| Clinical Use|
Elvitegravir is active against susceptible strains of HIV-1; little information is available about HIV-2. Elvitegravir requires pharmacokinetic boosting with either cobicistat or ritonavir.
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate the coformulation of elvitegravir + cobicistat + tenofovir + emtricitabine, as a "preferred" regimen for use in initial treatment of HIV infection, for patients whose estimated creatinine clearance is ≥70 mL/min.
Elvitegravir has been studied primarily in initial therapy in adults.
In a randomized, placebo-controlled Phase III study in antiretroviral-naive adults, the fixed-dose coformulation of elvitegravir/cobicistat/tenofovir/emtricitabine was compared with efavirenz/tenofovir/emtricitabine.(1) By intention-to-treat snapshot analysis, 88% of elvitegravir + cobicistat recipients and 84% of efavirenz recipients had HIV RNA levels of <50 copies/mL at 48 weeks; the difference was not statistically significant. Responses in the two groups also were similar in patients with pretreatment HIV RNA levels of >100,000 copies/mL. The mean increase in CD4 count was 239 cells/µL in the elvitegravir group and 206 cells/µL in the efavirenz group.
In a parallel Phase III study in antiretroviral-naive adults, the fixed-dose coformulation of elvitegravir/cobicistat/tenofovir/emtricitabine was compared with atazanavir + ritonavir + tenofovir/emtricitabine.(2) By intention-to-treat snapshot analysis, 89.5% of elvitegravir + cobicistat recipients and 87% of atazanavir + ritonavir recipients had HIV RNA suppression to <50 copies/mL; the difference was not statistically significant. In persons with baseline HIV RNA >100,000 copies/mL, rates of virologic suppression were very similar in the two treatment groups. Mean CD4 increases were approximately 210 cells/µL in each group.
A smaller Phase II trial of initial therapy also found similar efficacy between elvitegravir/cobicistat/tenofovir/emtricitabine and efavirenz/tenofovir/emtricitabine at 48 weeks: 90% and 83%, respectively, had HIV RNA levels of <50 copies/mL. The median CD4 increases were 138 cells/µL and 170 cells/µL, respectively.(3)
Two parallel studies randomized patients with suppressed HIV RNA on regimens containing either a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) to switch to elvitegravir/cobicistat/tenofovir/emtricitabine or to continue their stable regimen. Patients were on their 1st or 2nd treatment regimen and could not have resistance to either tenofovir or emtricitabine. At 48 weeks, by snapshot analysis, HIV RNA remained <50 copies/mL in higher percentages of elvitegravir/cobicistat/tenofovir/emtricitabine recipients (94% vs 87% of PI recipients [95% CI: 0.4-13.7]; 93% vs 88% of NNRTI recipients [95% CI: -0.5-12]).(4,5)
In treatment-experienced patients with resistance to at least 2 ARV classes, a Phase III randomized study compared elvitegravir with raltegravir, each given in combination with a ritonavir-boosted PI and at least 1 other active ARV. After 48 weeks of treatment, by modified intention-to-treat analysis, rates of HIV control were comparable in the two groups (<50 copies/mL in 59% and 58%, respectively), as were CD4 cell increases.(6)
| Adverse Effects|
Symptomatic side effects of elvitegravir appear to be few but may include diarrhea and rash. Laboratory abnormalities include elevations in hepatic transaminases. Adverse effects owing to coadministred cobicistat or ritonavir are expected (see specific ARV profiles).
It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with elvitegravir is initiated.
Elvitegravir has not been studied in pregnant women; the fixed-dose combination elvitegravir/cobicistat/tenofovir/emtricitabine is classified as an FDA Pregnancy Category B drug.
| Interactions with Other Drugs|
Elvitegravir is primarily metabolized by cytochrome P450 3A (CYP3A) enzymes, so drugs that induce or inhibit the action of CYP3A may affect serum levels of elvitegravir. In some cases, these interactions may be therapeutically significant. For example, the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine are expected to lower serum elvitegravir levels and should not be used with elvitegravir. Rifamycins (eg, rifampin and rifabutin), some anticonvulsants (eg, carbamazepine and phenytoin), and St. John's wort may decrease elvitegravir concentrations whereas azole antifungal drugs appear to increase them; concurrent treatment with elvitegravir is contraindicated.(7,8) Elvitegravir also induces CYP 2D9 and may lower concentrations of substrates of this enzyme.
