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. |
| Molecular Weight | Dolutegravir: 419.4 Da; Lamivudine: 229.3 Da; Tenofovir alafenamide: 476.5 Da. |
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 | Data insufficient; use only if benefit outweighs risk. Dolutegravir associated with neural tube defects in early pregnancy (limited data). Lamivudine and tenofovir alafenamide considered safe in pregnancy. Monitor viral load and liver function. |
| 2nd trimester | Generally considered safe; no major teratogenic risks identified for lamivudine and tenofovir alafenamide. Dolutegravir shows increased risk of neural tube defects if used at conception; continued use during second trimester has lower risk. Benefits of HIV suppression outweigh risks. |
| 3rd trimester | Safe to use; no increased risk of adverse fetal outcomes. All three components cross placenta. Tenofovir alafenamide shows lower bone and renal toxicity compared to tenofovir disoproxil fumarate. Monitor maternal HIV RNA and CD4 count. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer |
■ 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 componentConcurrent use with dofetilide (increased risk of arrhythmia)Coadministration with drugs that strongly induce CYP3A or P-glycoprotein (e.g., rifampin, St. John's wort) reduces tenofovir alafenamide levels
| 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. |
Loading safety data…
| All three drugs cross the placenta. Dolutegravir shows moderate transfer (cord blood/maternal plasma ratio ~0.6-1.0). Lamivudine readily crosses (ratio ~1.0). Tenofovir alafenamide crosses less than tenofovir disoproxil fumarate, but still significant. Ex vivo models confirm transfer. |
| Breastfeeding | Lamivudine and tenofovir alafenamide are excreted in human breast milk in low concentrations; dolutegravir is also excreted. In HIV-positive mothers, breastfeeding is not recommended due to risk of HIV transmission. In HIV-negative indications (e.g., PrEP), consider risk-benefit; limited data. |
| Lactation Rating | L4 - Possibly Hazardous (for HIV treatment; breastfeeding contraindicated) or L3 - Moderately Safe (for non-HIV use, if benefits outweigh risks). |
| 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. |
| Food/Dietary | Take with food to enhance absorption of tenofovir alafenamide; food also reduces gastrointestinal irritation. Avoid grapefruit juice? No significant interaction. No specific foods to avoid, but maintain a balanced diet. Calcium supplements, antacids, and iron supplements reduce absorption if taken concurrently; separate by at least 2-6 hours. Do not take with St. John's wort or cimetidine as they may reduce efficacy? Note: No strong interaction data; however, clinically dose caution with St. John's wort due to potential CYP induction? Actually, dolutegravir is metabolized by UGT1A1 and CYP3A4; lamivudine and tenofovir alafenamide have minimal CYP interactions. But St. John's wort may reduce dolutegravir levels; avoid combination. |
| Clinical Pearls | 1. This single-tablet regimen (Dovato) is indicated for HIV-1 treatment in adults and adolescents ≥12 years weighing ≥40 kg with no prior antiretroviral therapy or to replace current regimen in virologically suppressed patients (HIV-1 RNA <50 copies/mL) with no history of treatment failure and no known resistance to any component. 2. Screen for hepatitis B virus (HBV) coinfection before initiation; tenofovir alafenamide is active against HBV but lamivudine alone can cause HBV resistance; if HBV coinfection is present, use a fully active HBV regimen or discontinue with close monitoring for HBV flares. 3. Monitor renal function, serum creatinine, urine glucose, and urine protein at baseline and during therapy; tenofovir alafenamide has lower renal toxicity than tenofovir disoproxil fumarate but still requires monitoring. 4. Assess hepatic function; dolutegravir has been associated with hepatotoxicity in patients with underlying liver disease. 5. Dolutegravir can cause neural tube defects if administered periconceptionally; avoid use in women of childbearing potential unless no suitable alternative, and ensure negative pregnancy test before initiation; use effective contraception. 6. Check for drug interactions, particularly with dofetilide, pimozide, metformin, antacids, and supplements containing polyvalent cations (Ca, Mg, Fe, Zn); separate dosing by at least 2 hours for antacids or 6 hours for Fe/Mg supplements. 7. Administer with food to improve tenofovir alafenamide absorption and reduce gastrointestinal side effects. 8. In patients with creatinine clearance <30 mL/min, this combination is not recommended. 9. If a dose is missed within 18 hours, take it as soon as possible with food; if more than 18 hours, skip the dose and resume normal schedule. 10. Monitor for immune reconstitution syndrome, especially in patients with advanced HIV at initiation. |
| Patient Advice | Take this medication exactly as prescribed, usually once daily with food to improve absorption and reduce stomach upset. · Do not breastfeed while taking this medicine; HIV can be passed to the baby through breast milk. · Inform your doctor if you are pregnant, planning to become pregnant, or think you might be pregnant; this medicine can cause harm to an unborn baby, especially during the first 6-10 weeks of pregnancy. · Use effective birth control (contraception) during treatment and for at least 4 weeks after stopping. · Keep all appointments for blood tests to check kidney function, liver function, and viral load. · Tell your healthcare provider about all medicines you take, including prescription, over-the-counter, vitamins, and herbal supplements; especially antacids, calcium, iron, magnesium, or zinc supplements. · If you take antacids, take them at least 2 hours before or 6 hours after your dose. · If you take iron or magnesium supplements, take them at least 6 hours before or 6 hours after your dose. · If you miss a dose, take it as soon as you remember if it is within 18 hours of the missed dose. If more than 18 hours have passed, skip the missed dose and take the next dose at the regular time. Do not double the dose. · Do not run out of medication; this medicine must be taken regularly to keep HIV under control. · This medicine does not cure HIV infection. You may still develop opportunistic infections or other complications of HIV infection. Continue to practice safe sex and take other precautions to prevent spreading HIV to others. · Report any signs of liver problems (yellow skin or eyes, dark urine, pale stools, nausea, vomiting, loss of appetite, pain on right side of stomach) or kidney problems (change in amount of urine, swelling in legs or ankles) immediately. · If you have hepatitis B virus infection, do not stop this medicine without talking to your doctor; stopping can cause serious hepatitis flare. · You may experience headache, diarrhea, nausea, or trouble sleeping; these usually improve over time. Contact your doctor if they are severe or persist. · Your immune system may get stronger and start to fight infections that were hidden in your body; tell your doctor if you notice any new symptoms after starting treatment. |