149 research outputs found
Interrupting antiretroviral treatment needs particular care [9]
No full textContext Presenceoflow-frequency,orminority,humanimmunodeficiencyvirustype 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting. Objective To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)based antiretroviral virologic failure. Data Sources Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. Study Selection and Data Abstraction Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study
Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy
No full textBackground. Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London. Methods. A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. Results. Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01). Conclusions. This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D. © 2010 Easterbrook et al; licensee BioMed Central Ltd
Children's developing understanding of economic inequality and their place within it
No full textStatement of Contribution:
What is already known on this subject?
• Economic inequality affects the well-being of childrens and adolescents
• Children develop an understanding of the causes of economic inequality
• Little research has examined social influences on children's conceptions of inequality
What does this study add?
• A review of the role of developmental and social processes in emerging conceptions of inequality
• Analysis of how childrens' conceptions of inequality may affect their well-being
• Suggested pathways for research on social processes affecting conceptions of inequality and sense of selfData Availability Statement:
Data sharing is not applicable to this article as no new data were created or analysed in this study.Income inequality is growing in many parts of the world and, for the poorest children in a society, is associated with multiple, negative, developmental outcomes. This review of the research literature considers how childrens' and adolescents' understanding of economic inequality changes with age. It highlights shifts in conceptual understanding (from ‘having and not having’, to social structural and moral explanations), moral reasoning and the impact of the agents of socialization from parents to the media and cultural norms and discourses. It also examines how social processes affect judgements and the importance of an emerging sense of self in relation to questions of economic inequality. Finally, the review covers methodological considerations and suggests pathways for future research.This work was supported by The British Psychological Society Research Seminars Competition 2019
Evidence for onward transmission of HIV-1 non-B subtype strains in the United Kingdom
No full textAn increasing proportion of new HIV diagnoses in the United Kingdom and other European countries are attributable to non-B subtype infections, mainly among black Africans with infections heterosexually acquired in sub-Sabaran Africa. We examined whether there was evidence for onward transmission of non-B subtypes within an ethnically diverse HIV-1-infected cohort in South London. Three hundred eighty-four HIV-1-infected patients attending Kings College Hospital were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Epidemiologic data were obtained from medical chart review and the patients' physician and were used to establish the most likely source and country of infection. Overall, 344 patients (154 black African, 148 white UK-born, and 42 black Caribbean) had an identifiable subtype. The prevalence of non-B subtypes among the black African, white, and black Caribbean patients was 96.8%, 14.2%, and 31%, respectively. Most non-B subtype infections were identified in black Africans (149 of 183 cases) and were mainly acquired in sub-Saharan Africa, but 22.9% (42 of 183 cases) of all non-B infections were probably acquired in the United Kingdom. Among the 21 white UK-bom patients infected with a non-B subtype, 15 probably acquired the infection in the United Kingdom and only 6 of these patients reported a source sexual partner from an HIV endemic area. All 13 black Caribbean patients with a non-B infection most likely acquired their infection in the United Kingdom, most of whom (8 of 13 patients) were probably infected by a partner from an HIV endemic area. Potential acquisition of HIV infection in the United Kingdom was lowest among black African patients with a non-B infection, and most of these infections were probably acquired from a partner originating from an HIV endemic area. This study provides the first evidence for onward transmission of non-B subtypes in the United Kingdom, particularly among the black Caribbean populatio
Renal AA-amyloidosis in intravenous drug users - a role for HIV-infection?
No full textBackground: Chronic renal disease is a serious complication of long-term intravenous drug use (IVDU). Recent reports have postulated a changing pattern of underlying nephropathy over the last decades.
Methods: Retrospective investigation including all patients with prior or present IVDU that underwent renal biopsy because of chronic kidney disease between 01.04.2002 and 31.03.2012 in the city of Frankfurt/Main, Germany.
