Lamivudine is a prescription nucleoside reverse transcriptase inhibitor (NRTI) that is used in combination with other drugs as antiviral treatment for human immunodeficiency virus type-1 (HIV-1) and as a monotherapy for hepatitis B virus (HBV).[1] It reduces viral load and subsequently reduces disease signs and symptoms, increases CD4+ cell count, improves patient's quality of life, and can help prolong life. The ability to reduce viral load, rather than eradicate the virus in a human host, classifies lamivudine as a virustatic, rather than a virucidal agent. It is prescribed as part of other combination therapies. Lamivudine is globally important as first-line NRTI therapy; it is currently on the World Health Organization (WHO) "List of Essential Medications."

Lamivudine, also termed 2',3'-Dideoxy-3'-thiacytidine or 3TC, was approved to treat HIV-1 in 1995, then for HBV in 1998.[2] The currently manufactured lamivudine (3TC) is an isolated unnatural L-(-) enantiomer that was found to be more potent and less cytotoxic than the originally studied racemic mixture termed BCH-189.[2] Ensuing studies of lamivudine have shown that it is most efficacious as a monotherapy for HBV as well as in an HIV regimen that includes multiple antiretroviral therapies.[3][4] It is used in combination with two or more antivirals to prevent rapid mutations that can lead to drug resistance in HIV-1 patients, specifically via the M184V reverse transcriptase single substitution mutation that has shown to occur in as little as 8-weeks of mono- or combination antiviral therapy that contains lamivudine (3TC).[5] 

Treatment of HIV-1 by lamivudine is in combination with zanuvidine, didanosine, raltegravir, or zalcitabine.[6][7] The newest combination approved by the US Food and Drug Administration (FDA) in 2019, includes 300 mg of 3TC and 50 mg of dolutegravir (DTC), an integrase inhibitor, and is considered a complete therapy regimen for adults who are antiretroviral treatment naïve.[8] This newer dual therapy approach is proving just as effective as 3 or 4 drug regimens.[8][9]

As a virustatic agent, lamivudine has been studied as a possible treatment for SARS-CoV. However, in all known published trials and research, lamivudine has not been shown to be an efficacious treatment for SARS-CoV.[10]

Lamivudine is a dideoxynucleoside cytosine analog that inhibits viral DNA synthesis via reverse transcriptase DNA chain termination post phosphorylation. Once inside the cell, lamivudine, 2'-deoxy-3'-thiacytidine, is metabolized to the triphosphate form, lamivudine triphosphate (abbreviated as 3TC-TP or L-TP), and the monophosphate form, lamivudine monophosphate (abbreviated as 3TC-MP or L-MP), during intracellular kinase phosphorylation. Both forms, L-TP and L-MP, inhibit viral DNA synthesis. It is advantageous as an antiviral drug because it is primarily not recognized by human polymerase as a substrate. As an L-(-)-nucleoside enantiomer instead of D-enantiomer, active lamivudine (3TC) is not primarily recognized by human polymerases as a substrate, but actively competes with natural cytidine triphosphate to inhibit reverse transcriptase DNA synthesis seen in both HIV-1 and HBV infection.[11] The triphosphate metabolite can also weakly inhibit mammalian DNA polymerase (alpha and beta types) and mitochondrial DNA (mtDNA) polymerase.[12][13]

Lamivudine is absorbed rapidly, with maximum lamivudine concentration 0.5 to 1.5 hours following oral dose administration and absolute bioavailability of approximately 82% in adults and 68% in children.[11] Lamivudine can be taken with or without food.  While the systemic exposure of lamivudine does not change with food intake, taking lamivudine with food slows the absorption rate by 40%. Lamivudine is manufactured as an oral liquid and tablet form and has equitable bioavailability in adults. The solid tablet is preferred in children because bioavailability is 40% lower in children using the oral liquid form.  While both doses of the solid tablet have the similar steady-state concentrations and therapeutic effects, the larger dose, 300mg taken once daily, has shown to have larger trough and maximum serum levels and is less consistent throughout the day as compared to the smaller 150mg tablet taken twice daily.

Lamivudine distributes into the total body fluid/extravascular spaces. It has a long intracellular half-life of as long as 15.5 hours for HIV infected cell and 19 hours for HBV infected cell.[4] However, viral replication site reservoirs showed varying pharmacokinetics. Lamivudine has shown to have a longer half-life and higher IC50 after the first dose in seminal mononuclear cells and the female genital tract.[14] Conversely, the cerebral spinal fluid has shown minimal transmission of lamivudine across the blood-brain barrier, especially in adults.[15][16] Lamivudine freely traverses the placenta, often presenting with exceedingly high concentrations, as well as is readily found in breast milk.

