Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

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

    • Tenofovir (Viread)1

      • Tenofovir disoproxil lacks a complete ribose ring, as the drug is a derivative of adenosine 5'-monophosphate.¹

        •  

          Comparison of adenosine 5'- monophosphate structure (top) and Tenofivir disoproxil (bottom)

        • This drug is the only nucleotide analogue presently marketed for treatment of HIV.¹

        • Tenofovir exhibits poor oral bioavailability and therefore is available instead as the disoproxil prodrug.

          • This formulation enhances both oral absorption as well as cellular access.

        • Tenofovir, similar to lamivudine and emtricitabine, shows antiviral activity not only against HIV-1 and HIV-2 but also hepatitis B virus (HBV).

        • Much like other agents discussed to this point tenofovir disoproxil, following a hydrolysis step that forms tenofovir, subsequent phosphorylation is required for pharmacological activity.

          • Tenofovir, the monophosphate, is itself twice more phosphorylated, catalyzed by cellular kinases, forming a triphosphase to the active form, tenofovir diphosphate.

            • Tenofovir diphosphate exhibits competitive inhibition of viral reverse transcriptase and upon incorporation into HIV DNA causes DNA chain termination due to its incomplete ribose moiety.

              • Selected toxicity to viral DNA is due to tenofovir diphosphate low affinity for human DNA polymerases-α,-β and-γ.¹

    • Mutations and Resistance to Tenofovir (Viread):¹ 

      • Mutations associated with tenofovir resistance occur at amino acid 65 and amino acid 70.^7,9  

        • At amino acid 65 a naturally occurring lysine is substituted for by either arginine, glutamate or asparagine.

        • At amino acid 70 the naturally occurring lysine is substituted for by glutamate.⁹  

          • Of the two, the substitution at codon 65 (amino acid 65 of the viral reverse transcriptase) has been shown to decrease in vitro sensitivity by about 3-4 fold and appears associated with clinical failure of drug protocols containing tenofovir.¹  

            • Patients exhibiting HIV strains with substantial resistant to zidovudine or stavudine respond suboptimally to tenofovir administration.

            • HIV strains resistant to zidovudine, however, exhibit only partial tenofovir resistance.

            • The mutation at amino acid 65 was noted in only 2-3% of tenofovir-treated individuals in the initial clinical studies.¹

              • Patients not responding to tenofovir-containing multi-antiretroviral drugs are more likely to exhibit genotypic resistance to other drugs in the protocol.¹  

                • An alternative example is the once-per-day multidrug protocol involving three nucleosides, tenofovir + didanosine + lamivudine and tenofovir + abacavir + lamivudine.

                • For these regimens, very early high rates of serologic failure (nonresponse) may be noted and in those cases mutation at amino acid 65 was shown in ⅓ to ⅔ of viral isolates.

                • Accordingly, these particular combination protocols should probably not be administered.^1,11

    • Pharmacokinetics:^1,12

      • Tenofovir disoproxil fumarate (tenofovir DF) is much more readily transported across intestinal mucosal membranes compared to tenofovir.

        • Tenofovir DF exhibited dose-proportional pharmacokinetics based on a randomized, double-blind, placebo-controlled clinical study.

        • Oral bioavailability of tenofovir (tenofovir DF at 300 mg/day) was about 25% which increased about 40% when the drug was administered with a high-fat meal.¹²  

        • The plasma elimination half-life is about 12 hours.

          • Intracellular tenofovir diphosphate half-lives depend on the type of cell studied, ranging from about 11 hours in peripheral blood monocytes to about 49 hours in resting cells.¹²  

        • Tenofovir undergoes renal excretion by both glomerular filtration and active tubular secretion.

          • About 75% of the drug can be recovered as the parent compound in the urine.

          • Because of the extent of excretion by the kidneys, tenofovir doses should be reduced in patients with renal insufficiency.¹²

    • Adverse Effects:

      • Gastrointestinal complaints represent the most common set of adverse effects and include diarrhea, vomiting, flatulence and nausea.⁷ 

        • Individuals with lactose intolerance may be especially sensitive to G.I. effects since tenofovir is formulated with lactose.

