DOLUTEGRAVIR; LAMIVUDINE; 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 HIV-1 integrase strand transfer inhibitor (INSTI) that blocks the integration of HIV-1 DNA into host genomic DNA. Lamivudine and tenofovir disoproxil fumarate are nucleoside reverse transcriptase inhibitors (NRTIs) that inhibit HIV-1 reverse transcriptase by competing with natural substrates and causing chain termination.
| Metabolism | Dolutegravir is metabolized primarily by UGT1A1 with some contribution from CYP3A4. Lamivudine is minimally metabolized; its metabolites are trans-sulfoxide and glucuronide conjugate. Tenofovir disoproxil fumarate is rapidly converted to tenofovir, which is not significantly metabolized. |
| Excretion | Dolutegravir: ~64% feces (as unchanged drug), 31% urine (as unchanged and metabolites). Lamivudine: ~70% urine (as unchanged drug) via active tubular secretion, ~6% as inactive trans-sulfoxide metabolite. Tenofovir disoproxil fumarate: ~70-80% urine (as unchanged tenofovir) via glomerular filtration and active tubular secretion. |
| Half-life | Dolutegravir: ~14 hours (range 11-18) in HIV-1-infected adults, supports once-daily dosing. Lamivudine: ~18-19 hours in HIV-infected adults, allows once-daily dosing; prolonged in renal impairment. Tenofovir disoproxil fumarate: ~17 hours (tenofovir) in HIV-infected adults, supports once-daily dosing; extended in renal impairment. |
| Protein binding | Dolutegravir: ≥99% bound to plasma proteins (mainly albumin). Lamivudine: <36% bound to plasma proteins (not concentration-dependent). Tenofovir: <0.7% bound to plasma proteins; tenofovir disoproxil fumarate: <0.7% bound. |
| Volume of Distribution | Dolutegravir: ~17.4 L (0.23 L/kg for 70 kg) in HIV-infected adults; moderate tissue distribution. Lamivudine: ~1.3 L/kg (91 L for 70 kg), indicating extensive tissue distribution. Tenofovir: ~1.3 L/kg (91 L for 70 kg) following prodrug administration, reflecting wide tissue distribution. |
| Bioavailability | Dolutegravir: ~70% (absolute bioavailability under fasted conditions); increased to 75% with moderate-fat meal, decreased with high-fat meal. Lamivudine: ~86% (oral tablet; absolute bioavailability), not significantly affected by food. Tenofovir disoproxil fumarate: ~25% (as tenofovir) in fasted state; increased to ~39% with high-fat meal. |
| Onset of Action | Not applicable for oral fixed-dose combination; clinical antiviral effect typically detectable within 2-4 weeks of therapy based on viral load reduction. No parenteral route available. |
| Duration of Action | Duration of antiviral effect: sustained suppression of HIV-1 RNA over 24-hour dosing interval with once-daily administration. Plasma concentrations remain above protein-adjusted IC90 for each component throughout the dosing interval. Longer duration in renal impairment due to prolonged half-lives. |
| Molecular Weight | Dolutegravir: 419.38; Lamivudine: 229.26; Tenofovir disoproxil fumarate: 635.52 (combination product, no single MW). |
One tablet orally once daily containing dolutegravir 50 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg.
