Treatment of HIV Infection 
The fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (EVG/c/FTC/TAF) is used as a complete regimen for the treatment of HIV-1 infection in adult and pediatric patients weighing ≥25 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of EVG/c/FTC/TAF.1,2,3,4,5,27,28,29,30,31
EVG/c/FTC/TAF is a co-formulation of 2 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs; tenofovir alafenamide fumarate and emtricitabine), an integrase strand transfer inhibitor (INSTI; elvitegravir), and a pharmacokinetic enhancer (cobicistat); consult guidelines for the most current information on the place in therapy for this regimen.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202
Clinical Experience
Antiretroviral-naïve Adults
The comparative efficacy of EVG/c/FTC/TAF and the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF) was evaluated in 2 identical randomized, double blind, active-control, phase 3, noninferiority studies in antiretroviral-naïve HIV-infected adults (study 104 and study 111).1,2,3 Patients enrolled in these studies were adults (mean age 36 years, 85% male, 57% white, 25% Black, 10% Asian, 19% Hispanic, mean baseline plasma HIV-1 RNA level 4.5 log10 copies/mL, mean baseline CD4+ T-cell count 427 cells/mm3).1 Patients were randomized in a 1:1 ratio to receive EVG/c/FTC/TAF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg) or EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily.1,2,3 The primary end point was virologic response (defined as HIV-1 RNA <50 copies/mL).1,2 Pooled data from both studies at 144 weeks indicated that 84% of those receiving EVG/c/FTC/TAF had plasma HIV-1 RNA <50 copies/mL compared with 80% of those receiving EVG/c/FTC/TDF.1 The mean increase in CD4+ T-cell count from baseline to week 144 was 326 cells/mm3 in those receiving EVG/c/FTC/TAF compared with 305 cells/mm3 in those receiving EVG/c/FTC/TDF.1 Treatment outcomes were similar across subgroups (age, sex, race, baseline viral load, and baseline CD4+ T-cell count).1
Antiretroviral-experienced Adults
The efficacy of EVG/c/FTC/TAF in antiretroviral-experienced, virologically suppressed adults was evaluated in a randomized, open-label, active-control, phase 3 noninferiority study (study 109; NCT01815736).1,4 Patients enrolled in the study were adults with baseline plasma HIV-1 RNA <50 copies/mL for at least 6 months (mean age 41 years, 90% male, 67% white, 21% Black, mean baseline CD4+ T-cell count 705 cells/mm3).1 At initial screening, all patients were on a suppressive antiretroviral regimen ( ritonavir-boosted or cobicistat-boosted atazanavir in conjunction with the fixed combination of emtricitabine and tenofovir DF [42%], EVG/c/FTC/TDF [32%], or fixed combination of efavirenz, emtricitabine, and tenofovir DF [26%]) for at least 6 months with no known history of resistance to the antiretroviral components of EVG/c/FTC/TAF.1,4 Patients were randomized in a 2:1 ratio to either switch to EVG/c/FTC/TAF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg) or stay on their baseline antiretroviral regimen.1,4 The primary end point was virologic response (defined as HIV-1 RNA <50 copies/mL).1,4 At 96 weeks, 93% of those receiving EVG/c/FTC/TAF had plasma HIV-1 RNA <50 copies/mL compared with 89% of those who continued to receive their baseline antiretroviral regimen.1 The mean increase in CD4+ T-cell count from baseline was 60 cells/mm3 in those receiving EVG/c/FTC/TAF compared with 42 cells/mm3 in those who continued to receive their baseline antiretroviral regimen.1
The efficacy of EVG/c/FTC/TAF in antiretroviral-experienced, virologically suppressed adults with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-69 mL/minute) was evaluated in a single-arm, open-label study (study 112; NCT01818596).1,5 The study included 242 patients (mean age 58 years [26% 65 years of age or older], 79% male, 18% Black, median baseline CD4+ T-cell count 632 cells/mm3) with plasma HIV-1 RNA <50 copies/mL for at least 6 months on their existing antiretroviral regimen (65% had been receiving a regimen that included tenofovir DF)5 and also included 6 treatment-naive patients.1 All patients then received EVG/c/FTC/TAF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg) once daily with food.1,5 The primary end point was the change in eGFR from baseline to 24 weeks; a secondary end point was the proportion of patients maintaining virologic control.5 In the previously treated patients, eGFR (using the Cockcroft-Gault equation) was reduced by 0.4 mL/minute at 24 weeks after switching to EVG/c/FTC/TAF5 and there was no appreciable change in estimated creatinine clearance from baseline through 48 weeks.5 At 144 weeks after switching to EVG/c/FTC/TAF, 81% of previously treated patients had maintained plasma HIV-1 RNA <50 copies/mL; 5 patients experienced virologic failure.1
A similar open-label, single-arm study evaluated the efficacy and safety of switching to EVG/c/FTC/TAF in 55 antiretroviral-experienced, virologically suppressed adults with end-stage renal disease (eGFR <15 mL/minute; study 1825).1,29 Enrollees had, for at least 6 months, both an HIV-1 RNA <50 copies/mL with their previous antiretroviral regimen and were receiving chronic hemodialysis, and switched therapy to EVG/c/FTC/TAF once daily for up to 96 weeks.1 The primary endpoint was treatment-emergent grade 3 or higher adverse events up to week 48, with the proportion of patients with HIV-1 RNA <50 copies/mL as a secondary endpoint.29 At week 48, 45 patients (82%) maintained HIV-1 RNA <50 copies/mL, 7 of whom had discontinued EVG/c/FTC/TAF due to adverse events or other reasons while virologically suppressed; 2 patients had HIV-1 RNA ≥50 copies/mL.1
Two randomized noninferiority trials evaluated the efficacy of switching from other regimens to EVG/c/FTC/TAF in antiretroviral-experienced, virologically suppressed adults.27,28 The first study initially randomized treatment-naïve women to receive EVG/c/FTC/TDF or ritonavir-boosted atazanavir plus emtricitabine and tenofovir DF (ATV/RTV/FTC/TDF); patients in the ATV/RTV/FTC/TDF arm who achieved virologic suppression at 48 weeks were rerandomized (3:1) to switch to EVG/c/FTC/TAF or continue on ATV/RTV/FTC/TDF.27 The second study randomized virologically suppressed adults who were receiving abacavir plus lamivudine and a third antiretroviral 2:1 to switch to EVG/c/FTC/TAF or continue on their current regimen.28 Among 212 women who underwent re-randomization in the first study, similar rates of maintained virologic suppression were noted at 48 weeks in those who switched to EVG/c/FTC/TAF (94%) and those who continued on ATV/RTV/FTC/TDF (87%).27 Among 274 patients randomized and analyzed in the second study, similar rates of maintained virologic suppression were noted at 24 weeks in those who switched to EVG/c/FTC/TAF (93.4%) and those who continued on their current regimen (97.8%).28
