British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy British HIV Association Writing Committee HIV Med 2003 4 Suppl 1 1 41 14511246

Chelsea and Westminster Hospital, London, UK.
HIV Medicine (Impact Factor: 3.99). 11/2003; 4 Suppl 1(4):1-41. DOI: 10.1046/j.1464-2662.2001.00083.x
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    • "The advent of highly active antiretroviral therapy (HAART) has brought with it a significant decrease in AIDS-related deaths over the last ten years. Prior to the development of raltegravir, HAART had been recommended to consist of at least three different drugs targeting separate stages of the HIV life cycle: two nucleoside reverse transcriptase inhibitors, plus either a non-nucleoside reverse transcriptase inhibitor such as efavirenz, or a protease inhibitor [5,6]. Studies have shown that effective administration of these HAART regimens can result in a large-scale decrease in plasma levels of viral RNA, as well as a significant increase in CD4 cell count [7-9]. "
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    ABSTRACT: Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.
    Full-text · Article · Feb 2009 · Retrovirology
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    • "In order to improve HRQL and adherence, it is therefore crucial to find treatment combinations and strategies that minimise these negative effects and to individualize treatment. The simplified and less toxic treatment regimes available today, with antiretroviral therapy based on three nucleoside analogue reverse transcriptase inhibitors or nucleoside analogues combined with non-nucleoside analogue reverse transcriptase inhibitors or ritonavirboosted PIs once or twice daily [1], may be less liable to have a negative impact on HRQL. This was indicated in a randomised study comparing two nucleoside analogue reverse transcriptase inhibitors combined with either a PI or efavirenz, over a one year period and where the combination with efavirenz had a better influence on HRQL than the combination with the PI [46]. "
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    ABSTRACT: Protease inhibitor based antiretroviral therapy (PI-ART) was introduced in 1996 and has greatly reduced the incidence of HIV-related morbidity and mortality in the industrialised world. PI-ART would thus be expected to have a positive effect on health-related quality of life (HRQL). On the other hand, HRQL might be negatively affected by strict adherence requirements as well as by short and long-term adverse effects. The aim of this study was to assess the influence of two years of first generation PI-ART on HRQL in patients with a relatively advanced state of HIV-infection. Furthermore, we wanted to investigate the relation between developments in HRQL and viral response, self-reported adherence and subjective experience of adverse effects in patients with PI-ART. HRQL was measured by the Swedish Health-Related Quality of Life Questionnaire (SWED-QUAL). Sixty-three items from the SWED-QUAL forms two single-item and 11 multi-item dimension scales. For this study, two summary SWED-QUAL scores (physical HRQL composite score and emotional HRQL composite score) were created through a data reduction procedure. At the 2-year follow-up measurement (see below), items were added to measure adherence and subjective experience of adverse effects. Demographic and medical data were obtained from specific items in the questionnaires and from the medical files. Seventy-two patients who were among the first to receive PI-ART (indinavir or ritonavir based) responded to the questionnaire before the start of PI-ART. Of these, 54 responded to the same instrument after two years of treatment (13 had died, four had changed clinic and one did not receive the questionnaire). The main findings were that the emotional HRQL deteriorated during two years of PI-ART, while the physical HRQL remained stable. Multiple linear regression analyses showed that experience of adverse effects contributed most to the deterioration of emotional HRQL. In this sample of patients with relatively advanced state of HIV-infection, our data suggested that a negative development of physical HRQL had been interrupted by the treatment and that the emotional dimension of HRQL deteriorated during two years after start of PI-ART. Subjective experience of adverse effects made a major contribution to the decrease in emotional HRQL. The results underline the importance of including HRQL measures in the evaluation of new life prolonging therapies.
    Full-text · Article · Feb 2005 · Health and Quality of Life Outcomes
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    • "recommended to enhance intracellular nucleoside reverse transcriptase inhibitors levels (Pozniak et al. 2001). However, the cytostatic effect that hydroxyurea has on CD4 + T lymphocytes , the host cells for HIV, which consequently may lead to a reduction in viral replication, may still have beneficial effects (Lori and Lisziewic 2000; Pozniak et al. 2001). Overall, hydroxyurea, may still have a place in HIV treatment regimens such as structured treatment interruptions (Lori et al. 2000, 2002), or as a cost-effective treatment option that could be made accessible in countries with a limited AIDS budget (Paton et al. 2002), but does require further evaluation and must still be considered as an experimental drug. "
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    ABSTRACT: Hydroxyurea is used in the treatment of HIV infection in combination with nucleoside analogues, 2'3'-didehydro-3'deoxythymidine (D4T), 2'3'-dideoxyinosine or abacavir. It is distributed into human CSF and is transported from the CSF to sub-ependymal brain sites, but its movement into the brain directly from the blood has not been studied. This study addressed this by a brain perfusion technique in anaesthetized guinea-pigs. The carotid arteries were perfused with an artificial plasma containing [14C]hydroxyurea (1.6 microm) and a vascular marker, [3H]mannitol (4.6 nm). Brain uptake of [14C]hydroxyurea (8.0 +/- 0.9%) was greater than [3H]mannitol (2.4 +/- 0.2%; 20-min perfusion, n = 8). CSF uptake of [14C]hydroxyurea (5.6 +/- 1.5%) was also greater than [3H]mannitol (0.9 +/- 0.3%; n = 4). Brain uptake of [14C]hydroxyurea was increased by 200 microm hydroxyurea, 90 microm D4T, 350 microm probenecid, 25 microm digoxin, but not by 120 microm hydroxyurea, 16.5-50 microm D4T, 90 microm 2'3'-dideoxyinosine or 90 microm abacavir. [14C]Hydroxyurea distribution to the CSF, choroid plexus and pituitary gland remained unaffected by all these drugs. The metabolic half-life of hydroxyurea was > 15 h in brain and plasma. Results indicate that intact hydroxyurea can cross the brain barriers, but is removed from the brain by probenecid- and digoxin-sensitive transport mechanisms at the blood-brain barrier, which are also affected by D4T. These sensitivities implicate an organic anion transporter (probably organic anion transporting polypeptide 2) and possibly p-glycoprotein in the brain distribution of hydroxyurea and D4T.
    Full-text · Article · Nov 2003 · Journal of Neurochemistry
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