Suchergebnisse

AbstractIntroductionTo allow the continued participation of women enrolled in pre‐licensure clinical trials who become pregnant, and to potentially enrol pregnant women in clinical trials, non‐clinical developmental and reproductive toxicology studies (DART) are essential. Generally during pharmaceutical development, DART studies are conducted late during clinical development, leading to the exclusion of pregnant women from enrolment and withdrawal of women becoming pregnant during pre‐licensure trials.DiscussionCompleting all DART studies prior to or early during the conduct of phase 3 trials (i.e. earlier than current common practice) can accelerate and facilitate the inclusion of women who become pregnant during pre‐licensure trials to remain on study drug and to potentially enrol pregnant women more rapidly. Promoting complementary strategies, such as alternative combinations of DART study designs and physiologically based pharmacokinetic modelling, could better inform drug dosing and safety in pregnancy at an earlier stage in drug development. The interpretation of the results of non‐clinical DART studies is often complex. Institutional review boards/ethics committees should have access to relevant expertise for interpretation and application of results of non‐clinical developmental and reproductive toxicity studies. Clear communication and thorough understanding of non‐clinical findings and the overall benefit–risk profile of the product are critical to review protocols and determine if women who become pregnant during a clinical trial could continue on study drug and/or to enrol pregnant women in the trial. The informed consent document should be well written so that participants can make an informed decision to stay on study drug or participate in a trial during pregnancy. Ultimately, the decision to allow women who become pregnant during pre‐licensure trials to remain on study will depend on the totality of the evidence and benefit–risk considerations.ConclusionsWe propose that industry completes non‐clinical reproductive toxicity studies prior to or early during the conduct of phase 3 trials in HIV drug development, especially for priority agents, and potentially uses alternative DART study design strategies to achieve this goal.

"Although the pathogenesis of human immunodeficiency virus (HIV) infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, there are unique considerations needed for HIV-infected infants, children, and adolescents, including a) acquisition of infection through perinatal exposure for many infected children; b) in utero exposure to zidovudine (ZDV) and other antiretroviral medications in many perinatally infected children; c) differences in diagnostic evaluation in perinatal infection; d) differences in immunologic markers (e.g., CD4+ T-lymphocyte count) in young children; e) changes in pharmacokinetic parameters with age caused by the continuing development and maturation of organ systems involved in drug metabolism and clearance; f) differences in the clinical and virologic manifestations of perinatal HIV infection secondary to the occurrence of primary infection in growing, immunologically immature persons; and g) special considerations associated with adherence to treatment for children and adolescents. This report addresses the pediatric-specific issues associated with antiretroviral treatment and provides guidelines to health-care providers caring for infected infants, children, and adolescents." ; "April 17, 1998." ; "These guidelines were developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children convened by the National Pediatric and Family HIV Resource Center . the Health Resources and Services Administration . and the National Institutes of Health . The Co-Chairs of the Working Group were James Oleske . and Gwendolyn B. Scott ."--P. ii. ; "U.S. Government Printing Office: 1998-633-228/67064 Region IV."--P. [4] of cover. ; Includes bibliographical references (p. 28-31).

Shipping list no.: 2003-0024-S. ; Includes bibliographical references. ; Mode of access: Internet.

The response of human immunodeficiency virus type 1 (HIV-1) quasispecies to antiretroviral therapy is influenced by the ensemble of mutants that composes the evolving population. Low-abundance subpopulations within HIV-1 quasispecies may determine the viral response to the administered drug combinations. However, routine sequencing assays available to clinical laboratories do not recognize HIV-1 minority variants representing less than 25% of the population. Although several alternative and more sensitive genotyping techniques have been developed, including next-generation sequencing (NGS) methods, they are usually very time consuming, expensive and require highly trained personnel, thus becoming unrealistic approaches in daily clinical practice. Here we describe the development and testing of a HIV-1 genotyping DNA microarray that detects and quantifies, in majority and minority viral subpopulations, relevant mutations and amino acid insertions in 42 codons of the pol gene associated with drug- and multidrug-resistance to protease (PR) and reverse transcriptase (RT) inhibitors. A customized bioinformatics protocol has been implemented to analyze the microarray hybridization data by including a new normalization procedure and a stepwise filtering algorithm, which resulted in the highly accurate (96.33%) detection of positive/negative signals. This microarray has been tested with 57 subtype B HIV-1 clinical samples extracted from multi-treated patients, showing an overall identification of 95.53% and 89.24% of the queried PR and RT codons, respectively, and enough sensitivity to detect minority subpopulations representing as low as 5-10% of the total quasispecies. The developed genotyping platform represents an efficient diagnostic and prognostic tool useful to personalize antiviral treatments in clinical practice. ; This work was supported by the Spanish Ministerio de Ciencia e Innovación (MICINN grant BIO2010-20696 to CB), Ministerio de Economía y Competitividad (MINECO grants BIO2013-47228-R to CB and SAF2014-52400-R to ED), Comunidad Autónoma de Madrid (PLATESA, grant S2013/ABI-2906 to ED), Biotherapix, S.L.U. and FEDER funds from the European Union. Work at CIBERehd is funded by the Instituto de Salud Carlos III (ISCIII). MICINN provided funding for VM under grants RyC2010-06516 and AGL2015-64290-R. CP is supported by Miguel Servet program of the ISCIII (CP14/00121), co-financed by the European Regional Development Fund (ERDF). Funding for open access charge: Spanish National Research Council (CSIC). The funders provided support in the form of salaries and research materials for authors [MICINN and MINECO for VM, CP, MF-A, HGDS, VP, MM, DA, ED and CB; ISCIII for CP, JG-P and JA; Biotherapix, S.L.U. for PG, MP and JLT], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. ; Sí

