Tenofovir Monograph

Introduction

Tenofovir is a nucleotide analog reverse transcriptase inhibitor (NRTI) that has become a cornerstone of antiretroviral therapy for human immunodeficiency virus (HIV) infection and a first‑line agent for chronic hepatitis B virus (HBV) infection. The compound was first synthesized in the 1970s but did not gain clinical relevance until the late 1990s, when it was developed into oral formulations suitable for long‑term therapy. Since its introduction, tenofovir has substantially contributed to reduced morbidity and mortality among patients with HIV and HBV and has shaped contemporary treatment guidelines worldwide.

Students are expected to acquire a comprehensive understanding of tenofovir’s pharmacological profile, including its biochemical mechanisms, pharmacokinetic behavior, therapeutic indications, and potential adverse effects. The following learning objectives outline the core competencies addressed in this chapter:

• Describe the chemical structure and synthesis of tenofovir and its lipid‑conjugated prodrugs.
• Explain the antiviral mechanism of action at the cellular and molecular levels.
• Summarize the pharmacokinetic parameters influencing drug disposition and dosing strategies.
• Identify clinical indications, contraindications, and common drug interactions.
• Apply knowledge to case scenarios involving HIV, HBV, and prophylactic use, focusing on dose adjustments and toxicity monitoring.

Fundamental Principles

Core Concepts and Definitions

Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of tenofovir (TFV). Both are prodrugs designed to enhance oral bioavailability; TDF undergoes extensive first‑pass hepatic metabolism, whereas TAF is preferentially converted in peripheral cells, resulting in lower plasma concentrations and reduced systemic exposure. The active moiety, tenofovir diphosphate (TFV‑DP), competes with natural deoxyadenosine diphosphate for incorporation into viral DNA by reverse transcriptase, leading to chain termination.

Key terminology includes:

• Prodrug: An inactive compound that is metabolized to release the active drug.
• Chain termination: The cessation of nucleic acid polymerization due to incorporation of a nucleotide analogue lacking a 3′‑hydroxyl group.
• Pharmacodynamics: The relationship between drug concentration and its antiviral effect.
• Pharmacokinetics: The absorption, distribution, metabolism, and excretion (ADME) profile of the drug.

Theoretical Foundations

The therapeutic activity of tenofovir is grounded in nucleoside reverse transcriptase inhibitor (NRTI) pharmacology. Unlike nucleosides, which require phosphorylation to the triphosphate form, tenofovir is a nucleotide analog that bypasses the first phosphorylation step, thereby enhancing potency. Once phosphorylated to TFV‑DP, the analog is incorporated into nascent viral DNA strands. Because the 3′‑hydroxyl group is absent, further elongation is prevented, resulting in premature termination of the DNA chain.

Mathematical relationships are employed to quantify tenofovir exposure and effect. The concentration–time profile follows first‑order kinetics, expressed as:

C(t) = C₀ × e⁻ᵏᵗ

where C(t) is the plasma concentration at time t, C₀ is the initial concentration, and k is the elimination rate constant. The area under the concentration–time curve (AUC) is calculated as:

AUC = Dose ÷ Clearance

From the AUC, the half‑life (t_1/2) can be derived:

t_1/2 = 0.693 ÷ k

These equations aid in determining appropriate dosing intervals and in predicting steady‑state concentrations.

Detailed Explanation

Chemical Structure and Synthesis

Tenofovir is the 9‑(3′‑deoxythymidyl) analog of adenosine monophosphate with a phosphonate group at the 5′ position. The synthetic route typically involves the phosphorylation of the monophosphate precursor followed by esterification to yield the disoproxil or alafenamide prodrugs. TDF is formed by the esterification of the phosphonate with two butyl groups and a fumarate moiety, whereas TAF incorporates an alanine‑derived fatty acid ester, conferring improved stability in plasma.

These structural modifications serve to increase lipophilicity, thereby improving intestinal permeability. In the case of TAF, the conjugated fatty acid also facilitates direct delivery to lymphoid tissues, where it is preferentially activated.

Mechanism of Antiviral Action

Tenofovir’s primary target is the reverse transcriptase enzyme of HIV and HBV. The active diphosphate form competes with deoxyadenosine diphosphate (dATP) for incorporation into viral DNA. The incorporation of TFV‑DP results in chain termination due to the absence of a 3′‑hydroxyl group. Additionally, TFV‑DP can inhibit the terminal transferase activity of reverse transcriptase, further reducing viral replication.