Pediatric Patients
The efficacy of EVG/c/FTC/TAF in pediatric patients was evaluated in a 2-cohort, open-label study enrolling treatment-naïve adolescents (12 to <18 years of age, weighing ≥35 kg; cohort 1) and antiretroviral-experienced, virologically suppressed children (6 to <12 years of age, weighing ≥25 kg; cohort 2) (study 106).1,30,31 Cohort 1 included 50 patients (mean age 15 years, 44% male, 88% Black, 12% Asian, mean baseline CD4+ T-cell count 471 cells/mm3, mean CD4+ percentage 23.6%, mean baseline HIV-1 RNA 4.6 log10 copies/mL).1 Cohort 2 included 52 patients (mean age 10 years, 42% male, 71% Black, 25% Asian, mean baseline CD4+ T-cell count 961 cells/mm3, mean CD4+ percentage 38.2%).1 All patients received EVG/c/FTC/TAF once daily.1 In cohort 1, 92% had achieved plasma HIV-1 RNA <50 copies/mL at 48 weeks; the mean increase in CD4+ T-cell count from baseline was 224 cells/mm3.1 Virologic failure was observed in 3 adolescents; there was no evidence of treatment-emergent resistance to EVG/c/FTC/TAF.1 In cohort 2, 98% remained virologically suppressed 48 weeks after switching to EVG/c/FTC/TAF; all patients maintained CD4+ T-cell counts above 400 cells/mm3 and none qualified for resistance analysis.1
Clinical Perspective
Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202
The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial anti-retroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200
The fixed-dose combination of EVG/c/FTC/TAF is commonly used as a complete antiretroviral regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, EVG/c/FTC/TAF is listed among initial regimens recommended in certain clinical situations.200
In the 2023 HHS pediatric HIV treatment guideline, EVG/c/FTC/TAF is listed among alternative initial regimens for children and adolescents weighing ≥25 kg.201
In the 2023 HHS perinatal HIV treatment guideline, EVG/c/FTC/TAF is not recommended as an initial antiretroviral regimen in pregnancy due to data suggesting insufficient levels of cobicistat and elvitegravir in the second and third trimesters and risk of viral breakthrough at delivery.202 In patients who become pregnant while virologically suppressed on EVG/c/FTC/TAF, HHS recommends continuing therapy with frequent viral load monitoring or considering switching therapy.202
Contraindications
- Concomitant use with drugs highly dependent on cytochrome P-450 (CYP) 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.1 These drugs and other contraindicated drugs, which may lead to reduced efficacy of the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (EVG/c/FTC/TAF) and possible resistance include alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, lurasidone, pimozide, ergot derivatives, St. John's wort, lomitapide, lovastatin, simvastatin, sildenafil (when given for pulmonary arterial hypertension), triazolam, and orally administered midazolam.1
Warnings/Precautions
Warnings
HIV-infected Individuals Coinfected with Hepatitis B Virus
A boxed warning is included in the prescribing information for EVG/c/FTC/TAF regarding the risk of severe acute exacerbations of hepatitis B virus (HBV) infection following discontinuance of preparations containing emtricitabine and/or tenofovir disoproxil fumarate (tenofovir DF).1 In some patients receiving emtricitabine, exacerbations of HBV have been associated with hepatic decompensation and hepatic failure.1 Such reactions could occur with EVG/c/FTC/TAF.1
HIV-infected patients should be tested for HBV before or when antiretroviral therapy is initiated.1
EVG/c/FTC/TAF is not indicated for treatment of chronic HBV infection, and safety and efficacy of EVG/c/FTC/TAF have not been established in HIV-infected patients coinfected with HBV.1
Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after EVG/c/FTC/TAF is discontinued in patients coinfected with HIV and HBV.1 If appropriate, initiation of HBV treatment may be warranted, especially in patients with advanced liver disease or cirrhosis.1
Other Warnings/Precautions
New Onset or Worsening Renal Impairment
Post marketing cases of renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), have been reported in patients receiving TAF-containing products.1 Although the majority of these cases had potential confounding factors that may have contributed to the development of renal impairment, these confounding factors may have predisposed patients to tenofovir-related adverse events.1
EVG/c/FTC/TAF is not recommended in patients with estimated creatinine clearance of 15 to <30 mL/minute, or in patients with estimated creatinine clearance <15 mL/minute who are not receiving chronic hemodialysis.1
Cobicistat (a component of EVG/c/FTC/TAF) may cause a modest increase in serum creatinine and modest decrease in estimated creatinine clearance because of inhibition of tubular secretion of creatinine; there is a corresponding decrease in serum creatinine-based eGFR, but renal glomerular function is not affected.1,15 Elevated serum creatinine concentrations typically occurred within 2 weeks after the drug was initiated and generally were reversible after the drug was discontinued.1,15
Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein prior to initiating EVG/c/FTC/TAF and monitor routinely during treatment in all patients.1 In patients with chronic kidney disease, also assess serum phosphorus.1
Patients with a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline while receiving EVG/c/FTC/TAF should be closely monitored for renal toxicity.1 EVG/c/FTC/TAF should be discontinued in patients who develop clinically important decreases in renal function or evidence of Fanconi syndrome.1
