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)

Raltegravir (Isentress), an integrase inhibitor, inhibits the insertion of HIV-1 complementary DNA into the host genome. It is indicated in combination with other antiretroviral therapy (ART) agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple ART agents. It is the first of a new class of ART agents to be approved that, as a result of a different mechanism of action to other ART agents, has good activity against multidrug-resistant HIV-1 strains. In clinical trials in treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of oral raltegravir to an optimized background therapy (OBT) regimen improved virological and immunological responses at 16 and 48 weeks to a greater extent than placebo plus OBT. Raltegravir therapy was generally well tolerated, with a similar incidence of mild to moderate adverse events in the treatment and placebo arms. The introduction of integrase inhibitors extends the options available for managing treatment-experienced patients with multiple-drug-resistant HIV-1 infection. Results to date suggest that the combination of raltegravir and OBT will be a valuable treatment option for this difficult-to-treat patient group.
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PMID:Raltegravir: a review of its use in the management of HIV infection in treatment-experienced patients. 1949 31

Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug-drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176-890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6-14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT.
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PMID:Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. 1951 19

A novel class of tetrahydro-pyrazinopyrimidine-2-carboxamides have been identified as HIV-1 integrase inhibitors. Optimization of the initial lead culminated in the discovery of a series of compounds with high potency on the enzyme and an antiviral cell-based activity equivalent to that showed by Raltegravir, the first in class HIV-1 integrase inhibitor.
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PMID:N-(4-Fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamides a novel class of potent HIV-1 integrase inhibitors. 1952 19

Raltegravir, a novel HIV-1 integrase inhibitor, has superior efficacy with optimized background treatment (OBT) vs. placebo + OBT in treatment-experienced HIV-1 patients. This study assessed the long-term cost effectiveness of raltegravir from a Spanish National Healthcare System perspective. A cohort-state-transition model was used to estimate clinical and economic outcomes associated with raltegravir + OBT vs. OBT alone. Subjects were stratified into health states according to HIV RNA level, CD4 count, and opportunistic infection (OI) history, and could transition into different health states over time based on projected long-term efficacy. Each health state was associated with a distinct treatment cost and utility (QoL) score. Model inputs for mortality, resource utilization, unit costs, OI risk, and long-term durability of viral suppression were obtained from clinical trials, published studies, and database analyses. Model outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2007 Euros per quality-adjusted life-year (euro/QALY) gained. Costs and QALYs were discounted at 6% per year based on Spanish cost-effectiveness guidelines. Extensive sensitivity analyses were conducted. Five years of treatment with raltegravir + OBT resulted in an additional 4.5 years of undiscounted life expectancy vs. OBT alone. The ICER of raltegravir + OBT vs. OBT alone was euro22,908/QALY and euro31,431/QALY for 3- and 5-year use, respectively. Lower ICERs were observed with lower discount rates (3%) for costs and benefits, lower raltegravir price (20%), and shorter treatment duration (3 years). ICER was also sensitive to analytical time horizon and alternative sources of QoL scores. In treatment-experienced Spanish patients, raltegravir was projected to provide survival benefits and be cost effective.
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PMID:Cost-effectiveness analysis of raltegravir in treatment-experienced HIV type 1-infected patients in Spain. 1955 90

The early establishment of an HIV-1 reservoir with integrated provirus in the DNA of cells with latent infection hampers viral eradication, despite maintenance of viral loads lower than 50 copies/mL for years. By early initiation of highly suppressive antiretroviral therapy (ART), the half-life of this reservoir could be as short as 4.6 months and require only 7.7 years for complete elimination. The constant presence of low-grade viral replication probably indefinitely replenishes this resting CD4+ T cell reservoir. This reservoir probably results from both the release of virus stored in latently-infected cells that have become activated and from residual replication of some still-activated cells. This also allows new resistant mutants selected after therapeutic failure to be incorporated into the reservoir. Raltegravir has been demonstrated to significantly reduce elimination times in the first two viral decay phases after initiation of ART. On starting the second phase, the viral load was 70% lower in patients treated with raltegravir than in those treated with efavirenz. Through its late mechanism of action in the HIV-1 cell cycle, this drug could induce greater decreases in proviral DNA than other antiretroviral agents. The presence of unintegrated HIV DNA under prolonged effective ART indicates that either there is continual low-level viral replication or that this unintegrated DNA can persist for prolonged periods. In both cases, intensification of ART with raltegravir could provide beneficial effects on the speed of elimination of the HIV-1 reservoir.
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PMID:[Potential of integrase inhibitors to deplete HIV reservoirs or prevent their replenishment]. 1957 21

