Clinical safety rating: safe
Animal studies have demonstrated safety
Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor that inhibits HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and by incorporation into DNA causing chain termination. Lamivudine is a nucleoside reverse transcriptase inhibitor that inhibits HIV-1 reverse transcriptase via incorporation into viral DNA. Efavirenz is a non-nucleoside reverse transcriptase inhibitor that binds reversibly to HIV-1 reverse transcriptase at a non-substrate binding site, causing conformational change and enzyme inhibition.
| Metabolism | Tenofovir undergoes minimal metabolism; efavirenz is primarily metabolized by CYP2B6 and CYP3A4; lamivudine is metabolized intracellularly to its active triphosphate metabolite and undergoes limited hepatic metabolism. |
| Excretion | Tenofovir: 70-80% renal (glomerular filtration and tubular secretion); Lamivudine: 70% renal (glomerular filtration and tubular secretion); Efavirenz: 14-34% renal, 16-61% fecal (as unchanged drug and metabolites). |
| Half-life | Tenofovir: 17 hours (prolonged in renal impairment); Lamivudine: 5-7 hours (intracellular triphosphate 17-19 hours); Efavirenz: 52-76 hours (single dose), 40-55 hours (multiple doses). |
| Protein binding | Tenofovir: <7% bound to serum proteins; Lamivudine: <36% bound to serum proteins; Efavirenz: 99.5-99.75% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Tenofovir: 1.2-1.3 L/kg (distributes widely, including kidneys and lymph nodes); Lamivudine: 1.3 L/kg (distributes into cerebrospinal fluid); Efavirenz: 2.5-4.0 L/kg (extensive tissue binding, accumulates in adipose and brain). |
| Bioavailability | Tenofovir: 25% (oral) with high-fat meal; Lamivudine: 86% (oral, no food effect); Efavirenz: 50% (oral) with high-fat meal (increases absorption). |
| Onset of Action | Tenofovir: 4-7 days to maximal antiviral effect; Lamivudine: 1-2 weeks to clinical response; Efavirenz: 1-2 weeks to steady-state antiviral effect. |
| Duration of Action | Tenofovir: 24 hours (once-daily dosing); Lamivudine: 24 hours (once-daily dosing); Efavirenz: 24 hours (once-daily dosing, with long half-life allowing sustained suppression). |
| Molecular Weight | Tenofovir disoproxil fumarate: 635.52 g/mol; Lamivudine: 229.26 g/mol; Efavirenz: 315.67 g/mol |
One tablet (300 mg tenofovir disoproxil fumarate, 300 mg lamivudine, 600 mg efavirenz) orally once daily on an empty stomach, preferably at bedtime.
| Renal impairment | Not recommended for patients with creatinine clearance (CrCl) < 50 mL/min. For CrCl 50-80 mL/min: standard dose; CrCl 30-49 mL/min: no data, avoid; CrCl <30 mL/min or hemodialysis: contraindicated because tenofovir and lamivudine require dose reduction per component. |
| Liver impairment | Contraindicated in Child-Pugh Class B or C (moderate or severe hepatic impairment) due to efavirenz component. For Child-Pugh Class A (mild): use with caution; monitor for hepatotoxicity. |
| Pediatric use | Not recommended for pediatric patients due to lack of data for the fixed-dose combination. For children weighing ≥35 kg who can swallow tablets, individual components may be used with weight-based dosing: efavirenz 600 mg once daily (for ≥40 kg or age ≥12 years), lamivudine 300 mg once daily (for ≥30 kg), tenofovir 300 mg once daily (for ≥35 kg). Below these weights, alternative formulations or agents are required. |
| Geriatric use | No specific dose adjustment; use with caution due to age-related decline in renal function. Monitor creatinine clearance and adjust tenofovir and lamivudine per renal function as per individual components. |
| 1st trimester | Based on animal studies and limited human data, there is an increased risk of neural tube defects with efavirenz exposure during first trimester; use is not recommended unless benefit outweighs risk. |
| 2nd trimester | Data limited; monitor fetal growth and maternal viral load; generally considered acceptable if maternal benefit justifies potential risk. |
| 3rd trimester | Use with caution; tenofovir and lamivudine are generally considered safe; efavirenz may cause neonatal CNS depression; monitor for adverse effects. |
Clinical note
Standard first-line ART for HIV-positive pregnant women per WHO 2021 guidelines. Tenofovir disoproxil fumarate (TDF) + lamivudine (3TC) + efavirenz (EFV) as a fixed-dose combination. Efavirenz was historically avoided in T1 due to neural tube defect risk in animal studies; large human registry data (>2,000 T1 exposures) have not confirmed this risk in humans. WHO and UNAIDS now endorse EFV-based regimens throughout pregnancy. Starting or continuing ART is critical to prevent mother-to-child transmission (MTCT) of HIV — benefits far outweigh any theoretical risks.
