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The additional 48-week optional treatment extension of the T-20 versus Optimized Regimen Only (TORO) studies evaluated long-term safety and efficacy of enfuvirtide (ENF) through week 96 in patients receiving ENF plus optimized background (OB) and patients switching to ENF plus OB from OB alone. Patient randomization was 2:1 to ENF plus OB (n = 663) and OB (n = 334), of which 89.7% and 89.8% were male, 89.3% and 88.6% were Caucasian, and median age was 41 and 42 years, respectively. HIV risk factors were comparable between the ENF plus OB and OB groups with the major factors being 65.2% versus 66.2% homosexual contact, 17.8% versus 19.8% heterosexual contact, 4.1% versus 4.8% bisexual contact, respectively, and 6.9% injection drug use in both groups. OB patients were allowed to switch to ENF plus OB at virologic failure before week 48 and required to switch at week 48 to continue in the study (n = 230). Efficacy and safety assessments were conducted for each group. At week 96, 55% of ENF plus OB subjects completed the study and 26.5% achieved a viral load of less than 400 copies per milliliter (17.5% achieved less than 50 copies per milliliter). Viral load and CD4 mean change from baseline was -2.1 and -1.1 [log.sub.10] HIV-1-RNA copies per milliliter and +166 and +116 CD4 cells/[mm.sup.3] for ENF plus OB and switch patients, respectively. No new ENF-related safety issues emerged in weeks 48-96. Injection site reactions led to discontinuation in 7% and 10% of ENF plus OB and switch patients, respectively. In conclusion, these data demonstrate durable efficacy and safety of ENF over 96 weeks and that early use of ENF in combination with other agents for the treatment of antiretroviral-experienced HIV-infected subjects is beneficial.

Tocilizumab is a humanized anti-interleukin-6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24-week double-blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2-compartment population pharmacokinetic model, with first-order absorption (for subcutaneous) and linear and Michaelis-Menten elimination was used. Mean observed steady-state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every-week and every-2-week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population-predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every-2-week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every-2-week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every-week subcutaneous and every-4-week intravenous regimens and less pronounced with the every-2-week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every-week subcutaneous regimen to the every-4-week intravenous regimen and the superiority of the every-2-week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients. [ABSTRACT FROM AUTHOR]

Background: Generalised anxiety disorder (GAD) is an anxiety disorder characterised by excessive anxiety and worry. Worry is seen as a key‐defining feature of GAD. Several cognitive‐behavioural models of working with worry in GAD exist. More recently, there have been efforts to adapt emotion‐focused therapy (EFT) for GAD. This study focused on task analysis, observing therapist and client processes (using qualitative observations as well as observer‐used measures) in the clinically developed, two‐chair dialogue for worry (an intervention inspired by a similar EFT task of working with self‐criticism in depression). Method: A task analysis methodological approach was applied to 34 worry dialogues from eight clients. The worry dialogues were qualitatively analysed, focusing on therapist and client processes in the task and also using observer‐based measures such as Classification of Affective‐Meaning States, Client Emotion Arousal Scale and Client Emotion Productivity Scale. Results: A tentative model of worry transformation using the two‐chair dialogue for worry is presented. The model consists of marker identification, enactment of the worry, deepening the toll of the worry, articulation of the need towards the worry and the worry softening or the client's standing up to the worry. The results also focus on the progression in the dialogues across the series of dialogues. Implications: The model has an immediate practical application as it can inform therapists' actions when working with worry processes in GAD clients. Implications for future research are also discussed. A video abstract of this article can be viewed at: https://vimeo.com/182527407 [ABSTRACT FROM AUTHOR]

Objectives: To report 5-year efficacy and safety in rheumatoid arthritis (RA) patients with active disease treated with tocilizumab., Methods: LITHE was a 2-year, randomised, placebo-controlled study of tocilizumab in RA patients (ClinicalTrials.gov, NCT00106535), with an additional 3-year, open-label extension. Patients were randomly assigned to tocilizumab (4 or 8 mg/kg IV) or placebo every 4 weeks + methotrexate. They could receive rescue with tocilizumab from week 16; after week 52, patients could switch to open-label tocilizumab 8 mg/kg. Radiographs were analysed by randomized treatment using the Genant-modified Total Sharp Score (GmTSS). Patients with at least baseline, week 104 and post-week 104 radiographs were included. Clinical and safety data were pooled for all patients who received ≥1 dose of tocilizumab; results are presented from the first tocilizumab dose., Results: 1,149 patients were included with 4,380 patient-years of exposure; 34% received 5 years of treatment. Mean 5-year change in GmTSS revealed greater inhibition of radiographic progression in tocilizumab patients than placebo patients (1.34 vs. 3.02), with the greatest annualised progression rate in year 1. Overall, 53% of tocilizumab and 35% of placebo patients experienced no progression (GmTSS ≤0). Clinical benefit was maintained - determined by ACR response, DAS28-ESR <2.6, EULAR good/moderate response and Boolean remission - as was physical function. The safety profile over 5 years was similar to that over 2 years., Conclusions: Over 5 years, tocilizumab + MTX inhibited radiographic progression and maintained improvements in signs and symptoms and physical function in MTX-inadequate responders with active disease; no new safety signals occurred.

The effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC(0-12)), maximum observed concentration of drug in plasma (C(max)), and minimum observed concentration of drug in plasma at the end of the dosing interval (C(min)) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC(0-12), C(max), and C(min) were observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 (n = 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC(0-72) and C(max) of the active moiety (rifabutin plus 25-O-desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC(0-72) and by 86% for C(max). In group 3 (n = 13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC(0-96) and C(max) of the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC(0-96) of rifabutin was not affected, and C(max) increased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.

Objective: The aim of this study was to examine the influence of kidney disease and hemodialysis on the pharmacokinetics ofenfuvirtide., Design: An open-label, multicenter, parallel group study of HIV-1-infected patients with varying degrees of kidney dysfunction., Methods: A 90-mg dose of enfuvirtide was administered by subcutaneous injection to 3 groups of patients: group A, patients with normal kidney function; group B, patients with chronic kidney disease; and group C, patients with end-stage renal disease (ESRD) requiring dialysis. Patients with ESRD requiring dialysis received the 90-mg dose of enfuvirtide on 2 separate occasions; a dialysis day and a nondialysis day. After each dose, a full 48-hour pharmacokinetic profile was collected and pharmacokinetic parameters were estimated using model-independent techniques., Results: Enfuvirtide area under the curve (AUCinfinity) and maximum observed enfuvirtide plasma concentration (Cmax) for patients with normal kidney function (group A) was 49.6 microg h/mL and 3.79 microg/mL, respectively. Patients with chronic kidney disease (group B) had higher AUCinfinity (80.3 microg h/mL) and Cmax (5.72 microg/mL), which was similar to patients with ESRD (group C) on both nondialysis days (AUCinfinity 71.1 microg h/mL; Cmax 5.34 microg/mL) and dialysis days (AUCinfinity 66.9 microg h/mL; Cmax 6.31 microg/mL). An average of< 13% of enfuvirtide was removed during the dialysis procedure. The incidence of adverse events was comparable for all study groups., Conclusion: Enfuvirtide exposure observed in patients with ESRD requiring dialysis or chronic kidney disease was slightly higher than in patients with normal kidney function and similar to historical Cmax and AUC values from studies in patients with normal kidney function. Thus, enfuvirtide does not require dosage adjustment in patients with impaired kidney function.