Results: Twenty four patients with IVDU underwent renal biopsy because of progressive chronic kidney disease or proteinuria. Renal AA-amyloidosis was the predominant cause of renal failure in 50% of patients. Membranoproliferative glomerulonephritis (GN) was the second most common cause found in 21%. Patients with AA-amyloidosis were more likely to be HIV infected (67 vs.17%; p=0.036) and tended to have a higher rate of repeated systemic infections (92 vs. 50%; p=0.069). Patients with AA-amyloidosis presented with progressive renal disease and nephrotic-range proteinuria but most patients had no peripheral edema or systemic hypertension. Development of proteinuria preceded the decline of GFR for approximately 1--2 years.
Conclusions: AA-amyloidosis was the predominant cause of progressive renal disease in the last 10 years in patients with IVDU. The highest rate of AA-amyloidosis observed was seen in HIV infected patients with IVDU. We speculate that chronic HIV-infection as well as the associated immunosuppression might promote development of AA-amyloidosis by increasing frequency and duration of infections acquired by IVDU
Fate of research studies.
No full textA retrospective survey was conducted of 720 research protocols, approved by the Central Oxford Research Ethics Committee between 1984 and 1987, to determine the fate of research studies from inception. Forty-five per cent were clinical trials, 23% were observational studies and 32% were laboratory-based experimental studies. Further information was obtained on 487 studies, of which 287 (59%) had been completed, 100 (21%) had never started, 58 (12%) had been abandoned or were in abeyance and 42 (9%) were still ongoing, as of May 1990. Forty-three per cent of the original 487 studies were subsequently published or presented. The most frequent reason for not starting a study was failure to obtain funding (40%). The main reason for abandoning a study was difficulty in recruiting study participants (28%). Departure of one of the investigators from the institution and a variety of logistical problems were also common reasons for either not starting or abandoning a study. A thorough review of the pragmatic as well as the scientific aspects of a planned research project is important to minimize the initiation of studies that are unlikely to succeed
The multifocal pattern electroretinogram in chloroquine retinopathy
No full textPurpose: Optimal screening for ocular toxicity caused by chloroquine and hydroxychloroquine is still controversial. With the multifocal pattern electroretinogram (mfPERG), a new electrophysiological technique has recently become available to detect early changes of ganglion cells. In this study this new technique is applied to a series of 10 patients seen consecutively receiving long-term chloroquine medication. Methods: In 10 patients receiving chloroquine medication, clinical examination, Amsler visual field testing and computerized color vision testing were performed. If toxicity was suspected, automated perimetry was carried out. In addition, in all patients conventional pattern electroretinogram (PERG) and mfPERG testing were performed. Results: On clinical examination 8 patients showed no chloroquine-associated maculopathy, while 2 patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler chart, while automated perimetry showed typical, ring-like paracentral scotomas in both affected patients and color vision was significantly abnormal. In the normal patients, 4 of 8 had a mild color vision disturbance, which correlated to age-related macular changes. The amplitudes of the PERG and the central (approximately 10degrees) responses of the mfPERG were markedly reduced in chloroquine maculopathy, while the latencies were unchanged. The peripheral rings of mfPERG (ranging to 48degrees) were not affected by chloroquine toxicity. Both PERG and mfPERG were less affected by age-related macular changes. Conclusions: The reduction of PERG and central mfPERG responses in chloroquine maculopathy may help with the early detection of toxicity. Copyright (C) 2004 S. Karger AG, Basel
Comparison between HIV- and CMV-specific T cell responses in long-term HIV infected donors.
