Elvitegravir (EVG) + Cobicistat (COBI) + Emtricitabine (FTC) + Tenofovir alafenamide (TAF)

DOSAGE

Adult dosage

1 tablet DIE with food. For missed doses, the product monograph recommends an interval of 18 hours.

Take the missed dose as soon as possible, unless there are only 18 hours or less before the next dose. Do not double the dose.

Pediatric dosage

Child or adolescent ≥ 25 kg : 1 tablet DIE with food.

Safety and efficacy have not been established in pediatric population < 25 kg.

Adjustment in renal impairment

CrCl ≥ 30 mL/min :  No adjustment required

CrCl < 30 mL/min and ≥ 15 mL/min : Administration not recommended

CrCl < 15 mL/min (chronically treated with hemodialysis) : No adjustment required, administration after treatment sessions on hemodialysis day

CrCl < 15 mL/min (not chronically treated by hemodialysis) : Administration not recommended

No data are available on which to make a dosage recommendation in pediatric patients with renal impairment

Adjustment in hepatic impairment

Child-Pugh A : No adjustment required

Child-Pugh B or C : Administration not recommended (not studied in this population)

COMPARATIVE EFFICIENCY

Study in patients who have never received antiretrovirals

Study in patients with virological suppression and no documented resistance

* Current initial ART regimen (Stribild, Atripla, Truvada + ATZ/r)

Simplification study in patients experienced with antiretroviral therapy : Genvoya + darunavir (Prezista)

A simplification study demonstrated that the combination of two tablets (Genvoya + darunavir) made it possible to simplify therapy in individuals taking up to 5 antiretrovirals, to maintain viral suppression in 96% of patients and to improve specific markers of renal safety. Such a strategy can also lead to greater adherence to treatment and a better quality of life.

The patients in this study had resistance to 2 or 3 classes and had at least 2 previous virological failures.

RESISTANCE

Clinical studies in patients who have never received antiretrovirals

At 144 weeks, in 12 of 22 virologic failure patients who were screened for genotyping, one or more primary mutations were observed to confer resistance to elvitegravir, emtricitabine or tenofovir alafenamide.

The mutations that occurred were the mutations M184V/I (N=11) and K65R/N (N=2) in reverse transcriptase and the mutations T66T/A/I/V (N=2), E92Q (N=4), Q148Q/R (N=1) and N155H (N=2) in the integrase. The majority of patients with resistance to elvitegravir have experienced resistance to emtricitabine and elvitegravir. In addition, phenotypic analysis demonstrated that 7 out of 22 patients (32%) with HIV-1 isolates had reduced sensitivity to elvitegravir, 8 patients (36%) displayed reduced sensitivity to emtricitabine and 1 patient out of 22 (4.5%) had reduced sensitivity to tenofovir.

Cell culture studies

Primary integrase substitutions T66A/I, E92G/Q, S147G and Q148R show reduced sensitivity to elvitegravir. The other substitutions were D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K and V281M.

Substitution M184V/I in reverse transcriptase for reduced sensitivity to emtricitabine.

Substitution K65R in reverse transcriptase for reduced sensitivity to tenofovir.

ADVERSE REACTIONS

In short

• Gastrointestinal effects: diarrhea, nausea
• Metabolic effects: dyslipidemia and impaired blood sugar

Tenofovir alafenamide is hydrolyzed in cells and turns into an active metabolite called tenofovir diphosphate. A 10 mg dose of tenofovir alafenamide in Genvoya^® provides more than 4 times the concentration of tenofovir diphosphate in PBMCs. In addition, there is a much lower concentration of tenofovir in plasma (estimated > 90% lower) compared to an oral dose of 300 mg of tenofovir disoproxil fumarate. This decrease in the concentration of tenofovir in the bloodstream allows a more favorable safety of the molecule. Indeed, there is a clear advantage of tenofovir alafenamide for the kidneys and bones compared to tenofovir disoproxil.

Metabolic effects (lipids and blood sugar)

Genvoya^® may be involved in lipid abnormalities and elevations in blood glucose. These abnormalities must be managed according to the risk factors and the clinical impact for the patient. They may require modification of antiretroviral therapy for agents with a more favorable metabolic profile or the addition of a statin or hypoglycemic agent supplemented by non-pharmacological measures (diet, exercise and smoking cessation).

It is recommended to monitor serum lipid levels and blood sugar periodically, at least once a year and more frequently depending on the patient’s cardiovascular risk factors.

Immune reconstitution inflammatory syndrome (IRIS)

This effect can be seen with any antiretroviral therapy. An inflammatory response to poorly progressive or residual opportunistic infections (e.g. Mycobacterium avium complex, cytomegalovirus, Pneumocystis jerovinci pneumonia or tuberculosis) which may require treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed.

