"No genotoxic and mutagenic effects with raltegravir were discovered by Ames test with Salmonella typhimurium and Escherichia coli as well as in studies of micronuclei in mice . However, it is necessary to know the genotoxic and cytotoxic potential of transplacental exposure to high doses of raltegravir that could affect the offspring . Reports of European Medicine Agency  and FDA  show in vitro and in vivo genotoxicity studies in rat and dog; however, transplacental genotoxicity has not been evaluated in the offspring treated with raltegravir . "
[Show abstract][Hide abstract] ABSTRACT: The use of raltegravir in treating HIV/AIDS has been proposed due to its effectiveness in suppressing high loads of HIV RNA in pregnant women, thus preventing infection of the fetus. However, administration of raltegravir during pregnancy produces a compound which is transferred to high concentrations to the offspring. The objective of this study is to evaluate the transplacental genotoxic effect of raltegravir in newborn rats. We evaluated the number of micronucleated erythrocytes (MNE), micronucleated polychromatic erythrocytes (MNPCE), and polychromatic erythrocytes (PCE) in the peripheral blood samples of the offspring of Wistar rats treated 6 days before birth with oral administration of raltegravir. The animals were randomly assigned to five groups as follows: raltegravir at doses of 15, 30, or 60 mg/day, cyclophosphamide 10 mg/kg (positive control), or 0.5 ml of sterile water (negative control). In addition, the effect of these drugs on the weight and height of newborns was assessed. There were no differences in the number of MNE, MNPCE, and PCE, and a slight decrease in the weight and height was observed in the offspring of the rat mothers treated with raltegravir. Genotoxicity studies are required in pregnant women to determine the risk of using raltegravir to the fetuses.
BioMed Research International 05/2014; 2014:851820. DOI:10.1155/2014/851820 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Raltegravir is the first inhibitor of HIV integrase approved for clinical use. Integration is one of the essential steps in the HIV-1 replication cycle and integrase is responsible for the transfer of virally encoded DNA into the host chromosome. Raltegravir was initially approved for the treatment of HIV-infected patients failing other antiretroviral regimens and harbouring multi-drug-resistant HIV variants. Soon thereafter the drug was also approved as first-line therapy. The registrational trials that supported the development of raltegravir are BENCHMRK 1 and 2 and STARTMRK. 1–3 In these studies, raltegravir outperformed the control arm, exhibiting great efficacy and an excellent safety profile. The pivotal BENCHMRK trials evidenced that after 96 weeks of therapy in patients failing other antiretroviral agents, 58 % of patients on raltegravir achieved viral suppression compared with 26 % of patients in the placebo arm. Moreover, CD4 gains were also superior in the raltegravir group compared with the control arm, with a mean increase of 123 versus 49 cells/mm 3 , respectively. The best virological responses in the BENCHMRK studies were obtained when raltegravir was administered along with two fully active drugs, in most cases if darunavir or enfuvirtide were included in the optimised background therapy (OBT) and used for the first time. Overall, raltegravir was generally well tolerated in the BENCHMRK studies, with very few serious drug-related adverse events (2.8 % compared with 3.8 % in the placebo arm) and a low proportion of patients experiencing grade 3/4 laboratory abnormalities (always less than 10%). In the same way, the STARTMRK 1 and 2 trials supported the same good efficacy in naive patients. Both studies proved that raltegravir was non-inferior to efavirenz in its ability to suppress plasma HIV RNA to less than 50 copies/ml. At week 48, fewer virological failures occurred in patients allocated to raltegravir rather than efavirenz (10 % versus 14 %, respectively). Moreover, time to virological response was significantly shorter in the raltegravir arm than in patients on efavirenz. Patients receiving raltegravir experienced significantly fewer moderate to severe drug-related clinical adverse events than those treated with efavirenz (16% versus 32%, p=0.001), including fewer grade 3/4 lipid abnormalities. Subsequent studies reported compelling results regarding liver toxicity, even in the subset of patients with advanced liver disease or co-infected with chronic hepatitis viruses. 4–6 Raltegravir is mainly metabolised by uridine diphosphate glucuronyltransferase-1A1 (UGT1A1)-mediated glucuronidation and it neither inhibits cytochrome P450 (CYP450) enzymes nor induces cytochrome P450 3A4 (CYP3A4), which largely explains its favourable drug interaction profile. 7 More recently, raltegravir has been shown to be active against HIV-2. 8,9 Data regarding its potential clinical activity in patients with human T-cell lymphotropic virus type 1 (HTLV-1) infection are conflicting. 10 In this article we will give an update on the most novel indications of raltegravir in special patient populations. Raltegravir and Liver Safety Due to similar routes of transmission, co-infection of HIV with other sexually transmitted and blood-borne viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV) and/or hepatitis D virus (HDV) is relatively common. Chronic HBV infection affects 5–10 % of HIV-infected patients in Western countries, 11,12 while chronic hepatitis C may be recognised in up to 25–35% of this population. 13 The risk of antiretroviral-related liver toxicity is higher in this subset of patients and is one of the main reasons for treatment interruption. Severe hepatotoxicity has been reported in up to 10% of patients receiving conventional antiretroviral regimens. 14 Even if the risk of liver toxicity has been reduced with the arrival of new drugs, 4 it is still a major concern in HIV therapeutics. Abstract Raltegravir is the first inhibitor of HIV integrase approved for clinical use. It was first tested in heavily antiretroviral-experienced HIV-infected patients and subsequently the indication was extended to the treatment of HIV-naive subjects. The good safety profile of raltegravir has led more recently to consideration of the drug in other clinical situations, such as co-infection with hepatitis viruses and advanced liver disease. Moreover, the lack of relevant drug interactions of raltegravir has made it a good choice in patients requiring co-medications, including new antivirals for treating hepatitis C. Finally, its favourable tolerability, lack of reported teratogenicity, rapid effect and high potency have also established raltegravir as an interesting option in pregnancy. Altogether, current available data support the use of raltegravir in most distinct clinical scenarios.
[Show abstract][Hide abstract] ABSTRACT: HIV resides within anatomical 'sanctuary sites' where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect. Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivo pharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy.
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