DOLUTEGRAVIR, LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE
Clinical safety rating: safe
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
Dolutegravir is an integrase strand transfer inhibitor that blocks HIV-1 integration into host DNA. Lamivudine and tenofovir disoproxil fumarate are nucleoside reverse transcriptase inhibitors that inhibit HIV-1 reverse transcriptase via DNA chain termination.
| Metabolism | Dolutegravir is metabolized primarily by UGT1A1 with minor contribution by CYP3A4. Lamivudine is minimally metabolized; undergoes intracellular phosphorylation. Tenofovir disoproxil fumarate is a prodrug that undergoes hydrolysis to tenofovir, which is then phosphorylated; tenofovir is eliminated renally by glomerular filtration and active tubular secretion. |
| Excretion | Dolutegravir: ~64% feces (primarily as parent drug), ~32% urine (parent drug and glucuronide conjugate). Lamivudine: ~70% urine as unchanged drug (renal tubular secretion). Tenofovir disoproxil fumarate (TDF): Pro-drug; tenofovir is renally excreted ~70-80% unchanged (glomerular filtration and tubular secretion). |
| Half-life | Dolutegravir: ~14 hours (terminal), supports once-daily dosing with moderate PK variability. Lamivudine: ~18-22 hours (terminal), allows once-daily dosing; intracellular active metabolite (lamivudine triphosphate) has much longer half-life (~22-27 hours). Tenofovir: ~17 hours (terminal), increased to ~32 hours in intracellular diphosphate form; supports once-daily dosing. |
| Protein binding | Dolutegravir: ~99% bound to plasma proteins (mainly albumin). Lamivudine: <36% bound to plasma proteins (mainly albumin). Tenofovir: <7% bound to plasma proteins. |
| Volume of Distribution | Dolutegravir: Vd ~17–20 L/kg, indicating extensive tissue distribution. Lamivudine: Vd ~1.3 L/kg, primarily distributing into total body water. Tenofovir: Vd ~1.2 L/kg, distributing into total body water. |
| Bioavailability | Dolutegravir: Oral bioavailability ~94% (high); absorption unaffected by food but increased by high-fat meal. Lamivudine: Oral bioavailability ~86% (well absorbed). Tenofovir disoproxil fumarate: Oral bioavailability ~25% (pro-drug; TDF increases absorption relative to tenofovir alone). |
| Onset of Action | Oral: Not applicable for immediate clinical effect. Antiviral effect begins after first dose; significant viral load reduction typically seen within 1-4 weeks. |
| Duration of Action | 24 hours: Once-daily dosing maintains therapeutic concentrations. Continuous adherence required; missed doses may lead to virologic failure. Full viral suppression expected by 24 weeks. |
| Molecular Weight | Dolutegravir: 419.4 Da; Lamivudine: 229.3 Da; Tenofovir disoproxil fumarate: 635.5 Da |
One tablet (50 mg dolutegravir/300 mg lamivudine/300 mg tenofovir disoproxil fumarate) orally once daily
| Dosage form | TABLET |
| Renal impairment | Not recommended if creatinine clearance (CrCl) <30 mL/min. For CrCl 30-49 mL/min: administer every 48 hours. No adjustment for CrCl ≥50 mL/min. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not recommended for severe hepatic impairment (Child-Pugh C). |
| Pediatric use | Approved for patients weighing ≥40 kg: one tablet (50 mg dolutegravir/300 mg lamivudine/300 mg tenofovir disoproxil fumarate) orally once daily. For patients weighing 30-39 kg, alternative formulations are used. |
| Geriatric use | No specific dose adjustment; use with caution due to increased risk of renal impairment and decreased bone mineral density. Monitor renal function and bone density. |
| 1st trimester | Limited data; no increased risk of major birth defects in human studies. Use if benefit outweighs risk. |
| 2nd trimester | No specific safety concerns; monitor for anemia and LFTs. Pharmacokinetic changes may require dose adjustment of tenofovir. |
| 3rd trimester | Use if indicated; no known fetal harm. Monitor maternal renal function and bone density. |
Clinical note
Other nephrotoxic drugs increase risk of renal impairment Can cause renal impairment and decreased bone mineral density.
| FDA category | Animal |
| Placental transfer | All three components cross the placenta; tenofovir has moderate transfer (cord blood concentrations ~60% of maternal). |
| Breastfeeding |
■ 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 coinfected with HIV-1 and HBV and have discontinued lamivudine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue the drug.
