ABACAVIR, DOLUTEGRAVIR AND LAMIVUDINE
Clinical safety rating: safe
Abacavir, dolutegravir, and lamivudine is a fixed-dose combination antiretroviral therapy for HIV-1 infection. It combines two nucleoside reverse transcriptase inhibitors (abacavir and lamivudine) with an integrase strand transfer inhibitor (dolutegravir) to suppress viral replication.
Abacavir is a guanosine analogue reverse transcriptase inhibitor that is phosphorylated to carbovir triphosphate, which competitively inhibits HIV reverse transcriptase and causes DNA chain termination. Dolutegravir is an integrase strand transfer inhibitor that blocks the strand transfer step of HIV DNA integration into the host genome. Lamivudine is a cytidine analogue reverse transcriptase inhibitor that is phosphorylated to lamivudine triphosphate, which competitively inhibits HIV reverse transcriptase and causes DNA chain termination.
| Metabolism | Abacavir is metabolized primarily by alcohol dehydrogenase and glucuronyl transferase. Dolutegravir is metabolized primarily by UGT1A1, with minor contributions from CYP3A4. Lamivudine is eliminated renally as unchanged drug, with minor hepatic metabolism. |
| Excretion | Abacavir: 83% renal (metabolites via alcohol dehydrogenase and glucuronidation), 16% fecal. Dolutegravir: <1% renal, 64% fecal (as unchanged drug), 35% urinary (metabolites, mainly glucuronide). Lamivudine: 70% renal (unchanged via tubular secretion and glomerular filtration), 5-10% fecal. |
| Half-life | Abacavir: 1.5-2 h. Dolutegravir: 14 h (range 11-18 h) supporting once-daily dosing. Lamivudine: 13-19 h (intracellular triphosphate t1/2 16-19 h in cells). |
| Protein binding | Abacavir: 50% (low affinity). Dolutegravir: 98.9-99.3% (albumin, alpha-1-acid glycoprotein). Lamivudine: <36% (low). |
| Volume of Distribution | Abacavir: 0.8 L/kg (high tissue penetration, including CNS). Dolutegravir: 17.4 L/kg (extensive tissue distribution, high binding). Lamivudine: 1.3 L/kg (widely distributed, including cerebrospinal fluid). |
| Bioavailability | Abacavir: 83% (oral). Dolutegravir: not well characterized (fasted: about 80%, but can be decreased by polyvalent cations; high fat meal reduces rate but not extent). Lamivudine: 86-88% (oral). |
| Onset of Action | Not applicable due to the delayed mechanism of action (inhibition of viral replication leading to viral load reduction over days to weeks). For HIV therapy, initial viral load decline observed within 1-2 weeks. |
| Duration of Action | Dosing interval: once daily, sustained viral suppression over 24 h due to dolutegravir's long half-life and lamivudine's intracellular half-life. |
One tablet (600 mg abacavir / 50 mg dolutegravir / 300 mg lamivudine) taken orally once daily.
| Dosage form | TABLET |
| Renal impairment | Not recommended if CrCl <30 mL/min; lamivudine dose adjustment needed. Avoid in ESRD. |
| Liver impairment | Contraindicated in Child-Pugh Class C; use with caution in mild to moderate impairment. |
| Pediatric use | Approved for children weighing at least 40 kg (adult dose). For children <40 kg, separate components are used. |
| Geriatric use | No specific adjustments but monitor renal function and hematologic effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Abacavir/dolutegravir/lamivudine is recommended as a first-line regimen for HIV-1 during pregnancy, with no evidence of increased teratogenicity. Dolutegravir has been associated with a small increased risk of neural tube defects when taken at conception, but the overall risk is low.
| FDA category | Human |
| Placental transfer | All three drugs cross the placenta; dolutegravir achieves high concentrations in the fetal circulation. |
| Breastfeeding | Maternal treatment recommended during breastfeeding if HIV-positive; abacavir and lamivudine are excreted into breast milk; M/P ratio for abacavir ~0.9, lamivudine ~3.3; insufficient data on dolutegravir transfer; benefit of breastfeeding outweighs theoretical risks. |
■ FDA Black Box Warning
Abacavir: Hypersensitivity reactions, including life-threatening and fatal reactions, have occurred. Serious hypersensitivity reactions have occurred even without prior hypersensitivity and have included multiorgan failure. Discontinue immediately if hypersensitivity is suspected. Do not restart abacavir or any abacavir-containing product after a hypersensitivity reaction because more severe symptoms, including death, can occur within hours. HLA-B*5701 allele status must be documented before initiating therapy. Abacavir is contraindicated in patients with the HLA-B*5701 allele.
| Common Effects | Nausea, Headache, Diarrhea, Insomnia, Fatigue, Dizziness, Depression, Rash |
| Serious Effects | Abacavir hypersensitivity reaction (can be fatal), lactic acidosis, hepatotoxicity, pancreatitis, severe skin reactions. |
HLA-B*5701 allele positive patients; history of hypersensitivity reaction to abacavir, dolutegravir, or lamivudine; concurrent dofetilide (dolutegravir increases dofetilide levels); severe hepatic impairment (Child-Pugh class C).
| Precautions |
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| Teratogenic Risk | Inadequate human data; animal studies for abacavir and lamivudine show no evidence of teratogenicity; dolutegravir associated with increased risk of neural tube defects (NTDs) when used at conception (0.3% vs 0.1% background); risk primarily in first trimester; post-conception risk not established. |
| Fetal Monitoring | Monitor HIV viral load and CD4 count; assess liver and renal function; check for hypersensitivity reactions (especially with abacavir if HLA-B*5701 positive); fetal ultrasound for NTDs if dolutegravir exposure in first trimester; monitor for maternal anemia or neutropenia. |
| Fertility Effects | No known adverse effects on fertility in humans; animal studies show no impairment; dolutegravir may slightly increase ovulation rates in some women, but clinical significance unclear; men: no evidence of sperm abnormalities. |
| Hypersensitivity reactions (abacavir); hepatic toxicity, including exacerbation of hepatitis B (lamivudine discontinuation); immune reconstitution syndrome; risk of myocardial infarction (abacavir); pancreatitis in pediatric patients (lamivudine); lactic acidosis and severe hepatomegaly with steatosis; drug interactions (e.g., dofetilide, metformin, certain anticonvulsants); monitoring for renal function and serum aminotransferases. |
| Food/Dietary | Take without regard to food. Avoid taking with iron, calcium, magnesium, or antacids; separate by at least 2 hours. High-fat meals may slightly decrease absorption but not clinically significant. |
| Clinical Pearls | Triple therapy is first-line for HIV-1; contraindicated in HLA-B*5701-positive patients due to abacavir hypersensitivity; dolutegravir GI absorption requires gastric acid; avoid with dofetilide; renal dose adjustments for lamivudine; assess renal function, hepatitis B status before starting. |
| Patient Advice | Take exactly as prescribed; do not skip doses or stop without doctor's advice. · Genetic test required before starting abacavir to prevent severe allergic reaction. · Report any rash, fever, fatigue, nausea, vomiting, or abdominal pain immediately. · Must be taken with or without food; but avoid taking with iron or calcium supplements. · Use effective contraception if female of childbearing potential. · Do not breastfeed while on this medication. |