Lamivudine is eliminated in the urine as an active organic cation secretion.  The mean elimination half-life was 5 to 7 hours.[11] The average clearance of unaltered lamivudine is 71%, with 5 to 10% excreted as trans-sulfoxide.[11][17] This clearance indicates the necessity for sufficient kidney function in the patient, and dosing should be adjusted accordingly. Dialysis did not significantly increase the elimination of lamivudine to warrant dose modification. Pregnant women have a 22% increase in clearance of lamivudine without leading to sub exposure. [17][18]

Lamivudine does not undergo metabolism via the CYP450 pathway and minimally binds to plasma protein. Therefore, CYP450 inducers and inhibitors will not affect its metabolism, nor does it have many drug interactions with those that are protein-bound. While lamivudine has some drug-drug interactions, like interferon-alpha-blockers, ribavirin, zidovudine, and drugs that inhibit MATE-1, MATE-2K, OCT2transporters, like trimethoprim and indinavir, which increases the plasma concentration of lamivudine, no interactions have clinical significance.[19] One exception is sorbitol, which demonstrates dose-dependent decreases in the maximum serum concentration of lamivudine.

There are no known pharmacokinetic differences related to gender or race. Pharmacokinetic differences have not been sufficiently studied to extrapolate adjustments for either older age or glomerular filtration rate (GFR).

Lamivudine is available in 150 mg scored tablets, 300 mg tablets, and also as 5 mg or 10 mg/ml oral solutions. It may be taken with or without food and should be stored at room temperature. The patient should take a missed dose when they remember, but doses should not be doubled-up.

Doses should be adjusted accordingly for patient kidney function. Creatinine clearance greater than or equal to 50 mL/min should have a lamivudine dose of 150 mg twice per day or 300 mg once per day. Creatinine clearance of 30 to 49 mL/min should have a lamivudine dose of 150 mg once per day. If a patient's creatinine clearance is between 15 to 29 mL/min, they should receive 150 mg as a first dose, then 100 mg per day thereafter. Creatinine clearance of 5 to 14 mL/min equates to 150 mg as a first dose, then 50 mg per day thereafter. Creatinine clearance less than 5 mL/min, the patient would receive 50 mg as the first dose and then 25 mg per day.

Additional dosing is not necessary after either 4-hour routine hemodialysis or peritoneal dialysis.

Pediatric patients should be able to swallow tablets safely and should use a separate dosing schedule.  If the child is unable to swallow the tablet, oral solution dosage may need to increase because of the decrease in bioavailability.

Lower dose lamivudine is a once-daily 100 mg dose of lamivudine only indicated for HBV treatment without co-infection of HIV-1. Pre-administration testing and counseling are necessary, as well as subsequent testing while taking lower dose lamivudine.

Care is necessary if the patient is currently resistant to other previously prescribed antiviral medications. Chronic co-administration with sorbitol should be avoided to prevent a decrease in lamivudine concentration and a resultant decrease in lamivudine potency. Pharmacokinetic changes are minor with ZDV, ddI, cotrimoxazole, and interferon-alpha-2b, so no dose adjustment is recommended.[11] There is an increased risk of resistance with the administration of the oral solution to pediatric patients, so tablets are preferred whenever possible. Lamivudine is currently an FDA Category C drug.

Resistance to lamivudine as well as cross-resistance to other NRTI's, such as didanosine, abacavir, and emtricitabine, are seen in 10% of patients after treatment with lamivudine as a monotherapy or combined therapy after 48 weeks of treatment.[2] While this can result in a virologic failure, clinical observations suggest that there is a benefit to continuing lamivudine treatment even when an M184V substitution mutation causes resistance.[2][20]

Severe side effects include:

• Pancreatitis, particularly in children
• Hepatic decompensation
• Peripheral neuropathy
• Muscle pain
• Weakness
• Aplastic anemia
• Lactic acidosis with hepatomegaly and steatosis
• Stevens-Johnson syndrome*
• Immune reconstruction syndrome
• Fat redistribution

*Patients with HIV are already at a higher risk of acquiring Stevens-Johnson syndrome (SJS). Combined therapies also make it difficult to discern if one drug alone contributed to SJS or not. No direct cases appear in the literature.

Severe adverse effects occurred in about 5% of patients enrolled in all clinical trials. Children seemed to show a higher prevalence of fever and pancreatitis than adult patients.[21]

Several case studies have shown that lamivudine can cause unusual adverse effects like thrombocytopenia and paronychia.[22][23]

Common side effects:

• Headache
• Nausea
• Vomiting
• Diarrhea
• Weight loss
• Abdominal pain
• Fever
• Cough and nasal signs and symptoms

Lamivudine should not be administered to patients with known hypersensitivity.