Monograph of Lamivudine

Introduction

Lamivudine (3TC) is a nucleoside analogue reverse transcriptase inhibitor (NRTI) that has been widely employed in the management of human immunodeficiency virus (HIV) infection and hepatitis B virus (HBV) disease. The drug’s introduction in the early 1990s marked a pivotal advancement in antiretroviral therapy, owing to its favorable safety profile and oral bioavailability. Over the ensuing decades, lamivudine has become a cornerstone in combination regimens, influencing both virological suppression and long‑term clinical outcomes. Understanding its pharmacological properties, mechanisms of action, and therapeutic applications remains essential for clinicians, pharmacists, and researchers engaged in antiviral drug development.

Learning objectives for this chapter include:

• Describe the chemical structure and classification of lamivudine within the NRTI class.
• Explain the pharmacokinetic and pharmacodynamic characteristics that underpin its clinical use.
• Outline the mechanisms by which lamivudine interferes with viral replication.
• Identify therapeutic indications, dosing strategies, and potential resistance patterns.
• Apply knowledge of lamivudine to clinical case scenarios involving HIV and HBV management.

Fundamental Principles

Core Concepts and Definitions

Lamivudine is a synthetic analogue of the nucleoside cytidine, bearing a 3‑hydroxyl group that confers resistance to viral thymidine kinase. As an NRTI, it acts by competitive inhibition of viral reverse transcriptase (RT) and subsequent chain termination during viral DNA synthesis. The drug is classified as a pyrimidine analogue and is characterized by a 2′,3′‑dideoxy sugar moiety, which distinguishes it from ribavirin and other nucleoside analogues.

Theoretical Foundations

The therapeutic action of lamivudine can be conceptualized through the Michaelis–Menten kinetic framework, wherein the drug competes with endogenous deoxycytidine triphosphate (dCTP) for incorporation into viral DNA. The inhibition constant (K_i) for lamivudine triphosphate (3TC‑TP) is markedly lower than that of dCTP, enabling efficient displacement at clinically relevant concentrations. Once incorporated, the absence of a 3′‑hydroxyl group halts phosphodiester bond formation, thereby terminating chain elongation.

Key Terminology

• Reverse Transcriptase (RT) – Viral enzyme converting RNA to DNA.
• Nucleoside Analogue – Structurally similar to natural nucleosides but lacking essential functional groups.
• Chain Termination – Cessation of DNA synthesis following incorporation of an analogue.
• Resistance Mutation – Viral genetic change reducing drug efficacy.
• Pharmacokinetics (PK) – Study of drug absorption, distribution, metabolism, and excretion.
• Pharmacodynamics (PD) – Study of drug effects and mechanisms of action.

Detailed Explanation

Pharmacokinetic Profile

Lamivudine is administered orally, with a bioavailability of approximately 75–80 % when taken on an empty stomach. Peak plasma concentrations (C_max) are achieved within 1–2 h, and the terminal half‑life (t_1/2) is roughly 5–6 h in healthy adults. The drug undergoes minimal hepatic metabolism, primarily excreted unchanged via the kidneys. Renal clearance, therefore, constitutes the principal elimination pathway, and dose adjustment is warranted in patients with creatinine clearance (CrCl) < 50 mL min⁻¹.

Mathematical relationships governing lamivudine disposition include:

• AUC = Dose ÷ Clearance – Area under the concentration–time curve inversely proportional to clearance.
• C(t) = C₀ × e^-k_elt – Exponential decline of plasma concentration over time.
• t_1/2 = 0.693 ÷ k_el – Relationship between elimination rate constant and half‑life.

Mechanism of Action

Lamivudine is phosphorylated intracellularly by cellular kinases to its active triphosphate form (3TC‑TP). The triphosphate competes with dCTP for binding to the active site of viral RT. Upon incorporation, the missing 3′‑hydroxyl group prevents addition of the next nucleotide, resulting in abrupt termination of the nascent DNA chain. Unlike many other NRTIs, lamivudine exhibits a low affinity for mitochondrial DNA polymerase gamma, thereby reducing mitochondrial toxicity.

Factors Influencing Efficacy

Several variables modulate lamivudine’s antiviral potency:

• Viral Load – Higher baseline viral loads may necessitate combination therapy.
• Drug Concentration at the Site of Infection – Adequate tissue penetration is essential for optimal effect.
• Pharmacogenomics – Genetic polymorphisms affecting drug transporters (e.g., OATP1B1) may alter plasma exposure.
• Drug–Drug Interactions – Concomitant use of agents that inhibit renal transporters can elevate lamivudine levels.
• Resistance Mutations – The M204V/I mutation in HBV polymerase and the M184V mutation in HIV RT markedly reduce drug susceptibility.