Patients receiving a tenofovir prodrug who have impaired renal function or are receiving a nephrotoxic agent (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]) are at increased risk of developing adverse renal effects.1
Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs), including emtricitabine and the tenofovir prodrug tenofovir DF, in conjunction with other antiretroviral agents.1
EVG/c/FTC/TAF treatment should be interrupted in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (signs of hepatotoxicity may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1
Use of Fixed Combinations
The usual cautions, precautions, contraindications, and interactions associated with each component of EVG/c/FTC/TAF should be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.1,218
EVG/c/FTC/TAF is used alone as a complete regimen for the treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.1
EVG/c/FTC/TAF should not be used concomitantly with any preparation that contains any of its components (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide).1 In addition, EVG/c/FTC/TAF should not be used concomitantly with any preparation containing tenofovir DF, lamivudine, adefovir dipivoxil, or ritonavir.1
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including emtricitabine (a component of EVG/c/FTC/TAF).1 During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium , M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); such response may necessitate further evaluation and treatment.1
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1
Specific Populations
Pregnancy
The use of EVG/c/FTC/TAF is not recommended during pregnancy due to substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters.1
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to EVG/c/FTC/TAF during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1
The overall risk of birth defects with EVG/c/FTC/TAF use in pregnancy was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease.1 The rate of miscarriage is not reported in the APR.1
Lactation
Elvitegravir and cobicistat are distributed into milk in rats.1 Tenofovir is distributed into milk in rats and rhesus monkey following administration of tenofovir DF; it is not known whether tenofovir alafenamide is distributed into animal milk.1 It is not known whether elvitegravir, cobicistat, or tenofovir alafenamide are distributed into human milk.1 Emtricitabine is distributed into human milk.1
It is not known whether EVG/c/FTC/TAF affects human milk production or the breast-fed infant.1
Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.1
Pediatric Use
Safety and efficacy of EVG/c/FTC/TAF have not been established in pediatric patients weighing <25 kg.1
Use of EVG/c/FTC/TAF in pediatric patients <18 years of age and weighing at least 25 kg is supported by studies in adults and by an open-label study in antiretroviral treatment-naïve HIV-1 infected pediatric patients 12 to <18 years of age weighing at least 35 kg and in virologically-suppressed pediatric patients 6 to <12 years of age weighing at least 25 kg.1
Clinical trial data indicate that the safety and efficacy of EVG/c/FTC/TAF in HIV-1-infected, treatment-naïve pediatric patients 6 to <12 years of age weighing at least 25 kg is similar to that reported in antiretroviral naïve adults and adolescents with the exception of a decrease in baseline CD4+ count.1
Geriatric Use
No differences in safety or efficacy of EVG/c/FTC/TAF have been observed between individuals 65 years of age and older and individuals 18 to less than 65 years of age.1
Pharmacokinetics of EVG/c/FTC/TAF have not been fully evaluated in adults 65 years of age and older.1 Population pharmacokinetic analysis of EVG/c/FTC/TAF in HIV-infected individuals showed that age does not have a clinically important effect on tenofovir alafenamide exposures in adults up to 75 years of age.1
Hepatic Impairment
Mild hepatic impairment (Child-Pugh class A) does not have a clinically important effect on the pharmacokinetics of tenofovir alafenamide.1 Moderate hepatic impairment (Child-Pugh class B) does not have a clinically important effect on the pharmacokinetics of elvitegravir, cobicistat, or tenofovir alafenamide and is not expected to affect the pharmacokinetics of emtricitabine.1
EVG/c/FTC/TAF is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 Data are not available to date regarding the pharmacokinetics or safety of EVG/c/FTC/TAF in such patients.1
Renal Impairment
The pharmacokinetics of EVG/c/FTC/TAF were evaluated in HIV-1 infected patients with mild to moderate renal impairment (estimated creatinine clearance of 30-69 mL/minute) and in HIV-1 infected patients with ESRD (estimated creatinine clearance of <15 mL/minute) receiving chronic hemodialysis.1 The pharmacokinetics of elvitegravir, cobicistat, and tenofovir alafenamide in these patients were similar to those in healthy subjects.1 Increased emtricitabine and tenofovir exposures in patients with renal impairment were not considered clinically relevant.1
Not recommended in patients with severe renal impairment (estimated creatinine clearance of 15-29 mL/minute), or in patients with end-stage renal disease (ESRD) (estimated creatinine clearance <15 mL/minute) who are not receiving chronic hemodialysis.1
Common Adverse Effects
The most common adverse reaction (≥10%, all grades) is nausea.1
The following drug interactions are based on studies that used elvitegravir, elvitegravir administered with cobicistat ( cobicistat-boosted elvitegravir), elvitegravir administered with low-dose ritonavir ( ritonavir-boosted elvitegravir), cobicistat alone, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF) or are predicted to occur.1
Potential drug interactions associated with each drug in the fixed combination should be considered.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Elvitegravir is a substrate of cytochrome P-450 (CYP) 3A1 and a weak inducer and weak inhibitor of CYP3A;24,25 elvitegravir is an inducer of CYP2C9.1 The drug does not inhibit CYP1A, 2A6, 2C9, 2C19, 2D6, or 2E1 in vitro.24
Cobicistat is a substrate of CYP3A and, to a minor extent, CYP2D6; cobicistat also is an inhibitor of CYP3A and 2D6.1
Emtricitabine is not a substrate of CYP enzymes; emtricitabine does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.218
