Elvitegravir (EVG), Cobicistat (COBI), Emtricitabine (FTC), and Tenofovir Disoproxil Fumarate (TDF) (Stribild)


Stribild

Indication: Combination elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) (Stribild) is indicated for treatment of human immunodeficiency virus type 1 (HIV-1) in treatment-naïve adult patients.1

Pharmacology: EVG/COBI/FTC/TDF is a combination drug consisting of an integrase strand transfer inhibitor (INSTI), a CYP3A4 inhibitor, and 2 nucleoside reverse transcriptase inhibitors (NRTIs). EVG is an INSTI that works through inhibiting HIV-1 DNA integration into host DNA by stopping HIV-1 provirus formation and viral propagation. COBI is a selective CYP450 and CYP3A inhibitor enhancing the exposure of EVG, a CYP3A4 substrate, thus “boosting” its effects. FTC and TDF are both NRTIs, which inhibit viral replication through inhibition of HIV reverse transcriptase activity.1

Clinical Trials: The EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg combination received approval based on 48-week data from 2 pivotal phase 3, randomized, double-blind, multicenter trials of treatment-naïve HIV-1 patients. The first trial of 708 patients was initiated in an effort to assess EVG/COBI/FTC/TDF treatment noninferiority vs a ritonavir (RTV)-boosted regimen of atazanavir (ATV) plus FTC/TDF. DeJesus and colleagues found comparable viral suppression among the EVG/COBI/FTC/TDF-treated patients (316; 89.5%) compared with the RTV/ATV+FTC/TDF (308; 86.8%) group. Both regimens had favorable safety and tolerability; 13 (3.7%) vs 18 (5.1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 μmol/L vs 260 μmol/L, P=0.006).2

In the second trial, 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF; 352 with efavirenz (EFV) 600 mg/FTC 200 mg/TDF 200 mg). The results showed that EVG/COBI/FTC/TDF was noninferior to EFV/FTC/TDF; 305/348 (87.6%) vs 296/352 (84.1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3.6%, 95% CI -1.6% to 8.8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Moreover, CD4 counts were also higher among the EVG/COBI/FTC/TDF group (239 cells/μL) compared to the EFV/FTC/TDF group (206 cells/μL). Severe abnormal dreams were also noted as less frequent in the EVG/COBI/FTC/TDF group (1%) when compared to the EFV/FTC/TDF group (4%).3

Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, -6 to 8; P<.001). 3

Warnings/Precautions: All HIV-1-positive patients should be tested for the hepatitis B virus (HBV) before starting EVG/COBI/FTC/TDF, as reports of severe acute HBV exacerbations have been reported in patients who have discontinued FTC/TDF therapy. As per the FDA Black Box warning, “[this new combination] is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.”1 Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF, in combination with other antiretroviral (ARV) agents. Therefore, patients taking EVG/COBI/FTC/TDF should have their renal function strictly monitored. EVG/COBI/FTC/TDF use is not recommended in patients with a CrCl <70 mL/minute. Closely monitor patients with an increase of >0.4 mg/mL in SCr.1

EVG/COBI/FTC/TDF is intended to be a complete regimen and should not be coadministered with other ARVs, or combination agents containing FTC/TDF. TDF use has been associated with decreases in bone mineral density (BMD).1 Patients taking EVG/COBI/FTC/TDF should have their BMD assessed, as well as their history of bone fracture and risk profile for osteoporosis prior to initiating EVG/COBI/FTC/TDF. Patients taking EVG/COBI/FTC/TDF may also be susceptible to fat redistribution such as buffalo hump, or cushingoid appearance.1

Immune reconstitution inflammatory syndrome (IRIS) has been observed in the initial and later stages of therapy in patients taking combination ARV regimens. Observed in the initial stages is an inflammatory response as a result of residual opportunistic infections, where as in the later stages of therapy autoimmune disorders begin to develop.1

