Genvoya®
Elvitegravir 150 mg / Cobicistat 150 mg / Emtricitabine 200 mg / Tenofovir alafenamide 10 mg
Fabricant : Gilead
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.
Child or adolescent ≥ 25 kg : 1 tablet DIE with food.
Safety and efficacy have not been established in pediatric population < 25 kg.
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
Child-Pugh A : No adjustment required
Child-Pugh B or C : Administration not recommended (not studied in this population)
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
GS-US-292-0104 and GS-US-292-0111 |
EVG/COBI/FTC/TAF (N=866) vs EVG/COBI/FTC/TDF (N=867) |
Week 48 Week 144 |
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
Types of patients |
GS-US-292-0109 |
EVG/COBI/FTC/TAF (N=959) vs continue CAR* (N=477) |
Week 48 Week 96 |
Virological suppression since ≥ 6 months; majority of CD4+ ≥ 500 cells/µL; no résistance to EVG, FTC or TAF |
* Current initial ART regimen (Stribild, Atripla, Truvada + ATZ/r)
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.
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.
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.
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.
GS-US-292-0104 and GS-US-292-0111 Studies (week 48)
|
||
EVG/COBI/FTC/ TAF (Genvoya) (N=866) |
EVG/COBI/FTC/ TDF (Stribild) (N=867) |
|
Nausea |
1% |
1% |
Diarrhea |
1% |
< 1% |
Fatigue |
1% |
1% |
Headache |
1% |
1% |
GS-US-292-0104 and GS-US-292-0111 Studies (week 144)
|
||
EVG/COBI/FTC/ TAF (Genvoya) (N=866) |
EVG/COBI/FTC/ TDF (Stribild) (N=867) |
|
Nausea |
11% |
13% |
Diarrhea |
7% |
9% |
Fatigue |
6% |
5% |
Headache |
5% |
4% |
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.
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.
Integrase inhibitor
Reverse transcriptase inhibitors
Elvitegravir : 4 h
Cobicistat : 3 h
Emtricitabine : 3 h
Tenofovir alafenamide : 1 h
Elvitegravir : 12.9 h
Cobicistat : 3.5 h
Emtricitabine : 10 h
Tenofovir alafenamide : 0.51 h (tenofovir 32.37 h)
Tenofovir alafenamide : 150-180 h in mononuclear peripheral blood cells
Elvitegravir : CYP3A (mainly) and UGT1A1/3
Cobicistat : CYP3A (mainly) and 2D6
Tenofovir alafenamide : cathepsin A and CES1; transported by P-gp and BCRP
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)
Elvitegravir : 98-99 %
Cobicistat : 97-98 %
Emtricitabine : < 4 %
Tenofovir alafenamide : ~80 %
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.
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.
Patient co-infected with hepatitis B
Administration with other antiretrovirals
Drugs interactions
Drugs interactions
For a safer use of these drugs used in combination with Genvoya®, consult the product monograph or the drug interactions section.
A study in 12 healthy subjects (Massih et al, 2022) showed that the Genvoya® tablet dissolved in tap water was not bioequivalent for all components compared to whole tablets, but according to the authors no therapeutic difference is expected.
We also 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® (Jongbloed-de Hoon et al, 2017). 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.
Store the tablets at a maximum temperature of 30° C.
EVG, elvitegravir; COBI, cobicistat; FTC, emtricitabine; TAF, tenofovir alafenamide; DIE, once daily; CrCl, creatinine clearance; TDF, tenofovir disoproxyl furamate; ATZ/r, atazanavir/ritonavir.