DOLUTEGRAVIR AND LAMIVUDINE
Clinical safety rating: safe
Trimethoprim/sulfamethoxazole increases lamivudine exposure Severe acute exacerbations of hepatitis B have been reported upon discontinuation.
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration. Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) that is phosphorylated to its active metabolite, which competes with endogenous deoxycytidine triphosphate for incorporation into viral DNA, leading to chain termination.
| Metabolism | Dolutegravir is primarily metabolized by UGT1A1 with some contribution from CYP3A4. Lamivudine is metabolized intracellularly to its active triphosphate metabolite and is eliminated renally as unchanged drug by active tubular secretion. |
| Excretion | Dolutegravir: ~53% excreted unchanged in feces via biliary secretion, ~31% in urine. Lamivudine: ~70% excreted unchanged in urine via glomerular filtration and active tubular secretion. |
| Half-life | Dolutegravir: ~14 hours (terminal). Lamivudine: ~13-19 hours (terminal). Both support once-daily dosing. |
| Protein binding | Dolutegravir: >99% bound primarily to albumin. Lamivudine: <36% bound to albumin. |
| Volume of Distribution | Dolutegravir: ~17 L (approx. 0.24 L/kg in adults), indicating distribution into peripheral tissues. Lamivudine: ~1.3 L/kg, indicating extensive extravascular distribution. |
| Bioavailability | Dolutegravir: Not determined in absolute terms but well absorbed; food increases AUC slightly. Lamivudine: ~86% oral bioavailability. |
| Onset of Action | Oral: Time to maximum plasma concentration (Tmax) 2-3 hours for both; clinical antiviral effect typically within 1-2 weeks. |
| Duration of Action | Sustained virologic suppression for 24 hours with once-daily dosing; clinical suppression maintained with continuous therapy. |
One tablet (dolutegravir 50 mg/lamivudine 300 mg) orally once daily.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if CrCl <30 mL/min. For CrCl ≥30 mL/min, no dose adjustment required. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B or C: not recommended due to lack of data. |
| Pediatric use | Not approved for patients <12 years of age or weighing <40 kg; no pediatric dosing established. |
| Geriatric use | No specific dose adjustment; monitor renal function and consider age-related decline in CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Trimethoprim/sulfamethoxazole increases lamivudine exposure Severe acute exacerbations of hepatitis B have been reported upon discontinuation.
| FDA category | Human |
| Breastfeeding | Both dolutegravir and lamivudine are excreted in human breast milk. The milk-to-plasma (M/P) ratio for dolutegravir is approximately 0.033, and for lamivudine it is approximately 3.3. Lamivudine achieves significant infant exposure (estimated 5-10% of maternal therapeutic dose). Dolutegravir exposure to the infant is low (approximately <1% of maternal dose). The American Academy of Pediatrics recommends that breastfeeding is not contraindicated for mothers taking these drugs, but the infant should be monitored for adverse effects such as anemia, neutropenia, and mitochondrial toxicity due to lamivudine. HIV-infected mothers should not breastfeed to avoid postnatal transmission of HIV. |
■ FDA Black Box Warning
None
| Common Effects | Hepatitis B |
| Serious Effects |
["Patients with known hypersensitivity to dolutegravir, lamivudine, or any component of the formulation.","Coadministration with dofetilide due to potential for serious or life-threatening reactions.","Coadministration with drugs that are highly dependent on OCT2 or MATE1 transporters (e.g., metformin at doses >850 mg twice daily) due to potential for increased dolutegravir concentrations."]
| Precautions | ["Hepatotoxicity has been reported in patients receiving dolutegravir, including cases with underlying hepatitis B or C coinfection.","Immune reconstitution syndrome has been reported.","Risk of neural tube defects associated with dolutegravir use at the time of conception and early pregnancy; avoid use in pregnant individuals during the first trimester unless no appropriate alternative is available.","Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of NRTIs including lamivudine.","Exacerbation of hepatitis B may occur in patients coinfected with HBV who discontinue lamivudine; monitor hepatic function closely."] |
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| Teratogenic Risk | Dolutegravir has been associated with an increased risk of neural tube defects when used at the time of conception and during the first trimester (approximately 0.3% vs 0.1% background). The risk is highest with periconceptional use. For lamivudine, there is no increased risk of major birth defects based on large cohort studies. In the second and third trimester, no specific fetal risks have been consistently identified for either drug. However, due to the dolutegravir risk, avoid use in women attempting to conceive or during the first trimester unless alternative options are not available. |
| Fetal Monitoring | Maternal monitoring includes: complete blood count (CBC), serum creatinine, hepatic function tests, and HIV viral load at baseline and regularly (e.g., every 1-3 months). Fetal monitoring: in the first trimester, consider high-resolution ultrasound at 18-20 weeks gestation to assess for neural tube defects if dolutegravir exposure occurred periconceptionally. Third trimester monitor for gestational diabetes due to dolutegravir association with insulin resistance. Assess infant for hyperbilirubinemia and anemia postnatally due to lamivudine exposure. |
| Fertility Effects | Dolutegravir has no known direct effect on fertility in humans. In animal studies, no significant reproductive toxicity was observed. Lamivudine does not impair fertility in animal models. Human data do not suggest an adverse impact on male or female fertility. However, HIV infection itself can affect fertility, which may improve with effective antiretroviral therapy. |