Tenofovir alafenamide is a weak inhibitor of CYP3A in vitro, but is not an inhibitor or inducer of CYP3A in vivo.1 Tenofovir alafenamide does not induce or inhibit other CYP enzymes, including CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.1
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that are principally metabolized by CYP3A or 2D6 (increased plasma concentrations of the concomitant drug).1 Concomitant use of EVG/c/FTC/TAF with some drugs that are CYP3A substrates and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.1
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that induce CYP3A (decreased plasma concentrations of elvitegravir, cobicistat, and tenofovir alafenamide; possible decreased antiretroviral efficacy and development of resistance).1 Concomitant use of EVG/c/FTC/TAF with some drugs that are potent inducers of CYP3A is contraindicated.1
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that inhibit CYP3A (increased plasma concentrations of cobicistat).1
Drugs Affected by P-glycoprotein Transport
Cobicistat is an inhibitor of P-glycoprotein (P-gp) transport;1 tenofovir alafenamide is a substrate of P-gp.1,25
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that are P-gp substrates (increased plasma concentrations of the concomitant drug).1
Drugs that inhibit P-gp may increase absorption of tenofovir alafenamide.1 Cobicistat (a P-gp inhibitor) increases tenofovir alafenamide concentrations when the drugs are administered as the fixed combination EVG/c/FTC/TAF; further increases in tenofovir alafenamide concentrations are not expected if an additional P-gp inhibitor is used concomitantly with EVG/c/FTC/TAF.1
Drugs that induce P-gp are expected to decrease absorption of tenofovir alafenamide, resulting in decreased plasma concentrations of tenofovir alafenamide.1
Drugs Affected by Breast Cancer Resistance Protein
Cobicistat is an inhibitor of breast cancer resistance protein (BCRP);1 tenofovir alafenamide is a substrate of BCRP.1,25
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that are substrates for BCRP (increased plasma concentrations of the concomitant drug).1
Drugs that inhibit BCRP may increase absorption of tenofovir alafenamide.1 Cobicistat (a BCRP inhibitor) increases tenofovir alafenamide concentrations when the drugs are administered as the fixed combination EVG/c/FTC/TAF; further increases in tenofovir alafenamide concentrations are not expected if an additional BCRP inhibitor is used concomitantly with EVG/c/FTC/TAF.1
Drugs Affected by Organic Anion Transport Polypeptides
Elvitegravir and cobicistat are inhibitors of organic anion transport polypeptides (OATP) 1B1 and 1B3; tenofovir alafenamide is a substrate of OATP1B1 and 1B3.1
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that are substrates for OATP1B1 or 1B3 (increased plasma concentrations of the concomitant drug).1
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase
Elvitegravir is partially metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1/3 enzymes.1,24 Tenofovir alafenamide does not inhibit UGT1A1.1
Drugs Affecting Renal Function
The emtricitabine and tenofovir components of EVG/c/FTC/TAF are principally excreted by the kidneys by a combination of glomerular filtration and active tubular secretion.1
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that reduce renal function or compete for active tubular secretion (e.g., acyclovir, aminoglycosides [gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]); may result in increased concentrations of emtricitabine, tenofovir, and/or the concomitant drug and may increase the risk of adverse effects.1
Alfuzosin
Potential pharmacokinetic interaction with alfuzosin (increased plasma concentrations of alfuzosin); may result in hypotension.1
Concomitant use of alfuzosin and EVG/c/FTC/TAF is contraindicated.1
Anticoagulants
Apixaban, Dabigatran, Edoxaban, Rivaroxaban
Pharmacokinetic interactions are expected if apixaban, dabigatran, edoxaban, or rivaroxaban is used concomitantly with EVG/c/FTC/TAF (increased anticoagulant concentrations).1
Due to an increased risk of bleeding, recommendations for the concomitant use of apixaban with EVG/c/FTC/TAF depend on the dosage of apixaban.1 Refer to apixaban prescribing information for dosing instructions on the concomitant use of apixaban with strong CYP3A and P-gp inhibitors.1
Due to an increased risk of bleeding, dosing recommendations for the concomitant use of dabigatran and edoxaban with a P-gp inhibitor such as EVG/c/FTC/TAF are dependent upon underlying renal function and the indication for anticoagulant use.1 Refer to the prescribing information for the direct oral anticoagulant (DOAC) in use for dosage recommendations with a P-gp inhibitor.1
Concomitant use of rivaroxaban with EVG/c/FTC/TAF is not recommended.1
Warfarin
The effect of concomitant use of warfarin and EVG/c/FTC/TAF on the pharmacokinetics of warfarin is unknown.1
If warfarin is used concomitantly with EVG/c/FTC/TAF, monitor the international normalized ratio (INR).1
Anticonvulsants
Carbamazepine, Phenobarbital, Phenytoin
Concomitant use of carbamazepine and cobicistat-boosted elvitegravir results in decreased elvitegravir plasma concentrations and area under the plasma concentration-time curve (AUC); increased carbamazepine plasma concentrations and AUC also occur.1 Potential pharmacokinetic interactions if carbamazepine, phenobarbital, or phenytoin is used concomitantly with EVG/c/FTC/TAF (decreased elvitegravir, cobicistat, and tenofovir alafenamide plasma concentrations with possible decreased antiretroviral efficacy and development of resistance).1
Concomitant use of EVG/c/FTC/TAF and carbamazepine, phenobarbital, or phenytoin is contraindicated.1
Ethosuximide
Potential pharmacokinetic interaction if ethosuximide is used concomitantly with EVG/c/FTC/TAF (increased ethosuximide plasma concentrations and decreased elvitegravir, cobicistat, and tenofovir alafenamide plasma concentrations).1
If ethosuximide and EVG/c/FTC/TAF are used concomitantly, the patient should be monitored clinically.1
Oxcarbazepine
Potential pharmacokinetic interaction if oxcarbazepine is used concomitantly with EVG/c/FTC/TAF (decreased elvitegravir, cobicistat, and tenofovir alafenamide plasma concentrations).1 An alternative anticonvulsant should be considered.1
Antifungal Agents
Itraconazole