For management of adverse effects associated with antiretrovirals, see section adverse effects management.

IMPACT ON LABORATORY

Creatinine increase

Cobicistat increases the serum concentration of creatinine via an inhibition of tubular secretion. This should not be interpreted as an impairment of kidney function. The increase usually occurs within the first two weeks of treatment and is reversible upon discontinuation of Genvoya^®. This should be taken into account when estimating a patient’s kidney function. Some will subtract the serum creatinine observed when adding Genvoya^® before calculating the estimated glomerular filtration rate.

MECHANISM OF ACTION

Elvitegravir

Integrase inhibitor

Emtricitabine and tenofovir alafenamide

Reverse transcriptase inhibitors

PHARMACOKINETICS

Tmax

Elvitegravir : 4 h
Cobicistat : 3 h
Emtricitabine : 3 h
Tenofovir alafenamide : 1 h

Elimination T½ (plasma)

Elvitegravir : 12.9 h
Cobicistat : 3.5 h
Emtricitabine : 10 h
Tenofovir alafenamide : 0.51 h (tenofovir 32.37 h)

T½ intracellular

Tenofovir alafenamide : 150-180 h in mononuclear peripheral blood cells

Metabolism

Elvitegravir : CYP3A (mainly) and UGT1A1/3
Cobicistat : CYP3A (mainly) and 2D6
Tenofovir alafenamide : cathepsin A and CES1; transported by P-gp and BCRP

Elimination

Elvitegravir : excreted in the faeces (94.8%) and in the urine (6.7%) (> 1% unchanged)
Emtricitabine : ~86 % urinary excretion and ~14 % in the faeces unchanged
Tenofovir alafenamide : urinary excretion < 1% unchanged and in the faeces; in the urine by glomerular filtration and by active tubular secretion (tenofovir)

Binding to plasma proteins

Elvitegravir : 98-99 %
Cobicistat : 97-98 %
Emtricitabine : < 4 %
Tenofovir alafenamide : ~80 %

PREGNANCY AND BREAST FEEDING

Pregnancy

There are few data from pregnant women. The product monograph and guidelines do not recommend Genvoya^® as the first choice of treatment for pregnant women. If the choice of Genvoya^® is maintained, the decision must be made according to the potential benefits and the risks for the fetus and the mother.

If Genvoya^® is given to a pregnant woman, note that lower exposure to elvitegravir and cobicistat has been observed. It is therefore necessary to monitor viral load more closely and more particularly in the 2nd and 3rd trimester of pregnancy to avoid virological failure and increase the risk of mother-to-child transmission.

Professionals are encouraged to report pregnancy cases with a view to adding them to the register:
www.apregistry.com/  Telephone : 1-800-258-4263 Fax : 1-800-800-1052.

Breast feeding

Elvitegravir, cobicistat, tenofovir alafenamide : It is not known whether elvitegravir, cobicistat or tenofovir alafenamide (TAF) are secreted in breast milk.

Emtricitabine : Emtricitabine is secreted in breast milk in low concentrations suggesting a potential risk of resistance in the infant.

Given the potential for HIV transmission and the potential for adverse reactions in infants, the HIV+ mother on antiretroviral therapy should be advised not to breastfeed her child.

PRECAUTIONS AND CONTRAINDICATIONS

Precautions

Patient co-infected with hepatitis B

• If Genvoya^® is discontinued in a patient co-infected with HBV, caution should be exercised. Indeed, severe acute exacerbations of hepatitis B (hepatic decompensation and hepatic failure) have been observed in patients co-infected with HBV and HIV-1. Therefore, stopping treatment with Genvoya^® without initiating alternative hepatitis B therapy is not recommended.

Administration with other antiretrovirals

• Genvoya^® should not be coadministered with other antiretrovirals that contain elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide, lamivudine, tenofovir DF or ritonavir (Atripla, Biktarvy, Combivir, Complera, Descovy, Emtriva, Epivir, Kaletra, Kivexa, Kaletra, Norvir, Odefsey, Prezcobix, Stribild, Symtuza, Truvada, Tybost, Triumeq, Trizivir, Truvada, Vemlidy, Viread), nor with adefovir dipivoxil (Hepsera).

Drugs interactions

• Cobicistat, a compound of Genvoya^®, is an inhibitor of CYP3A and CYP2D6 and the transporters P-gp, BCRP, OATP1B1 and OATP1B3. Genvoya^® therefore has a high potential for interaction with several drugs. It is important to check whether there is a drug interaction each time a new drug is prescribed or when Genvoya^® is started in an individual who is already taking other medications.

