OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Elvitegravir – Vitekta®

Elvitegravir, Cobicistat, Emtricitabine, Tenofovir disoproxil fumarate – Stribild®

Elvitegravir, Cobicistat, Emtricitabine, Tenofovir alafenamide – Genvoya®

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

View in own window

DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Elvitegravir	697761-98-1	C23-H23-Cl-F-N-O5
Cobicistat	1004316-88-4	C40-H53-N7-O5-S2
Emtricitabine	[Refer to Emtricitabine Record.]
Tenofovir	[Refer to Tenofovir Record.]

ANNOTATED BIBLIOGRAPHY

References updated: 30 January 2018

• Núñez M. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 505-18.

  (Review of hepatotoxicity of antiviral agents; elvitegravir is not specifically discussed).
• Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1623-64.

  (Textbook of pharmacology and therapeutics).
• https://hivinfo​.nih.gov​/hiv-source/medical-practice-guidelines​/hiv-treatment-guidelines .

  (Regularly updated guidelines on therapy of HIV infection in adults, adolescents and children).
• Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283:74–80. [PubMed: 10632283]

  (Among 298 patients with HIV infection, ALT elevations above 5 times ULN occurred in 10.4% per year during antiretroviral treatment; factors associated with ALT elevations included ritonavir [27.3%] and coinfection with either HCV or HBV; ALT with bilirubin elevations occurred in 3 patients; all 3 had coinfection and 2 were on indinavir).
• Torti C, Lapadula G, Casari S, Puoti M, Nelson M, Quiros-Roldan E, Bella D, et al. EPOKA-MASTER Study Group. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort. BMC Infect Dis. 2005;5:58. [PMC free article: PMC1188059] [PubMed: 16018804]

  (Among 1038 HIV-HCV coinfected patients starting antiretroviral therapy, the risk of ALT elevations above 5 times ULN was 17.1% yearly in treatment naive and 8.2% in treatment experienced patients; risk factors being baseline ALT levels and use of nonnucleoside reverse transcriptase inhibitors).
• Jain MK. Drug-induced liver injury associated with HIV medications. Clin Liver Dis. 2007;11:615–39. vii-viii. [PubMed: 17723923]

  (Review of hepatotoxicity of antiretroviral medications; ALT elevations occur in 2-18% of patients during treatment, but often resolve spontaneously even without dose modification; classes of injury include hypersensitivity [nevirapine, efavirenz, abacavir], mitochondrial injury [stavudine, didanosine, zidovudine], flares of hepatitis B [lamivudine, emtricitabine, tenofovir], flares of hepatitis C [any potent regimen], idiosyncratic injury [ritonavir, nevirapine, efavirenz], cholestatic hepatitis [many agents]).
• Soriano V, Puoti M, Garcia-Gascó P, Rockstroh JK, Benhamou Y, Barreiro P, McGovern B. Antiretroviral drugs and liver injury. AIDS. 2008;22:1–13. [PubMed: 18090386]

  (Review of hepatotoxicity of antiretroviral drugs with recommendations on management; therapy should be stopped if symptoms arise or with overt jaundice [direct bilirubin] or there is evidence of mitochondrial toxicity or ALT is above 10 times ULN; therapy should be stopped at lower ALT levels if a newly marketed agent is being used; important to rule out other causes; problematic agents include didanosine, stavudine and zidovudine; nevirapine and efavirenz, full dose ritonavir and tipranavir).
• Cohen C, Elion R, Ruane P, Shamblaw D, DeJesus E, Rashbaum B, Chuck SL, 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;25:F7–12. [PubMed: 21412057]

  (Controlled trial of at least 48 weeks of elvitegravir with cobicistat versus efavirenz, both combined with emtricitabine and tenofovir in 71 treatment naive adults with HIV infection; found similar efficacy and safety; no mention of ALT elevations or hepatotoxicity).
• Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, Zhong L, 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;12:27–35. [PubMed: 22015077]

  (Controlled trial of elvitegravir vs raltegravir, both combined with a ritonavir boosted protease inhibitor and a second antiretroviral agent in 702 treatment experienced patients with HIV infection; found similar efficacy and safety; 2 patients on elvitegravir and 5 on raltegravir stopped therapy because of acute hepatitis, but details were not given; ALT elevations above 5 times the ULN occurred in 2% of patients on elvitegravir versus 5% on raltegravir).
• Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, Gallant JE, 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;379(9835):2439–48. [PubMed: 22748591]

