Objective: To examine the pain relief effects of comparators (placebos and untreated control groups) in hand osteoarthritis trials and the impact of contextual factors. Methods: We systematically... Show moreObjective: To examine the pain relief effects of comparators (placebos and untreated control groups) in hand osteoarthritis trials and the impact of contextual factors. Methods: We systematically searched PubMed, EMBASE and CENTRAL from inception to December 26, 2021. We included randomised controlled trials of people with hand osteoarthritis with a placebo or an untreated control group. We assessed the Risk of Bias with Cochrane Risk-of-Bias tool version 2. Each comparator was contrasted with a null-arm, imputed as having a zero change from baseline with the same standard deviation as the comparator. We combined the standardised mean differences with a random effects meta-analysis. The contextual factors’ effect was explored in meta-regression and stratified models with pain as the dependent variable. Results: 84 trials (7262 participants) were eligible for quantitative synthesis, of which 76 (6462 participants) were eligible for the stratified analyses. Placebos were superior to their matched null-arms in relieving pain with an effect size of −0.51 (95% confidence interval −0.61 to −0.42), while untreated control groups were not. When analysing all comparators, blinded trial designs and low risk of bias were associated with higher pain relief compared to an open-label trial design and some concern or high risk of bias. Conclusion: The placebo response on pain for people with hand osteoarthritis was increased by appropriate blinding and a lower risk of bias assessment. Placebos were superior to a null-arm, while untreated control groups were not. Results emphasise the importance of using appropriate comparators in clinical trials. PROSPERO registration ID: CRD42022298984 Show less
Objectives: To compare reliabilities of assessing synovitis in hand osteoarthritis (OA) using Magnetic Resonance Imaging (MRI) with/without gadolinium (Gd). Methods: Three readers scored synovitis... Show moreObjectives: To compare reliabilities of assessing synovitis in hand osteoarthritis (OA) using Magnetic Resonance Imaging (MRI) with/without gadolinium (Gd). Methods: Three readers scored synovitis on non-enhanced two-dimensional (2D) proton density (PD)weighted MRI and Gd-enhanced (3D) MRI of hand joints in 20 patients. Inter-reader reliabilities were examined. Results: Reliability was good for Gd-enhanced MRI, but poor for non-enhanced PD-weighted MRI (intraclass correlation coefficient 0.83 and 0.21, respectively). Agreement between the two sequences was poor (weighted kappa 0.18). Conclusion: Gd-enhanced MRI was more reliable than PD-weighted MRI for assessing synovitis. Gd-enhancement, but also resolution and tissue contrast, might have contributed to this. (c) 2021 Elsevier Inc. All rights reserved. Show less
Objective To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1 alpha/beta dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand... Show moreObjective To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1 alpha/beta dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).Methods Patients with >= 1 erosive and >= 3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates.Results Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1 alpha and IL-1 beta levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67).Conclusion Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo. Show less
Background: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors... Show moreBackground: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005. Methods: From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM. Results: The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM. Conclusion: The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines. Show less
Zhang, S.; Sighem, A. van; Gras, L.; Reiss, P.; Smit, C.; Kroon, F.; ... ; Wolf, F. de 2010
Background: Transient episodes of HIV type-1 viraemia are frequently observed in patients on suppressive combination antiretroviral therapy (cART). We studied the effect of such episodes and of... Show moreBackground: Transient episodes of HIV type-1 viraemia are frequently observed in patients on suppressive combination antiretroviral therapy (cART). We studied the effect of such episodes and of treatment interruptions on clinical outcome and immunological response. Methods: A total of 3,321 patients from the ATHENA cohort had virological suppression (HIV type-1 RNA<50 copies/ml) after 24 weeks of cART. The association between subsequent episodes of treatment interruptions, viral suppression, low-level (50-400 copies/ml) and high-level (>400 copies/ml) viraemia and the outcomes death, AIDS or immunological response (CD4(+) T-cell count increase >= 50% from 24 weeks) was studied with Poisson regression models, including either time-updated cumulative follow-up, time spent per type of episode or modelling episodes as binary status indicators. Results: During 11,165 person-years of follow-up, 88 patients died, 111 developed AIDS and 2,019 had an immunological response. Longer follow-up time in treatment interruptions increased the risk of AIDS (relative risk [RR] 8.07, 95% confidence interval [CI] 3.98-16.4 per year longer) and impaired immunological response (RR 0.22, 95%) CI 0.12-0.41). High-level viraemia was only associated with immunological response (RR 0.55, 95% CI 0.40-0.74), whereas low-level viraemia was not associated with any of the three outcomes. Status indicator models gave similar results. When also including time-updated CD4(+) T-cell counts, the observed associations diminished. Conclusions: Treatment interruptions and high-level, but not low-level, viraemia are strongly associated with clinical outcome, mainly via their effect on CD4(+) T-cell counts Show less
Luin, M. van; Ende, M.E. van der; Richter, C.; Visser, M.; Faraj, D.; Ven, A. van der; ... ; Burger, D.M. 2010
HIV-infected travellers frequently use atovaquone/ proguanil as malaria prophylaxis. We compared atovaquone/ proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking... Show moreHIV-infected travellers frequently use atovaquone/ proguanil as malaria prophylaxis. We compared atovaquone/ proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)(0 -> t) for atovaquone relative to the healthy volunteers was 0.25 (0.16-0.38), 0.26 (0.17-0.41) and 0.54 (0.350.83) for patients on efavirenz, lopinavir/ ritonavir and atazanavir/ ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38-43%). Physicians should be alert for atovaquone/ proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ ritonavir or atazanavir/ ritonavir. Show less
