Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug resistance is a major problem affecting the clinical efficacy of antiretroviral agents, including protease inhibitors, in the treatment of infection with human immunodeficiency virus type 1 (HIV-1)/AIDS. Consequently, the elucidation of the mechanisms by which HIV-1 protease inhibitors maintain antiviral activity in the presence of mutations is critical to the development of superior inhibitors. Tipranavir, a nonpeptidic HIV-1 protease inhibitor, has been recently approved for the treatment of HIV infection. Tipranavir inhibits wild-type protease with high potency (K(i) = 19 pM) and demonstrates durable efficacy in the treatment of patients infected with HIV-1 strains containing multiple common mutations associated with resistance. The high potency of tipranavir results from a very large favorable entropy change (-TDeltaS = -14.6 kcal/mol) combined with a favorable, albeit small, enthalpy change (DeltaH = -0.7 kcal/mol, 25 degrees C). Characterization of tipranavir binding to wild-type protease, active site mutants I50V and V82F/I84V, the multidrug-resistant mutant L10I/L33I/M46I/I54V/L63I/V82A/I84V/L90M, and the tipranavir in vitro-selected mutant I13V/V32L/L33F/K45I/V82L/I84V was performed by isothermal titration calorimetry and crystallography. Thermodynamically, the good response of tipranavir arises from a unique behavior: it compensates for entropic losses by actual enthalpic gains or by sustaining minimal enthalpic losses when facing the mutants. The net result is a small loss in binding affinity. Structurally, tipranavir establishes a very strong hydrogen bond network with invariant regions of the protease, which is maintained with the mutants, including catalytic Asp25 and the backbone of Asp29, Asp30, Gly48 and Ile50. Moreover, tipranavir forms hydrogen bonds directly to Ile50, while all other inhibitors do so by being mediated by a water molecule.
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PMID:Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. 1736 Jul 59

Tipranavir is a recently approved nonpeptidic protease inhibitor specifically developed for the management of human immunodeficiency virus (HIV) infection in treatment-experienced patients with protease inhibitor-resistant infection. It is active against a wide range of drug-resistant laboratory- and patient-derived isolates. Tipranavir requires pharmacokinetic boosting by ritonavir (200 mg) to achieve therapeutic levels with twice-daily dosing and must be administered with food for optimal absorption. It is a potent protease inhibitor with a unique drug-resistance profile that offers advantages in the management of cases of multidrug-resistant HIV infection. Tipranavir (in combination with ritonavir) is both an inhibitor and inducer of cytochrome p450, with significant potential for drug-drug interactions, and therefore, it must be used cautiously when administered to patients who are receiving other drugs. Evolution of drug resistance after treatment failure with tipranavir is complex and is not yet fully understood. There is limited overlap in the resistance mutations that predict response to tipranavir and another new protease inhibitor, darunavir, which is active against drug-resistant isolates. Tipranavir is associated with elevations in alanine aminotransferase and aspartate aminotransferase levels, as well as elevated cholesterol and triglyceride levels, and can cause the typical gastrointestinal adverse effects associated with all protease inhibitors.
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PMID:Tipranavir: a new option for the treatment of drug-resistant HIV infection. 1771 62

Week 48 HIV-RNA treatment response to the protease inhibitor tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.
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PMID:Treatment response to ritonavir-boosted tipranavir versus ritonavir-boosted lopinavir in HIV-1 patients with higher lopinavir mutation scores. 1920 59

A 55-year-old HIV-infected patient on antiretroviral treatment with Ritonavir-boosted Tipranavir as part of HAART developed intracranial haemorrhage during the acute phase of cryptococcal meningitis. CT scan and MRI confirmed the intracranial haemorrhage. Positive cryptococcal antigen and cultures of both blood and CSF confirmed the diagnosis of meningitis caused by Cryptococcus neoformans. There was no evidence of any bleeding disorder, use of aspirin or antiplatelet agents. The patient was treated with Liposomal Amphotericin B for cryptococcal meningitis. No special treatment was needed for the intracranial haemorrhage, but Tipranavir was discontinued and replaced by Kaletra and Saquinavir. Intracranial haemorrhage could be related to Tipranavir and cryptococcal meningitis was a predisposing factor. Headache stopped 3 days after starting antifungal treatment. To the best of our knowledge, this is the first reported case of intracranial haemorrhage related to Tipranavir treatment after the end of the "RESIST" studies and the only one related to meningitis.
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PMID:Intracranial haemorrhage possibly related to Tipranavir in an HIV-1 patient with cryptococcal meningitis. 1831 96

