72 months; 2-year and 5-year retention rates were 75% and 60%, respectively. Survival curves for anti-TNFα/anti-IL12/23/anti-IL17 were similar (p = 0.66). Main reasons for switching were inefficacy (67.52%) and adverse events (25.7%). Female sex was associated with a higher risk of first bDMARD discontinuation (HR = 2.39; 95% CI: 1.50–3.81) and failure of multiple bDMARDs (OR = 1.99; 95% CI: 1.07–3.69); initiating therapy before 2015 was protective (HR = 0.40; 95% CI: 0.22–0.73).ConclusionsSurvival rate was good for anti-TNFα and other bDMARDs. Female sex was a predictor of first bDMARD discontinuation, unlike mechanism of action, comorbidities, and BMI.Key Points• Drug survival in PsA patients was confirmed be greater for the first bDMARD administered.• In case of failure of the first bDMARD, switching/swapping proved a good treatment option, as reflected by a persistent satisfactory effectiveness with second-line bDMARDs and so subsequent switches.• Female sex may constitute a predisposing risk factor for flare and therapeutic switches.• Discontinuation or switching of biologics due to mechanism of action, comorbidities tolerability and BMI did not seem to impact first bDMARD withdrawal.

Infliximab Therapeutic Drug Monitoring in Inflammatory Bowel Disease Virtual Biologics Clinic Leads to Durable Clinical Results

Background: Therapeutic drug monitoring (TDM) of infliximab (IFX) trough levels and anti-drug antibodies in conjunction with symptoms, disease history, and investigations can aid decision-making. This study evaluated 1-year outcomes of patients with decisions that were altered on the basis of TDM results, in order to investigate whether outcomes from TDM-based decisions to adjust or stop IFX treatment are durable. Methods: We retrospectively collected clinical outcomes 12 months post treatment decisions based on proactive TDM. Patients whose initial treatment decisions were altered on the basis of TDM results were compared with those where the decision remained unchanged. Events of interest were inpatient admissions with active inflammatory bowel disease (IBD), further changes to biologic therapy, and IBD-related health-care costs. Results: Of 189 patients, 54 (28%) had initial treatment decisions altered in the light of TDM results. The 135 patients whose initial decision was not altered in light of TDM results served as the comparator. There were no differences in hospitalization rates or subsequent biologic switches between the altered decision groups and the comparator group. IBD-related health-care costs were higher in those whose initial decision was altered (median GBP 7,912 vs. GBP 6,521; p < 0.0001) due to higher drug costs (median GBP 7,062 vs. GBP 6,012; p < 0.0001). Conclusion: Our study demonstrates good outcomes from changes to IFX treatment based on TDM. Patients with a decision to stop, switch, or continue with an adjusted IFX dose experienced comparable clinical outcomes but had higher drug-related expenditure than those whose treatment decision was not altered in light of TDM.

Bivalent genes that undergo transcriptional switching identify networks of key regulators of embryonic stem cell differentiation

BackgroundBivalent promoters marked with both H3K27me3 and H3K4me3 histone modifications are characteristic of poised promoters in embryonic stem (ES) cells. The model of poised promoters postulates that bivalent chromatin in ES cells is resolved to monovalency upon differntiation. With the availability of single-cell RNA sequencing (scRNA-seq) data, subsequent switches in transcriptional state at bivalent promoters can be studied more closely.ResultsWe develop an approach for capturing genes undergoing transcriptional switching by detecting ‘bimodal’ gene expression patterns from scRNA-seq data. We integrate the identification of bimodal genes in ES cell differentiation with analysis of chromatin state, and identify clear cell-state dependent patterns of bimodal, bivalent genes. We show that binarization of bimodal genes can be used to identify differentially expressed genes from fractional ON/OFF proportions. In time series data from differentiating cells, we build a pseudotime approximation and use a hidden Markov model to infer gene activity switching pseudotimes, which we use to infer a regulatory network. We identify pathways of switching during differentiation, novel details of those pathway, and transcription factor coordination with downstream targets.ConclusionsGenes with expression levels too low to be informative in conventional scRNA analysis can be used to infer transcriptional switching networks that connect transcriptional activity to chromatin state. Since chromatin bivalency is a hallmark of gene promoters poised for activity, this approach provides an alternative that complements conventional scRNA-seq analysis while focusing on genes near the ON/OFF boundary of activity. This offers a novel and productive means of inferring regulatory networks from scRNA-seq data.

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches.