Potential pharmacokinetic interactions with itraconazole (increased plasma concentrations of itraconazole, elvitegravir, and cobicistat).1
If itraconazole and EVG/c/FTC/TAF are used concomitantly, itraconazole dosage should not exceed 200 mg daily.1
Ketoconazole
Pharmacokinetic interactions with ketoconazole (increased plasma concentrations of ketoconazole, elvitegravir, and cobicistat).1
If ketoconazole and EVG/c/FTC/TAF are used concomitantly, ketoconazole dosage should not exceed 200 mg daily.1
Voriconazole
Potential pharmacokinetic interactions with voriconazole (increased plasma concentrations of voriconazole, elvitegravir, and cobicistat).1
Voriconazole and EVG/c/FTC/TAF should not be used concomitantly unless potential benefits outweigh risks.1
Antimycobacterial Agents
Rifabutin
Pharmacokinetic interactions when cobicistat-boosted elvitegravir (elvitegravir 150 mg and cobicistat 150 mg once daily) was used concomitantly with rifabutin 150 mg once every other day (decreased elvitegravir plasma concentrations and AUC, increased 25- O -desacetyl-rifabutin concentrations and AUC relative to those achieved with rifabutin 300 mg once daily without concomitant cobicistat-boosted elvitegravir).1 Concomitant use of EVG/c/FTC/TAF also may decrease plasma concentrations of tenofovir alafenamide.1 Possible decreased antiretroviral efficacy and development of resistance.1
Concomitant use of rifabutin and EVG/c/FTC/TAF is not recommended.1
Rifampin
Potential pharmacokinetic interactions with rifampin (decreased elvitegravir, cobicistat, and tenofovir alafenamide plasma concentrations);1 possible decreased antiretroviral efficacy and development of resistance.1
Concomitant use of rifampin and EVG/c/FTC/TAF is contraindicated.1
Rifapentine
Potential pharmacokinetic interactions with rifapentine (decreased elvitegravir, cobicistat, and tenofovir alafenamide plasma concentrations); possible decreased antiretroviral efficacy and development of resistance.1
Concomitant use of rifapentine and EVG/c/FTC/TAF is not recommended.1
Antiplatelet Agents
Clopidogrel, Prasugrel,Ticagrelor
Pharmacokinetic interactions are expected if clopidogrel or ticagrelor are used concomitantly with EVG/c/FTC/TAF (increased ticagrelor concentrations, decreased clopidogrel active metabolite concentrations).1
Concomitant use of EVG/c/FTC/TAF and clopidogrel is not recommended due to the potential for decreased antiplatelet activity with clopidogrel.1
Concomitant use of EVG/c/FTC/TAF and ticagrelor is not recommended.1
Concomitant use of EVG/c/FTC/TAF and prasugrel is not expected to result in clinically important drug interactions.1
Antipsychotic Agents
Lurasidone
Concomitant use of lurasidone and EVG/c/FTC/TAF may result in serious and/or life-threatening reactions.1
Concomitant use of lurasidone and EVG/c/FTC/TAF is contraindicated.1
Perphenazine, Risperidone, Thioridazine
Potential pharmacokinetic interactions with antipsychotics, including perphenazine, risperidone, and thioridazine (increased antipsychotic plasma concentrations).1
If EVG/c/FTC/TAF is used concomitantly with certain antipsychotics (e.g., perphenazine, risperidone, thioridazine), decreased dosage of the antipsychotic may be necessary.1
Pimozide
Potential pharmacokinetic interaction with pimozide (increased pimozide plasma concentrations); potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1
Concomitant use of pimozide and EVG/c/FTC/TAF is contraindicated.1
Quetiapine
Pharmacokinetic interaction with quetiapine (increased quetiapine plasma concentrations expected).1
Alternative antiretroviral therapy should be considered.1 If EVG/c/FTC/TAF is necessary in a patient receiving quetiapine, the quetiapine dosage should be reduced to one-sixth of the original dosage and the patient monitored for quetiapine-associated adverse effects.1
Antiretroviral Agents
EVG/c/FTC/TAF should not be used in conjunction with any other antiretroviral agents.1
HIV Integrase Inhibitors (INSTIs)
EVG/c/FTC/TAF contains elvitegravir and should not be used concomitantly with any preparation containing elvitegravir.1
HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Emtricitabine
EVG/c/FTC/TAF contains emtricitabine and should not be used concomitantly with any preparation containing emtricitabine.1
Lamivudine
EVG/c/FTC/TAF and lamivudine (or preparations containing lamivudine) should not be used concomitantly.1
Tenofovir Disoproxil Fumarate
EVG/c/FTC/TAF and tenofovir disoproxil fumarate (tenofovir DF) (or preparations containing tenofovir DF) should not be used concomitantly.1
HIV Protease Inhibitors (PIs)
Ritonavir
EVG/c/FTC/TAF and ritonavir (or preparations containing ritonavir) should not be used concomitantly.1
Beta-Adrenergic Blocking Agents
Potential pharmacokinetic interactions with β-adrenergic blocking agents, including metoprolol and timolol (increased β-adrenergic blocking agent plasma concentrations).1
If EVG/c/FTC/TAF is used concomitantly with a β-adrenergic blocking agent, patients should be monitored clinically and decreased dosage of the β-adrenergic blocking agent may be necessary.1
Benzodiazepines
Diazepam
Potential pharmacokinetic interaction with diazepam (increased diazepam plasma concentrations).1
Concomitant use of diazepam and EVG/c/FTC/TAF should be undertaken in a monitored setting where respiratory depression and/or prolonged sedation can be managed.1
Midazolam or Triazolam
Potential pharmacokinetic interaction with midazolam or triazolam (increased benzodiazepine plasma concentrations); potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1
Concomitant use of oral midazolam or triazolam with EVG/c/FTC/TAF is contraindicated.1
Concomitant use of parenteral midazolam and EVG/c/FTC/TAF should be undertaken in a monitored setting where respiratory depression and/or prolonged sedation can be managed.1 In addition, use of a reduced midazolam dosage should be considered, especially if more than a single dose of the drug will be administered.1
Other Benzodiazepines
Potential pharmacokinetic interactions with clorazepate, estazolam, or flurazepam (increased benzodiazepine plasma concentrations).1
Bosentan
Potential pharmacokinetic interaction with bosentan (increased bosentan plasma concentrations).1
In patients who have already been receiving EVG/c/FTC/TAF for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1