The impact of tipranavir plasma levels (TPV C(min)) on virological response was examined in 36 antiretroviral-experienced HIV-infected individuals. Although TPV C(min) did not predict outcome in patients with less than five or more than eight baseline TPV-associated resistance mutations, TPV C(min) values were greater in responders than in nonresponders with five to seven baseline TPV-associated resistance mutations (38.8 vs. 13.8 g/ml, p = 0.017). Thus, therapeutic drug monitoring might be helpful in ensuring a viral response in this subset of patients.
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PMID:Association between tipranavir plasma levels and virological response in HIV-infected patients. 1837 31

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((R))) 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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PMID:Review of tipranavir in the treatment of drug-resistant HIV. 1847 87

Tipranavir (Aptivus) is a selective nonpeptidic HIV-1 protease inhibitor (PI) that is used in the treatment of treatment-experienced adults with HIV-1 infection. Tipranavir is administered orally twice daily and must be given in combination with low-dose ritonavir, which is used to boost its bioavailability. The durable efficacy of tipranavir, in combination with low-dose ritonavir (tipranavir/ritonavir 500 mg/200 mg twice daily), has been demonstrated in well designed trials in treatment-experienced adults infected with multidrug-resistant strains of HIV-1. In treatment-experienced adults with HIV-1 infection receiving an optimized background regimen, viral suppression was greater and immunological responses were better with regimens containing tipranavir/ritonavir than with comparator ritonavir-boosted PI-containing regimens. The efficacy benefit appeared to be more marked in patients receiving two fully active drugs in the regimen, with the combination of tipranavir/ritonavir and enfuvirtide (for the first time) appearing to be the most successful. Although tipranavir is generally well tolerated, clinical hepatitis and hepatic decompensation, and intracranial haemorrhage have been associated with the drug. Tipranavir also has a complex drug-interaction profile. Thus, tipranavir, administered with ritonavir, is an effective treatment option for use in the combination therapy of adults with HIV-1 infection who have been previously treated with other antiretroviral drugs.
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PMID:Tipranavir: a review of its use in the management of HIV infection. 1857 60

Tipranavir (TPV), a protease inhibitor, has box warnings for intracranial hemorrhage (ICH) and hepatotoxicity (including hepatic failure and death). A box warning is a labeling statement about serious adverse events leading to significant injury and/or death. A box warning is the most serious warning placed in the labeling of a prescription medication. As a result of the respective morbidity and mortality associated with ICH and hepatic failure, the Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS) was searched for reports of these adverse events in HIV-infected patients receiving a tipranavir/ritonavir (TPV/r)-based regimen. This search comprised part of the FDA's safety analysis for traditional approval. From July 2006 to March 2007, 10 cases of ICH were identified in AERS. From June 2005 to March 2007, 12 cases of liver-associated deaths were identified. One patient experienced liver failure and fatal ICH. Most patients with these events had additional risk factors. Among patients with liver-associated deaths, 3 had HIV-RNA less than 400 copies per milliliter at the time of hepatic failure. Among 10 patients who discontinued TPV/r when hepatic failure developed, median number of days post-TPV/r to death was 23 (range, 2-69 days). Review of AERS did not identify new safety concerns regarding ICH. Among most patients with liver-associated deaths, death appears to occur soon after hepatic failure develops. If considering TPV/r, careful assessment of risk/benefit is suggested for patients at risk for ICH and hepatic failure.
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PMID:Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System. 1902 78

Highly active antiretroviral therapy can provide sustained viral suppression and a beneficial immunological response in both antiretroviral-naive and -experienced pediatric patients infected with HIV. While there have been many antiretroviral studies in adults infected with HIV, considerably less information is available in similar HIV-infected pediatric or adolescent patients. Tipranavir, a new-generation protease inhibitor approved for use in adults with resistant HIV strains, has recently been studied in HIV-infected children and adolescents. In this article, we summarize available pharmacokinetic, safety, tolerability and efficacy data obtained from children and adolescents treated with a pediatric tipranavir formulation.
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PMID:Tipranavir: a new protease inhibitor for the pediatric population. 1905 93

Gender-related differences in the efficacy and safety of ritonavir-boosted tipranavir [tipranavir/ritonavir (TPV/r) 500/200 mg twice daily (b.i.d.)] were evaluated in a subanalysis of the Randomized Evaluation of Strategic Intervention in Multidrug Resistant Patients with Tipranavir (RESIST) trials. Data from HIV-1-infected women (203; TPV/r = 117) and men (1280; TPV/r = 629) showed no significant gender-related differences in HIV RNA response rates (at 48 weeks) and safety (at 96 weeks) despite higher mean steady-state plasma TPV trough concentrations in women. Significantly greater increases in CD4 cell count (+81.2 vs. +48.6; P = 0.0012) were observed in women at week 48.
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PMID:Multidrug-experienced HIV-1-infected women demonstrated similar virological and immunological responses to tipranavir/ritonavir compared with men. 1911 62


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