EFAVIRENZ, LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
EFAVIRENZ: Non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to HIV-1 reverse transcriptase, causing allosteric inhibition and blocking RNA-dependent DNA polymerase activity. LAMIVUDINE: Nucleoside reverse transcriptase inhibitor (NRTI) that is phosphorylated to its active triphosphate metabolite, which competes with endogenous deoxycytidine triphosphate for incorporation into viral DNA, causing chain termination. TENOFOVIR DISOPROXIL FUMARATE: Prodrug of tenofovir, an NRTI that, after hydrolysis and phosphorylation, inhibits HIV-1 reverse transcriptase by competing with deoxyadenosine triphosphate and causing DNA chain termination.
| Metabolism | EFAVIRENZ: Primarily metabolized by CYP2B6 and CYP3A4 to inactive hydroxylated metabolites. LAMIVUDINE: Minimally metabolized; intracellularly phosphorylated to active triphosphate. TENOFOVIR DISOPROXIL FUMARATE: Rapidly converted to tenofovir via esterases in plasma, then to tenofovir diphosphate intracellularly. Tenofovir is renally excreted by glomerular filtration and active tubular secretion. |
| Excretion | Efavirenz: 14-34% renal (mostly metabolites), 16-61% fecal (parent drug and metabolites). Lamivudine: ~70% renal (unchanged via active tubular secretion). Tenofovir disoproxil fumarate: 70-80% renal (unchanged as tenofovir via glomerular filtration and active secretion). |
| Half-life | Efavirenz: 40-55 h (single dose), 50-76 h (multiple doses). Lamivudine: 5-7 h (adults). Tenofovir: 17 h (single dose), 12-17 h (multiple doses) in cells up to 48-60 h. Clinical context: Efavirenz's long half-life allows once-daily dosing; tenofovir's long intracellular half-life supports once-daily dosing. |
| Protein binding | Efavirenz: 99.5-99.8% (primarily albumin). Lamivudine: <36% (minimal). Tenofovir: <7% (minimal). |
| Volume of Distribution | Efavirenz: 2.3-4.0 L/kg (extensive tissue distribution). Lamivudine: 1.3 L/kg (total body water). Tenofovir: 1.2-1.3 L/kg (extracellular fluid). |
| Bioavailability | Oral: Efavirenz: ~40-45% (with food increases). Lamivudine: ~86-88% (no food effect). Tenofovir disoproxil fumarate: ~25-30% (fasting), increased with high-fat meal (bioequivalent to 300 mg tenofovir disoproxil fumarate). |
| Onset of Action | Oral: Efavirenz: 1-2 weeks for maximal viral suppression (plasma levels steady by ~1 week). Lamivudine: 1-2 weeks for clinical effect. Tenofovir: 1-2 weeks for clinical effect. |
| Duration of Action | Oral: Efavirenz: 24 hours (once-daily dosing). Lamivudine: 12-24 hours (once-daily dosing). Tenofovir: 24 hours (once-daily dosing). Clinical notes: Long half-lives and intracellular persistence allow once-daily fixed-dose combination. |
| Molecular Weight | Efavirenz: 315.68 Da; Lamivudine: 229.26 Da; Tenofovir disoproxil fumarate: 635.52 Da (as TDF). |
One tablet (efavirenz 600 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg) orally once daily on an empty stomach, preferably at bedtime.