In patients who have already been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating EVG/c/FTC/TAF; after at least 10 days of EVG/c/FTC/TAF therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1
Bupropion
Potential pharmacokinetic interaction with bupropion (increased bupropion plasma concentrations).1
If bupropion is used concomitantly with EVG/c/FTC/TAF, dosage of the antidepressant should be titrated carefully while monitoring for antidepressant response.1
Buspirone
Potential pharmacokinetic interaction with buspirone (increased buspirone plasma concentrations).1
If buspirone is used concomitantly with EVG/c/FTC/TAF, patients should be monitored clinically; reduced buspirone dosage may be necessary.1
Calcium-channel Blocking Agents
Potential pharmacokinetic interactions with calcium-channel blocking agents, including amlodipine, diltiazem, felodipine, nicardipine, nifedipine, and verapamil (increased plasma concentrations of the calcium-channel blocking agent).1
Calcium-channel blocking agents and EVG/c/FTC/TAF should be used concomitantly with caution;1 the patient should be clinically monitored.1
Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations
Oral calcium supplements, oral iron preparations, other oral supplements containing calcium, iron, aluminum, magnesium, or zinc (e.g., multivitamins), and laxatives, buffered medications, sucralfate, or other preparations containing polyvalent cations may decrease plasma concentrations of elvitegravir when used concomitantly.1 Separate administration of medications, antacids, and oral supplements containing polyvalent cations from EVG/c/FTC/TAF administration by at least 2 hours.1
Cardiac Drugs
Antiarrhythmic Agents
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used with certain antiarrhythmic agents (e.g., amiodarone, bepridil [no longer commercially available in the US], disopyramide, dronedarone, flecainide, lidocaine [systemic], mexiletine, propafenone, quinidine) (increased plasma concentrations of the antiarrhythmic agent).1 Concomitant use of digoxin (single 0.5-mg dose) and cobicistat (150 mg once daily) has resulted in increased plasma concentrations of digoxin.1
EVG/c/FTC/TAF and antiarrhythmic agents or digoxin should be used concomitantly with caution; plasma concentrations of the antiarrhythmic agents or cardiac glycoside should be monitored, if possible.1
Cisapride
Potential pharmacokinetic interaction with cisapride (increased cisapride plasma concentrations); potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1
Concomitant use of cisapride and EVG/c/FTC/TAF is contraindicated.1
Cobicistat
Pharmacokinetic interaction with elvitegravir (increased plasma concentrations and AUC of elvitegravir); occurs because cobicistat inhibits CYP3A.1 Cobicistat acts as a pharmacokinetic enhancer when used concomitantly with elvitegravir ( cobicistat-boosted elvitegravir) and is used to therapeutic advantage in the EVG/c/FTC/TAF fixed combination.1
Pharmacokinetic interaction with tenofovir alafenamide (increased tenofovir alafenamide plasma concentrations and AUC).1
Cobicistat does not antagonize the antiretroviral effects of elvitegravir, emtricitabine, or tenofovir.1
Colchicine
Potential pharmacokinetic interaction with colchicine (increased colchicine plasma concentrations).1
Colchicine and EVG/c/FTC/TAF should not be used concomitantly in patients with renal or hepatic impairment.1
When colchicine is used for treatment of gout flares in patients receiving EVG/c/FTC/TAF, an initial colchicine dose of 0.6 mg should be given followed by 0.3 mg 1 hour later; the colchicine course should be repeated no earlier than 3 days later.1
When colchicine is used for prophylaxis of gout flares in patients receiving EVG/c/FTC/TAF, colchicine dosage should be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1
When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving EVG/c/FTC/TAF, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.1
Corticosteroids
Corticosteroids Affected by Potent CYP3A Inhibition
Concomitant use of EVG/c/FTC/TAF and corticosteroids via all routes of administration whose exposures are substantially affected by potent CYP3A inhibitors (e.g., betamethasone, budesonide, ciclesonide, fluticasone, methylprednisolone, mometasone, triamcinolone) may increase plasma concentrations of the corticosteroid, which may result in adrenal insufficiency or Cushing syndrome.1 Alternative corticosteroids (e.g., beclomethasone, prednisone, prednisolone) less affected by CYP3A inhibition relative to other corticosteroids should be considered in patients receiving EVG/c/FTC/TAF, particularly if long-term corticosteroid therapy is required.1
Dexamethasone
Concomitant use of systemic dexamethasone or other systemic corticosteroids that induce CYP3A may decrease elvitegravir and cobicistat plasma concentrations and may lead to decreased antiretroviral efficacy and development of resistance to elvitegravir.1
An alternative corticosteroid should be considered in patients receiving EVG/c/FTC/TAF.1
Ergot Alkaloids
Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) if EVG/c/FTC/TAF is used concomitantly with ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine).1
Concomitant use of ergot alkaloids and EVG/c/FTC/TAF is contraindicated.1
Estrogens and Progestins
Pharmacokinetic interactions are possible with oral contraceptives containing ethinyl estradiol and norgestimate (decreased ethinyl estradiol plasma concentrations and increased norgestimate plasma concentrations).1
Effects of increased norgestimate plasma concentrations are not established, but may include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis.1 The potential risks and benefits of concomitant use of EVG/c/FTC/TAF and oral contraceptives containing ethinyl estradiol and norgestimate should be considered, particularly in women with risk factors for these effects.1
Pharmacokinetic interactions are possible with oral contraceptives containing ethinyl estradiol and drospirenone (decreased ethinyl estradiol plasma concentrations and increased drospirenone plasma concentrations).1 Clinical monitoring is recommended due to an increased risk for hyperkalemia.1
Pharmacokinetic interactions are possible with contraceptives containing levonorgestrel (increased plasma concentrations of levonorgestrel).1
