ELVITEGRAVIR, COBICISTAT, EMTRICITABINE AND TENOFOVIR ALAFENAMIDE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Elvitegravir is an HIV-1 integrase strand transfer inhibitor, blocking viral DNA integration. Cobicistat is a CYP3A inhibitor boosting elvitegravir exposure. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI). Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) that, after conversion to tenofovir, inhibits HIV reverse transcriptase.
| Metabolism | Elvitegravir: CYP3A (primary), glucuronidation (UGT1A1/3). Cobicistat: CYP3A (metabolized), CYP2D6 (minor). Emtricitabine: largely unchanged renal excretion; minimal hepatic metabolism via oxidation and glucuronidation. Tenofovir alafenamide: hydrolyzed to tenofovir by cathepsin A and CES1; tenofovir is renally excreted. |
| Excretion | Elvitegravir: 94% fecal, 6.7% renal; Cobicistat: 86% fecal, 8% renal; Emtricitabine: 86% renal (unchanged); Tenofovir alafenamide: 31% renal (as tenofovir), 46% fecal (as tenofovir alafenamide). |
| Half-life | Elvitegravir: 12.9 h; Cobicistat: 3.5 h; Emtricitabine: 10 h; Tenofovir alafenamide: 0.51 h (active metabolite tenofovir has half-life of 12-18 h). All half-lives are terminal elimination half-lives; once-daily dosing is supported by boosted pharmacokinetics. |
| Protein binding | Elvitegravir: ~99% bound to albumin and alpha-1 acid glycoprotein; Cobicistat: ~97-98% bound to albumin; Emtricitabine: <4% bound; Tenofovir alafenamide: ~80% bound to plasma proteins. |
| Volume of Distribution | Elvitegravir: 0.27 L/kg; Cobicistat: 0.16 L/kg; Emtricitabine: 0.57 L/kg; Tenofovir alafenamide: 0.24 L/kg. These values indicate distribution primarily into total body water with some tissue binding. |
| Bioavailability | Oral: Elvitegravir: ~10% (increased to 85-90% with cobicistat boosting); Cobicistat: ~65%; Emtricitabine: 93%; Tenofovir alafenamide: ~20% (higher with food). |
| Onset of Action | Oral: Antiviral effect begins within 2-4 weeks of therapy with maximal suppression typically by 24 weeks. |
| Duration of Action | Oral: 24 hours (once-daily dosing) due to boosted pharmacokinetics; missed dose should be taken as soon as possible if within 12 hours of scheduled time. |
| Molecular Weight | Elvitegravir: 447.9 Da; Cobicistat: 776.0 Da; Emtricitabine: 247.2 Da; Tenofovir alafenamide: 476.5 Da |
One tablet (150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, 10 mg tenofovir alafenamide) orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | Not recommended for patients with CrCl < 30 mL/min. No dose adjustment for CrCl ≥ 30 mL/min. For patients with CrCl 15-29 mL/min, use emtricitabine/tenofovir alafenamide-containing regimen only if alternative not available, with reduced dose of emtricitabine/tenofovir alafenamide (consider separate components). |
| Liver impairment | No dose adjustment for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Not recommended for severe hepatic impairment (Child-Pugh C). |
| Pediatric use | For patients weighing ≥ 35 kg: one tablet (same strength) once daily with food. Not recommended for patients weighing < 35 kg. |
| Geriatric use | No specific dose adjustment required; however, monitor renal function due to age-related decline and potential for decreased CrCl. |
| 1st trimester | Contraindicated due to risk of fetal nephrotoxicity and bone toxicity; alternative regimens recommended. |
| 2nd trimester | Use only if benefit outweighs risk; limited data suggest potential for renal and bone adverse effects in fetus. |
| 3rd trimester | Use only if benefit outweighs risk; potential for neonatal nephrotoxicity and bone toxicity post-exposure. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer | Elvitegravir and cobicistat: limited placental transfer; emtricitabine: extensive placental transfer; tenofovir alafenamide: limited placental transfer but active metabolite tenofovir crosses placenta. |
■ FDA Black Box Warning
Post-treatment acute exacerbation of hepatitis B (HBV) in patients co-infected with HIV-1 and HBV who discontinue products containing emtricitabine and/or tenofovir disoproxil fumarate. Cases of fatal renal impairment have been reported with tenofovir-containing products; tenofovir alafenamide has lower renal risk but caution advised.