  (Controlled trial of at least 48 weeks of elvitegravir/cobicistat vs efavirenz, combined with emtricitabine and tenofovir in 700 treatment naive patients with HIV infection; found similar efficacy and safety; side effects included diarrhea, nausea, fatigue, dizziness, headache and rashes leading to discontinuation in 4% of patients; ALT elevations occurred in 15% of elvitegravir treated subjects; no mention of clinically apparent liver injury).
• DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, 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;379(9835):2429–38. [PubMed: 22748590]

  (Controlled trial of at least 48 weeks of elvitegravir/cobicistat versus atazanavir/ritonavir, combined with emtricitabine and tenofovir in 708 treatment naive patients with HIV infection; found similar efficacy and safety; ALT elevations occurred in 15% of elvitegravir treated patients, but "patients with clinically significant liver function test abnormalities generally had concurrent underlying hepatic disease").
• Olin JL, Spooner LM, Klibanov OM. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Single Tablet for HIV-1 Infection Treatment. Ann Pharmacother. 2012;46:1671–7. [PubMed: 23136357]

  (Systematic review of pharmacology, safety and efficacy of the elvitegravir based 4 drug regimen for HIV infection; the most common side effects were diarrhea, nausea, abnormal dreams, depression, ALT elevations [15%] and renal abnormalities [1%]).
• Wills T, Vega V. Elvitegravir: a once-daily inhibitor of HIV-1 integrase. Expert Opin Investig Drugs. 2012;21:395–401. [PubMed: 22321026]

  (Review of the mechanism of action, pharmacokinetics, efficacy and safety of elvitegravir; no discussion of ALT elevations or hepatotoxicity).
• Lee FJ, Carr A. Tolerability of HIV integrase inhibitors. Curr Opin HIV AIDS. 2012;7:422–8. [PubMed: 22886031]

  (Review of safety and adverse events associated with HIV integrase inhibitors – raltegravir, elvitegravir and dolutegravir – focusing largely on myopathy, renal dysfunction and serum lipid abnormalities; no discussion of ALT elevations or hepatotoxicity).
• A 4-drug combination (Stribild) for HIV. Med Lett Drugs Ther. 2012;54(1404):95–6. [PubMed: 23183388]

  (Concise review of the efficacy and safety of Stribild, shortly after its approval in the US; does not mention ALT elevations or hepatotoxicity).
• Zolopa A, Sax PE, DeJesus E, Mills A, Cohen C, Wohl D, Gallant JE, et al. GS-US-236-0102 Study Team. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013;63:96–100. [PubMed: 23392460]

  (Analysis of the second year of study described by Sax et al. [2012] found no new safety concerns; no mention of ALT elevations or hepatotoxicity).
• Rockstroh JK, DeJesus E, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, et al. GS-236-0103 Study Team. A randomized, double-blind comparison of coformulated Evitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013;62:483–6. [PubMed: 23337366]

  (Analysis of the second year of study described by DeJesus et al. [2012] found no new safety concerns; no mention of ALT elevations or hepatotoxicity).
• Surgers L, Lacombe K. Hepatoxicity of new antiretrovirals: a systematic review. Clin Res Hepatol Gastroenterol. 2013;37:126–33. [PubMed: 23522569]

  (Systematic review of hepatotoxicity of new antiretroviral agents including etravirine, rilpivirine, maraviroc, raltegravir, elvitegravir, dolutegravir and darunavir; in 3 large clinical trials of elvitegravir vs raltegravir or efavirenz-based regimens, ALT elevations were less frequent with elvitegravir than raltegravir [15% vs 22%] or efavirenz [18% vs 31%]).
• Genvoya--a new 4-drug combination for HIV. Med Lett Drugs Ther. 2016;58(1488):19–21. [PubMed: 26859659]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of Genvoya, a single tablet regimen of elvitegravir, tenofovir alafenamide, emtricitabine and cobicistat as therapy of HIV infection, mentions the advantage of tenofovir alafenamide in having less renal and bone toxicity than the disoproxil fumarate and gives the standard warnings about immune reconstitution syndrome with potential liver injury on starting, and reactivation of hepatitis B on stopping antiretroviral reigimens).
• Squillace N, Ricci E, Quirino T, Gori A, Bandera A, Carenzi L, De Socio GV, et al. CISAI Study Group. Safety and tolerability of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in a real life setting: data from surveillance cohort long-term toxicity antiretrovirals/antivirals (SCOLTA) project. PLoS One. 2017;12(6):e0179254. [PMC free article: PMC5478131] [PubMed: 28632758]

  (Among 280 patients with HIV infection started on therapy with elvitegravir/cobicistat, emtricitabine and tenofovir and monitored for a median of 11 months, serum enzyme elevations occurred in 23 subjects [8%], but most were less than 5 times the upper limit or normal and only 3 led to treatment interruptions).