No full textThe mechanisms underlying non-progression in HIV-1 infection are not well understood; however, this state has been associated previously with strong HIV-1-specific CD8+ T cell responses and the preservation of proliferative CD4+ T cell responses to HIV-1 antigens. Using a combination of interferon-gamma (IFN-gamma) ELISpot assays and tetramer staining, the HIV-1-specific CD8+ T cell populations were quantified and characterized in untreated long-term HIV-1-infected non-progressors and individuals with slowly progressive disease, both in relation to CD4+ T cell responses, and in comparison with responses to cytomegalovirus (CMV) antigens. High levels of CD8+ T cell responses specific for HIV-1 or CMV were observed, but neither their frequency nor their phenotype seemed to differ between the two patient groups. Moreover, while CMV-specific CD4+ T cell responses were preserved in these donors, IFN-gamma release by HIV-1-specific CD4+ T cells was generally low. These data raise questions with regard to the role played by CD8+ T cells in the establishment and maintenance of long-term non-progression
The Plasma, Whole Blood and Intracellular Concentrations of Antiretroviral Agents in South African Children Receiving Combination Antiretroviral Therapy with and without Concomitant Antitubercular Treatment
No full textBackground: Tuberculosis (TB) is the most common opportunistic infection in children with human immunodeficiency virus (HIV) infection in developing countries, and co-treatment for HIV infection and TB is frequently indicated. Efavirenz and lopinavir/ritonavir (ratio 1:1) as part of antiretroviral therapy are used in combination with rifampicin-based antitubercular treatment in South African TB/HIV co-infected children. Adult studies show that concomitant rifampicin significantly reduces efavirenz and lopinavir plasma concentrations. However, the pharmacokinetics (PK) of efavirenz and lopinavir/ritonavir are poorly characterized in children, especially African children and no study has evaluated the effect of rifampicin-based antitubercular treatment on efavirenz and lopinavir/ritonavir plasma concentrations in children. Although therapeutic drug monitoring (TDM) is recommended in selected patients (including young children and patients receiving concomitant antitubercular treatment), TDM is seldom available in resource-constrained countries. There is an urgent need to develop a field friendly method which requires small volumes of blood, and inexpensive processing and storage conditions. Furthermore, because HIV replicates in the cells, efavirenz and lopinavir need to penetrate into these infected cells to inhibit viral replication. Therefore, directly measurement of intracellular concentrations of these drugs in HIV-infected children could provide better understanding of drug exposure at the action site. It is also important to evaluate the effects of frequently co-administered drugs on intracellular accumulation of efavirenz and lopinavir. Objectives: 1) To evaluate efavirenz and lopinavir/ritonavir plasma concentrations and determine the effects of rifampicin on efavirenz and lopinavir/ritonavir PK in HIV-infected African children with and without rifampicin-based antitubercular treatment. 2) To develop and validate the dried blood spot (DBS) method as an alternative to conventional plasma methods of drug concentration measurement in TDM. 3) To evaluate in vivo intracellular concentrations of efavirenz and lopinavir/ritonavir in HIV-infected children with and without concomitant antitubercular treatment. 4) To determine the in vitro modulation effects on the intracellular accumulation of efavirenz IV and lopinavir in human peripheral blood mononuclear cells (PBMCs) by drug efflux protein inhibitors, as well as frequently co-administered rifampicin and ritonavir (at low dose; as pharmacoenhancer). Methods: 1) Plasma efavirenz and lopinavir/ritonavir concentrations were measured by validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method in TB/HIV co-infected children during and after rifampicin-based antitubercular treatment as well as in a group of controls (HIV-infected children without TB). Children in the efavirenz study (n= 30) were receiving standard doses of efavirenz as part of antiretroviral treatment. Trough concentrations (Cmin) of efavirenz were estimated by extrapolation of the log-linear concentration-time line to 24 hours after the previous dose. Children in the lopinavir/ritonavir study were receiving additional ritonavir (lopinavir: ritonavir ratio 1:1) during antitubercular treatment (n= 15), and standard doses of lopinavir/ritonavir (LPV/r; ratio 4:1) after antitubercular treatment, and in controls (n= 15). The PK of lopinavir and ritonavir were characterized from concentration-time curves using WinNonlin version 4.1 by non-compartmental analysis. 2) Aliquots of 50 μ L of whole blood from the efavirenz and lopinavir/ritonavir studies were dried onto filter paper. The drug concentrations were analyzed using validated LC/MS/MS method. The effects of high temperature and direct sunlight on the stabilities of these antiretroviral drugs in DBS samples were tested. 