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to any componentConcomitant use with drugs highly dependent on CYP3A for clearance (e.g., alfuzosin, rifampin, St. John's wort, etc.)Severe hepatic impairment (Child-Pugh C)
| Precautions | Hepatotoxicity: monitor liver enzymes especially in HBV co-infection., Renal impairment: assess CrCl before and during therapy; not recommended if CrCl <30 mL/min., Lactic acidosis/severe hepatomegaly with steatosis: reported with NRTIs., Bone mineral density decreases: monitor if history of fracture or osteoporosis., Immune reconstitution syndrome: may occur with combination therapy., Drug interactions: cobicistat is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates or drugs with narrow therapeutic index. |
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| Breastfeeding |
| Emtricitabine and tenofovir alafenamide are excreted in human milk; cobicistat and elvitegravir are expected to be excreted. Risk of viral resistance and adverse effects in infants. Alternative antiretroviral regimens preferred. |
| Lactation Rating | Avoid |
| Teratogenic Risk | Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (TAF) is classified as FDA Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. In animal studies, no evidence of teratogenicity was observed with elvitegravir, cobicistat, emtricitabine, or TAF. However, tenofovir disoproxil fumarate (TDF) has been associated with reduced fetal growth and bone effects; TAF results in lower tenofovir exposure. The Antiretroviral Pregnancy Registry monitors outcomes. First trimester: risk cannot be ruled out; use only if benefit outweighs risk. Second and third trimesters: no increased risk of major malformations reported in registry data. There is a potential for lactic acidosis and hepatic steatosis in pregnant women receiving nucleoside analogues. |
| Fetal Monitoring | Monitor maternal HIV RNA, CD4 count, liver function tests, renal function (serum creatinine, estimated creatinine clearance, urine glucose and protein) at baseline and periodically during pregnancy. Assess fetal growth and development via ultrasound. Monitor for lactic acidosis and hepatotoxicity. Check for anemia (due to emtricitabine). |
| Fertility Effects | No known significant effects on fertility. Animal studies with elvitegravir, cobicistat, emtricitabine, and TAF showed no impairment of fertility. No human data on fertility impact. |
| Food/Dietary | Take with food to increase elvitegravir and tenofovir alafenamide absorption. Avoid grapefruit juice as it may affect drug metabolism. No other specific food restrictions. |
| Clinical Pearls | ELVITEGRAVIR/COBICISTAT/EMTRICITABINE/TENOFOVIR ALAFENAMIDE (EVG/COBI/FTC/TAF) is a fixed-dose combination for HIV-1 treatment. Dose adjustment required for CrCl 30-59 mL/min; contraindicated if CrCl <30 mL/min. Cobicistat boosts elvitegravir levels but also inhibits CYP3A4 and transporters, risking interactions with drugs like simvastatin, lovastatin, and sildenafil. Monitor renal function, urine glucose, and bone density due to TAF. Avoid with rifampin, St. John's wort, and antacids (separate by 2 hours). |
| Patient Advice | Take one tablet daily with food to improve absorption. · Do not miss doses; adherence critical to prevent resistance. · Report symptoms of kidney injury (decreased urination, swelling) or bone pain. · Avoid taking with antacids; separate by at least 2 hours. · Do not use St. John's wort or rifampin while on this medication. · Inform all healthcare providers about HIV medications to avoid interactions. · Use effective contraception; discuss pregnancy plans with doctor. |