Results of Antiretroviral Treatment Interruption and Intensification in Advanced Multi-Drug Resistant HIV Infection from the OPTIMA Trial

BACKGROUND: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. METHODS AND FINDINGS: We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. CONCLUSIONS: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. TRIAL REGISTRATION: Clinicaltrials.gov NCT00050089

MEE-DBD Plasma Actuator Effect on Aerodynamics of a NACA0015 Aerofoil: Separation and 3D Wake

© 2020, Springer Nature Switzerland AG. Dielectric barrier discharge (DBD) plasma actuators have received considerable attention by many researchers for various flow control applications. Having no moving parts, being light-weight, easily manufacturable, and their ability to respond almost instantly are amongst the advantages which has made them a popular flow control device especially for application on aircraft wings. The new configuration of DBDs which uses multiple encapsulated electrodes (MEE) has been shown to produce a superior and more desirable performance over the standard actuator design. The objective of the current study is to examine the effect of this new actuator configuration on the aerodynamic performance of an aerofoil under leading edge separation and wake interaction conditions. The plasma actuator is placed at the leading edge of a symmetric NACA 0015 aerofoil which corresponds to the location of the leading edge slat. The aerofoil is operated in a chord Reynolds number of 0.2×106. Surface pressure measurements along with the mean velocity profile of the wake using pitot measurements are used to determine the lift and drag coefficients, respectively. Particle image velocimetry (PIV) is also utilised to visualise and quantify the induced flow field. The results show improvement in aerodynamic performances of aerofoil under leading edge separation and also facing the wake region

DETERMINING MENTAL HEALTH CONDITION PATTERNS IN VETERANS WITH A LIFETIME PTSD DIAGNOSIS

Background: Post-traumatic stress disorder (PTSD) is a mental health condition with symptoms that negatively affect social and work situations, as well as permanent employment and income. A randomized, controlled, multisite clinical trial was carried out by the Veterans Affairs Cooperative Study Program (VACSP) from 2013 to 2017 to compare two different interventions aimed at helping Veterans obtain and maintain competitive employment: the Individual Placement and Support (IPS) intervention, and the Transitional Work (TW) program. The IPS intervention included individual career and job counseling while the TW program provided temporary, ‘set-aside’ employment within VA facilities. The primary outcome was “steady worker” status, defined as holding competitive jobs for at least 50% of the trial follow-up time. The results showed that a higher proportion of participants randomized to IPS gained steady employment compared to those randomized to TW. The primary analysis did not, however, investigate the interactions between the severity of PTSD Symptoms and the participant’s ability to function in social and work settings. In the current analysis we explored the relationships between these aspects and assessed how these relationships varied among groups of Veterans with common baseline characteristics. Method: We conducted a latent profile analysis using data from this trial, searching for possible subgroups of participants with distinct mental health condition patterns. The profiles were determined using scores derived from four baseline assessments designed to measure: (i) the severity of PTSD Symptoms; (ii) the Veteran’s quality of life; (iii) the Veteran’s level of disability, and (iv) the Veteran’s self-esteem prior to the interventions. We subsequently examined the relationships between the resultant profiles and the probability of achieving competitive employment. We also compared the cumulative earnings of Veterans in the different profiles who acquired competitive jobs. Results: We identified three distinct groups: Group 1 was composed of Veterans with severe PTSD Symptoms, high disability, low quality of life and low self-esteem. Group 2 was characterized by Veterans with both a low PTSD Symptoms score and disability score, and good quality of life and self-esteem. Lastly, Group 3 included Veterans with better conditions than Veterans in Group 1 but worse than those in Group 2. Regardless of the treatment, Veterans in Group 3 were more likely to become steady workers compared to Veterans in Group 1 and Group 2. The probability of achieving permanent employment increased for Veterans in Group 3 who were randomized to IPS compared to Veterans randomized to the same intervention but belonging to Group 1 and 2. Coherently, Veterans in Profile 3 worked significantly more hours/days and earned higher incomes from competitive jobs than those in the other two group profiles. Conclusion: Our analysis found a difference in severity of PTSD symptoms and baseline function characteristics among Veterans with lifetime PTSD diagnosis. The identification of such baseline characteristics that increase an individual’s chances of gaining permanent employment can perhaps be used to guide more individualized interventions

Determining Mental Health Condition Patterns in Veterans with a Lifetime PTSD Diagnosis

Post-traumatic stress disorder (PTSD) is a mental disorder with symptoms that affect social and work situations, employment, and income. A randomized, controlled, multisite clinical trial was carried out by the VA Cooperative Study Program to compare two different interventions aimed at helping Veterans obtain and maintain competitive employment: the Individual Placement and Support (IPS) intervention, and the Transitional Work (TW) program. The IPS intervention included individual job counseling while the TW program provided temporary employment within VA facilities. We performed a latent profile analysis, searching for classes of patients with distinct mental health condition patterns. Classes were determined by 4 scores derived from Veterans’ baseline assessments which measured: severity of PTSD Symptoms, quality of life, level of disability, and selfesteem. We studied the relationships between the classes and the probability of achieving permanent employment. We also compared the cumulative earnings of Veterans across classes. The identification of aspects that increase the chances of gaining a permanent job could guide more individualized interventions

The VACS index accurately predicts mortality and treatment response among multi-drug resistant HIV infected patients participating in the options in management with antiretrovirals (OPTIMA) study

Abstract Objectives The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. Methods Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel’s C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. Results Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14–0.49) and 0.39(95% CI 0.22–0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27–3.38) and 1.51 (95%CI 0.90–2.53) for the 25% least improved scores. Conclusions The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research

The VACS index accurately predicts mortality and treatment response among multi-drug resistant HIV infected patients participating in the options in management with antiretrovirals (OPTIMA) study

Abstract Objectives The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. Methods Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel’s C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. Results Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14–0.49) and 0.39(95% CI 0.22–0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27–3.38) and 1.51 (95%CI 0.90–2.53) for the 25% least improved scores. Conclusions The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research

Cost-effectiveness of newer antiretroviral drugs in treatment-experienced patients with multidrug-resistant HIV disease.

OBJECTIVE: Newer antiretroviral drugs provide substantial benefits but are expensive. The cost-effectiveness of using antiretroviral drugs in combination for patients with multidrug-resistant HIV disease was determined. DESIGN: A cohort state-transition model was built representing treatment-experienced patients with low CD4 counts, high viral load levels, and multidrug-resistant virus. The effectiveness of newer drugs (those approved in 2005 or later) was estimated from published randomized trials. Other parameters were estimated from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of 2 newer drugs and 1 conventional drug, compared with 3 conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness. RESULTS: Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared with conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost$54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting 3 newer drugs cost$105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued. CONCLUSIONS: In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost-effective, given a cost-effectiveness threshold in the range of$50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior