EFAVIRENZ, 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.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds directly and reversibly to the reverse transcriptase enzyme, causing a conformation change and inhibiting RNA-dependent and DNA-dependent DNA polymerase activity. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) that is phosphorylated to its active triphosphate form, which competes with deoxycytidine triphosphate and incorporates into viral DNA, causing chain termination. Tenofovir alafenamide is a prodrug of tenofovir, an NRTI; it is taken up by hepatocytes and activated to tenofovir diphosphate, which inhibits reverse transcriptase by competing with deoxyadenosine triphosphate and causing DNA chain termination.
| Metabolism | Efavirenz is metabolized primarily by cytochrome P450 (CYP) 2B6, with minor contributions from CYP3A4 and CYP2A6. Emtricitabine is not extensively metabolized; it undergoes phosphorylation intracellularly. Tenofovir alafenamide is metabolized by cathepsin A (CatA) and carboxylesterase 1 (CES1) to its active metabolite tenofovir; it is also minimally metabolized by CYP3A4. |
| Excretion | Efavirenz: 14-34% renal (as unchanged drug <1%), 16-61% fecal (as parent drug/metabolites). Emtricitabine: ~86% renal (as unchanged drug). Tenofovir alafenamide: <1% renal (as unchanged drug), ~31.5% fecal (as parent drug), remainder as tenofovir (metabolite) which undergoes renal filtration and active tubular secretion. |
| Half-life | Efavirenz: 52-76 h (single dose), 40-55 h (multiple doses). Emtricitabine: ~10 h. Tenofovir alafenamide: 0.51 h (parent drug), 32.4 h (tenofovir, terminal half-life). |
| Protein binding | Efavirenz: >99% (primarily albumin). Emtricitabine: <4%. Tenofovir alafenamide: ~80% (to plasma proteins). |
| Volume of Distribution | Efavirenz: 252 L (approximately 3.6 L/kg for 70 kg). Emtricitabine: 1.3 L/kg. Tenofovir alafenamide: 0.13 L/kg (parent drug); tenofovir: 0.6 L/kg. |
| Bioavailability | Oral: Efavirenz ~45% (under fed conditions). Emtricitabine: ~93% (fasting). Tenofovir alafenamide: ~25% (fasting), ~40% (with light meal); high-fat meal increases exposure. |
| Onset of Action | Oral: Efavirenz achieves maximal antiviral effect within 1-2 weeks; Emtricitabine and Tenofovir alafenamide begin inhibition within hours of first dose, with clinical benefit reducing viral load within 2-4 weeks. |
| Duration of Action | Oral: Efavirenz duration ~24 h (once-daily dosing). Emtricitabine ~24 h. Tenofovir alafenamide ~24 h. Missing doses may allow viral rebound; adherence critical. |
One tablet (600 mg efavirenz/200 mg emtricitabine/25 mg tenofovir alafenamide) orally once daily on an empty stomach, preferably at bedtime.
| Dosage form | TABLET |
| Renal impairment | Not recommended in patients with estimated creatinine clearance (CrCl) <30 mL/min. No dose adjustment required for CrCl ≥30 mL/min. |
| Liver impairment | Contraindicated in patients with Child-Pugh Class C hepatic impairment. Use with caution in Child-Pugh Class A or B; no specific dose adjustment available; clinical monitoring recommended. |
| Pediatric use | Approved for pediatric patients weighing ≥35 kg: one tablet (600 mg efavirenz/200 mg emtricitabine/25 mg tenofovir alafenamide) orally once daily on an empty stomach. For weight <35 kg, alternative formulations are recommended. |
| Geriatric use | No specific dose adjustment required. Use standard adult dosing. Monitor renal function (CrCl) due to age-related decline, and consider risk of CNS effects (efavirenz) and bone toxicity (tenofovir alafenamide). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Breastfeeding | Efavirenz is excreted into human breast milk in low concentrations; the estimated infant dose is approximately 0.8–1.0% of the maternal weight-adjusted dose. Emtricitabine is extensively excreted into breast milk; the M/P ratio is approximately 0.8–1.0. Tenofovir alafenamide is excreted in low amounts; the M/P ratio is not well established but likely low due to rapid hydrolysis to tenofovir. The combination is generally not recommended during breastfeeding due to potential for toxicity in the infant; alternative agents with a better safety profile are preferred. |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (but not specifically tenofovir alafenamide; however, tenofovir alafenamide is a tenofovir prodrug). Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
| Common Effects | Hepatitis B |
| Serious Effects |
["Hypersensitivity to any component","Co-administration with drugs that are CYP2B6 or CYP3A4 inducers that may reduce efavirenz efficacy","Co-administration with drugs that are sensitive CYP3A4 substrates or CYP2B6 substrates leading to toxicity (e.g., cisapride, midazolam, triazolam, ergot derivatives, pimozide, voriconazole; specific list varies)","Patients with severe hepatic impairment (Child-Pugh Class C)"]
| Precautions | ["Risk of hepatotoxicity and exacerbation of hepatitis B upon discontinuation","Severe psychiatric adverse reactions (e.g., depression, suicidal ideation) with efavirenz","Nervous system symptoms (e.g., dizziness, insomnia) common with efavirenz","Renal impairment: monitor renal function; tenofovir alafenamide is not recommended in severe renal impairment (CrCl <15 mL/min)","Decreased bone mineral density observed with tenofovir-containing regimens","Immune reconstitution syndrome","Lactic acidosis and severe hepatomegaly with steatosis (with NRTIs)"] |
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| Teratogenic Risk | Efavirenz is contraindicated in the first trimester due to significant risk of neural tube defects and other CNS malformations; data from the Antiretroviral Pregnancy Registry show increased incidence of defects with first-trimester exposure. Emtricitabine and tenofovir alafenamide (TAF) have not been associated with increased risk of major birth defects based on registry data, though data are limited for TAF. For the combination, first-trimester efavirenz exposure should be avoided; alternative regimens are recommended. In second and third trimesters, efavirenz risk is less defined but generally considered lower; however, avoidance throughout pregnancy is preferred. |
| Fetal Monitoring | Monitor liver function tests (LFTs), renal function, serum creatinine, estimated creatinine clearance, urine glucose and protein, and complete blood count (CBC) monthly during pregnancy. Perform HIV viral load at baseline, monthly until suppressed, then every 2–3 months; monitor CD4 count every 3–6 months. Fetal ultrasound at 18–20 weeks to assess for neural tube defects if efavirenz exposure occurred in the first trimester. Monitor for maternal adverse effects such as central nervous system symptoms, rash, and hepatotoxicity. |
| Fertility Effects | In animal studies, efavirenz has been associated with impaired fertility at high doses; human data are limited but no significant adverse effects on fertility have been reported. Emtricitabine and tenofovir alafenamide have shown no significant effects on fertility in animal studies. Overall, the combination is not expected to cause major fertility impairment in humans, but the underlying HIV infection may affect fertility. |