Summary Background The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a ...phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs). Methods We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response TLOVR algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00543725. Findings From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3·5% 95% CI −1·7 to 8·8; pnon-inferiority <0·0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2–4 treatment-related adverse events were less common with rilpivirine (16% 54 patients) than they were with efavirenz (31% 104; p<0·0001), as were rash and dizziness (p<0·0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0·0001). Interpretation Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1. Funding Tibotec.
Dual antiplatelet therapy is recommended for secondary prevention of ischaemic events in coronary artery disease. Some patients, who may be at high bleed risk if other factors are present, should be ...considered for gastroprotection. In our survey, we assessed whether gastroprotection was prescribed for hospital inpatients, especially high-risk patients, who were receiving dual antiplatelet therapy at discharge, and the type of gastroprotection prescribed. We found that over 13 months, a total of 1,693 patient episodes were prescribed dual antiplatelet therapy at discharge, of which 71% also received gastroprotection. Of the patient episodes who were not prescribed gastroprotection, 46% (223/483) met the criterion of age as a risk factor for gastroprotection. A further 30 episodes met other risk criteria of certain concomitant drugs or prior comorbidity. There is a need among clinicians and pharmacy teams within the hospital for recognition and management of this opportunity to improve the care of these patients.
Oligonucleotides (oligos) have been under clinical development for approximately the past 30 years, beginning with antisense oligonucleotides (ASOs) and apatmers and followed about 15 years ago by ...siRNAs. During that lengthy period of time, numerous clinical trials have been performed and thousands of trial participants accrued onto studies. Of all the molecules evaluated as of January 2017, the regulatory authorities assessed that six provided clear clinical benefit in rigorously controlled trials. The story of these six is given in this review.
This review discusses the six oligonucleotide therapeutic agents that have been FDA approved as of January 2017. They are fomivirsen (Vitravene), indicated for cytomegalovirus retinitis in HIV patients, a condition that no longer exists; pegaptanib (Macugen) indicated for wet macular degeneration of the retina; mipomersen (Kynamro), indicated for familial hypercholesterolemia; eteplirsen (Exondys 51), indicated for Duchenne’s muscular dystrophy; Defibrotide (Defitelio) indicated for hepatic veno-occlusive disease after bone marrow transplantation; and nusinersen (Spinraza), indicated for spinal muscular atrophy in infants.
Background Morphea (localized scleroderma) is a skin disorder with significant morbidity. No consistent recommendations exist for therapy, impeding patient care. Objective We sought to create an ...evidence-based therapeutic algorithm. Methods We reviewed English-language literature using search engines and hand searches for therapeutic interventions in morphea. Results were summarized. Results Narrowband ultraviolet B is appropriate for progressive or widespread superficial dermal lesions; broadband ultraviolet A/ultraviolet A-1 is appropriate for widespread or progressive deeper dermal lesions. Systemic treatment with methotrexate, corticosteroids, or both is indicated for deep or function-impairing lesions and rapidly progressive or widespread (severe) disease. Topical treatment with calcipotriene or tacrolimus is supported for limited, superficial, inflammatory lesions. Use of oral calcipotriol, D-penicillamine, interferon gamma, and antimalarials is not supported. Limitations Limitations are publication bias; lack of adequately powered, controlled trials; and no validated outcome measures. Conclusion Phototherapy, methotrexate/systemic corticosteroids, calcipotriene, and topical tacrolimus have the most evidence for efficacy in morphea. Treatment works best in inflammatory disease. Disease activity, severity, progression, and depth should play a role in therapeutic decision making.
A wide range of medications including antimalarial preparations (chloroquine, hydroxychloroquine), macrolide antibiotics (azithromycin) and the interleukin-6 inhibitor (tocilizumab) may be effective ...in treating patients with coronavirus disease 2019 (COVID-19). Such agents may be associated with cardiotoxicity, and the purpose of this brief review is to draw attention to potential areas of pharmacovigilance. These include prolongation of the QT-interval and the development of occult cardiomyopathy. Alternatively, some of the agents seem to have minimal impact on the cardiovascular system. The review highlights the need for an ongoing evaluation of such agents within carefully constructed clinical trials with embedded attention to cardiovascular safety.
The reason to be cautious when evaluating curative or symptomatic treatments is the fact that SARS-CoV-2 has affected large segments of the population, with disproportionate mortality rates within certain subgroups. Some of the enhanced mortality may reflect inherent cardiovascular disease risk factors related to acute COVID-19 infection.
It is hoped that the review will stimulate a greater awareness of potential cardiovascular side effects and encourage reporting of those in future trials.
The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced ...prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.
Natural as well as synthetic antioxidants are constantly being investigated for their efficiency in combatting the effects of oxidative stress, which appears to be the responsible cause of several ...diseases, including cancer, central nervous system disorders, ischaemia‐reperfusion disorders, cardiovascular conditions, and diabetes. Superoxide dismutases (SODs) constitute the ubiquitous antioxidant defences against oxidative stress that underlies numerous pathological conditions. Therefore, the development of therapeutics aimed at either delivering MnSOD more effectively to target tissues in the body in the form of MnSOD gene therapy, or the synthesis of molecules that mimic the activity of superoxide dismutase is constantly being explored. Classes that have been developed as SOD mimetics include the Mn‐metalloporphyrins, Mn‐cyclic polyamines, Mn‐salen complexes, MnPLED derivatives as well as the nitroxides. Thus far, SOD mimetics have shown remarkable efficacy in several animal models suffering from oxidative stress injuries. A promising approach for the future of SOD and SOD mimic therapeutics appears to involve combination treatment of the antioxidants with radiotherapy or chemotherapy.
Mimicking SOD: Methods that use native MnSODs or molecules that mimic the activity of SOD to treat oxidative stress injuries are in constant development.
To compare the treatment efficacy and safety of tofacitinib (TOF) versus methotrexate (MTX) in Takayasu arteritis (TAK).
Fifty-three patients with active disease from an ongoing prospective TAK ...cohort in China were included in this study. Twenty-seven patients were treated with glucocorticoids (GCs) and TOF, and 26 patients were treated with GCs with MTX. The observation period was 12 months. Complete remission (CR), inflammatory parameter changes, GCs tapering and safety were assessed at the 6th, 9th and 12th month. Vascular lesions were evaluated at the 6th and 12th month, and relapse was analysed during 12 months.
The CR rate was higher in the TOF group than in the MTX group (6 months: 85.19% vs 61.54%, p=0.07; 12 months: 88.46% vs 56.52%, p=0.02). During 12 months' treatment, patients in the TOF group achieved a relatively lower relapse rate (11.54% vs 34.78%, p=0.052) and a longer median relapse-free duration (11.65±0.98 vs 10.48±2.31 months, p=0.03). Average GCs dose at the 3rd, 6th and 12th month was lower in the TOF group than that in the MTX group (p<0.05). A difference was not observed in disease improvement or disease progression on imaging between the two groups (p>0.05). Prevalence of side effects was low in both groups (3.70% vs 15.38%, p=0.19).
TOF was superior to MTX for CR induction, a tendency to prevent relapse and tapering of the GCs dose in TAK treatment. A good safety profile for TOF was also documented in patients with TAK.
PDF