Concomitant use of EVG/c/FTC/TAF with oral contraceptives containing progestins other than drosperinone, levonorgestrel, and norgestimate or with other hormonal contraceptives (e.g., transdermal contraceptive systems, vaginal ring, injections) have not been studied; alternative nonhormonal methods of contraception should be considered when estrogen-based contraceptives are used.1
Additional or nonhormonal methods of contraception should be used when estrogen-based contraceptives are used concomitantly with EVG/c/FTC/TAF.1
GI Drugs
Antacids
Antacids containing aluminum, calcium, and/or magnesium decrease plasma concentrations and AUC of elvitegravir.1
EVG/c/FTC/TAF should be given at least 2 hours before or at least 2 hours after antacids containing aluminum, calcium, or magnesium.1
Histamine H2-receptor Antagonists
Concomitant use of famotidine and cobicistat-boosted elvitegravir did not have a clinically important effect on elvitegravir plasma concentrations or AUC.1
Concomitant use of EVG/c/FTC/TAF and famotidine is not expected to result in clinically important drug interactions.1
Proton-pump Inhibitors
Concomitant use of omeprazole and cobicistat-boosted elvitegravir did not result in clinically important alterations in elvitegravir pharmacokinetics.1
Concomitant use of EVG/c/FTC/TAF and proton-pump inhibitors is not expected to result in clinically important drug interactions.1
HCV Antivirals
HCV Polymerase Inhibitors
Sofosbuvir
Clinically important pharmacokinetic interactions are not expected if EVG/c/FTC/TAF is used concomitantly with sofosbuvir.1
Sofosbuvir and Velpatasvir
No clinically important pharmacokinetic interactions were observed when EVG/c/FTC/TAF was used concomitantly with sofosbuvir or velpatasvir.1
Concomitant use of the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) with cobicistat-boosted elvitegravir or with tenofovir alafenamide did not have a clinically important effect on elvitegravir or tenofovir alafenamide concentrations.1
Sofosbuvir, Velpatasvir, and Voxilaprevir
Clinically important pharmacokinetic interactions are not expected if EVG/c/FTC/TAF is used concomitantly with the fixed combination of sofosbuvir/velpatasvir/voxilaprevir.1
HCV Replication Complex Inhibitors
Ledipasvir, Sofosbuvir, and Voxilaprevir
Concomitant use of the fixed combination of ledipasvir, sofosbuvir, and voxilaprevir (ledipasvir/sofosbuvir/voxilaprevir) with cobicistat-boosted elvitegravir or with tenofovir alafenamide does not have a clinically important effect on elvitegravir or tenofovir alafenamide concentrations.1
Clinically important pharmacokinetic interactions are not expected if EVG/c/FTC/TAF is used concomitantly with ledipasvir, sofosbuvir, or voxilaprevir.1
HMG-CoA Reductase Inhibitors
Concomitant use of certain hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) metabolized by CYP3A (e.g., atorvastatin, lovastatin, simvastatin) and EVG/c/FTC/TAF may increase plasma concentrations of the HMG-CoA reductase inhibitor resulting in increased effects and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.1
Atorvastatin
If atorvastatin is used concomitantly with EVG/c/FTC/TAF, the statin should be initiated at the lowest dosage and titrated carefully while monitoring for atorvastatin-associated adverse effects.1 Do not exceed a dosage of atorvastatin 20 mg daily with concomitant EVG/c/FTC/TAF therapy.1
Lovastatin
Concomitant use of lovastatin and EVG/c/FTC/TAF is contraindicated.1
Rosuvastatin
Pharmacokinetic interaction when rosuvastatin is used concomitantly with cobicistat-boosted elvitegravir (increased rosuvastatin plasma concentrations and AUC; no clinically important effect on elvitegravir pharmacokinetics).1
Simvastatin
Concomitant use of simvastatin and EVG/c/FTC/TAF is contraindicated.1
Immunosuppressive Agents
Cyclosporine
Potential pharmacokinetic interactions with cyclosporine (increased plasma concentrations of cyclosporine, elvitegravir, and cobicistat).1
If EVG/c/FTC/TAF is used concomitantly with cyclosporine, plasma concentrations of the immunosuppressive agent should be monitored and the patient monitored for adverse effects associated with EVG/c/FTC/TAF.1
Everolimus, Sirolimus, or Tacrolimus
Potential pharmacokinetic interactions with everolimus, sirolimus, or tacrolimus (increased plasma concentrations of the immunosuppressant agent).1
If EVG/c/FTC/TAF is used concomitantly with everolimus, sirolimus or tacrolimus, plasma concentrations of the immunosuppressive agent should be monitored.1
Lomitapide
Concomitant use of lomitapide and EVG/c/FTC/TAF is contraindicated due to the potential for marked increases in transaminase levels.1
Macrolides
Clarithromycin
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with clarithromycin (increased plasma concentrations of the macrolide and cobicistat).1
Modification of the usual dosage of clarithromycin is not necessary in those with creatinine clearances of 60 mL/minute or greater; however, clarithromycin dosage should be reduced by 50% in those with creatinine clearances of 50-60 mL/minute.1
Nucleoside and Nucleotide Antivirals
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with drugs that compete for active tubular secretion, including acyclovir, cidofovir, ganciclovir, valacyclovir, and valganciclovir; increased plasma concentrations of certain components of EVG/c/FTC/TAF (i.e., emtricitabine, tenofovir) or the concomitant drug may occur and increase the risk of adverse effects.1
Adefovir
EVG/c/FTC/TAF should not be used concomitantly with adefovir dipivoxil.1
Entecavir or Famciclovir
Clinically important interactions are not expected if EVG/c/FTC/TAF is used concomitantly with entecavir or famciclovir.1
Ribavirin
Clinically important interactions are not expected if EVG/c/FTC/TAF is used concomitantly with ribavirin.1
Opiate Agonists, Opiate Partial Agonists, and Opiate Antagonists
Buprenorphine
Concomitant use of the fixed combination of buprenorphine and naloxone (buprenorphine/naloxone) with cobicistat-boosted elvitegravir increased plasma concentrations and AUC of buprenorphine and norbuprenorphine and decreased peak plasma concentrations and AUC of naloxone.1
If buprenorphine/naloxone is used concomitantly with EVG/c/FTC/TAF, dosage adjustments are not necessary; however, patients should be monitored closely for sedation and adverse cognitive effects.1