Raltegravir is the first integrase inhibitor approved for the treatment of HIV-1 infection in pretreated adults with evidence of viral replication despite receiving antiretroviral therapy. Raltegravir is administered orally at a dose of 400 mg every 12 hours, with or without food. This drug is mainly eliminated through UGT1A1-mediated glucuronidation and is not an inhibitor or inducer of the main liver cytochrome P450 isoenzymes; consequently there is virtually no risk of pharmacological interactions with most commonly used drugs such as methadone, azole antifungal agents or drugs used to treat erectile dysfunction. Studies of interaction with other antiretroviral agents show that raltegravir can be used in combination with tenofovir, efavirenz, atazanavir, ritonavir or tipranavir/ritonavir without the need for dose adjustments. When combined with rifampicin, the dose of raltegravir should be increased to 800 mg/12 h. Proton pump inhibitors increase plasma levels of raltegravir (a 3-fold increase in exposure or AUC levels), and consequently their combined use should be avoided as far as posible. Raltegravir is well tolerated and does not require dose adjustments in patients with severe renal impairment or mild-to-moderate liver impairment. There are no studies in patients with severe liver impairment.
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PMID:[Pharmacokinetics and interactions of raltegravir]. 1957 22

Raltegravir is the first in a new class of antiretroviral treatments called integrase inhibitors, which work by preventing HIV from inserting its genetic material into the DNA of the human chromosome. Phase I-III studies have shown this drug to have potent antiretroviral action, which is more rapid than that of protease inhibitors. The dose selected in efficacy studies is 400 mg every 12 h. However, due to the favorable pharmacokinetic profile of raltegravir, the possibility of administration of 600 to 800 mg once daily is under study. Given that this drug is not metabolized by the cytochrome P450 system, the potential for pharmacological interactions is low. Moreover, because humans lack a cellular homologue for HIV integrase, raltegravir has a low potential for toxicity. Raltegravir has an intermediate genetic barrier and consequently there may be cross-resistance across the integrase inhibitor class. For all these reasons, raltegravir is an attractive option in treatment-naive and pretreated patients and in those receiving simplification regimens.
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PMID:[Efficacy of raltegravir: from healthy volunteers to phase III trials]. 1957 23

Integrase inhibitors are a new therapeutic modality against HIV. Raltegravir is the first integrase inhibitor to have been approved by the health authorities for human use. This drug acts by inhibiting the HIV enzyme that catalyzes integration of the virus inside the genome of the host cell. In the host cell, there is no homologue to viral integrase and consequently the potential toxicity of this drug is probably low. The results of safety studies in animal models have shown that the recommended dose in humans is lower than the dose below which no secondary effects are observed. Studies of genotoxicity and carcinogenicity, as well as of fertility and embryo development, have been negative to date. During clinical trials, raltegravir has been shown to have a very good safety profile, with few adverse effects, which were mild-to-moderate and similar to those of the comparator. The most notable were diarrhea, nausea and headache. The lipid profile of raltegravir was better than that of efavirenz. In view of the above, the risk-benefit ratio for raltegravir is positive.
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PMID:[Secondary effects associated with raltegravir]. 1957 24

Antiretroviral rescue therapy has been revolutionized by the development of new drugs in the last few years: enfuvirtide (a fusion inhibitor), tipranavir/ritonavir (a high genetic barrier protease inhibitor), darunavir/ritonavir (a high genetic barrier protease inhibitor), etravirine (a non-nucleoside reverse transcriptase inhibitor active against nevirapine- and efavirenz- resistant HIV), maraviroc (a CCR5 coreceptor inhibitor) and raltegravir (an integrase inhibitor). The use of these drugs in rescue regimens has allowed the goal of antiretroviral rescue therapy to be the same as that in treatment naive-patients: to achieve a viral load lower than 50 copies of RNA of HIV/ml. Raltegravir is the first integrase inhibitor available for clinical use in Spain. This drug is primarily metabolized through UGT1A1-mediated glucuronidation and consequently has a low potential for interactions with drugs metabolized by the cytochrome P450 pathway. Raltegravir has been demonstrated to have high efficacy in two large clinical trials of rescue therapy, especially when combined with darunavir/ritonavir and enfuvirtide. Preliminary data suggest that raltegravir could also be an effective drug in treatment-naive patients and as substitution therapy in patients with toxicity due to boosted protease inhibitor therapy. The drug's unusual mechanism of action has reopened the possibility of a positive effect on latent HIV reservoirs.
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PMID:[Role of the new molecules in antiretroviral therapy. Position of raltegravir]. 1957 27

Virologic failure during treatment with raltegravir, the first effective drug targeting HIV integrase, is associated with two exclusive pathways involving either Q148H/R/K, G140S/A or N155H mutations. We carried out a detailed analysis of the molecular and structural effects of these mutations. We observed no topological change in the integrase core domain, with conservation of a newly identified Omega-shaped hairpin containing the Q148 residue, in particular. In contrast, the mutations greatly altered the specificity of DNA recognition by integrase. The native residues displayed a clear preference for adenine, whereas the mutant residues strongly favored pyrimidines. Raltegravir may bind to N155 and/or Q148 residues as an adenine bioisoster. This may account for the selected mutations impairing raltegravir binding while allowing alternative DNA recognition by integrase. This study opens up new opportunities for the design of integrase inhibitors active against raltegravir-resistant viruses.
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PMID:HIV-1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations. 1962 2


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