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to any componentSevere hepatic impairment (Child-Pugh class C)Lactation when alternative availableConcurrent use with dofetilide or other drugs with narrow therapeutic window that are strong P-gp/BCRP substratesSevere renal impairment (CrCl <30 mL/min) for fixed-dose combination
| Precautions | Hepatitis B exacerbation upon discontinuation in HIV/HBV coinfected patients, Hepatotoxicity including hepatic steatosis and lactic acidosis, Risk of nephrotoxicity including acute renal failure, Fanconi syndrome, and proximal tubulopathy; monitor renal function before and during therapy, Bone loss and osteomalacia; increased risk of fractures with tenofovir disoproxil fumarate, Immune reconstitution syndrome, including autoimmune disorders, Redistribution/accumulation of body fat, Hypersensitivity reactions, including skin reactions and drug reaction with eosinophilia and systemic symptoms (DRESS), Pancreatitis, especially in children with history of pancreatitis or risk factors |
Loading safety data…
| Dolutegravir and lamivudine are excreted into human milk; tenofovir excreted in low amounts. Potential for infant toxicity (lactic acidosis, hepatotoxicity). Consider alternative agents unless benefit clearly outweighs risk. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Dolutegravir: First trimester exposure associated with neural tube defects (NTD) (odds ratio 1.7, absolute risk 0.3%). Increased risk of NTD with periconceptional use. Lamivudine and Tenofovir disoproxil fumarate: No increased risk of birth defects in human studies. Second and third trimester: No specific fetal risks documented; combination ART recommended for maternal health and prevention of vertical transmission. |
| Fetal Monitoring | First trimester: Neural tube defect screening (ultrasound at 18-20 weeks, folate supplementation). Throughout pregnancy: HIV viral load every 4-8 weeks; renal function (serum creatinine, eGFR) at baseline and every 3 months; liver function tests; complete blood count. Third trimester: Repeat HIV RNA at 36 weeks to determine mode of delivery. Fetal: Standard obstetric ultrasound. |
| Fertility Effects | No evidence of impaired fertility in women or men with dolutegravir, lamivudine, or tenofovir disoproxil fumarate. Animal studies show no adverse effects on mating or fertility. Hormonal contraceptive interactions: None significant. |
| Food/Dietary | Take with food if experiencing gastrointestinal upset; absorption is not significantly affected. Avoid excessive alcohol consumption as it may increase risk of liver toxicity. No known specific food contraindications. |
| Clinical Pearls | Fixed-dose combination for HIV-1. Assess renal function before initiation and monitor during therapy; tenofovir may cause nephrotoxicity. Test for hepatitis B coinfection; lamivudine and tenofovir are active against HBV but discontinuation can cause severe HBV flares. Monitor for immune reconstitution syndrome. Dolutegravir may cause neural tube defects; use effective contraception in women of childbearing potential. Administer with or without food. |
| Patient Advice | Take this medication exactly as prescribed, at the same time each day. · Do not miss doses; skipping doses can lead to drug resistance. · This drug does not cure HIV but reduces viral load and improves immune function. · It does not prevent transmission; use condoms to reduce risk. · Report symptoms of pancreatitis (severe abdominal pain, nausea, vomiting) or liver problems (yellowing skin/eyes, dark urine). · Stay hydrated to reduce kidney side effects. · If pregnant or planning pregnancy, discuss risks with healthcare provider. · Do not stop treatment without medical advice, especially if you have hepatitis B. |