Continuing Education Activity

Lamivudine is a medication used in the management and treatment of HIV-1 and hepatitis B. It is in the nucleoside reverse transcriptase inhibitor (NRTI) class of medications. This activity outlines the indications, mechanism of action, and contraindications for lamivudine as a valuable agent in the therapy for HIV (and other disorders when applicable). This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the care of patients with HIV and hepatitis B.

Objectives:

• Identify the mechanism of action of lamivudine.
• Describe the adverse effects of lamivudine.
• Review the appropriate monitoring of lamivudine.
• Outline some interprofessional team strategies for improving care coordination and communication to advance lamivudine and improve outcomes.

Indications

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 patients' 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's (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 lamivudine, 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. It 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]

Mechanism of Action

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 a 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 a maximum lamivudine concentration of 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 systemic exposure to 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 similar steady-state concentrations and therapeutic effects, the larger dose, 300 mg taken once daily, has shown to have larger trough and maximum serum levels and is less consistent throughout the day compared to the smaller 150 mg 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 cells and 19 hours for HBV-infected cells.[4] However, viral replication site reservoirs showed varying pharmacokinetics. Lamivudine has been 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, and 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 protein-bound medications. 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).

Administration

Lamivudine is available in 150 mg scored tablets, 300 mg tablets, and 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 the patient's 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. With a creatinine clearance of 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 cannot swallow the tablet, the 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 administering 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 NRTIs, 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 a benefit to continuing lamivudine treatment even when an M184V substitution mutation causes resistance.[2][20]

Adverse Effects

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

Contraindications

Lamivudine should not be administered to patients with known hypersensitivity.

Monitoring

NRTIs as a class have more cases with resulting hepatomegaly, with some fatalities. Lactic acidosis, a usual NRTI toxicity, is not seen as frequently with lamivudine; however, females who are obese and have been on immunotherapy for an extended time seem to be at an increased risk. If a patient presents with symptoms, lamivudine should be discontinued immediately.[24] Additionally, the patient's liver function should be considered before beginning lamivudine; those with liver disease should rank as high risk.

Patients treated with interferon-alpha inhibitors with or without ribavirin when they are co-infected with HCV should be monitored closely for liver toxicities, especially hepatic decompensation, due to their pyrimidine phosphorylation reduction effects.  If decompensation or increased liver toxicity occurs, interferon-alpha inhibitors with or without ribavirin should be decreased or discontinued.

A patient using lamivudine for HBV should have testing for HIV-1, and patients with HIV-1 should be tested for HBV.  If the patient has a co-infection, the lower dose of lamivudine (EPIVIR-HBV) is not adequate for patients and could lead to increased antiviral resistance of either virus for both adults and children.[25][26] Patients should not discontinue lamivudine while co-infected with HIV-1 and HBV. Severe, acute hepatitis B exacerbation can occur. Hepatic function (ALT levels) should be closely monitored for several months after stopping treatment, and initiation of anti-hepatitis B treatment may be appropriate with physician-guided discontinuation.

CD4+ cell count and viral load should have frequent checking to determine HIV-1 disease progression and efficacy and extent of virologic failure resulting in lamivudine resistance in combination therapy.[27] Patients should also receive monitoring for the development of inflammatory responses to opportunistic infections commonly seen in HIV patients (mycobacterium avium, CMV, PCP, TB) as well as autoimmune disorders within the first few months of starting combination antiviral therapy, including lamivudine as symptoms of immune reconstitution syndrome. 

Kidney indicators require monitored throughout treatment, especially in chronic kidney disease (CKD) patients. CKD is a natural occurrence as we age, so special attention may be necessary in the treatment of older patients.

Pediatric patients who have a history of antiviral therapy or a history of pancreatitis need monitoring for lamivudine-induced pancreatitis. Pediatric patients should also know to avoid sorbitol-containing medicines when using oral lamivudine because antiviral resistance and lower virologic suppression rates can occur due to lower plasma lamivudine exposure.[21][28]

Fat redistribution in a "cushingoid appearance," lipoatrophy, and insulin resistance should also be monitored in patients using NRTIs.[29]

Toxicity

Lamivudine is usually well tolerated with milder toxicities compared to other NRTIs.[30] If an overdose of lamivudine occurs, supportive care should be provided with monitoring. Dialysis is not a reliable treatment for an overdose of lamivudine.

No human trials to date have provided evidence of carcinogenesis, mutagenesis, or fertility impairment.

Enhancing Healthcare Team Outcomes

Proper patient education on dosage, monitoring, and stopping treatment will help improve outcomes. Proper physician education on considerations when prescribing, comorbidities, monitoring, and stopping treatment is also necessary. Care is essential when prescribing the oral solution for pediatric patients due to the possibility of pancreatitis or worsening existing pancreatitis. Consideration is also required when prescribing the correct formula for the proper condition(s). Lower dose lamivudine is indicated for patients with HBV only. If a patient is co-infected with HIV-1, a larger dose of lamivudine is necessary to prevent HIV-1 mutation and resistance. Additionally, co-administered sorbitol-containing medicines should be avoided to limit the sub-exposure of medication. All these factors require the efforts of an interprofessional healthcare team that includes clinicians (MDs, DOs, PAs, NPs), specialists (particularly with infectious disease and HIV specialized training), nurses, and pharmacists, collaborating so that lamivudine and other antiviral measures can be optimized and issues that can limit therapeutic effectiveness avoided. This will result in better patient outcomes. [Level 5]