Department of Chemistry,Government Model Science College, Gwalior-474 009 Manuscript received 9 Jul 1991, accepted 28 October 1991 Synthesis and Anti-HIV Activity of some New lmidazolones

The lipid components of pathogen cell membranes have been considered as a poor pharmacological target, due to their universal distribution and apparent homogeneity throughout living organisms. Among the rare exceptions to this view one could mention polyene antibiotics such as amphotericin, or peptide antibiotics such as the polymyxins and the gramicidins. In the last two decades, however, the above notion has been challenged by two main lines of discovery; first, natural antimicrobial peptides (AMPs) that kill pathogens by interaction with phospholipids and membrane permeabilization, and secondly, cell-penetrating peptides (CPPs), capable of introducing into cells a variety of cargoes in the absence of specific receptors, again by interaction at some point with membrane phospholipids. For both AMPs and CPPs, the pharmacological proof-of-concept has been successfully demonstrated, and promising applications as nanobiotechnological tools have been envisaged though not hitherto materialized in clinical settings. In this review we briefly examine the pros and cons of these two classes of therapeutic agents, as well as strategies aimed at rationalizing and expanding their potentiality ; Work supported by the European Union (HEALTH-2007-223414, Leishdrug, to L.R. and D.A.), the Fondo de Investigaciones Sanitarias (PI061125, PS09/01928 and RETICS-FEDER RD 06/0021/0006 to L.R.), the regional governments of Madrid (S-BIO-0260/2006 to L.R) and Catalonia (2009 SGR 492 to D.A.), and the Spanish Ministry of Science and Innovation (PET2006-0139 to L.R. and D.A.).

