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)

(1) Maraviroc belongs to a new class of antiretroviral drugs designed to block entry of HIV-1 into CD4+ T-cells via the CCR5 coreceptor. It is indicated for combination therapy in treatment-experienced adults infected with CCR5-tropic HIV-1 that is resistant to multiple antiretroviral agents. (2) Results from two randomized controlled trials (RCTs) indicate that in treatment experienced patients, maraviroc, combined with optimized background therapy (OBT), significantly decreases the level of HIV-1 RNA in the blood (viral load) when compared with OBT alone. The number of patients achieving undetectable viral loads and CD4+ cell count increases were also significantly higher in those receiving maraviroc. (3) Most patients experiencing treatment failure with maraviroc exhibit tropism changes from CCR5-tropic to CXCR4-using virus, but there is no evidence of disease progression. (4) Adverse effects reported with maraviroc include cough, fever, upper respiratory tract infections, rash, muscle and joint pain, abdominal pain, and postural hypotension (dizziness). No significant increases in cardiovascular events, hepatotoxicity, infections or malignancies have been reported with short-term maraviroc therapy. Several post-marketing studies will assess maraviroc's long-term safety for immune function, liver function, malignancy, cardiac events, and risks associated with changes in tropism. (5) Results from an ongoing trial in treatment naive patients suggest that maraviroc may not be superior in terms of viral suppression to standard therapy, but may significantly increase the number of CD4+ T-cells.
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PMID:Maraviroc (Celsentri) for multidrug-resistant human immunodeficiency virus (HIV)-1. 1808 Mar 99

Maraviroc, first in a new pharmacological class of antiretroviral agents known as CCR5 antagonists, has been approved by the U.S. Food and Drug Administration for the treatment of HIV-infected adult patients who are infected with only CCR5-tropic HIV-1 virus and who have HIV-1 strains resistant to multiple antiretroviral agents. Maraviroc has demonstrated in vitro activity against a wide range of CCR5 tropic clinical isolates, including those resistant to the four currently existing drug classes of antiretroviral agents. In the two pivotal phase III studies, MOTIVATE-1 and -2, maraviroc, in combination with optimized background therapy (OBT), demonstrated superior virologic and immunologic treatment outcomes than OBT alone in treatment-experienced patients infected with CCR5-tropic HIV-1. In these studies, maraviroc also demonstrated acceptable safety and tolerability profiles with adverse events and discontinuation rates in general comparable to those noted in the placebo arms.
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PMID:Maraviroc. 1817 62

Maraviroc (Pfizer's UK-427857, Selzentry or Celsentri outside the US) is the first agent in the new class of oral HIV-1 entry inhibitors to acquire FDA and EMEA approval. It is expected that this drug will be effective only in a subpopulation of HIV-1-infected people, namely those harbouring only the R5 virus. The wide use of this drug is currently hampered by the lack of a readily available R5 virus only determination test (tropism test) and by insufficient scientific insight into the dynamics of R5 and X4 viruses during infection. We discuss the challenges associated with the currently available assay, as well as the potential role of alternative assays.
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PMID:Maraviroc: integration of a new antiretroviral drug class into clinical practice. 1840 Aug 7

Human immunodeficiency virus type 1 (HIV-1) entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (enfuvirtide [Fuzeon]) and, more recently, the CCR5 blocker maraviroc (Selzentry). T1249 is a second-generation fusion inhibitor with improved antiviral potency compared to the first-generation peptide T20. We selected T1249-resistant HIV-1 variants in vitro by serial virus passage in the presence of increasing T1249 doses after passage with wild-type and T20-resistant variants. Sequence analysis revealed the acquisition of substitutions within the HR1 region of the gp41 ectodomain. The virus acquired mutations of residue V38 to either E or R in 10 of 19 cultures. Both E and R at position 38 were confirmed to cause resistance to T1249, as well as cross-resistance to T20 and C34, but not to the third-generation fusion inhibitor T2635. We also observed substitutions at residues 79 and 90 (Q79E and K90E), which provide modest resistance to T1249 and, interestingly, T2635. Thus, the gp41 amino acid position implicated in T20 resistance (V38 replaced by A, G, or W) is also responsible for T1249 resistance (V38 replaced by E, R, or K). These results indicate that T20 and T1249 exhibit very similar inhibition modes that call for similar but not identical resistance mutations. All T1249-resistant viruses with changes at position 38 are cross resistant to T20, but not vice versa. Furthermore, substitutions at position 38 do not provide resistance to the third-generation inhibitor T2635, while substitution at positions 79 and 90 do, suggesting different resistance mechanisms.
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PMID:Selection of T1249-resistant human immunodeficiency virus type 1 variants. 1843 91

Maraviroc (MVC, UK-427,857) is the first member of a new class, the CCR5 antagonists. By an original mechanism of action, maraviroc binds to the CCR5 receptor in order to prevent HIV from binding and entering human cells. Maraviroc (Celsentri) is an orally administered drug available as 150 and 300 mg film-coated tablets. The current approved daily dosage of maraviroc is 300 mg bid in combination with other antiretroviral medications. Maraviroc plasma exposure is not dose proportional. After a rapid (but moderate) intestinal absorption, several inactive oxidized metabolites are produced via cytochrome P450 3A4 pathway. According to this liver metabolism, dosage adjustments are required when maraviroc is administered in combination with cytochrome P450 inhibitors or inducers. The potential for drug-drug interactions and the well-defined relationship between plasma concentrations and virological response suggest the usefulness of Therapeutic Drug Monitoring of maraviroc in HIV-infected patients.
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PMID:[Clinical pharmacokinetic of maraviroc]. 1845 57