HIV-1 subtypes A1 and D cocirculate in a rural community in Mbarara, Uganda. This study examines HIV-1 intersubtype recombination in this community under a full-genome sequencing context. We aim to estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with intersubtype recombinants. Near-full-genome HIV-1 Sanger sequence data were collected from plasma samples of 504 treatment-naïve individuals, who then received protease inhibitor or nonnucleoside reverse transcriptase inhibitor-containing regimens and were monitored for up to 7.5 years. Subtypes were inferred by Los Alamos Recombinant Identification Program (RIP) 3.0 and compared with Sanger/REGA and MiSeq/RIP. 'Nonrecombinants' and 'recombinants' infections were compared in terms of pretherapy viral load, CD4 cell count, posttherapy time to virologic suppression, virologic rebound, first CD4 rise above baseline and sustained CD4 recovery. Prevalence of intersubtype recombinants varied depending on the genomic region examined: gag (15%), prrt (11%), int (8%), vif (10%), vpr (2%), vpu (9%), GP120 (8%), GP41 (18%), and nef (4%). Of the 200 patients with near-full-genome data, prevalence of intersubtype recombination was 46%; the most frequently observed recombinant was A1-D (25%). Sanger/REGA and MiSeq/RIP yielded generally consistent results. Phylogenetic tree revealed most recombinants did not share common ancestors. No temporal trend was observed (all P > 0.1). Subsequent subtype switches were detected in 27 of 143 (19%) study participants with follow-up sequences. Nonrecombinant versus recombinants infections were not significantly different in any pre nor posttherapy clinical correlates examined (all P > 0.2). Intersubtype recombination was highly prevalent (46%) in Uganda if the entire HIV genome was considered, but was neither associated with clinical correlates nor therapy outcomes.

A strategy to improve phasing of whole-genome sequenced individuals through integration of familial information from dense genotype panels

BackgroundHaplotype reconstruction (phasing) is an essential step in many applications, including imputation and genomic selection. The best phasing methods rely on both familial and linkage disequilibrium (LD) information. With whole-genome sequence (WGS) data, relatively small samples of reference individuals are generally sequenced due to prohibitive sequencing costs, thus only a limited amount of familial information is available. However, reference individuals have many relatives that have been genotyped (at lower density). The goal of our study was to improve phasing of WGS data by integrating familial information from haplotypes that were obtained from a larger genotyped dataset and to quantify its impact on imputation accuracy.ResultsAligning a pre-phased WGS panel [~5 million single nucleotide polymorphisms (SNPs)], which is based on LD information only, to a 50k SNP array that is phased with both LD and familial information (called scaffold) resulted in correctly assigning parental origin for 99.62% of the WGS SNPs, their phase being determined unambiguously based on parental genotypes. Without using the 50k haplotypes as scaffold, that value dropped as expected to 50%. Correctly phased segments were on average longer after alignment to the genotype phase while the number of switches decreased slightly. Most of the incorrectly assigned segments, and subsequent switches, were due to singleton errors. Imputation from 50k SNP array to WGS data with improved phasing had a marginal impact on imputation accuracy (measured as r2), i.e. on average, 90.47% with traditional techniques versus 90.65% with pre-phasing integrating familial information. Differences were larger for SNPs located in chromosome ends and rare variants. Using a denser WGS panel (~13 millions SNPs) that was obtained with traditional variant filtering rules, we found similar results although performances of both phasing and imputation accuracy were lower.ConclusionsWe present a phasing strategy for WGS data, which indirectly integrates familial information by aligning WGS haplotypes that are pre-phased with LD information only on haplotypes obtained with genotyping data, with both LD and familial information and on a much larger population. This strategy results in very few mismatches with the phase obtained by Mendelian segregation rules. Finally, we propose a strategy to further improve phasing accuracy based on haplotype clusters obtained with genotyping data.

Ecological forensics: using single point stable isotope values to infer seasonal schedules of animals after two diet switches

Summary Animals adjust to seasonal challenges in physical, behavioural and spatial ways. Such adjustments are commonly associated with diet changes that often can be characterised isotopically. We introduce the ‘double diet switch model’, with which the occurrence and timing of two subsequent diet switches of an individual animal can be traced with a single sample assayed for stable isotopes. We demonstrate the model for Sanderling, Calidris alba, a small shorebird that migrates from the Nearctic tundra breeding grounds to the intertidal flats of the Wadden Sea; during this migration some birds may stage in the North Atlantic areas. The ‘double diet switch model’ successfully predicted the occurrence and timing of two diet switches in 59 Sanderlings captured in the Wadden Sea in July–September. Excluding birds that likely had over‐summered at North Atlantic staging areas, the model predicted that Sanderlings departed from the Arctic on 13 July (range: 9–17 July), had a staging duration of 18·6 days in the North Atlantic, and arrived in the Wadden Sea on 1 August (31 July–1 August).The estimated mean Arctic departure dates coincided with the mean hatching date, suggesting that many individuals failed to produce young or left the care to a partner. Estimated mean arrival date matched the main arrival period in the Wadden Sea obtained from observation data. In this study we did not use lipid‐free tissues, which may bias model predictions. After correcting for lipid components, the estimated departure date was 11 days later and the staging duration 8·5 days shorter, while arrival date was similar. The ‘double diet switch model’ successfully identified the occurrence and timing of two subsequent diet switches. The ‘double diet switch model’ will not only apply to switches between three isotopic levels (as in the case study on Sanderling) but also to scenarios where the second switch reverses to the initial isotopic level. Due to this general applicability, the model can be adapted to a wide range of taxa and situations. Foreseeable applications include changes in habitat and food type, ontogenetic development or drastic phenotypic changes such as the metamorphosis in insects and amphibians.