        • Other possible adverse effects involve dizziness, asthenia, rash, and headache.

        • Reduced renal function has been noted, although this effect was considered most likely due to concurrent enhanced protease inhibitor protocol components.⁷  

          • However, recent clinical studies establish association between tenofovir and renal dysfunction.^6,14 

            • 50% of individuals receiving 10 years of tenofovir therapy exhibited a GFR below 90 ml/min/1.73 m².

            • Kidney disease events, likely irreversible, were identified.

            • These events included proteinuria and chronic kidney disease (CKD).^6,14   

              • Pre-existing renal disease was not shown to exacerbate the effects of tenofovir.

              • Also, other antiretroviral drugs exhibited weaker or inconsistent associations with kidney disease.^6,14 

          • As a result of the dependence on the kidneys for tenofovir excretion, this drug must be used with caution for patients at risk for renal dysfunction.⁷

            • Patients with renal dysfunction should probably not receive tenofovir, although whether or not this is an absolute contraindication may be dependent of the extent of renal dysfunction varies depending on conclusions by government agencies in different countries.⁷  

          • Excessive renal phosphate and calcium loss with 1-hydroxylation "defects" of vitamin D has been described to tenofovir-associated proximal renal tubular effects.⁷  

            • Osteomalacia has been noted in several animal species with tenofovir use identified as an independent bone fracture risk factor.

              • Accordingly, with long-term tenofovir use, monitoring of bone mineral density may be appropriate.⁷  

              •  

                "Newborns Exposed to Tenofovir Have Lower Bone Density"

                Attribution: Silberry G Newborns Exposed to Tenofovir Have Lower Bone Density https://www.youtube.com/watch?v=H3VvbZr0LEk (3/2014) HIVandHepatitis YouTube Channel:  https://www.youtube.com/channel/UCVR_clqbkKpGdU0WGZmT9-A

        • Other drugs dependent on the kidney for elimination may compete with tenofovir.⁷  

          • Such examples include cidofovir, ganciclovir and acyclovir. Tenofovir exhibits activity against hepatitis B virus (HBV).

            • As a result, discontinuation of tenofovir in patients co-infected with HBV and in those regions with high HBV seroprevalence, a rebound of HBV tenofovir-suppressed replication with worsening of hepatitis is a concern.⁷  

          • Although tenofovir is not metabolized significantly by the microsomal cytochrome P450 system (CYP) and does not either induce or inhibit these enzymes, some non-CYP dependent drug interactions may occur.¹ 

            • For example tenofovir administration may increase didanosine AUC (area under the curve) by about 50%, due to combined tenofovir + tenofovir monophosphate purine nucleoside phosphorylase inhibition.

              • This observation has led to the suggestion that these two drugs, tenofovir and didanosine perhaps should not be used in combination, although if combination is required a reduction in didanosine dosage would seem appropriate.¹

         

    • Therapeutics:

      • Tenofovir (Viread) Formulation Example

      • Administration of tenofovir in "antiretroviral-experienced" patients was associated with a further long-term reduction in HIV plasma RNA concentrations.¹ 

        • This reduction was of the order of 6 fold compared to placebo and sustainable at least 48 weeks into treatment.

        • Tenofovir-associated antiretroviral activity (when administered in 3-drug combinations with other antiretrovirals) has been validated in several large clinical trials.¹   

          • These other antiretroviral agents include nucleoside analogues, protease inhibitors and/or non-nucleoside reverse transcriptase inhibitors (nnRTIs).

        • In treatment-naïve patients evaluated in a randomized, double-blind trial and who also received lamivudine and efavirenz, tenofovir was demonstrated as effective but less toxic than stavudine.^1,16 

      • Tenofovir is undergoing investigation as part of a prophylactic regimen, including prevention of mother-to-child transmission.

        • In this context, tenofovir may have some advantages compared to zidovudine.^1,15

      • Tenofovir in combination with emtricitabine (combination=Truvada), a fixed-dose combination of two antiretroviral drugs, has been approved for pre-exposure prophylaxis against HIV infection.^17,7 

        •  

          Truvada