9 research outputs found

    Rights theory in a specific healthcare context: “Speaking ill of the dead”

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    Generally physicians have a legal and ethical obligation of keeping confidentiality regarding their communication with patients and it is clear that we all have rights. The application of rights theorem, which usually refers to the recognition of individual human rights, to the deceased offers possible answers to the problematic question of patient confidentiality after death. Philosophical considerations broadly support utilitarian ideals concerning the ‘common good'. However, it may be possible to rank rights according to a hierarchy of need and thus preserve individual rights where they do not impinge upon the publics' right to protection from harm and the physician's right to tell the truth. This has broad implications for confidentiality, anonymity and health care information in general for patients, their families and healthcare workers. We discuss these issues, with specific reference to an individual case

    Dynamics of raltegravir resistance profile in an HIV type 2-infected patient.

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    The evolutionary dynamics of RAL resistance in the HIV-2 virus were examined through population and clonal sequence analysis of the IN from baseline, during treatment, and after stopping RAL therapy. The treatment failure of an RAL regimen in the HIV-2 patient studied was associated with the emergence of mutations via the N155H resistance pathway and subsequent switching to the Y143C mutational route. This study has also identified four novel secondary mutations, Q91R, S147G, A153G, and M183I, not previously reported in HIV-1 patients failing RAL therapy. Resistant variants involving the Y143C pathway were noted to have persisted beyond 4 weeks following the cessation of RAL therapy. All resistance-associated mutations were lost at 20 weeks after stopping RAL therapy. Our findings provide evidence supporting the supposition that substantial cross-resistance between strand transfer IN-Is is likely in HIV-2 as shown in HIV-1

    Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients

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    Ritonavir-boosted saquinavir (SQV/r) is currently licensed as a twice-daily regimen. Reducing the pill burden with once-daily dosing may improve adherence. Intracellular concentrations of drugs must be related to the clinical efficacy of protease inhibitors. The aims of the study were to determine the cellular and plasma saquinavir and ritonavir concentrations, to determine the half-lives (t(1/2)s) of the drugs in each compartment, and to examine relationships between drug accumulation and lymphocyte subset P glycoprotein (P-gp) expression. Venous blood samples from 12 human immunodeficiency virus-infected patients receiving a hard-gel formulation of SQV/r (1,600/100 mg once daily) were collected at 2, 6, 12, and 24 h after dosing. Peripheral blood mononuclear cells were separated by density gradient centrifugation, and P-gp expression was measured by dual-color flow cytometry. Plasma and intracellular (cell-associated) drug concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The ratio of the intracellular drug area under the concentration-time curve from 0 to 24 h (AUC(0-24 h)) to plasma drug AUC(0-24 h) was calculated to determine cellular drug accumulation. The median (range) AUC(0-24 h) of saquinavir in plasma was 16.2 (5.7 to 39.3) mg · h · liter(−1), and that in cells was 46.3 (24.7 to 114.6) mg · h · liter(−1). Corresponding ritonavir values were 7.5 (1.5 to 14.6) mg · h · liter(−1) and 10.4 (3.2 to 13.7) mg · h · liter(−1), respectively. The median accumulation ratios of cellular AUC to plasma AUC for saquinavir and ritonavir were 3.31 (range, 1.49 to 6.69) and 1.46 (range, 0.83 to 4.15), respectively. Significant differences between the plasma and intracellular saquinavir t(1/2)s (4.5 h [range, 2.5 to 9.3 h] and 5.9 h [range, 4.0 to 17.7 h]; P = 0.034) and between the plasma and intracellular ritonavir t(1/2)s (4.1 h [range, 2.6 to 8.3 h] and 6.2 h [range, 3.9 to 18.6 h]; P = 0.032) were observed. No relationship was observed between the accumulation of saquinavir or ritonavir and lymphocyte subset P-gp expression. The intracellular t(1/2)s of saquinavir and ritonavir were longer than the plasma t(1/2)s, indicating that intracellular drug may be available at a time when concentrations in plasma are below the minimum effective concentration

    Human challenge trials in vaccine development, Rockville, MD, USA, September 28–30, 2017

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    © 2018 The International Alliance for Biological Standardization organized the second workshop on human challenge trials (HCT) in Rockville, MD, in September 2017. The objective of this meeting was to examine the use of HCT, in response to the continuing human suffering caused by infectious diseases, preventable by the development of new and improved vaccines. For this, the approach of HCT could be valuable, as HCT can provide key safety, tolerability, immunogenicity, and efficacy data, and can be used to study host-pathogen biology. HCT can generate these data with speed, efficiency and minimal expense, albeit not with the same level of robustness as clinical trials. Incorporated wisely into a clinical development plan, HCT can support optimization or down-selection of new vaccine candidates, assuring that only the worthiest candidates progress to field testing. HCT may also provide pivotal efficacy data in support of licensure, particularly when field efficacy studies are not feasible. Many aspects of HCT were discussed by the participants, including new and existing models, standardization and ethics. A consensus was achieved that HCT, if ethically justified and performed with careful attention to safety and informed consent, should be pursued to promote and accelerate vaccine development

    Third human challenge trial conference, Oxford, United Kingdom, February 6–7, 2020, a meeting report

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    The third Human Challenge Trial Meeting brought together a broad range of international stakeholders, including academia, regulators, funders and industry, with a considerable delegation from Low- and Middle-Income Countries. Controlled human infection models (CHIMs) can be helpful to study pathogenesis and for the development of vaccines. As challenge agents are used to infect healthy volunteers, ethical considerations include that the challenge studies need to be safe and results should be meaningful. The meeting provided a state-of-the-art overview on a wide range of CHIMs, including viral, bacterial and parasitic challenge agents. Recommendations included globally aligned guidance documents for CHIM studies; further definition of a CHIM, based on the challenge agent used; standardization of methodology and study endpoints; capacity building in Low- and Middle-Income Countries, in performance as well as regulation of CHIM studies; guidance on compensation for participation in CHIM studies; and preparation of CHIM studies, with strong engagement with stakeholders

    Detection of drug resistance mutations at low plasma HIV-1 RNA load in a European multicentre cohort study

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    Guidelines indicate a plasma HIV-1 RNA load of 500-1000 copies/mL as the minimal threshold for antiretroviral drug resistance testing. Resistance testing at lower viral load levels may be useful to guide timely treatment switches, although data on the clinical utility of this remain limited. We report here the influence of viral load levels on the probability of detecting drug resistance mutations (DRMs) and other mutations by routine genotypic testing in a large multicentre European cohort, with a focus on tests performed at a viral load <1000 copies/mL
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