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Antimicrobials during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Raltegravir is an integrase inhibitor used to treat HIV. Among 312 infants whose mothers took raltegravir during the first trimester of pregnancy, the frequency of birth defects was not increased (Antiretroviral Registry, 2018). Notably, the pharmacokinetics of this drug during pregnancy are not sufficiently altered to warrant any dose change, suggesting the regimen dose may remain constant during gestation without loss of efficacy (Blonk et al., 2015).
Human immunodeficiency virus and other infectious diseases
Published in Catherine Nelson-Piercy, Handbook of Obstetric Medicine, 2020
Dolutegravir (50 mg once daily) has been associated with a small increase in neural tube defects and therefore it should only be considered from 6 weeks’ gestation. If women present or are diagnosed late (after 28 weeks), then a three- or four-drug regimen containing raltegravir is suggested.
HIV neurological complications
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Of the antiretrovirals, zidovudine was the first to be associated with toxic myopathy. These patients develop a mitochondrial myopathy, as evidenced by the presence of ragged-red fibers and abnormal mitochondria on electron microscopy [241,242]. Hypothesized mechanisms of toxicity include inhibition of DNA polymerase γ, directly induced oxidative stress, inhibition of mitochondrial machinery and depletion of l-carnitine [243]. Oral steroids and discontinuation of zidovudine may lead to an improvement in these patients. More recently, the integrase inhibitor raltegravir has been associated with myalgia, proximal myopathy, CK elevation, and, rarely, rhabdomyolysis [244–246]. Cohort data suggest that myopathy is an uncommon side effect of raltegravir in 3%–5% of treated patients [244,247]. Other integrase inhibitors (e.g., elvitegravir, dolutegravir) are also uncommonly associated with a rise in creatine kinase, but not with myopathy [248].
The use of antiviral drugs in children
Published in Journal of Chemotherapy, 2022
Marco Antonio Motisi, Agnese Tamborino, Sara Parigi, Luisa Galli, Maurizio de Martino, Elena Chiappini
The FDA and EMA have recently approved blood dosing of raltegravir (RAL) for babies born at a gestational age ≥37 weeks and weighing ≥2 kg. Dosing information for RAL is not available for preterm or low birth weight infants. RAL is metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1, the same enzyme responsible for the elimination of bilirubin. UGT enzyme activity is low at birth and RAL elimination is prolonged in infants. Bilirubin and RAL may compete for albumin binding sites, so extremely high neonatal plasma concentrations of RAL could pose a risk of kernicterus [24]. Paediatric formulations of protease inhibitors are available for lopinavir/ritonavir, darunavir, tipranavir and fosamprenavir; however, the use of these drugs is recommended in newborns with a postmenstrual age of 42 weeks from at least 14 days after birth, due to a lack of information on dosing and safety. In literature, ritonavir/lopinavir therapy has been associated with heart block (reversible upon discontinuation) and adrenal insufficiency with life-threatening dyselectrolycaemia to the point of cardiogenic shock [24].
Lack of impact of protease inhibitor resistance-associated mutations on the outcome of HIV-1-infected patients switching to darunavir-based dual therapy
Published in Infectious Diseases, 2020
Pilar Vizcarra, José L. Blanco, Rocío Montejano, Eugenia Negredo, Nuria Espinosa, José L. Casado
This was a phase IV, multicentre, retrospective cohort study performed at 14 HIV clinics in Spain throughout 12 January 2017–6 January 2018. Eligible HIV-infected patients aged >18 were switched to raltegravir (400 mg twice daily) plus darunavir/cobicistat (800 mg/150 mg once daily) or darunavir/ritonavir (800 mg plus 100 mg once daily) due to simplification, toxicity, intolerance and/or poor adherence, after ≥12 months of virological suppression. The study was approved by our institutional review board (EC211/17) and registered at ClinicalTrials.gov (NCT03348449). For the purpose of this analysis, we only included patients with previous PIs-failure and at least one genotypic resistance test performed. Exclusion criteria were HBV coinfection, pregnancy and prior documented/suspected major raltegravir-RAMs. Resistance to nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) was permitted. End of follow-up was considered after 96 weeks of switching.
Prevention and treatment of HIV infection in neonates: evidence base for existing WHO dosing recommendations and implementation considerations
Published in Expert Review of Clinical Pharmacology, 2018
Diana F Clarke, Martina Penazzato, Edmund Capparelli, Tim R Cressey, George Siberry, Nandita Sugandhi, Mark Mirochnick
Raltegravir, the first integrase inhibitor licensed for use in HIV infected adults and children, has a mechanism of action distinct from previously approved antiretrovirals, is effective in rapidly clearing plasma virus, and is well tolerated in children and adults. In adults, raltegravir has a terminal elimination (β) t½ of approximately 7–12 h, with considerable interindividual variability [57]. Raltegravir is metabolized primarily by UDPGT 1A1, which is also the only enzyme that metabolizes bilirubin [58,59]. UDPGT 1A1 activity is low in fetuses and in the newborn immediately after birth but increases exponentially over the first weeks and months of life [60]. In neonates whose mothers received raltegravir prior to delivery, raltegravir elimination in the first days of life is prolonged and highly variable, with a median t½ of 26.6 h (range of 9.3–184 h) [61]. Raltegravir and bilirubin also share albumin binding sites, raising concern that raltegravir displacement of unconjugated bilirubin from albumin binding sites could increase the risk of kernicterus, especially in low birth weight neonates. An in vitro evaluation of the effect of raltegravir on bilirubin–albumin binding reassuringly demonstrated that the effect of raltegravir on neonatal bilirubin binding is unlikely to be clinically significant unless raltegravir concentrations exceed typical peak concentrations of 4.44 mg/L (10 µM) by 50–100-fold [62]. A safe neonatal dosing regimen for raltegravir must take into account the developmental changes in UDPGT 1A1 activity to avoid accumulation of raltegravir in plasma to potentially toxic concentrations.