Resistance and Genotypic Considerations

Lamivudine resistance emerges predominantly through specific point mutations. In HBV, the M204V/I mutation alters the active site of polymerase, diminishing drug incorporation. In HIV, the M184V mutation substitutes alanine for valine at position 184, conferring high-level resistance to lamivudine but enhancing sensitivity to other NRTIs (e.g., zidovudine). Monitoring for resistance via genotypic assays is therefore recommended in patients with virological failure.

Clinical Significance

Therapeutic Indications

Lamivudine is approved for use in:

• HIV‑1 Infection – As part of combination antiretroviral therapy (cART) regimens.
• Hepatitis B Virus (HBV) Infection – Adjunctive therapy in combination with other antivirals (e.g., tenofovir).
• Hepatitis D Virus (HDV) Co‑infection – When used in combination with interferon and other agents.

Practical Applications

In HIV therapy, lamivudine is frequently paired with tenofovir disoproxil fumarate (TDF) and efavirenz (EFV) or integrase strand transfer inhibitors (INSTIs) such as dolutegravir. For HBV, lamivudine is often combined with tenofovir alafenamide (TAF) or adefovir to mitigate resistance. The drug’s once‑daily dosing and minimal drug–drug interactions enhance adherence, particularly in resource‑constrained settings.

Clinical Examples

Case 1: A 32‑year‑old woman with newly diagnosed HIV presents with a CD4 count of 350 cells mm⁻³ and a viral load of 150,000 copies mL⁻¹. Initiation of a regimen containing lamivudine 150 mg bid, tenofovir 300 mg qd, and dolutegravir 50 mg qd results in a 1.5‑log reduction in viral load within 12 weeks. The patient remains virologically suppressed at 48 weeks, with no signs of renal impairment (CrCl = 90 mL min⁻¹). This illustrates lamivudine’s efficacy as part of a potent cART combination in a treatment‑naïve patient.

Case 2: A 45‑year‑old man with chronic HBV infection and a baseline viral load of 1 × 10⁸ IU mL⁻¹ is started on lamivudine 100 mg qd. After 18 months, viral suppression is achieved; however, a rise in HBV DNA to 5 × 10⁵ IU mL⁻¹ is detected. Genotypic analysis reveals the M204V mutation. The regimen is switched to tenofovir alafenamide 25 mg qd, and the viral load declines below the detection limit within 6 months. This scenario underscores the importance of resistance testing and timely regimen modification.

Safety and Tolerability

Lamivudine is generally well tolerated. Common adverse effects include headache, dizziness, and mild gastrointestinal discomfort. Hepatotoxicity is rare but may present as elevated alanine aminotransferase (ALT) levels; regular monitoring is advised. The risk of lactic acidosis, a concern with other NRTIs, is negligible with lamivudine, attributable to its low mitochondrial toxicity.

Clinical Applications/Examples

Case Scenarios

Scenario A: A 28‑year‑old man with HIV and concomitant hepatitis C virus (HCV) infection is on a regimen of lamivudine, tenofovir, and dolutegravir. He initiates direct‑acting antiviral (DAA) therapy for HCV. Drug interactions between lamivudine and sofosbuvir are minimal, allowing uninterrupted HIV control. Post‑therapy, the patient maintains undetectable HIV RNA and achieves sustained virologic response for HCV.

Scenario B: A 60‑year‑old woman with chronic kidney disease (CKD) stage 3 (CrCl ≈ 45 mL min⁻¹) and HBV is treated with lamivudine 100 mg qd. Dose adjustment is considered due to reduced renal clearance. A reduced dose of 50 mg qd maintains therapeutic levels while preventing accumulation and potential nephrotoxicity. Follow‑up demonstrates stable renal function and suppressed viral replication.

Problem‑Solving Approaches

• Assessing Virological Failure – Monitor viral load every 3–6 months; confirm adherence and rule out drug resistance.
• Managing Renal Impairment – Calculate CrCl using the Cockcroft–Gault equation; adjust lamivudine dose accordingly.
• Addressing Resistance – Perform genotypic testing; switch to regimens incorporating tenofovir or entecavir for HBV; consider zidovudine or abacavir for HIV if M184V is detected.
• Optimizing Adherence – Simplify dosing schedule; provide counseling on pill organization; use electronic reminders where feasible.

Summary/Key Points

• Lamivudine is a pyrimidine NRTI that inhibits viral reverse transcriptase by chain termination.
• Its pharmacokinetics are characterized by high oral bioavailability, minimal hepatic metabolism, and renal excretion; dose adjustment is required in renal impairment.
• Key resistance mutations include M204V/I (HBV) and M184V (HIV); monitoring and timely regimen modification are essential.
• Lamivudine’s favorable safety profile and once‑daily dosing enhance adherence in both HIV and HBV therapy.
• Clinical decision‑making should integrate viral genotyping, renal function assessment, and drug–drug interaction screening to optimize outcomes.

References

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