| Dosage form | TABLET |
| Renal impairment | Not recommended for CrCl <30 mL/min. For CrCl 30-49 mL/min, use separate components to adjust dolutegravir (50 mg once daily) and reduce lamivudine to 150 mg once daily, and tenofovir disoproxil fumarate to 300 mg every 48 hours. For CrCl ≥50 mL/min, no adjustment. |
| Liver impairment | No adjustment for mild to moderate hepatic impairment (Child-Pugh A or B). Contraindicated in severe hepatic impairment (Child-Pugh C) due to tenofovir disoproxil fumarate. |
| Pediatric use | Approved for adolescents weighing ≥35 kg: one tablet orally once daily containing dolutegravir 50 mg, lamivudine 300 mg, tenofovir disoproxil fumarate 300 mg. For children <35 kg, use individual components. |
| Geriatric use | No specific dose adjustment; monitor renal function closely due to age-related decline in CrCl. Avoid if CrCl <30 mL/min. |
| 1st trimester | Use during first trimester is acceptable if benefit outweighs risk; no increased risk of major birth defects observed in prospective studies. |
| 2nd trimester | No increased risk of adverse fetal outcomes; dose adjustment may be needed for physiological changes. |
| 3rd trimester | Safe; monitor for maternal anemia and neonatal hyperbilirubinemia (atazanavir component if boosted, but not applicable here). |
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 drugs cross the placenta: dolutegravir (moderate transfer), lamivudine (extensive transfer, cord blood levels similar to maternal), tenofovir (limited transfer, cord blood levels ~60% of maternal). |
■ FDA Black Box Warning
Post-treatment acute exacerbation of hepatitis B; severe acute exacerbation of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine or tenofovir disoproxil fumarate. Close monitoring of hepatic function for at least several months is recommended.
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to any componentCo-administration with dofetilide (dolutegravir increases dofetilide levels)
| Precautions | Hepatotoxicity: Hepatic events, including cases of hepatic injury, have been reported; monitor liver enzymes., Lactic acidosis/severe hepatomegaly with steatosis: Reported with NRTIs; risk factors include female sex, obesity, and prolonged nucleoside exposure., Renal impairment: Tenofovir is associated with renal toxicity; monitor renal function., Bone effects: Decreased bone mineral density observed with tenofovir; consider monitoring in patients with osteoporosis risk., Immune reconstitution syndrome: May occur during initial phase of treatment., Drug interactions: Do not coadminister with dofetilide due to increased dofetilide concentrations; monitor with other drugs affecting UGT1A1 or CYP3A4. |
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| Breastfeeding |
| Dolutegravir and lamivudine are excreted into human breast milk; tenofovir disoproxil fumarate is excreted in low concentrations. Breastfeeding while on ART is recommended per WHO guidelines for HIV-infected mothers; benefits outweigh theoretical risks. |
| Lactation Rating | L2 |
| Teratogenic Risk | Dolutegravir: First-trimester neural tube defects (NTD) risk (0.3% vs 0.1% background). Avoid in first trimester unless benefit > risk. Lamivudine: Low risk; no evidence of major malformations. Tenofovir disoproxil fumarate: Low risk; no increased malformation rate. Second/third trimester: No known specific fetal risks beyond standard antiretroviral effects. |
| Fetal Monitoring | Monitor HIV viral load and CD4 count at least every trimester. Assess renal function (creatinine, eGFR) at baseline and periodically due to tenofovir. First-trimester ultrasound for NTD assessment with dolutegravir exposure. Perform glucose tolerance testing at 24-28 weeks (tenofovir may affect renal glucose handling). |
| Fertility Effects | No known adverse effects on fertility in men or women. In vitro studies: Dolutegravir may reduce progesterone levels in endometrial cells but clinical significance unclear. No evidence of impaired spermatogenesis or ovulation in clinical trials. |
| Food/Dietary | No significant food interactions. May be taken with or without food. Avoid excessive alcohol use as it may worsen liver effects. |
| Clinical Pearls | Dolutegravir/lamivudine/tenofovir DF is a complete HIV-1 regimen; do not coadminister with other antiretrovirals. Avoid in patients with known integrase inhibitor resistance. Monitor renal function due to tenofovir DF; adjust dose if CrCl <30 mL/min. Dolutegravir may cause neural tube defects; avoid in pregnancy unless benefit outweighs risk. Check for hepatitis B coinfection before starting; lamivudine and tenofovir are active against HBV, but discontinuation may cause HBV flare. |
| Patient Advice | Take exactly as prescribed, with or without food, at the same time each day. · Do not miss doses; skip only if recommended by your doctor. · Tell your doctor if you are pregnant or planning to become pregnant. · Report symptoms like nausea, diarrhea, or headache; these are common. · Watch for signs of liver problems (dark urine, yellowing eyes/skin) or kidney issues (decreased urination). · Get tested for hepatitis B before starting treatment. · Use effective contraception while on this medication if you are a woman of childbearing age. · Do not take with other HIV medicines unless directed. |