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DRUG RECORD

 

ELVITEGRAVIR, COBICISTAT, EMTRICITABINE, TENOFOVIR

OVERVIEW
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir

 

Introduction

Elvitegravir is a human immunodeficiency virus (HIV) integrase inhibitor which is used largely in a four drug combination with cobicistat, emtricitabine and tenofovir as therapy of HIV infection.  Therapy with this elvitegravir based regimen is often associated with transient serum aminotransferase elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury.

 

Background

Elvitegravir (el" vi teg' ra vir) is a 4-quinolone-3-glyoxylic acid and antiretroviral agent that acts by inhibition of viral DNA strand transfer by the HIV integrase, a necessary step in HIV replication.  Elvitegravir has been shown to lower serum levels of HIV RNA and to raise CD4 counts.  In multiple prospective clinical trials, the combination of elvitegravir with tenofovir and emtricitabine has been found to be as effective as other standard antiretroviral combinations.  Elvitegravir is given with cobicistat, a pharmacokinetic enhancer that inhibits CYP 3A4 activity, causing increased levels and more prolonged activity of drugs like elvitegravir that are metabolized by the hepatic cytochrome P450 isomer CYP 3A4.  Elvitegravir was approved as a part of a four drug combination including cobicistat, emtricitabine and tenofovir in 2012 as therapy of HIV infection.  This combination is available as tablets of 150 mg of elvitegravir with 150 mg of cobicistat, 200 mg of emtricitabine and 300 mg of tenofovir under the brand name Stribild.  The recommended dose is one tablet daily, this combination being one of several "single tablet regimens" (STRs) for therapy of HIV infection.  Elvitegravir was the second HIV integrase to be approved in the United States and shares structural similarity and resistance patterns with the initial agent, raltegravir.  Common side effects of the four drug combination include fatigue, diarrhea, nausea, dizziness, headache, depression, abnormal dreams and skin rashes.  Cobicistat has inhibitory activity against several drug metabolizing enzymes besides CYP 3A4, including CYP 2D6 and the P-glycoprotein transporter, making it likely to cause drug-drug interactions and important to avoid when using other agents that are metabolized by the P450 system.  Cobicistat also inhibits creatinine secretion, which artificially raises serum creatinine levels without affecting the glomerular filtration rate.

 

Hepatotoxicity

In premarketing clinical trials, serum ALT elevations greater than 5 times the upper limit of normal occurred in 15% of patients treated with elvitegravir combined with cobicistat, emtricitabine and tenofovir.  This rate was somewhat lower than what occurred in comparator arms.  Most serum enzyme elevations with elvitegravir based regimens were transient and asymptomatic, and occurred in patients with known underlying chronic liver disease such as hepatitis B or C or alcoholic liver disease.  In at least one study, 1% of patients on the elvitegravir based four drug regimen developed "acute hepatitis", but the relatedness of the liver injury to elvitegravir was unclear and clinical details were not provided.  No specific reports of clinically apparent liver injury attributed to elvitegravir have appeared in the published literature, but clinical use of the agent has been limited.

 

Mechanism of Injury

The possible mechanism of liver injury due to elvitegravir is unknown.  Elvitegravir is extensively metabolized in the liver via the cytochrome P450 system (predominantly CYP 3A4), and production of a toxic or immunogenic intermediate may trigger liver injury.

 

Outcome and Management

The severity of the liver injury linked to elvitegravir therapy has been mild and self-limited, and characterized by serum enzyme elevations without jaundice and few or no symptoms.  The enzyme elevations often resolve even with continuation of elvitegravir.  There is no information on cross sensitivity to hepatic injury between elvitegravir and raltegravir, although cross reactivity is likely to occur.

 

Drug Class:  Antiviral Agents

 

Other Drugs in the Subclass, Integrase Strand Transfer Inhibitors:  Dolutegravir, Raltegravir

 

See also drugs used in combination, Nucleoside Analogues:  Emtricitabine, Tenofovir

 

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PRODUCT INFORMATION
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir

 

REPRESENTATIVE TRADE NAMES
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir – Stribild®

 

DRUG CLASS
Antiviral Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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

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REFERENCES
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir

 

References updated: 15 May 2014

  1. 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).

  2. 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).

  3. http://aidsinfo.nih.gov/guidelines.  (Regularly updated guidelines on therapy of HIV infection in adults, adolescents and children).

  4. 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 Citation (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).

  5. 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. PubMed Citation (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).

  6. Jain MK. Drug-induced liver injury associated with HIV medications. Clin Liver Dis 2007; 11: 615-39, vii-viii. PubMed Citation  (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]).

  7. 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 Citation  (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).

  8. 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 Citation  (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).

  9. 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 Citation  (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).

  10. 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 Citation  (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).

  11. 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 Citation  (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").

  12. 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 Citation  (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%]).

  13. Wills T, Vega V. Elvitegravir: a once-daily inhibitor of HIV-1 integrase. Expert Opin Investig Drugs 2012; 21: 395-401. PubMed Citation  (Review of the mechanism of action, pharmacokinetics, efficacy and safety of elvitegravir; no discussion of ALT elevations or hepatotoxicity).

  14. Lee FJ, Carr A. Tolerability of HIV integrase inhibitors. Curr Opin HIV AIDS 2012; 7: 422-8. PubMed Citation  (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).

  15. A 4-drug combination (Stribild) for HIV. Med Lett Drugs Ther 2012; 54 (1404): 95-6. PubMed Citation  (Concise review of the efficacy and safety of Stribild, shortly after its approval in the US; does not mention ALT elevations or hepatotoxicity).

  16. 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 Citation  (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).

  17. 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 Citation  (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).

  18. Surgers L, Lacombe K. Hepatoxicity of new antiretrovirals: a systematic review. Clin Res Hepatol Gastroenterol 2013; 37: 126-33. PubMed Citation  (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%]).

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OTHER REFERENCE LINKS
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir
  1. PubMed logoRecent References on Elvitegravir, Cobicistat, Emtricitabine, Tenofovir

  2. Clinical Trials logoTrials on Elvitegravir, Cobicistat, Emtricitabine, Tenofovir

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