In HBV, tenofovir also inhibits the viral polymerase, which shares structural features with reverse transcriptase. Consequently, tenofovir demonstrates potent activity against HBV strains resistant to lamivudine and other nucleoside analogs.

Pharmacokinetics

Absorption. Oral TDF achieves a maximum plasma concentration (C_max) of approximately 1.2 µg mL⁻¹ within 2–3 hours post‑dose. TAF reaches a C_max of 0.06 µg mL⁻¹ in plasma but achieves higher intracellular concentrations of TFV‑DP due to efficient cellular uptake and activation. The bioavailability of TAF is roughly 50 % lower than TDF, yet the clinically relevant exposure is maintained through intracellular activation.

Distribution. Tenofovir distributes extensively into tissues, including the liver, kidney, and lymphoid organs. The drug exhibits a volume of distribution (V_d) of 23 L kg⁻¹ for TDF and 15 L kg⁻¹ for TAF, reflecting differences in plasma protein binding and tissue partitioning.

Metabolism. TDF undergoes hydrolysis by esterases in the gastrointestinal tract and liver, releasing tenofovir. This process generates a significant amount of plasma tenofovir, which is subsequently phosphorylated. TAF is hydrolyzed primarily by cathepsin A in peripheral cells, producing tenofovir with minimal systemic exposure. Tenofovir itself is not further metabolized; it is eliminated unchanged.

Excretion. Renal excretion is the principal elimination route, with approximately 70–80 % of an administered dose cleared via glomerular filtration and active tubular secretion. The estimated renal clearance (CL_r) is 80 mL min⁻¹ for TDF and 60 mL min⁻¹ for TAF. The half‑life of tenofovir is roughly 17 hours, permitting once‑daily dosing in most regimens.

Factors Influencing Pharmacokinetics

Age and renal function are pivotal determinants of tenofovir exposure. In patients with reduced glomerular filtration rate (GFR), accumulation of tenofovir may occur, necessitating dose adjustments. Hepatic impairment generally has limited impact, given the minimal role of hepatic metabolism in elimination.

Drug–drug interactions can modulate tenofovir disposition. Concomitant use of potent P‑glycoprotein inhibitors (e.g., ritonavir) can increase systemic exposure, whereas inducers (e.g., rifampin) may reduce plasma concentrations. Interaction with tenofovir’s prodrugs must also be considered, particularly when combining TDF with other antiretrovirals that alter CYP450 activity.

Pharmacodynamics and Efficacy

The antiviral potency of tenofovir is reflected in its half‑maximum inhibitory concentration (IC₅₀) for HIV reverse transcriptase, which lies in the low nanomolar range (≈0.4 µM). For HBV, the IC₅₀ is similarly low, underscoring its clinical efficacy.

Clinical trials have demonstrated that tenofovir is highly effective in achieving viral suppression. In HIV, TDF achieves a mean reduction in viral load of >4 log₁₀ copies mL⁻¹ within 12 weeks of therapy. In HBV, sustained suppression of viral replication is observed in >90 % of patients over 48 weeks of TAF therapy.

Resistance. Tenofovir has a high genetic barrier to resistance. The primary resistance mutations in HBV are rtN2366 and rtA181T, which arise infrequently. In HIV, the K65R mutation confers reduced susceptibility but requires multiple co‑existing mutations to significantly diminish efficacy.

Clinical Significance

Therapeutic Indications

Tenofovir is approved for use in several clinical scenarios:

• First‑line antiretroviral therapy for HIV-1 infection, usually in combination with other agents.
• First‑line treatment for chronic HBV infection and as part of combination therapy for HBV/HIV co‑infection.
• Post‑exposure prophylaxis (PEP) for HIV, typically administered as a 28‑day course following high‑risk exposure.

In HIV, TDF is often combined with emtricitabine (FTC) to form a single‑tablet regimen, while TAF is combined with FTC or lamivudine (3TC) in newer formulations. In HBV, TAF is preferred in patients with renal impairment or bone disease due to its lower systemic exposure.

Practical Applications and Dosing

Standard dosing recommendations include:

• TDF 300 mg once daily for HIV and HBV.
• TAF 25 mg once daily for HIV and HBV.
• PEP: TDF 300 mg plus FTC 200 mg daily for 28 days, with optional addition of dolutegravir 50 mg once daily.