This report updates and combines into one document earlier versions of guidelines for preventing and treating opportunistic infections (OIs) among HIV-exposed and HIV-infected children, last published in 2002 and 2004, respectively. These guidelines are intended for use by clinicians and other health-care workers providing medical care for HIV-exposed and HIV-infected children in the United States. The guidelines discuss opportunistic pathogens that occur in the United States and one that might be acquired during international travel (i.e., malaria). Topic areas covered for each OI include a brief description of the epidemiology, clinical presentation, and diagnosis of the OI in children; prevention of exposure; prevention of disease by chemoprophylaxis and/or vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; and discontinuation of secondary prophylaxis after immune reconstitution. A separate document about preventing and treating of OIs among HIV-infected adults and postpubertal adolescents (Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents) was prepared by a working group of adult HIV and infectious disease specialists. The guidelines were developed by a panel of specialists in pediatric HIV infection and infectious diseases (the Pediatric Opportunistic Infections Working Group) from the U.S. government and academic institutions. For each OI, a pediatric specialist with content-matter expertise reviewed the literature for new information since the last guidelines were published; they then proposed revised recommendations at a meeting at the National Institutes of Health (NIH) in June 2007. After these presentations and discussions, the guidelines underwent further revision, with review and approval by the Working Group, and final endorsement by NIH, CDC, the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Disease Society (PIDS), and the American Academy of Pediatrics (AAP). The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of the evidence supporting the recommendation so readers can ascertain how best to apply the recommendations in their practice environments. An important mode of acquisition of OIs, as well as HIV infection among children, is from their infected mother; HIV-infected women coinfected with opportunistic pathogens might be more likely than women without HIV infection to transmit these infections to their infants. In addition, HIV-infected women or HIV-infected family members coinfected with certain opportunistic pathogens might be more likely to transmit these infections horizontally to their children, resulting in increased likelihood of primary acquisition of such infections in the young child. Therefore, infections with opportunistic pathogens might affect not just HIV-infected infants but also HIV-exposed but uninfected infants who become infected by the pathogen because of transmission from HIV-infected mothers or family members with coinfections. These guidelines for treating OIs in children therefore consider treatment of infections among all children, both HIV-infected and uninfected, born to HIV-infected women. Additionally, HIV infection is increasingly seen among adolescents with perinatal infection now surviving into their teens and among youth with behaviorally acquired HIV infection. Although guidelines for postpubertal adolescents can be found in the adult OI guidelines, drug pharmacokinetics and response to treatment may differ for younger prepubertal or pubertal adolescents. Therefore, these guidelines also apply to treatment of HIV-infected youth who have not yet completed pubertal development. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for preventing and treating OIs, especially those OIs for which no specific therapy exists; 2) information about the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information about managing antiretroviral therapy in children with OIs, including potential drug--drug interactions; 4) new guidance on diagnosing of HIV infection and presumptively excluding HIV infection in infants that affect the need for initiation of prophylaxis to prevent Pneumocystis jirovecii pneumonia (PCP) in neonates; 5) updated immunization recommendations for HIV-exposed and HIV-infected children, including hepatitis A, human papillomavirus, meningococcal, and rotavirus vaccines; 6) addition of sections on aspergillosis; bartonella; human herpes virus-6, -7, and -8; malaria; and progressive multifocal leukodystrophy (PML); and 7) new recommendations on discontinuation of OI prophylaxis after immune reconstitution in children. The report includes six tables pertinent to preventing and treating OIs in children and two figures describing immunization recommendations for children aged 0--6 years and 7--18 years. Because treatment of OIs is an evolving science, and availability of new agents or clinical data on existing agents might change therapeutic options and preferences, these recommendations will be periodically updated and will be available at http://AIDSInfo.nih.gov. ; Background -- Bacterial Infections -- Mycobacterial Infections -- Fungal Infections -- Parasitic Infections -- Viral Infections ; prepared by Lynne M. Mofenson, Michael T. Brady, Susie P. Danner, Kenneth L. Dominguez, Rohan Hazra, Edward Handelsman, Peter Havens, Steve Nesheim, Jennifer S. Read, Leslie Serchuck, Russell Van Dyke ; "September 4, 2009." ; "The material in this report originated in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention."- p. 1 ; Also available via the World Wide Web. ; Includes bibliographical references (p. 99-126).

Reviews the health & human rights implications of the HIV prevention "anti-prostitution policy" in the US Leadership against HIV/AIDS, Tuberculosis, & Malaria Act. References. Adapted from the source document.

Following the rising profile of trafficking in persons globally and Nigeria's position as a critical country in the African region, significant—though insufficient and poorly spent—funding has been deployed towards tackling the problem. This funding, however, is provided in a 'principal-agent' relationship by donors to the government of Nigeria and anti-trafficking organisations. Donors (the principals) fund organisations (the agents) to do work they deem important, though organisations tend to have significantly different needs and preferences for the funding. The consequence is that interventions paid for by these funds are 'not fit for purpose', making their outcomes often invisible, undesirable or unsustainable. An ancillary and critical issue related to anti-trafficking funding in Nigeria is accountability, or rather a lack of accountability. Where key actors in addressing trafficking are not accountable to beneficiaries, they miss out on critical feedback to help them improve services or design appropriate interventions.Intervenciones contra la trata en Nigeria y el Modelo de Ayuda Agente-PrincipalResumenSiguiendo el creciente perfil internacional de la trata de personas a nivel global, así como la posición de Nigeria como un país fundamental en la región de África, son significativos -aunque insuficientes y débilmente utilizados- los esfuerzos de financiación que se han desplegado para afrontar el problema. Esta financiación sigue una relación de principal-agente entre los donantes que financian al gobierno de Nigeria y las organizaciones contra la trata. Los donantes (los principales) financian organizaciones (los agentes) para hacer el trabajo que ellos consideran que es importante, a través de organizaciones que contemplan necesidades y preferencias de financiación significativamente diferentes. Como consecuencia, las intervenciones financiadas por estos financiadores están diseñadas "sin encajar en las necesidades", haciendo que sus resultados con frecuencia sean invisibles, indeseables o no sostenibles en el tiempo. Una cuestión secundaria, pero sin embargo fundamental, relacionada con la financiación contra la trata en Nigeria es la rendición de cuentas o, mejor dicho, la falta de rendición de cuentas. Cuando los actores principales en la lucha contra la trata no tienen que rendir cuentas frente a los beneficiarios, se pierde la capacidad de aprender de los éxitos y fracasos de las actividades ya implementadas, lo que ayudaría a mejorar los servicios o diseñar intervenciones adecuadas.

OBJECTIVES: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years. METHODS: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. RESULTS: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years. CONCLUSIONS: Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes. ; This work was supported by the UK Medical Research Council (MRC) MR/J002380/1—http://www.mrc.ac.uk/— and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. ; Sí