Sequential Temporal Discrimination in Humans and Mice

Previous studies showed that humans and mice can maximize their rewards in two alternative temporal discrimination tasks by incorporating exogenous probabilities and endogenous timing uncertainty into their decisions. The current study investigated if the probabilistic relations modulated the temporal discrimination performance in scenarios with more than two temporal options. In order to address this question, we tested humans (Experiment 1) and mice (Experiment 2) in the dual-switch task, which required subjects to discriminate three time intervals (short, medium, and long durations) in a sequential fashion. The latencies of switches from short to medium and from medium to long option were the main units of analysis. The results revealed that the timing of switches between the first two options (short-to-medium) were sensitive to probabilistic information in both humans and mice. However, mice but not humans adapted the timing of their subsequent switches between the last two options (medium-to-long) based on the probabilistic information associated with these latter options. These results point at a suboptimal tendency in the temporal decisions of humans with multiple options.

Abstract 213: Fat Tissue specific Adipose Triglyceride Lipase as a major determinant for the development of pressure overload-induced heart failure

Introduction: Myocardial metabolism undergoes change in response to pathological cardiac hypertrophy (PH), characterized by increased reliance on glucose oxidation, decreased free fatty acid (FFA) oxidation and a loss of metabolic flexibility. Cardiac metabolism is influenced by other organs such as adipose tissue. Hence, we aimed to investigate the effect of Adipose Triglyceride Lipase (ATGL) in adipose tissue on the development of PH and heart failure (HF) in a pressure overload-induced cardiac hypertrophy model in mice. Methods: Male adipose tissue specific ATGL-knock out (atATGL-KO) and wild type mice (WT) underwent sham surgery (sham) or transverse aortic constriction (TAC). After 11 weeks, mice were sacrificed and organs were harvested. We performed echocardiography one week before and 11 weeks after surgery. Left ventricular mass (LVM), left ventricular mass/tibia length (LVM/TL) and ejection fraction (EF) were calculated. Beta-myosin heavy chain (β-MyHC) was measured in RNA of hearts. Insulin resistance was assessed by an intraperitoneal glucose tolerance test (GTT) and an insulin tolerance test (ITT). FFAs were measured in serum in total. Results: LVM and LVM/TL in WT was significantly higher compared to atATGL-KO after TAC (LVM/TL [mg/mm] WT-TAC: 18,0±2,2; atATGL-KO-TAC: 13,1±2,3; p&lt;0,01). The higher increase of LVM in WT was associated with a larger left ventricle internal diameter. Reduction of EF was significantly more pronounced in WT compared to atATGL-KO ([%] WT: 28,81±6,9 atATGL-KO: 42,39±4,5; p&lt;0,01). Beta-MyHC, a marker for PH, was markedly higher in WT-TAC than in atATGL-KO-TAC (WT-TAC: 11,3±3,6; atATGL-KO-TAC: 1.9±0,6; p&lt;0,01). While WT-TAC showed higher Serum FFA-levels than atATGL-KO-TAC ([mmol/l] WT-TAC: 0,97±0,086; atATGL-KO-TAC: 0,49±0,032; p&lt;0,001), GTT and ITT revealed a higher insulin sensitivity in atATGL-KO-TAC compared to WT-TAC. Conclusion: The present study demonstrates that atATGL is a crucial determinant for the development of pressure overload-induced PH and HI. The lack of ATGL in adipose tissue, the associated reduction of fatty acid release in the circulation and subsequent switches in cardiac energy substrates from free fatty acids to glucose are potential underlying mechanisms of this process.