Dose adjustments are guided by renal function. For patients with estimated GFR <30 mL min⁻¹, TDF is contraindicated, whereas TAF may be reduced to 15 mg daily if eGFR <30 mL min⁻¹ or to 10 mg daily if eGFR <15 mL min⁻¹. Monitoring of serum creatinine, phosphate, and bone mineral density is recommended at baseline and periodically during therapy.

Safety and Adverse Effects

Tenofovir’s most common adverse effects include renal tubular dysfunction, manifested as Fanconi syndrome, and decreased bone mineral density. These risks are more pronounced with TDF, particularly in patients with pre‑existing renal impairment or osteoporosis. TAF’s improved safety profile results from lower plasma concentrations and reduced systemic exposure.

Other potential adverse reactions involve gastrointestinal upset, headache, and mild elevations in liver enzymes. Hypersensitivity reactions are rare but should be monitored. The risk of drug resistance is low but remains a concern in patients with subtherapeutic exposure.

Clinical Applications/Examples

Case Scenario 1 – HIV Treatment in a Patient with Normal Renal Function

A 35‑year‑old male presents with newly diagnosed HIV infection, CD4 count 600 cells µL⁻¹, and viral load 120,000 copies mL⁻¹. His estimated GFR is 95 mL min⁻¹. The recommended regimen includes TDF 300 mg daily plus FTC 200 mg daily, with a third agent selected based on resistance profile and comorbidities. Baseline labs include renal panel, liver enzymes, and baseline bone mineral density assessment. Follow‑up at 4, 12, and 24 weeks includes viral load measurement and renal function testing. If viral suppression is achieved and renal function remains stable, the regimen may be maintained; otherwise, dose adjustment or switch to TAF is considered.

Case Scenario 2 – HBV Treatment in a Patient with Chronic Kidney Disease

A 58‑year‑old female with HBV infection and stage 3 chronic kidney disease (eGFR 48 mL min⁻¹) presents for initiation of antiviral therapy. The optimal choice is TAF 25 mg daily, owing to its lower renal exposure. Baseline serum phosphate and calcium levels are measured to screen for subclinical tubular dysfunction. The patient is advised to maintain adequate hydration and to avoid nephrotoxic agents. At 12‑month follow‑up, serum creatinine remains stable, and HBV DNA is undetectable, indicating effective viral suppression.

Case Scenario 3 – Post‑Exposure Prophylaxis in a Healthcare Worker

A nurse is exposed to a patient with unknown HIV status via needlestick injury. The nurse’s baseline HIV test is negative. Tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg are prescribed daily for 28 days, with dolutegravir 50 mg added for enhanced efficacy. Renal function is assessed before initiation, and the nurse is monitored for side effects during the course. At day 30, a repeat HIV test remains negative, and the prophylaxis is considered successful.

Problem‑Solving Approach to Tenofovir‑Associated Renal Toxicity

1. Identify risk factors: pre‑existing renal impairment, concomitant nephrotoxic drugs, dehydration.
2. Monitor serum creatinine, eGFR, and urine analysis for glycosuria, phosphaturia, and aminoaciduria.
3. If Fanconi syndrome is suspected, discontinue tenofovir and provide supportive care.
4. Consider switching to TAF or alternative NRTI with lower renal burden.
5. Re‑evaluate renal function periodically after the switch to confirm recovery.

Summary / Key Points

• Tenofovir is a nucleotide analog reverse transcriptase inhibitor with proven efficacy in HIV and HBV infection.
• Prodrugs TDF and TAF differ in absorption, plasma exposure, and safety profiles.
• The active metabolite, TFV‑DP, inhibits viral DNA synthesis by chain termination.
• Key pharmacokinetic parameters: C_max ≈ 1.2 µg mL⁻¹ (TDF), t_1/2 ≈ 17 h, renal clearance 80 mL min⁻¹.
• Renal function dictates dosing: TDF contraindicated when eGFR <30 mL min⁻¹; TAF may be used with dose reduction.
• Clinical pearls: monitor renal function, bone mineral density, and serum phosphate; use TAF in patients at risk of renal or bone toxicity; avoid concomitant nephrotoxic agents.
• Resistance remains rare; K65R in HIV and rtN2366 in HBV are the principal mutations.
• Post‑exposure prophylaxis requires a 28‑day course of TDF/FTC with optional dolutegravir.

Through rigorous understanding of tenofovir’s pharmacology and clinical application, students can effectively integrate this agent into therapeutic regimens, ensuring optimal patient outcomes while mitigating adverse effects.

References

1. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.