3) Intracellular concentrations of efavirenz, lopinavir and ritonavir were measured in trough concentrations of 11 TB/HIV co-infected children using a validated LC/MS/MS method. Six children were receiving double dose of LPV/r (4:1) with concomitant rifampicin; 5 children were receiving standard doses of efavirenz with rifampicin-based antitubercular treatment, 3 of them had intracellular concentrations measured again after completing rifampicin-based antitubercular treatment. 4) in vitro intracellular accumulation of efavirenz and lopinavir were measured in human PBMCs in the absence and presence of P-glycoprotein inhibitors (verapamil at 50 μ M, V furosemide at 50 μ M and cyclosporine A at 20 μ M) and frequently co-administered drugs at levels representing the average concentrations found in patients (ritonavir at 5 mg/L and rifampicin at 4 mg/L). The concentrations of efavirenz and lopinavir in PBMCs were determined by LC/MS/MS. Results and Conclusions: 1) The co-administration of rifampicin did not significantly reduce efavirenz estimated Cmin concentrations. A high proportion of children with and without concomitant antitubercular treatment had sub-therapeutic efavirenz concentrations despite being correctly dosed according to the manufacturer's instructions, raising concerns about the adequacy of current efavirenz dosing recommendations in children. The lopinavir key PK parameter, Cmin, was not significantly different in same group of children during and after rifampicin-based antitubercular treatment or compared to HIV-infected children without tuberculosis. The recommended minimum therapeutic concentration was achieved in 87% of children during antitubercular treatment and in 92% without concomitant antitubercular treatment. Therefore, in the context of limited options, LPV/r with additional ritonavir (ratio 1:1) is an acceptable approach to treat young children receiving concomitant rifampicin-based antitubercular treatment, although safety remains a concern and hepatic alanine transaminase levels should be monitored regularly. 2) Plasma and DBS concentrations of efavirenz, lopinavir and ritonavir were strongly correlated. The median (interquartile range, IQR) DBS/plasma concentration ratios for efavirenz, lopinavir and ritonavir were 0.93 (IQR 0.83, 1.08), 0.73 (IQR 0.61, 0.90) and 1.05 (IQR 0.74, 1.21), respectively. PK parameters of efavirenz and ritonavir were closely similar between DBS and plasma; whereas lopinavir pre-dose and Cmin (at 12 hours after lopinavir intake) concentrations were 16% lower in DBS samples. The 3 antiretroviral drugs in DBS samples were stable at 37 deg C for 7 days and with exposure to direct sunlight for 2 hours. DBS can be used as an alternative field-friendly method for efavirenz, lopinavir and ritonavir concentration monitoring. However, pre-dose and Cmin concentrations of lopinavir in DBS samples need to be increased by 16% when used to predict plasma concentrations. VI 3) In vivo median intracellular/plasma concentration ratios for efavirenz, lopinavir and ritonavir amongst 11 TB/HIV co-infected children during antitubercular treatment were 0.91 (IQR 0.54, 1.19), 0.22 (IQR 0.09, 0.31) and 4.17 (IQR 1.30, 7.33), respectively. Two children had efavirenz intracellular/plasma concentration ratios during vs. after antitubercular treatment: 1.00 vs. 0.61 and 0.27 vs. 0.79. 4) Furosemide significantly increased efavirenz and lopinavir accumulation in healthy human PBMC samples by 1.2- 1.5 fold. Whereas, neither verapamil nor cyclosporin A had significant effects on efavirenz or lopinavir intracellular accumulation. Despite being an inducer of P-glycoprotein, rifampicin increased the accumulation of both efavirenz and lopinavir to different extents in all 3 PBMC samples. The low-dose ritonavir (at the concentration found in HIV-infected patients) had no effect on intracellular accumulation of efavirenz and lopinavir at therapeutic concentrations
Pathogenesis and prevention of immune reconstitution disease during antiretroviral therapy.
No full textThe risks of unmasking and paradoxical forms of immune reconstitution disease in HIV-infected patients starting antiretroviral therapy (ART) are fuelled by a combination of the late presentation of patients with advanced immunodeficiency, the associated high rates of opportunistic infections (OIs) and the need for rapid initiation of ART to minimize overall mortality risk. We review the risk factors and our current knowledge of the immunopathogenesis of immune reconstitution disease, leading to a discussion of strategies for prevention. Initiation of ART at higher CD4 counts, use of OI-preventive therapies prior to ART eligibility, intensified screening for OIs prior to ART initiation and optimum therapy for OIs are all needed. In addition, use of a range of pharmacological agents with immunosuppressive and immunomodulatory activity is being explored
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