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Elvitegravir
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Adverse Effects
Interactions with Other Drugs
Resistance
Implications of resistance to elvitegravir for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for treatment with elvitegravir
References
Related Resources
DHHS Guidelines
Characteristics of Integrase Inhibitors
Drug Interactions with Integrase Inhibitors
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Elvitegravir
Class

Integrase inhibitor

Background
U.S. Manufacturer

Gilead Sciences

Approval

Elvitegravir was granted approval by the U.S. Food and Drug Administration (FDA) in August 2012 as part of a coformulation that also includes the pharmacokinetic enhancer cobicistat and the two nucleoside/nucleotide analogues (NRTIs) tenofovir and emtricitabine. Elvitegravir requires pharmacokinetic enhancement with either cobicistat or ritonavir. In the FDA-approved fixed-dose coformulation, it is intended for use in initial therapy of adults with HIV-1 infection. Elvitegravir is not currently approved for use in other combinations.

Approval was based primarily on 48-week results of 2 Phase III studies showing that previously untreated individuals who received elvitegravir/cobicistat/tenofovir/emtricitabine had rates of viral suppression and CD4 T-cell increases that were similar to those of individuals who received either efavirenz + 2 NRTIs or atazanavir + ritonavir + 2 NRTIs.(1,2)

Formulation and Dosing

Elvitegravir is available only in a fixed-dose combination tablet formulation with cobicistat, tenofovir, and emtricitabine (Stribild). It is dosed once daily.

Dosing of Elvitegravir
AdultTreatment naiveElvitegravir 150 mg + cobicistat 150 mg + tenofovir 300 mg + emtricitabine 200 mg, 1 tablet QD (fixed-dose combination tablet)
Treatment experiencedNot FDA approved
Pediatric Not FDA approved

Abbreviations: QD = once daily

Elvitegravir should be taken with food.
Elvitegravir has recognized interactions with several antiretroviral medications and the combination of elvitegravir + cobicistat (or ritonavir) interacts with a number of antiretrovirals; see product labeling for further information.
The fixed-dose combination elvitegravir/cobicistat/tenofovir/emtricitabine should not be initiated in patients with CrCl <70 mL/min and should be discontinued in those with CrCl <50 mL/min.
Dosage adjustment for mild or moderate hepatic impairment is not required. No data are available to guide use in persons with severe liver disease.
FDA Pregnancy Category B.
Consult product labeling for detailed dosing information.

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.(3) The median CD4 increases were 138 cells/µL and 170 cells/µL, respectively.(3)

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.(4)

Adverse Effects

Symptomatic side effects of elvitegravir appear to be few but may include diarrhea and rash. Laboratory abnormalities include elevations in hepatic transaminases. If used in combination with cobicistat or ritonavir, adverse effects owing to these agents 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, 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.(5,6) 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.(6) (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.(6) 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

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 (with or without other mutations), which confer resistance to lamivudine and emtricitabine.

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.(1,2,4,5) In limited in vitro studies, cross-resistance to the investigational integrase inhibitor dolutegravir appears to be less common.(7,8)

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.(4,5,9) In in vitro studies, the raltegravir-associated resistance mutations Y143R, Q148H/K/R, and N155H were associated with high levels of resistance to elvitegravir.

References
1.   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.
2.   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.
3.   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.
4.   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.
5.  Stribild [prescribing information]. Gilead Sciences: Foster City, CA; August 2012.
6.   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.
7.  Seki T, Kobayashi M, Wakasa-Morimoto C, et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco. Abstract 555.
8.   Canducci F, Ceresola ER, Boeri E, et al. Cross-resistance profile of the novel integrase inhibitor dolutegravir (S/GSK1349572) using clonal viral variants selected in patients failing raltegravir. J Infect Dis. 2011 Dec 1;204(11):1811-5.
9.  Margot NA, Rhee M, Szwarcberg J, et al; GS-US-183-0145 Study Team. Low rates of integrase resistance for elvitegravir and raltegravir through week 96 in the phase 3 clinical study GS-US-183-0145. In: Program and abstracts of the XIX International AIDS Conference; July 22-27, 2012; Washington. Abstract TUPE050.