DOLUTEGRAVIR; EMTRICITABINE; TENOFOVIR ALAFENAMIDE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Dolutegravir is an HIV-1 integrase strand transfer inhibitor (INSTI) that blocks the integration of HIV-1 DNA into host genomic DNA. Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) that inhibits HIV-1 reverse transcriptase by competing with the natural substrate and causing chain termination. Tenofovir alafenamide is an NRTI that is converted to tenofovir, which inhibits HIV-1 reverse transcriptase after phosphorylation.
| Metabolism | Dolutegravir is metabolized primarily by UGT1A1 with minor contribution by CYP3A4. Emtricitabine is not significantly metabolized. Tenofovir alafenamide is metabolized by cathepsin A in PBMCs and by CES1 in hepatocytes; it is not significantly metabolized by CYP450 enzymes. |
| Excretion | Dolutegravir: 64% fecal (unchanged), 31% renal (parent and metabolites). Emtricitabine: 86% renal (unchanged). Tenofovir alafenamide: ~80% renal (as tenofovir); <1% fecal. |
| Half-life | Dolutegravir: ~14 hours (single dose), ~12 hours (steady state). Emtricitabine: ~10 hours. Tenofovir alafenamide: ~0.5 hours; active metabolite tenofovir diphosphate intracellular half-life ~150-180 hours. |
| Protein binding | Dolutegravir: >99%, primarily to albumin. Emtricitabine: <4% (albumin). Tenofovir alafenamide: ~80% (albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Dolutegravir: 17.4 L (not weight-based, ~0.25 L/kg for 70 kg). Emtricitabine: ~1.4 L/kg (high tissue penetration). Tenofovir alafenamide: ~0.65 L/kg (distributes into cells). |
| Bioavailability | Oral: Dolutegravir ~90%; emtricitabine ~93%; tenofovir alafenamide ~40% (fed) to 25% (fasted). Administer with food to increase TAF absorption. |
| Onset of Action | Oral: Dolutegravir achieves >1 log10 reduction in HIV RNA within 24 hours; emtricitabine and TAF contribute to rapid viral suppression. Clinical effect seen within 1-2 weeks. |
| Duration of Action | Dosing interval 24 hours for all components. Missed dose: take as soon as remembered unless within 12 hours of next dose. Intracellular TAF metabolite supports once-daily dosing. |
One tablet (dolutegravir 50 mg; emtricitabine 200 mg; tenofovir alafenamide 25 mg) orally once daily.
| Dosage form | TABLET |
| Renal impairment | Not recommended for patients with CrCl <30 mL/min. For CrCl 30-49 mL/min: use single-tablet regimen of dolutegravir 50 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg instead. |
| Liver impairment | No dose adjustment required for mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Not recommended in severe (Child-Pugh C) hepatic impairment. |
| Pediatric use | Approved for patients weighing ≥40 kg: one tablet orally once daily. For patients ≥25 kg and aged ≥12 years: consider dolutegravir/abacavir/lamivudine or other regimens pending weight-based dosing. |
| Geriatric use | No specific dose adjustment recommended. Monitor renal function due to age-related decline in CrCl; not recommended if CrCl <30 mL/min. |
| 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 breast milk (M/P ratio ~0.4). Emtricitabine: Excreted in breast milk (M/P ratio ~1.9). Tenofovir alafenamide: Excreted in breast milk (M/P ratio unknown). Infant exposure is low but not negligible. In HIV, breastfeeding is not recommended where formula is available. In HBV, benefits may outweigh risks; consult guidelines. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis B 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, and may occur with discontinuation of tenofovir alafenamide. 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 |
["Do not co-administer with dofetilide due to risk of increased dofetilide levels and serious or life-threatening events.","Coadministration with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin) due to decreased dolutegravir concentrations.","Coadministration with rifampin due to decreased dolutegravir and tenofovir alafenamide concentrations.","Coadministration with St. John's wort due to decreased dolutegravir concentrations.","Not recommended in patients with severe renal impairment (CrCl < 30 mL/min) or requiring hemodialysis."]
| Precautions |
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| Dolutegravir: Human studies show an increased risk of neural tube defects (NTDs) during first trimester exposure (0.3% vs 0.1% baseline). Emtricitabine: Limited human data; no major teratogenicity observed in animal studies. Tenofovir alafenamide: Limited human data; no major teratogenicity in animal studies. Overall, avoid dolutegravir in first trimester if alternatives exist. Second/third trimester risks are not well-defined but no specific malformations reported. |
| Fetal Monitoring | Monitor maternal HIV viral load and CD4 count regularly. Perform hepatitis B serology. Assess renal function (creatinine, urine protein) due to tenofovir. First trimester ultrasound for NTD screening if on dolutegravir. Fetal growth ultrasound in third trimester. Monitor for anemia and liver function tests. |
| Fertility Effects | Dolutegravir: No known adverse effects on fertility in men or women. Emtricitabine: No known effects on fertility. Tenofovir alafenamide: No known effects on fertility. However, HIV itself may impair fertility; ART improves outcomes. |
| ["Risk of post-treatment acute exacerbation of hepatitis B (see black box warning).","Risk of hepatotoxicity, including elevated liver enzymes and bilirubin.","Risk of immune reconstitution syndrome.","Risk of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, with use of nucleoside analogues (emtricitabine and tenofovir alafenamide).","Risk of renal impairment: Monitor serum creatinine, creatinine clearance, urine glucose, and urine protein when appropriate.","Risk of decreases in bone mineral density with tenofovir alafenamide; monitor in patients with a history of bone fractures or osteoporosis.","Drug interactions: Avoid coadministration with dofetilide due to risk of toxicity; use with caution with other nephrotoxic drugs."] |