Using OPNET to Model and Evaluate the MU Performance based on IEC 61850-9-2LE

The growth of IEC61850-9-2 process bus as a high data rate communication network have a great improved the capability of substation automation system (SAS). This paper discuss a modelling concept of intelligent electronic devices (IED) using OPNET modeller simulation tool. Simulation tool provides a comprehensive development environment for the specification modelling, system simulation and also facilitate performance evaluation of the system under study with different topologies that guide the SAS network engineers based on planning and design. Several testing has been made based on the modelled merging unit (MU) IED within two scenarios. The behaviour of the Ethernet switches with the sampled value (SV) traffic stream has been discussed within the first scenario. It shows that the first Ethernet switch experienced more latency than the subsequent switches based on it serialized the bunched SV frames whereas the subsequent switches experienced less latency in which that may facilitate the design of the large SAS that consist more than one Ethernet switch to reduce the cabling between switchyard and control station. SV traffic stream latencies have been evaluated to assess the limits and capacity of the process bus network critical components and shows that the overall of the 19 MUs latency is within the acceptable latency range (250μs). However based on adding MUs 20-23 the latency has been increased significantly within scenario two.

Performance Analysis of IEC 61850 Sampled Value Process Bus Networks

Process bus networks are the next stage in the evolution of substation design, bringing digital technology to the high-voltage switchyard. Benefits of process buses include facilitating the use of nonconventional instrument transformers, improved disturbance recording and phasor measurement, and the removal of costly, and potentially hazardous, copper cabling from substation switchyards and control rooms. This paper examines the role a process bus plays in an IEC 61850-based substation automation system. Measurements taken from a process bus substation are used to develop an understanding of the network characteristics of “whole of substation” process buses. The concept of “coherent transmission” is presented, and the impact of this on Ethernet switches is examined. Experiments based on substation observations are used to investigate in detail the behavior of Ethernet switches with sampled value traffic. Test methods that can be used to assess the adequacy of a network are proposed, and examples of the application and interpretation of these tests are provided. Once sampled value frames are queued by an Ethernet switch, the additional delay incurred by subsequent switches is minimal, and this allows their use in switchyards to further reduce communications cabling, without significantly impacting operation. The performance and reliability of a process bus network operating close to the theoretical maximum number of digital sampling units (merging units or electronic instrument transformers) was investigated with networking equipment from several vendors and has been demonstrated to be acceptable.

Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA cohort.

Toxicity is the most important reason for premature switching of highly active antiretroviral therapy (HAART). In order to optimize the benefit-risk ratio of HAART, guidelines for toxicity management are needed. An observational cohort study to estimate the incidence and identify determinants of toxicity-driven switches on second-line HAART after having switched first-line HAART despite successful viral suppression. Patients were selected from those in the ATHENA cohort (n = 2470) who switched the initial HIV protease inhibitor (PI)-containing HAART while plasma HIV-1 RNA was <or= 500 copies/ml (n = 775). One-year cumulative incidences of subsequent toxicity-driven switches and adjusted relative risks (RR) for potential determinants were calculated. The 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24% [95% confidence interval (CI), 21-28], mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch (RR, 2.5; 95% CI, 1.7-3.5). Switching from PI to nevirapine while continuing the other antiretroviral drugs was more protective against a subsequent switch because of further toxicity than changing to another PI-containing regimen (RR, 0.2; 95% CI, 0.1-0.6). As for first-line HAART, toxicity is responsible for the majority of switches during second-line HAART. Prior switching for toxicity increased the risk of having to switch the subsequent regimen for toxicity, but this risk is reduced when switching to nevirapine rather than to an alternative PI. The latter should be taken into account when designing toxicity-management guidelines.

Cost Implications of Initial Antidepressant Selection in Primary Care

While fluoxetine is considerably more expensive than tricyclic antidepressants (TCAs), some previous studies have suggested that general medical expenditures are lower among patients treated with fluoxetine. In this study, computerised pharmacy and cost-accounting records of a large health plan were used to examine overall treatment costs for 5169 primary-care patients beginning antidepressant treatment with fluoxetine or one of 2 TCAs, imipramine or desipramine. Comparison was based on initial medication prescribed, regardless of subsequent switches or discontinuation. Patients treated with fluoxetine were older, with a higher burden of medical illness and higher overall health-service costs before starting antidepressant treatment, compared with patients receiving the other 2 drugs. Initial choice of fluoxetine was associated with approximately $US140 higher mean antidepressant costs and approximately $US300 higher mean costs for all other health services (1995 costs). Alternative methods of accounting for baseline differences (age, medical comorbidity, prior costs) indicated that adjusted 'non-antidepressant' costs (total costs minus costs of antidepressant therapy) in the fluoxetine group were $US75 to $US300 lower than in either of the TCA groups, but these differences were not statistically significant. Subgroup analyses suggested that the use of fluoxetine was associated with lower overall costs only among those incurring high costs in the pretreatment period. These findings support earlier studies suggesting that the use of fluoxetine as a first-line antidepressant in primary care will increase antidepressant drug costs, but will not significantly increase total treatment costs.