Fel PublishersTHE USE OF INTEGRASE INHIBITORS IN TREATMENT-EXPERIENCED PATIENTSHospital Cl ic
Fel PublishersTHE USE OF INTEGRASE INHIBITORS IN TREATMENT-EXPERIENCED PATIENTSHospital Cl ic, University of Barcelona, Barcelona, SpainJose M. GatellAbstract Raltegravir, the first approved HIV-1 integrase L-660711 sodium salt manufacturer 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 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27797473 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.The main objective of combined antiretroviral therapy (cART) is to fully and permanently suppress the Human Immunodeficiency Virus (HIV) replication and to achieve a plasma viral load (VL) level below the limit of detection by ultra- sensitive techniques (in general <20-50 copies of HIV RNA per ml of plasma) [1]. The immediate consequence is a self recovery of the immune system enough to dramatically reduce the incidence of new AIDS and PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26240184 non-AIDS associated events and the overall mortality [2]. This is feasible in almost 100 of na e patients complying with the prescribed medications. In the real world, however,1. BACKGROUNDthe virologic failure rate at 48 weeks is about 5-10 and even higher when studies are prolonged up to 96144 weeks or longer [3]. The HIV is wild type in about 30-50 of failing patients (failures due to lack of adherence to the prescribed regimen). Resistance associated mutations (to one or more components of the cART) can be detected in the remaining 50-70 of failing patients (less frequently when the initial regimen contains a ritonavir boosted protease inhibitor) [4]. The resistance profile after failure to first cART is relatively predictable and the response to a second line regimen is usually high even when resistance tests are not available and the salvage regimen are selected exclusively on the basis of best clinical judgment. Conversely, after two or more consecutive failing regimens most patients have accumulated a variety of resistance mutations (some of them only detectable under pharmacologic pressure if the usual bulk sequencing methodology is used) [5]. In these circumstances, and just a few years ago, response rate (measured as percentage of patients below 50 copies/ml at 48 weeks) was very low (<20-30 ).