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      Review of tipranavir in the treatment of drug-resistant HIV

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      Therapeutics and Clinical Risk Management

      Dove Medical Press

      tipranavir, resistance, salvage, AIDS

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          Abstract

          Highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of patients with HIV. Low adherence and toxicity among HIV-positive patients starting HAART, however, can lead to discontinuation of therapy and limit long-term treatment success. Moreover, increasing prevalence of primary resistance (>10%) as well as the accumulation of mutations resulting from continued selection pressure exerted by ongoing antiretroviral treatment in patients failing virologically, mean that new compounds are needed that retain antiretroviral activity against resistant strains. Tipranavir (Aptivus ®) is a novel protease inhibitor (NPPI), which is characterized by a unique genetic resistance profile that allows it to remain active against HIV strains resistant to currently licensed protease inhibitors (PIs). Tipranavir was approved and licensed in the US and Europe in 2005 for treatment-experienced patients. This review summarizes the currently available data and studies on tipranavir and discusses the possible position of tipranavir in the currently available armamentarium of antiretroviral drugs.

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          Most cited references 59

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          Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel.

          Substantial changes in the field of human immunodeficiency virus (HIV) treatment have occurred in the last 2 years, prompting revision of the guidelines for antiretroviral management of adults with established HIV infection. To update recommendations for physicians who provide HIV care regarding when to start antiretroviral therapy, what drugs to start with, when to change drug regimens, and what drug regimens to switch to after therapy fails. Evidence was identified and reviewed by a 16-member noncompensated panel of physicians with expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care. The panel was designed to have broad US and international representation for areas with adequate access to antiretroviral management. Evidence considered included published basic science, clinical research, and epidemiological data (identified by experts in the field or extracted through MEDLINE searches using terms relevant to antiretroviral therapy) and abstracts from HIV-oriented scientific conferences between July 2002 and May 2004. Data were reviewed to identify any information that might change previous guidelines. Based on panel discussion, guidelines were drafted by a writing committee and discussed by the panel until consensus was reached. Four antiretroviral drugs recently have been made available and have broadened the options for initial and subsequent regimens. New data allow more definitive recommendations for specific drugs or regimens to include or avoid, particularly with regard to initial therapy. Recommendations are rated according to 7 evidence categories, ranging from I (data from prospective randomized clinical trials) to VII (expert opinion of the panel). Further insights into the roles of drug toxic effects, drug resistance, and pharmacological interactions have resulted in additional guidance for strategic approaches to antiretroviral management.
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            The prevalence of antiretroviral drug resistance in the United States.

            Antiretroviral therapy has dramatically reduced the morbidity and mortality of infection due to HIV. The emergence of drug-resistant virus has limited the usefulness of many drugs. To determine the prevalence of HIV drug resistance in the population of adults receiving care in the United States. HIV drug susceptibility assays were performed on plasma virus from a random sample representative of the 132500 HIV-infected American adults who had received medical care in early 1996 yet were viremic with > 500 copies/ml of HIV RNA in late 1998. A blood sample was obtained from 1797 patients who comprised a representative sample of the 208900 adults receiving urban care for HIV infection in early 1996 who survived to late 1998. The sampling procedure permitted weighting each evaluated patient to reflect demographic and other characteristics of the target population. We estimated that 132500 (63%) of the target population had HIV viremia of > 500 copies/ml. Among viremic patients, an estimated 76% had resistance to one or more antiretroviral drugs. The odds of resistance were significantly higher in patients with a history of antiretroviral drug use, advanced HIV disease, higher plasma HIV viral load and lowest CD4 cell count by self-report. The frequent selection for drug-resistant virus among viremic patients during the first 3 years of widespread use of potent antiretroviral combination therapy has significant implications for HIV treatment and transmission.
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              Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

              To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                August 2007
                August 2007
                : 3
                : 4
                : 641-651
                Affiliations
                Department of Medicine I, University of Bonn Bonn, Germany
                Author notes
                Correspondence: Jurgen Kurt Rockstroh, Department of Medicine I, Sigmund-Freud-Str. 25, D - 53105 Bonn, Germany Tel +49 228/287-6558 Fax +49 228/287-5034 Email rockstroh@ 123456uni-bonn.de
                Article
                2374948
                18472987
                © 2007 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                salvage, resistance, tipranavir, aids

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