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. |
| Molecular Weight | Dolutegravir: 419.38 Da; Emtricitabine: 247.24 Da; Tenofovir alafenamide: 476.53 Da |
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 | Dolutegravir-containing regimen is contraindicated in first trimester due to risk of neural tube defects (NTDs). Alternative agents should be considered. Emtricitabine and tenofovir alafenamide are generally considered safe, but avoidance of dolutegravir is recommended. |
| 2nd trimester | Dolutegravir may be used if benefit outweighs risk; NTD risk is limited after first trimester. Emtricitabine and tenofovir alafenamide are safe. Monitor for anemia and renal function. |
| 3rd trimester | Same as second trimester. Continue if well-tolerated. Use standard obstetric monitoring. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer | Dolutegravir: Moderate placental transfer (cord blood: maternal plasma ratio ~1.2). Emtricitabine: Extensive transfer (ratio ~1.0). Tenofovir alafenamide: Minimal transfer due to rapid conversion to tenofovir; tenofovir crosses placenta (ratio ~0.8). |
■ 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 |
Concurrent use with dofetilide or pilsicainide (dolutegravir increases their concentrations, risk of arrhythmia)Hypersensitivity to any component
| Precautions | 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. |
Loading safety data…
| Breastfeeding | Dolutegravir and emtricitabine are excreted in human breast milk at low levels; tenofovir alafenamide has limited data. In HIV-infected mothers, breastfeeding is not recommended in developed countries due to potential transmission. In resource-limited settings, WHO recommends breastfeeding on ART with monitoring. Risk of infant toxicity is low. |
| Lactation Rating | L3 (Moderately Safe) - Limited data; caution advised. |
| Teratogenic Risk | 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. |
| Food/Dietary | No significant food interactions. Dolutegravir absorption is slightly increased with high-fat meals; however, taking with or without food is acceptable. Avoid alcohol as it may increase liver toxicity risk. |
| Clinical Pearls | Dolutegravir-containing regimens should not be initiated in women of childbearing potential unless alternative antiretroviral therapy is unavailable, due to neural tube defect risk; pregnancy testing and effective contraception are required. Tenofovir alafenamide has less renal and bone toxicity than tenofovir disoproxil fumarate; still monitor renal function at baseline and periodically. Emtricitabine and tenofovir alafenamide are active against HBV; discontinuation may cause severe acute HBV exacerbations. Administer without regard to food; dolutegravir absorption is increased with food but not required. Avoid coadministration with dofetilide or dalfampridine due to QT prolongation risk and renal clearance competition. |
| Patient Advice | Take this medication once daily, with or without food, at the same time each day. · Do not miss doses; if you miss a dose by less than 12 hours, take it as soon as possible and take the next dose at the regular time. If more than 12 hours have passed, skip the missed dose and resume the normal schedule. · This medication does not cure HIV or prevent transmission; use condoms and practice safe sex. · Inform your healthcare provider immediately if you become pregnant or plan to become pregnant. · Tell your doctor if you have hepatitis B infection; stopping treatment may worsen hepatitis. · Report any signs of kidney problems (decreased urination, swelling in legs) or liver problems (yellowing skin/eyes, dark urine, abdominal pain). · Avoid taking St. John's wort, antacids, or supplements containing calcium, iron, magnesium, or zinc within 2 hours of this medication. · Do not take any other medications without consulting your healthcare provider, especially dofetilide or dalfampridine. |