Just over a decade after identification of chemokine receptors CCR5 and CXCR4 as coreceptors for HIV, maraviroc (Celsentri), the first CCR5 antagonist, has recently obtained its Marketing Authorization in the United States and Europe, for treatment of treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable. CCR5 antagonists, after fusion inhibitor enfuvirtide available since 2003, also belong to entry inhibitors. These molecules, unlike previous antiretrovirals, do not target the virus but its target cell by blocking viral penetration. Maraviroc has shown its clinical efficacy in patients failing other antiretroviral classes. Its safety profile was similar to placebo in two large phase III trials. However, careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed. Viral tropism testing has to be investigated before using maraviroc in the clinic, because CCR5 antagonists are not active against CXCR4 viruses. For the moment indicated for the treatment-experienced patient population, maraviroc could in the future benefit to other types of patients, depending on ongoing trials results.
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PMID:[Maraviroc: clinical trials results]. 1845 58

Maraviroc is the first US Food and Drug Administration-approved drug from a new class of antiretroviral agents that targets a host protein, the chemokine receptor CCR5, rather than a viral target. Binding of maraviroc to this cell-surface protein results in blocking human immunodeficiency virus type 1 (HIV-1) attachment to the coreceptor and prevents the virus from entering CD4+ cells. In this review, we include the details of the discoveries that led to the development of this drug. The drug's pharmacology, including pharmacokinetics and drug interactions, is discussed, as are the clinical efficacy studies that led to licensure. HIV-1 mechanisms of resistance to maraviroc, assays to determine viral coreceptor use (tropism), drug safety, and clinical use of maraviroc are discussed at length.
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PMID:Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. 1853 88

In this article, you'll learn about eight new drugs, including: doripenem, an antibiotic for complicated intra-abdominal and urinary tract infections. Maraviroc, a new antiretroviral agent to treat HIV infection. Ixabepilone, a new drug for refractory metastatic breast cancer. Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug's safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.
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PMID:New drugs08, part 2. 1858 Jun 63

(1) The choice of treatment for HIV-infected patients in whom several lines of antiretroviral therapy have failed is particularly difficult. Some antiretroviral drugs (enfuvirtide and some HIV protease inhibitors) remain effective, at least in the short term. (2) Maraviroc is the first CCR5 antagonist to be licensed for use in this setting. It acts by blocking one of the two coreceptors, CCR5, needed for HIV entry into CD4+ lymphocytes. It is approved for use in HIV-infected patients with multiple antiretroviral failure. (3) Two double-blind placebo-controlled trials including 1076 patients infected by HIV strains using only the CCR5 coreceptor tested the effect of adding maraviroc at a dose of 300 mg twice a day to an optimised treatment. After 8 weeks, maraviroc was more effective than placebo in reducing viral load (undetectable in 45.5% versus 16.7% of patients) and in increasing the CD4+ cell count (+124 cells/mm3 versus +61 cells/mm3); both of these differences are statistically significant. (4) After treatment with maraviroc, 50% to 60% of patients harboured viruses that did not exclusively rely on CCR5 for host cell entry. The possible clinical consequences of this change in tropism are unclear. (5) A double-blind trial of maraviroc included 190 patients with multiple antiretroviral failure who were infected by HIV variants not requiring CCR5 for host cell entry; maraviroc was not shown to be effective. (6) Data obtained with other CCR5 antagonists, and preclinical data obtained with maraviroc, point to a possible increase in the risk of hepatitis, infections, cancer, and QT prolongation. More data are also needed concerning the risk of muscle toxicity and ischaemic cardiovascular events. (7) Maraviroc is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of interactions with CYP 3A4 inducers and inhibitors. (8) In practice, given the absence of long-term evaluation, clinical assessment of maraviroc is too limited to recommend the use of this drug outside the clinical trial setting.
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PMID:Maraviroc: new drug. Multiple antiretroviral treatment failure: too soon to reach conclusions. 1862 8

Human immunodeficiency virus (HIV) infection shows that knowledge of the molecular mechanisms involved in the pathogenesis can lead to the rapid development of new drugs to treat infected patients. Since the description of acquired immunodeficiency syndrome (AIDS) in 1981 and the identification of its causal agent in 1983, twenty-three antiretrovirals, belonging to 5 families, have been marketed. The viral entry point is one of the preferred therapeutic treatment targets, but the development of antagonists against the different HIV receptors has been a long process and fraught with difficulties. Maraviroc is the first CCR5 antagonist drug approved for clinical use and represents a milestone in the development of new treatments against HIV infection. Maraviroc is a novel drug and different from the rest of the antiretrovirals due to the special characteristics of its mechanism of action and is also the first antiretroviral directed towards a cell target. The different aspects of treatment with Maraviroc are analysed in this article; mechanism of action, toxicity, efficacy, resistance mechanisms, and its role in the context of antiretroviral treatment of the HIV infected patient.
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PMID:[Introduction. A brief history of AIDS]. 1913 14


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