Fentanyl
Potential pharmacokinetics interactions with fentanyl (increased fentanyl plasma concentrations.1 If fentanyl and EVG/c/FTC/TAF are used concomitantly, carefully monitor for therapeutic and adverse effects of fentanyl.1
Methadone
Concomitant use of methadone and cobicistat-boosted elvitegravir did not result in clinically important alterations in methadone pharmacokinetics.1
Concomitant use of methadone and EVG/c/FTC/TAF is not expected to result in clinically important drug interactions.1
Tramadol
Potential pharmacokinetics interactions with tramadol (increased tramadol plasma concentrations).1 A dose decrease of tramadol may be necessary if used concomitantly with EVG/c/FTC/TAF.1
Phosphodiesterase Type 5 Inhibitors
Concomitant use of EVG/c/FTC/TAF and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) is expected to result in increased plasma concentrations of the PDE5 inhibitor and increase the risk of adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) associated with these agents.1
Sildenafil
Concomitant use of EVG/c/FTC/TAF is contraindicated in patients receiving sildenafil for treatment of pulmonary arterial hypertension (PAH).1
If sildenafil is used for treatment of erectile dysfunction in a patient receiving EVG/c/FTC/TAF, sildenafil dosage should not exceed 25 mg once every 48 hours and the patient should be monitored for sildenafil-related adverse effects.1
Tadalafil
If tadalafil is used for treatment of PAH in a patient who has been receiving EVG/c/FTC/TAF for at least 1 week, tadalafil should be initiated at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1 EVG/c/FTC/TAF should not be initiated in patients receiving tadalafil for treatment of PAH; tadalafil should be discontinued for at least 24 hours prior to initiating EVG/c/FTC/TAF.1 After at least 1 week, tadalafil may be resumed at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1
If tadalafil is used for treatment of erectile dysfunction in a patient receiving EVG/c/FTC/TAF, tadalafil dosage should not exceed 10 mg once every 72 hours and the patient should be monitored for tadalafil-related adverse effects.1
Vardenafil
If vardenafil is used for treatment of erectile dysfunction in a patient receiving EVG/c/FTC/TAF, vardenafil dosage should not exceed 2.5 mg once every 72 hours and the patient should be monitored for vardenafil-related adverse effects.1
Salmeterol
Potential pharmacokinetic interaction with salmeterol (increased salmeterol plasma concentrations); may result in increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia.1
Concomitant use of salmeterol and EVG/c/FTC/TAF is not recommended.1
Selective Serotonin-reuptake Inhibitors (SSRIs)
Potential pharmacokinetic interaction with SSRIs (increased SSRI plasma concentrations).1 However, clinically important interactions are not expected if EVG/c/FTC/TAF is used concomitantly with sertraline.1
If an SSRI is used concomitantly with EVG/c/FTC/TAF, dosage of the SSRI should be carefully titrated and antidepressant response monitored.1
Trazodone
Potential pharmacokinetic interaction with trazodone (increased trazodone plasma concentrations).1
If trazodone is used concomitantly with EVG/c/FTC/TAF, dosage of trazodone should be carefully titrated and antidepressant response monitored.1
Tricyclic Antidepressants
Potential pharmacokinetic interactions if EVG/c/FTC/TAF is used concomitantly with tricyclic antidepressants, including amitriptyline, desipramine, doxepin, imipramine, and nortriptyline (increased tricyclic antidepressant plasma concentrations).1 Increased desipramine plasma concentrations and AUC reported when used concomitantly with cobicistat-boosted elvitegravir.1
If a tricyclic antidepressant is used concomitantly with EVG/c/FTC/TAF, the lowest initial dosage of the tricyclic antidepressant should be used and dosage of the antidepressant should be carefully titrated according to clinical response.1
Zolpidem
Possible pharmacokinetic interaction with zolpidem (increased zolpidem plasma concentrations).1
If zolpidem is used concomitantly with EVG/c/FTC/TAF, patients should be monitored clinically; reduced zolpidem dosage may be necessary.1
Dietary and Herbal Supplements
St. John's Wort
Potential pharmacokinetic interactions with St. John's wort ( Hypericum perforatum ) (decreased elvitegravir, cobicistat, and tenofovir alafenamide plasma concentrations); possible decreased antiretroviral efficacy and development of resistance.1
Concomitant use of St. John's wort and EVG/c/FTC/TAF is contraindicated.1
1. Gilead Sciences. Genvoya® (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) tablets prescribing information. Foster City, CA; 2022 Jan.
2. 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. [PubMed 25890673]
3. 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. [PubMed 26829661]
4. 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. [PubMed 26538525]
5. 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. [PubMed 26627107]
6. Callebaut C, Stepan G, Tian Y et al. In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate. Antimicrob Agents Chemother . 2015; 59:5909-16. [PubMed 26149992]
7. Ray AS, Fordyce MW, Hitchcock MJ. Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res . 2016; 125:63-70. [PubMed 26640223]
8. Birkus G, Wang R, Liu X et al. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother . 2007; 51:543-50. [PubMed 17145787]
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14. Mathias AA, German P, Murray BP et al. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther . 2010; 87:322-9. [PubMed 20043009]
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16. Garrido C, Villacian J, Zahonero N et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother . 2012; 56:2873-8. [PubMed 22450969]
18. Goethals O, Clayton R, Van Ginderen M et al. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol . 2008; 82:10366-74. [PubMed 18715920]
22. Malet I, Thierry E, Wirden M et al. Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance. J Antimicrob Chemother . 2015; 70:2870-80. [PubMed 26205139]
23. Malet I, Gimferrer Arriaga L, Artese A et al. New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors. J Antimicrob Chemother . 2014; 69:2118-22. [PubMed 24710029]
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