| Dosage form | TABLET |
| Renal impairment | Not recommended if CrCl < 50 mL/min. For CrCl 50-80 mL/min: no adjustment required. For CrCl < 50 mL/min: use separate components with dose adjustments. Avoid if CrCl < 30 mL/min, or if on hemodialysis. |
| Liver impairment | Contraindicated in Child-Pugh Class C. For Child-Pugh Class B: reduce efavirenz dose to 400 mg once daily (use separate components). |
| Pediatric use | Approved for children ≥3 years and ≥40 kg: same as adult dose. For weight <40 kg: use individual components with weight-based dosing (efavirenz: 15-20 mg/kg once daily; lamivudine: 4 mg/kg twice daily; tenofovir: 8 mg/kg once daily). |
| Geriatric use | No specific dose adjustment, but monitor renal function (CrCl) and consider increased risk of CNS effects from efavirenz. Use with caution due to age-related renal decline. |
| 1st trimester | Avoid unless benefit outweighs risk; neural tube defects reported with efavirenz in first trimester; use only if no alternative and with effective contraception. |
| 2nd trimester | Use if clearly needed; monitor for hepatotoxicity and lactic acidosis; tenofovir may cause bone and renal issues. |
| 3rd trimester | Use if clearly needed; monitor for neonatal lactic acidosis; tenofovir may affect fetal bone growth. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer | All three components cross the placenta. Lamivudine and tenofovir exhibit significant transfer; efavirenz also crosses with cord blood concentrations about 50% of maternal. |
■ FDA Black Box Warning
WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B: Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued lamivudine or tenofovir disoproxil fumarate. 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 componentConcurrent use with rilpivirineSevere hepatic impairment (Child-Pugh C) for efavirenzCreatinine clearance <50 mL/min (tenofovir disoproxil fumarate contraindicated)
| Precautions | Acute exacerbation of hepatitis B upon discontinuation in HIV/HBV coinfected patients., Hepatotoxicity, including hepatic steatosis and exacerbation of hepatitis C., Renal impairment: monitor creatinine clearance, avoid with creatinine clearance <50 mL/min., Bone effects: decreased bone mineral density, risk of fractures., Lipodystrophy and metabolic effects: redistribution/accumulation of body fat, hyperlipidemia., Immune reconstitution syndrome., Central nervous system symptoms (e.g., dizziness, insomnia, impaired concentration) with efavirenz., Rash, including Stevens-Johnson syndrome., QTc prolongation with efavirenz at supratherapeutic doses, avoid with drugs that prolong QTc. |
Loading safety data…
| Breastfeeding |
| Efavirenz, lamivudine, and tenofovir are excreted into breast milk in low to moderate amounts. The WHO recommends avoiding breastfeeding if replacement feeding is acceptable, feasible, affordable, sustainable, and safe, especially when maternal HIV viral load is not fully suppressed. |
| Lactation Rating | L3 (Moderately Safe) - limited data; benefits likely outweigh risks if mother requires therapy and infant HIV infection risk low. |
| Teratogenic Risk | First trimester: Increased risk of neural tube defects with efavirenz; contraindicated in first trimester. Second and third trimesters: Limited data; potential for hepatotoxicity and mitochondrial toxicity; lamivudine and tenofovir disoproxil fumarate are generally considered lower risk. Overall, avoid efavirenz in pregnancy; use alternative antiretroviral regimen. |
| Fetal Monitoring | Maternal: Liver function tests (baseline and periodic), renal function (serum creatinine), complete blood count, viral load, HIV genotype before therapy. Fetal: Ultrasound for neural tube defects (first trimester if efavirenz exposure), growth monitoring. Consider therapeutic drug monitoring for efavirenz. |
| Fertility Effects | No significant adverse effects on fertility reported for lamivudine or tenofovir. Efavirenz may cause hormonal contraceptive failure (decreased ethinyl estradiol levels); use barrier or alternative contraception. No specific impairment of male or female fertility in animal studies. |
| Food/Dietary | Take on an empty stomach (at least 1 hour before or 2 hours after a meal) to reduce efavirenz-related central nervous system effects. Grapefruit juice may increase efavirenz levels; avoid concurrent consumption. |
| Clinical Pearls | Monitor renal function (serum creatinine, estimated creatinine clearance, urine glucose and protein) before and during therapy; tenofovir can cause nephrotoxicity. Assess liver function and hepatitis B status before initiation; lamivudine and tenofovir are active against HBV, and discontinuation may cause severe HBV exacerbation. Use with caution in patients with psychiatric history; efavirenz may cause CNS symptoms (e.g., dizziness, insomnia, abnormal dreams) that are more common at higher doses and often improve within 2 weeks. Administer on an empty stomach to reduce efavirenz-related CNS effects. Avoid concurrent use with drugs that are substrates of CYP2B6 or CYP3A4 due to enzyme induction. Pregnancy category D; avoid in first trimester due to risk of neural tube defects. |
| Patient Advice | Take this medication once daily on an empty stomach, preferably at bedtime to minimize CNS effects like dizziness and abnormal dreams. · Do not stop taking this medicine without consulting your doctor; stopping can cause your HIV to become resistant or worsen hepatitis B infection. · Report any signs of kidney problems: decreased urination, swelling in legs/ankles, or foamy urine. · Use effective contraception during treatment and for 12 weeks after stopping, as efavirenz can harm an unborn baby. · Avoid alcohol and other drugs that cause drowsiness, as efavirenz may enhance these effects. · This medicine does not cure HIV or prevent transmission; practice safe sex and avoid sharing needles. · Common side effects include dizziness, trouble sleeping, rash, and diarrhea; contact your doctor if severe or persistent. |