| Placental transfer | All three components cross the placenta: efavirenz (high, ~49% of maternal concentration), lamivudine (moderate, ~70-90%), tenofovir (moderate, ~60-70%). |
■ FDA Black Box Warning
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B
| Serious Effects |
Hypersensitivity to any componentConcurrent use with voriconazole or boceprevirSevere hepatic impairment (Child-Pugh C)Pregnancy (first trimester) with efavirenz
| Precautions | Lactic acidosis and severe hepatomegaly with steatosis; exacerbation of hepatitis B upon discontinuation; hepatotoxicity; renal impairment; decreased bone mineral density; immune reconstitution syndrome; fat redistribution; CNS effects including depression, dizziness, and suicide risk; rash; seizure risk; drug interactions. |
| Food/Dietary | Administer on an empty stomach (at least 1 hour before or 2 hours after food) to optimize efavirenz absorption and reduce variability. Avoid high-fat meals as they increase efavirenz absorption and exacerbate CNS side effects. No significant interactions with food for tenofovir or lamivudine. |
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| Breastfeeding | Mothers should not breastfeed while taking efavirenz due to potential adverse effects in infant; tenofovir and lamivudine are excreted in breast milk; risk of HIV transmission outweighs benefits. |
| Lactation Rating | L5 - Avoid |
| Teratogenic Risk | Efavirenz is contraindicated in the first trimester due to significant risk of neural tube defects and other CNS malformations. Lamivudine and tenofovir are generally considered low risk but limited data. Overall, avoid in pregnancy unless no alternative. |
| Fetal Monitoring | Monitor maternal liver function, renal function (creatinine, BUN), CBC, and viral load. Fetal ultrasound for neural tube defects if exposed in first trimester. Monitor for maternal bone mineral density loss (tenofovir). |
| Fertility Effects | No known significant impact on fertility. Efavirenz may cause false positive urine cannabinoid tests. |
| Clinical Pearls | Efavirenz causes CNS side effects (dizziness, vivid dreams) that typically resolve within 2-4 weeks; administer at bedtime to mitigate. Tenofovir may cause renal toxicity; monitor CrCl and urine glucose/protein at baseline and periodically. Lamivudine is primarily renally excreted; adjust dose for CrCl <50 mL/min. Assess for efavirenz-induced hepatotoxicity, especially in patients with hepatitis B or C co-infection. Perform HLA-B*5701 testing before abacavir if switching; not applicable here but remember drug interactions: efavirenz induces CYP3A4, reducing levels of protease inhibitors, methadone, and hormonal contraceptives. |
| Patient Advice | Take this medication on an empty stomach at bedtime to reduce dizziness and strange dreams. · Do not breastfeed while taking this medicine; HIV can be transmitted through breast milk. · Use reliable contraception (barrier method plus another method) because efavirenz can cause birth defects. · Report any new or worsening symptoms like depression, suicidal thoughts, or confusion. · Do not stop this medicine without consulting your doctor; stopping can cause the virus to become resistant. · Drink plenty of water to help prevent kidney problems from tenofovir. · Tell your doctor about all other medicines you take, especially rifampin, St. John's wort, or anticonvulsants. |