Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):

    • Lamivudine (3TC, Epivir)1

      • Lamivudine (Epivir), a cytidine analog which inhibits reverse transcriptase, shows activity against HIV-1, HIV-2, and hepatitis B virus (HBV).¹ 

        • Structural Comparison Between Cytosine and Lamivudine⁶

        • Upon entering the cell, lamivudine, a prodrug similar to zidovudine and stavudine, must be converted to the triphosphate form to exhibit antiretroviral activity.

        • The conversion to the triphosphate occurs stepwise.

          • Firstly, deoxycytidine kinase catalyzes lamivudine monophosphate synthesis.

          • Secondly, the diphosphate form synthesis is catalyzed by deoxycytidine monophosphate kinase.

          • Lastly, the triphosphate form is catalyzed by nucleoside diphosphate kinase resulting in lamivudine 5'-triphosphate.

        • Lamivudine exhibits relatively low host toxicity probably because of its low tendency to associate with human DNA polymerases (low affinity).¹

      • Mutations and Lamivudine Resistance:¹

        • Two mutational sites have been identified in the reverse transcriptase gene associated with resistance to lamivudine.¹  

          • The first site at position 65 involves a replacement of the naturally occurring lysine with either arginine, glutamate, or asparagine.

          • The second site is localized at position 184 and involves a substitution of the naturally occurring methionine with either valine or isoleucine.

            • The second mutation is described as conferring "high-level resistance" to lamivudine and based on in vitro sensitivity to the drug, the reduction in sensitivity may be up to 1000-fold.^1,10  

          • The second mutation, termed M184V, appears to restore sensitivity to zidovudine in zidovudine-resistant HIV¹² and may partially restore tenofovir susceptibility in tenofovir-HIV resistance due to a mutation at position 65, the first site of lamivudine resistance.¹¹ 

            • This first site, termed K65R (arginine for lysine) also confers resistance to the antiretroviral drugs emtricitabine, didanosine, stavudine, abacavir as well as lamivudine.¹

          • As noted earlier above, lamivudine may also be administered to treat hepatitis B infection (HBV).

            • Mutational resistance to lamivudine also occurs in the HBV DNA polymerases gene.

              • The most significant mutation is a methionine-to-valine substitution at the enzyme catalytic site.

              • Up to 90% of HIV/HBV co-infected patients exhibit lamivudine resistance after about four years of therapy.¹

              • For individuals receiving lamivudine to manage HIV + HBV co-infection, lamivudine discontinuation may induce a hepatitis flare.⁷

      • Pharmacokinetics:^1,7

        • Lamivudine exhibits oral bioavailability of >80%, not influenced by food.^1,7  

          In children, CSF: plasma lamivudine ratio is about 0.2.⁷

          • Serum half-life of the parent, prodrug, lamivudine is about 2.5 hours although the intracellular half-life of the active, triphosphorylated drug is about 11-14 hours.⁷

          • Lamivudine is mainly eliminated, about 70%, unchanged in the urine.^1,7,13

            • Renal elimination is at least in part due to active tubular secretion.¹³

            • Dosage adjustment may be appropriate if creatine clearance drops below 50mL/min.^1,13

              • Half-life of lamivudine with normal renal function was estimated at about hours, rising to 22 hours in patients with end-stage renal disease.¹³

          • Lamivudine is an antiretroviral agent recommended for use in pregnant patients.⁷

      • Adverse Effects:

        • Lamivudine has relatively few significant adverse effects and is considered among the least toxic antiviral agents.¹ 

          • However, neutropenia, nausea and headache may occur at doses higher than that recommended.

          • As noted earlier, lamivudine exhibits antiviral activity against hepatitis B, reducing plasma HBV DNA levels.

          • In HIV patients co-infected with HBV or in areas in which HBV is endemic, abrupt lamivudine discontinuation may induce rebound HBV replication with worsening hepatitis.¹  

          • Mild adverse effects, however infrequent, include dizziness, fatigue, insomnia, gastrointestinal issues, dry mouth and headache.⁷ 

            • Bioavailability of lamivudine is increased if coadministered with trimethoprim-sulfamethoxazole (Bactrim).

            • Additionally, lamivudine and zalcitabine inhibit intracellular phosphorylation of each other; accordingly, concurrent use should be avoided.⁷

      • Therapeutics:

        • Lamivudine has been approved for treating HIV in both adults and children (≥ 3 months of age).¹ 

          • When used in monotherapy, lamivudine-resistance develops following an initial up to 90% reduction in plasma HIV-1RNA levels, typically observed within two weeks.

            • Reduction in plasma HIV-1 RNA and 52 weeks following lamivudine + zidovudine combination exceeds results obtained with zidovudine alone.

            • Combination of lamivudine with zidovudine or stavudine also is effective in promoting substantial decline in viral load (at 24 weeks), using zidovudine or stavudine monotherapy for comparison.

            • Lamivudine is effective in combination with other antiretroviral drugs and represents a common or "backbone" component of contemporary therapy.

              • Lamivudine efficacy and safety are important considerations.¹ 

          • Lamivudine (or the chemically related agent emtricitabine) is considered a "backbone" agent in many, nearly all, currently endorsed antiretroviral protocols.⁶ 

            • Lamivudine is available coformulated with abacavir, with zidovudine or with the combination abacavir and zidovudine.

            • Emtricitabine is available in several fixed-dose combinations with other antiretroviral agents.

              • These other drugs include tenofovir, efavirenz, rilpivirine, and elvitegravir.⁶

          •  

            Lamivudine (Epivir) Formulation Examples