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. |
| Molecular Weight | Dolutegravir: 419.38 Da; Lamivudine: 229.26 Da |
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 | Limited human data; however, available studies do not show an increased risk of major birth defects. Clinical experience suggests use is acceptable if clearly needed. |
| 2nd trimester | Clinical experience with dolutegravir and lamivudine during pregnancy, when administered as part of combination therapy, has not shown fetal harm. Therapeutic doses are considered safe. |
| 3rd trimester | Use in the third trimester is considered safe. Monitor for adverse effects; no dose adjustment required in pregnancy. |
Clinical note
Trimethoprim/sulfamethoxazole increases lamivudine exposure Severe acute exacerbations of hepatitis B have been reported upon discontinuation.
| FDA category | Human |
| Placental transfer | Both drugs cross the placenta. Lamivudine demonstrates rapid and extensive placental transfer, with cord blood concentrations similar to maternal blood. Dolutegravir also crosses the placenta, with cord-to-maternal plasma ratios of approximately 0.5-1.0. |
■ FDA Black Box Warning
None
| Common Effects | Hepatitis B |
| Serious Effects |
Hypersensitivity to dolutegravir, lamivudine, or any component of the formulationConcurrent use with dofetilideConcurrent use with a short-acting form of dolutegravir or lamivudine (if already on fixed-dose combination)
| 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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| Breastfeeding | Both dolutegravir and lamivudine are excreted in human milk. Lamivudine reaches concentrations in milk similar to maternal plasma; dolutegravir concentrations are lower. Due to potential for HIV transmission in breastfeeding mothers with HIV, breastfeeding is not recommended in high-resource settings. In low-resource settings, benefits may outweigh risks. Infant should be monitored for adverse effects. |
| Lactation Rating | L3 (Moderately Safe) |
| 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. |
| Food/Dietary |
| No significant food interactions; can be taken with or without food. Avoid excessive alcohol as it may worsen hepatotoxicity risk. |
| Clinical Pearls | Dolutegravir/lamivudine is a complete regimen for HIV-1; no need for additional antiretrovirals. Contraindicated in patients with known or suspected integrase inhibitor resistance (e.g., raltegravir failure). Avoid in women of childbearing potential unless effective contraception is used due to neural tube defect risk with dolutegravir at conception. Renal function must be assessed prior to initiation; lamivudine dose adjustment needed if CrCl <30 mL/min. Monitor for immune reconstitution inflammatory syndrome (IRIS) and hepatotoxicity, especially in HCV co-infection. |
| Patient Advice | Take one tablet daily at the same time without regard to food. · Do not miss doses; skipping can lead to viral resistance and treatment failure. · Use reliable contraception if you are able to become pregnant; dolutegravir may harm an unborn baby. · Report any signs of allergic reaction (rash, fever, difficulty breathing) or liver problems (nausea, dark urine, jaundice) immediately. · HIV is not curable, but this medication reduces viral load and risk of transmission; continue safe sex practices. · Do not take with other HIV medicines unless directed by your doctor. |