EVG/COBI/FTC/TDF is a pregnancy category B drug. The Centers for Disease Control and Prevention (CDC) strongly recommends that HIV-infected mothers NOT breastfeed their infants, as it increases risk of postnatal HIV transmission. Samples of breast milk from HIV-1 infected mothers have shown TDF and FTC to be excreted in breast milk. Breastfed infants with mothers taking FTC have been shown to be at risk for developing viral resistance to FTC. Similar risks for breastfed infants with mothers taking TDF are unknown at this time. Due to potential HIV transmission and medication-associated risks, practitioners should instruct mothers to NOT breastfeed if they are taking EVG/COBI/FTC/TDF.1 Health care providers should encourage pregnant women taking ARV medications to enroll in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263, or on the web through www.APRegistry.com.1 Health care providers with questions regarding the treatment of pregnant HIV-infected women can call the National Perinatal HIV Hotline at 1-888-448-8765.4    

Adverse Reactions: The most common adverse effects associated with EVG/COBI/FTC/TDF are: proteinuria (39%); diarrhea (12%); nausea (16%); and abnormal dreams (9%). While rare (<1%), renal impairment or failure, as well as Fanconi syndrome, IRIS, and decreased BMD have been observed in patients taking EVG/COBI/FTC/TDF.1

Drug Interactions: EVG/COBI/FTC/TDF is a CYP2D6, CYP3A4, and P-gp inhibitor, as well as a mild CYP2C9 inducer. Therefore, concomitant use with CYP2D6, CYP3A4, and P-gp substrates should be avoided. This includes drugs such as apixaban, alfuzosin, conivaptan, simvastatin, and St. John’s Wort.1

The EVG and COBI components of EVG/COBI/FTC/TDF are metabolized by CYP3A4. Coadministration of EVG/COBI/FTC/TDF with CYP3A4 inducers can potentially lower EVG and COBI plasma levels, leading to therapeutic failure. Coadministration of EVG/COBI/FTC/TDF with rifabutin, rifapentine is contraindicated. Concomitant use of EVG/COBI/FTC/TDF with carbamazepine, phenytoin, oxcarbazepine, phenobarbital, dexamethasone warrants strict monitoring for any changes in EVG/COBI/FTC/TDF therapeutic effect and the possibility of alternate steroid or anticonvulsant therapy.1

The TDF and FTC components of EVG/COBI/FTC/TDF are excreted through active renal tubular secretion and glomerular filtration. As such, concomitant use of EVG/COBI/FTC/TDF with drugs that compete for active tubular secretion or are nephrotoxic, such as acyclovir, valacyclovir, or ganciclovir should be avoided. Continued use of EVG/COBI/FTC/TDF is not recommended in patients with a CrCl of <50 mL/minute.1 

As EVG/COBI/FTC/TDF is intended to be a complete regimen for HIV-1 naïve patients, concomitant use with other ARVs, especially other protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is contraindicated, as they can interfere with the pharmacokinetics of Stribild.1

Coadministration of antacids and EVG/COBI/FTC/TDF is contraindicated as plasma concentrations of EVG/COBI/FTC/TDF have been found to be lower when coadministered with antacids. Patients should separate administration of antacids and EVG/COBI/FTC/TDF by 2 hours.1

Dosage and Administration: EVG/COBI/FTC/TDF is taken orally once a day with food.1


References

  1. Stribild [package insert]. Foster City, CA: Gilead Sciences Inc; 2012. http://www.gilead.com/pdf/stribild_pi.pdf. Accessed April 10, 2013.
  2. DeJesus E, Rockstroh JK, Henry K, et al. 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):2429-2438.
  3. Sax PE, DeJesus E, Mills A, et al. 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):2439-2448.
  4. National HIV/AIDS Clinicians’ Consultation Center. Perinatal Hotline. http://www.nccc.ucsf.edu/about_nccc/perinatal_hotline/. Accessed April 2, 2013.


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