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)

Human immunodefi ciency virus type-1 integrase (IN) is a new and novel target for inhibitors. Strand transfer inhibitors effectively prevent concerted integration of viral DNA by IN into the host chromosomes. Raltegravir is the fi rst approved strand transfer inhibitor for the treatment of HIV-1/AIDS. We propose a mechanistic hypothesis as to "when and where" these inhibitors are active in virus-infected cells. Using native agarose gel electrophoresis, we identified a transient synaptic complex (SC) wherein IN non-covalently juxtaposes two viral DNA ends. SC possesses many properties associated with the cytoplasmic preintegration complex (PIC) in infected cells, including concerted integration. Our results show that the strand transfer inhibitors effectively "trap" or inactivate the SC preventing concerted integration. It follows that the IN-viral DNA complex is "trapped" by the inhibitors via a transient intermediate within the cytosolic PIC before entry into the nucleus.
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PMID:HIV-1 Integrase Strand Transfer Inhibitors: Novel Insights into their Mechanism of Action. 1991 84

Raltegravir has recently been licensed for the treatment of HIV-1 infection. Currently its use is limited to treatment-experienced patients and subjects with resistant virus. In addition to its activity in the setting of resistance and treatment failure, it appears to have great potential for first-line therapy and as a switch option for subjects with intolerance to other agents, as well. Overall tolerability in clinical trials was excellent, and the toxicity profile is non-overlapping with other agents, with no clear neuropsychiatric, gastrointestinal, or metabolic toxicity. Its metabolization occurs mainly via UGT1A1 rather than by the CYP450 system, resulting in a relatively unproblematic drug interaction profile. The independence of the compound from "boosting" of drug levels with ritonavir is an attractive feature for many patients suffering from ritonavir-associated side effects. However, it has to be dosed twice daily.The unique effect of raltegravir on the establishment of viral latency makes it a logical component of treatment attempts aiming at reducing and controlling this viral sanctuary.This review summarizes the clinical view on the role of this novel compound in HIV therapy.
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PMID:Raltegravir in the management of HIV-infected patients. 1992 Sep 14

Raltegravir is a recently, Food and Drug Administration-approved, small-molecule drug that inhibits retroviral integrase, thereby preventing HIV DNA from inserting itself into the human genome. We report here that the activity profile of raltegravir on the replication of murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role. While NZW and BALB/c mice, which do not succumb to autoimmune disease, are not affected by raltegravir, lupus-prone (NZBxNZW) F(1) mice die of glomerulonephritis more than a month earlier than untreated mice. Raltegravir-treated NZB mice, which share the H-2 haplotype with BALB/c mice, but which are predisposed to autoimmune hemolytic anemia, develop auto-antibodies to their red blood cells >3 months earlier than untreated mice of the same strain. Because nonautoimmune mice are not affected by raltegravir, we consider off-target effects unlikely and attribute the exacerbation of autoimmunity to the inhibition of retroviral integrase.
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PMID:Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir. 1992 37

Raltegravir is the first integrase inhibitor approved for the treatment of HIV infection based on the superior efficacy it showed compared to optimized backbone therapy alone in patients harboring multidrug resistant viruses. Studies on naive patients showed comparable efficacy of raltegravir and efavirenz and just recently the US Food and Drug Administration (FDA) approved raltegravir for the use in naive patients based on the favorable results of the international double-blind phase III STARTMRK trial. Additional interesting findings were the faster, and not yet explained, decay of HIV-1 RNA and the higher CD4+ cells increase in the raltegravir group as compared to the efavirenz group. Raltegravir is generally well tolerated and adverse events were generally similar in raltegravir and comparator arms throughout all studies. When compared to efavirenz, patients on raltegravir showed less incidence of central nervous system-related adverse events. In studies on experienced patients higher incidence of cancers was found in the raltegravir arm: a relationship with the drug was, however not confirmed in a recent review considering all raltegravir studies. Raltegravir also showed a safe lipid profile especially in naive patients, finding that renders the drug attractive for patients with other cardiovascular risk factors. All this characteristics in association with its specific mechanism of action, make raltegravir an interesting drug for naive patients and a large use in this type of patients is predictable. Only time and experience, however, will tell us whether raltegravir will maintain its promises in the long run.
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PMID:Raltegravir in treatment naive patients. 1995 13

