DOLUTEGRAVIR;LAMIVUDINE;TENOFOVIR ALAFENAMIDE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Dolutegravir: HIV integrase strand transfer inhibitor; inhibits viral DNA integration. Lamivudine: Nucleoside reverse transcriptase inhibitor (NRTI); chain terminator. Tenofovir alafenamide: Nucleotide reverse transcriptase inhibitor (NRTI); prodrug that converts to tenofovir diphosphate.
| Metabolism | Dolutegravir: Metabolized via UGT1A1, with minor contribution by CYP3A. Lamivudine: Metabolized intracellularly to its active triphosphate form; minimal hepatic metabolism. Tenofovir alafenamide: Metabolized intracellularly to tenofovir by cathepsin A; also hydrolyzed by CES1 in hepatocytes. |
| Excretion | Dolutegravir: ~53% unchanged in feces, ~34% unchanged in urine. Lamivudine: ~70% unchanged in urine via glomerular filtration and active tubular secretion. Tenofovir alafenamide: <1% renal as unchanged, mostly metabolized to tenofovir (which is eliminated renally via tubular secretion) and other metabolites. |
| Half-life | Dolutegravir: ~14 hours (once daily dosing). Lamivudine: ~13-19 hours (once daily). Tenofovir alafenamide: ~0.51 hours (terminal half-life of tenofovir ~34-46 hours). |
| Protein binding | Dolutegravir: ~98.9% to plasma albumin. Lamivudine: <36% to plasma proteins. Tenofovir alafenamide: ~80% to plasma proteins. |
| Volume of Distribution | Dolutegravir: 12.5 L/kg (extensive tissue distribution). Lamivudine: 1.3 L/kg (total body water). Tenofovir alafenamide: 0.30 L/kg (limited distribution due to hydrophilic nature; active metabolite tenofovir diphosphate accumulates in cells). |
| Bioavailability | Dolutegravir: 79% (fasted) to 89% (fed). Lamivudine: 86-90% (fasted). Tenofovir alafenamide: 25-30% (fasted); increased with moderate/high-fat meal. |
| Onset of Action | Oral: Antiviral effect begins within 24-48 hours based on viral load decline. Clinical response assessed at week 4-8. |
| Duration of Action | Oral: Dosing interval 24 hours for all components. Once-daily dosing maintains therapeutic concentrations. Missed dose: take as soon as remembered if within 12 hours. |
One tablet (50 mg dolutegravir, 300 mg lamivudine, 25 mg tenofovir alafenamide) orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | Not recommended for patients with creatinine clearance (CrCl) <30 mL/min. No dose adjustment required for CrCl ≥30 mL/min. |
| Liver impairment | No dose adjustment for mild or moderate hepatic impairment (Child-Pugh A or B). Not recommended for severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Approved for adolescents weighing ≥40 kg: one tablet (same adult strength) orally once daily. For children weighing <40 kg, safety and efficacy not established. |
| Geriatric use | No specific dose adjustment. Use caution due to age-related renal impairment; monitor renal function regularly. |
| 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 | Dolutegravir: excreted in human milk; infant dose approximately 2% of maternal weight-adjusted dose; M/P ratio ~0.8. Lamivudine: excreted in human milk; infant dose ~2-8% of maternal dose; M/P ratio ~3.5. TAF: excreted in human milk; data limited but expected low due to high protein binding. Benefits of breastfeeding likely outweigh risks for infants >2 weeks old. In HIV infection, WHO recommends exclusive breastfeeding for 6 months while mother on ART. |
■ 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 coinfected with HIV-1 and HBV and have discontinued lamivudine and/or tenofovir alafenamide. Hepatic function should be monitored closely in these patients.
| Common Effects | Hepatitis B |
| Serious Effects |
["Hypersensitivity to any component of the product","Co-administration with dofetilide"]
| Precautions | ["Hepatotoxicity: Elevations in aminotransferases and bilirubin have been reported, especially in patients with HBV or hepatic impairment.","Lactic acidosis/severe hepatomegaly with steatosis: Reported with NRTIs, including lamivudine and tenofovir alafenamide.","Renal impairment: Tenofovir alafenamide may cause renal toxicity; monitor renal function.","Immune reconstitution syndrome: Observed during initial treatment.","Drug interactions: Avoid coadministration with dofetilide due to suspected interaction; use with caution with other UGT1A1/CYP3A substrates."] |
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| Teratogenic Risk |
| Dolutegravir is associated with increased risk of neural tube defects when used at conception and during first trimester; risk estimated 0.3% vs 0.1% background. Lamivudine and tenofovir alafenamide (TAF) have low teratogenic risk; no evidence of major congenital malformations in human studies. Per trimester: First trimester: Avoid dolutegravir in women of childbearing potential unless no alternative; use alternative integrase inhibitor if possible. Second and third trimesters: Dolutegravir appears safe with low risk. Lamivudine and TAF are acceptable throughout pregnancy. |
| Fetal Monitoring | Monitor HIV viral load and CD4 count every 1-3 months during pregnancy. Perform renal function tests (serum creatinine, eGFR, urine protein) at baseline and every 3 months due to TAF. Check liver function tests at baseline and periodically. Assess for neural tube defects by ultrasound at 18-20 weeks if exposed to dolutegravir at conception. Monitor for anemia (CBC) as lamivudine may cause neutropenia. Assess adherence to therapy. |
| Fertility Effects | Dolutegravir: No significant adverse effects on female fertility in animal studies; in men, mild effects on sperm parameters but reversible. Lamivudine: No evidence of impaired fertility in animals or humans. TAF: No adverse effects on fertility in animal studies. Overall, combination is not associated with clinically relevant fertility impairment. |