Elvitegravir
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Elvitegravir is approved by the US FDA and European commission to treat HIV-1 infection as part of combination therapy in treatment-naive and treatment-experienced patients. See Table 250.5 for a summary of major clinical trials of elvitegravir.
Antimicrobials during Pregnancy
“Bert” Bertis Britt Little in Drugs and Pregnancy, 2022
An integrase inhibitor, elvitegravir is used to treat HIV infection. 213 women used it during the first trimester (Antiretroviral Registry, 2018). The frequency of congenital anomalies was not increased above background (www.apregistry.com/forms/interim_report.pdf).
Care of Critically Ill Patients with HIV
Cheston B. Cunha, Burke A. Cunha in Infectious Diseases and Antimicrobial Stewardship in Critical Care Medicine, 2020
Integrase inhibitors (InSTIs) entered clinical care with the approval of raltegravir by the US FDA in 2007. They have quickly become the backbone of initial treatment regimens due to their excellent tolerability, relatively few drug-drug interactions, and low incidence of pre-existing resistance. All three currently available agents are part of first-line regimens. Raltegravir is well-absorbed and has a half-life of 9 hours. It is hepatically metabolized by glucuronidation and is not affected by even severe renal dysfunction, or moderate hepatic dysfunction. It has a good side effect profile, though drug-induced hypersensitivity syndrome (DIHS) and a creatine kinase elevation that can range from mild to frank rhabdomyolysis, have been observed. Headache, diarrhea, and nausea have also been observed with this drug. There are very few drug-drug interactions of clinical consequence besides rifampin and divalent cations, which inhibit oral absorption of all integrase inhibitors [51]. Elvitegravir is almost always prescribed as part of a combination pill of elvitegravir, cobicistat, emtricitabine, and TDF (Stribild, by Gilead), or elvitegravir, cobicistat, emtricitabine, and TAF (Genvoya, by Gilead). It has a half-life of 8.7 hours when administered with a CYP 3A4 inhibitor (such as cobicistat). It is hepatically metabolized and requires no adjustment for renal impairment. Because it must be co-administered with a CYP 3A4 inhibitor, there are a large number of drug-drug interactions to consider (see “cobicistat” section). Divalent cations, as discussed above, inhibit intestinal absorption of elvitegravir [52]. Dolutegravir has a half-life of 13–15 hours, allowing for once-daily dosing without boosting. It is metabolized through UGT1A1, with a minor contribution for CYP3A4. It does not require dose adjustment for renal disease. It does have some drug-drug interactions with other antivirals, including the uncommonly used protease inhibitors fosamprenavir and tipranavir, and the NNRTIs efavirenz and etravirine. Co-administration with rifampin requires dolutegravir dosing be increased to twice-daily. Antacids and other divalent cations should not be administered within 6 hours prior or 2 hours after dolutegravir. Side effects are rare but include insomnia, headache, and rare GI side effects. Dolutegravir has a high genetic barrier to resistance and is often used in patients with underlying resistance mutations [53]. Bictegravir, the newest integrase inhibitor, received FDA approval in 2018 and is marketed in a combination tablet with TAF and emtricitabine (Biktarvy, by Gilead). Similar to dolutegravir, it has a half-life of 18 hours, allowing for once-daily dosing. It is metabolized equally by both CYP3A4 and glucuronidation UGT 1A1. There is no dose-adjustment required for even advanced renal disease. Drug-drug interactions are expected to be relatively few because of its multiple pathways to metabolism, but data are not yet published confirming this. It has a high barrier to resistance. Side effects in early trials appear comparable to dolutegravir [54].
Antiretroviral treatment for HIV infection: Swedish recommendations 2019
Published in Infectious Diseases, 2020
Jaran Eriksen, Christina Carlander, Jan Albert, Leo Flamholc, Magnus Gisslén, Lars Navér, Veronica Svedhem, Aylin Yilmaz, Anders Sönnerborg
Dolutegravir does not affect CYP450 enzymes and treatment is therefore not expected to affect the pharmacokinetics of other drugs to the same extent as PI and NNRTI. An important exception is the commonly used medicine metformin, which increases in concentration in co-treatment and must therefore be given at a low dose. Dolutegravir is eliminated mainly through UGT1A1 but is also metabolized to a certain extent through CYP 3A4 and other medicines may therefore affect dolutegravir exposure. Dolutegravir exposure decreases in co-treatment with inducers such as efavirenz, carbamazepine, and rifampicin. In such co-treatment in patients without INSTI resistance dolutegravir should be given twice daily. The co-treatment should not be given in patients with suspected or confirmed INSTI resistance. Raltegravir and elvitegravir interact similarly to dolutegravir. Note that elvitegravir is given in fixed combinations containing cobicistat, which inhibits CYP3A and thereby interacts with several other medicines (see PI above).
Beyond one pill, once daily: current challenges of antiretroviral therapy management in the United States
Published in Expert Review of Clinical Pharmacology, 2019
Mary Clare Masters, Karen M. Krueger, Janna L. Williams, Lindsay Morrison, Susan E. Cohn
Cobicistat is not recommended during pregnancy. Cobicistat’s reliance on metabolic inhibition raised concern that metabolic changes in pregnancy might affect its efficacy. Initial case reports of pregnant women treated with elvitegravir/cobicistat containing ART revealed 44% lower cobicistat exposure during pregnancy than in the postpartum period [93]. Subsequently, a multicenter phase IV trial evaluating cobicistat and elvitegravir pharmacokinetics during the second trimester, third trimester, and postpartum period found that elvitegravir exposure was lower during pregnancy than during the postpartum period [94]. In this study, the lowest values were noted during the third trimester. In fact, only 47% of participants in the 2nd trimester and 38% in the 3rd trimester met the target area under the concentration curve (AUC) goal. Similarly, cobicistat exposure was found to be lower during pregnancy than during the postpartum period. Such unfavorable pharmacokinetics preclude the use of cobicistat-containing regimens during pregnancy. Presently ritonavir is the preferred boosting agent during pregnancy [90].
Pharmacological approaches to prevent vertical transmission of HIV and HBV
Published in Expert Review of Clinical Pharmacology, 2022
Emanuela Zappulo, Agnese Giaccone, Nicola Schiano Moriello, Ivan Gentile
Elvitegravir (EVG) when boosted with cobicistat showed drug levels below the inhibitory concentration during the third trimester and postpartum, and a consistent incidence of viral breakthroughs has been reported [Momper 2018, Boyd 2019]. Based on these data, EVG/c is not recommended for initial use in pregnancy. Limited data are available concerning the EVG safety in this setting: despite sporadic birth defects have been reported in infants exposed to EVG in utero, a clearly increased risk of adverse outcomes has never been observed [61].
Related Knowledge Centers
- Combination Drug
- Protease Inhibitor
- Randomized Controlled Trial
- Viral Load
- Integrase Inhibitor
- HIV
- Elvitegravir/Cobicistat/Emtricitabine/Tenofovir
- Tenofovir Alafenamide
- Ritonavir
- Management of HIV/AIDS