Cobicistat and ritonavir strongly inhibit CYP3A, thus increasing plasma concentrations of elvitegravir; elvitegravir must be coadministered with one of these two drugs in order to achieve serum levels adequate to suppress HIV replication. The coadministered cobicistat or ritonavir, however, will have extensive interactions with other medications including other antiretroviral medications.(8) (See the Database of Antiretroviral Drug Interactions.)
Divalent cations (eg, magnesium- or aluminum-containing antacids) may bind elvitegravir and interfere with its activity against integrase. A pharmacokinetic study showed that administration of antacids containing divalent cations at the same time as elvitegravir lowered serum elvitegravir concentration by more than 40%. The effect was minimal if antacids were taken 4 hours apart from the integrase inhibitor.(8) Antacid medications and other agents with divalent cations should be used cautiously with (and taken separately from) elvitegravir. Proton pump inhibitors and H2 receptor antagonists do not affect elvitegravir concentrations.
Adequate pharmacokinetic data and clinical correlates are not yet available for many potential interactions. Information on drug interactions should be consulted, as dosage adjustments may be required and some combinations are contraindicated. Pending further study, coadministration of the elvitegravir/cobicistat/tenofovir/emtricitabine coformulation with other antiretrovirals is not recommended.
For additional information, see the Database of Antiretroviral Drug Interactions.
Resistance to elvitegravir is associated with the selection of 1 or more resistance mutations, but the elvitegravir resistance profile has not been characterized fully. In vitro and in vivo studies show the emergence of a number of integrase mutations, including T66I, E92Q, Q148R, and N155H. Phenotypic analysis shows reduced susceptibility to elvitegravir if any of these mutations is present.
In the studies of initial therapy, emergent resistance to elvitegravir also usually involved development of the reverse transcriptase mutations M184I or M184V, which confer resistance to lamivudine and emtricitabine, with or without other mutations.
| Implications of resistance to elvitegravir for treatment with other antiretrovirals|
Among patients with resistance to elvitegravir, cross-resistance to raltegravir appears to occur in the majority of cases. The type and number of mutations appear to correlate with the degree of cross-resistance to raltegravir.(1,2,6,7) Resistance mutations selected by elvitegravir may contribute to dolutegravir resistance, particularly if the Q148H/R mutation plus 2 or more other integrase inhibitor mutations is present.(9,10)
| Implications of resistance to other antiretrovirals for treatment with elvitegravir|
Data on the effects of baseline integrase resistance mutations on elvitegravir efficacy are limited. In studies conducted to date, resistance to raltegravir was associated with phenotypic resistance to elvitegravir in nearly all cases.(6,7,11) In in vitro studies, the raltegravir-associated resistance mutations Y143R, Q148H/K/R, and N155H were associated with high levels of resistance to elvitegravir.
|| || Sax PE, DeJesus E, Mills A, et al; GS-US-236-0102 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012 Jun 30;379(9835):2439-48.|
|| || DeJesus E, Rockstroh JK, Henry K, et al; GS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012 Jun 30;379(9835):2429-38.|
|| || Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011 Mar 27;25(6):F7-12.|
|| ||Arribas J, Pialoux G, Gather J, et al. Simplification of PI + RTV + FTC/TDF to E/C/F/TDF maintains HIV suppression and is well tolerated. In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 551LB.|
|| ||Pozniak A, Markowitz M, Mills A, et al. Switch from NNRTI plus FTC/TDF to E/C/F/TDF maintains HIV suppression and is well tolerated. In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 553LB.|
|| || Molina JM, LaMarca A, Andrade-Villanueva J, et al; Study 145 Team. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis. 2012 Jan;12(1):27-35.|
|| ||Stribild [prescribing information]. Gilead Sciences: Foster City, CA.|
|| || Ramanathan S, Mathias AA, German P, et al. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011 Apr;50(4):229-44.|
|| || Kobayashi M, Yoshinaga T, Seki T, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011 Feb;55(2):813-21.|
|| || Castagna A, Maggiolo F, Penco G, et al; VIKING-3 Study Group. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J Infect Dis. 2014 Aug 1;210(3):354-62.|
|| || Abram ME, Hluhanich RM, Goodman DD, et al. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob Agents Chemother. 2013 Jun;57(6):2654-63.|