Raltegravir, the first approved HIV-1 integrase inhibitor, is able to block the strand transfer step of the HIV proviral DNA integration process into the cellular host DNA. The selected dosage for the pivotal phase III studies (subsequently approved by the regulatory agencies) was 400mg bid by oral route with or without food. Raltegravir has a week effect (either inhibition or induction) on the hepatic cytochrone P450 activity. There is not need of dose adjustments in renal insufficiency or in mild-to-moderate hepatic impairment. The emerging paradigm in the field of salvage therapy was to achieve a viral load below limit of detection in almost all patients. Pretty soon it became apparent that this was feasible in more than 70-90% of patients. Raltegravir proved to be pivotal for this new paradigm. Raltegravir vs placebo both with an optimized background therapy has been tested for salvage therapy in the 005 and in the BENCHMRK studies (018 and 019). In all three studies proved to be superior to the placebo at 24, 48 and 96 weeks. Tolerance was remarkably good and virological failure was often associated with selection of integrase gene resistance mutations following the Y143C/H/R, Q148H/K/R o less frequently the NI55H paths. Finally, in the two SWITCHMRK studies non-inferiority vs Lopinavir/r could not be demonstrated in virogically suppressed patients with an stable cART containing Lopinavir/r. Most likely explanation was the presence of archived resistance mutationts to background therapy leading to a functional monotherapy with raltegravir.
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PMID:The use of integrase inhibitors in treatment-experienced patients. 1995 14

Raltegravir concentrations and human immunodeficiency virus type 1 (HIV-1) RNA levels in semen samples from 10 treatment-experienced HIV-1-infected patients were measured after 24 weeks of raltegravir-based highly active antiretroviral therapy (HAART). Semen and plasma HIV-1 RNA levels were below 100 copies/ml and 50 copies/ml, respectively, in all samples. The median raltegravir concentrations in semen samples (n=10) and in plasma samples (n=9) drawn simultaneously were 345 (range, 83 to 707) ng/ml and 206 (range, 106 to 986) ng/ml, respectively. The median semen-to-plasma ratio of raltegravir concentration was 1.42 (range, 0.52 to 6.66), indicating good although variable levels of drug penetration of raltegravir in the seminal compartment.
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PMID:High concentration of raltegravir in semen of HIV-infected men: results from a substudy of the EASIER-ANRS 138 trial. 1999 25

Raltegravir (Isentress) is the first approved HIV integrase inhibitor. Agents in this class target a different viral enzyme compared with agents inhibiting reverse transcriptase and protease. A wide number of patients are currently susceptible to integrase inhibitors, including heavily antiretroviral-experienced patients harbouring drug-resistant viruses. The good tolerability and convenience of raltegravir have recently begun to be appreciated, leading to the consideration of other indications for the drug. Data recently released using the drug as first-line therapy or in switch strategies are very promising and the role of raltegravir in intensification therapy is currently under investigation. Altogether, the current information supports a broad use of raltegravir beyond its initial approval for antiretroviral-experienced HIV-infected patients.
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PMID:New therapeutic strategies for raltegravir. 2001 17

A randomized, placebo-controlled, 2-period crossover study in subjects on methadone maintenance therapy was conducted to assess the effect of the HIV-1 integrase inhibitor, raltegravir, on the pharmacokinetics of methadone. Twelve HIV-negative male and female subjects stabilized on an oral methadone program were enrolled. Subjects maintained their prescribed oral doses of methadone throughout the study and, in each of 2 periods, received either 400 mg of raltegravir or matching placebo every 12 hours on days 1 through 10 of each treatment period with a washout of 7 days between periods. Plasma samples for analysis of methadone pharmacokinetics were collected over 24 hours postdose on day 10 of each treatment period. Safety and tolerability were assessed throughout the study. The geometric mean ratio (90% confidence interval) for methadone when administered with raltegravir relative to methadone alone was 1.00 (0.93-1.09) for area under the methadone concentration time curve from time 0 to 24 hours and 1.00 (0.94-1.07) for maximal concentration. There were no serious clinical or laboratory adverse experiences. There were no discontinuations due to an adverse experience. Coadministration of raltegravir and methadone is generally well tolerated. Raltegravir has no clinically meaningful effect on methadone pharmacokinetics. No dose adjustment is required for methadone when coadministered with raltegravir.
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PMID:Effect of raltegravir on the pharmacokinetics of methadone. 2017 85

Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.
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PMID:HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. 2037 41

More than 25 years have passed since HIV was identified as a causative agent of AIDS. In the monotherapy era, the efficacy of antiretroviral therapy was limited due to emergence of drug resistance. In late 1990s when the highly active antiretroviral therapy (HAART) was started to apply, the mortality of HIV infected people dramatically declined. Nowadays, more than 20 drugs are applicable and treatment regimen has become more potent and more convenient. However, emergence of multi-drug resistant HIV and long-term toxicity of antiretroviral is still remarkable concern. Raltegravir, the first approved integrase inhibitor (INI), shows preferable safety profile. When long-term reliability of INI is proven, antiretroviral combination will be individualized by choosing the optimal drug from 4 classes.
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PMID:[Advance and perspective of antiretroviral therapy]. 2022 79


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