Contraindications

• Hypersensitivity to the active or inactive molecules contained in the tablet.

Drugs interactions

• Co-administration with the following drugs as it may cause serious or life-threatening events, or loss of virologic response and possible resistance to Genvoya^®: alfuzosin, carbamazepine, phenobarbital, phenytoin, astemizole, terfenadine, rifampin, midazolam (administered orally), triazolam, salmeterol, apixaban, rivaroxaban, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John’s wort (Hypericum perforatum), lovastatin, simvastatin, lurasidone, pimozide, sildenafil (treatment of pulmonary arterial hypertension).

For a safer use of these drugs used in combination with Genvoya^®, consult the product monograph or the drug interactions section.

FURTHER INFORMATION

Administration

No data on whether the Genvoya^® tablet can be cut or crushed.

However, we know that the crushed and suspended Stribild^® tablet (EVG/COBI/FTC/TDF) in combination with enteral nutrition is bio-equivalent to the whole tablet of Stribild^®. Also, taking Stribild^® crushed and suspended and with lunch shows a variation in Cmax compared to Stribild^® tablet swallowed whole but this difference is not clinically significant.

It is therefore possible to cut or crush Genvoya^® tablet.

However, it should be noted that the tenofovir alafenamide (TAF) contained in Genvoya^® would have a bitter and burnt taste which could be an issue when taking Genvoya^® crushed.

Storage

Store the tablets at a maximum temperature of 30° C.

REFERENCES

• Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya), Gilead Sciences, Ontario, Canada, November 13, 2020.

• Foisy M, Pharm.D., AAHIVP, Northern Alberta Program, Royal Alexandra Hospital Site, Edmonton, C. Hughes, Pharm.D., AAHIVP, Northern Alberta Program, KEC Site,Edmonton, Alberta, Sarah Lamb, PharmD Student (2017 updates), and A. Tseng, Pharm.D, AAHIVP, Toronto General Hospital. ORAL ANTIRETROVIRAL ADMINISTRATION: INFORMATION ON CRUSHING AND LIQUID DRUG FORMULATIONS.

• Jongbloed-de Hoon M, Colbers A, Velthoven-Graafland K, Duisenberg-van Essenberg M, Kruijssen M et al. Brief Report: Pharmacokinetics of Crushed Elvitegravir Combination Tablet Given With or Without Enteral Nutrition. J Acquir Immune Defic Syndr. 2017 Apr 15; 74(5): 571-574.

• Eron JJ Jr, Lelievre JD, Kalayjian R, et al. Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial. Lancet HIV. 2018 Dec 13.: S2352-3018(18) 30296-0.

• Pozniak A, Arribas JR, Gathe J, et al. Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr. 2016; 71: 530-7.

• Gallant J, Brunetta J, Crofoot G, et al. Brief Report: Efficacy and Safety of Switching to a Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in HIV-1/Hepatitis B-Coinfected Adults. J Acquir Immune Defic Syndr. 2016; 73: 294-8.

• Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial. Lancet HIV. 2016; 3: e561-e568.

• Giacomet V, Cossu MV, Capetti AF, Zuccotti G, Rizzardini G. An evaluation of elvitegravir plus cobicistat plus tenofovir alafenamide plus emtricitabine as a single-tablet regimen for the treatment of HIV in children and adolescents. Expert Opin Pharmacother. 2018 Dec 26: 1-8.

• Greig SL, Deeks ED. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 Infection. Drugs. 2016; 76: 957-68.

• Huhn GD, Tebas P, Gallant J, et al. A Randomized, Open-Label Trial to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Darunavir in Treatment-Experienced HIV-1-Infected Adults. J Acquir Immune Defic Syndr. 2017; 74: 193-200.

• Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2016; 16: 43-52.

• Margot NA, Kitrinos KM, Fordyce M, McCallister S, Miller MD, Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. HIV Clin Trials. 2016; 17: 78-87.

• Post FA, Tebas P, Clarke A, et al. Brief Report: Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Adults With Renal Impairment: 96-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 Study. J Acquir Immune Defic Syndr. 2017; 74: 180-184.

• Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015; 385: 2606-15.

• Wohl D, Oka S, Clumeck N, et al. Brief Report: A Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results. J Acquir Immune Defic Syndr. 2016; 72: 58-64.

ABBREVIATIONS

EVG, elvitegravir; COBI, cobicistat; FTC, emtricitabine; TAF, tenofovir alafenamide; DIE, once daily; CrCl, creatinine clearance; TDF, tenofovir disoproxyl furamate; ATZ/r, atazanavir/ritonavir.