Pharmacology of Tenofovir

Introduction/Overview

Tenofovir represents a cornerstone nucleoside reverse transcriptase inhibitor (NRTI) in the contemporary management of chronic viral infections, specifically human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Its development marked a significant advancement in antiretroviral therapy, offering potent viral suppression with a generally favorable resistance profile. The clinical importance of tenofovir is underscored by its inclusion in multiple first-line treatment regimens globally, both for treatment-naïve patients and as a backbone in complex salvage therapies. The evolution from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) exemplifies progress in drug design, aiming to enhance therapeutic efficacy while mitigating dose-limiting toxicities associated with systemic drug exposure.

The following learning objectives are intended to guide the study of this chapter:

• Describe the chemical classification, prodrug mechanisms, and active metabolite of tenofovir formulations.
• Explain the detailed molecular mechanism of action by which tenofovir inhibits viral reverse transcriptase and DNA polymerase.
• Compare and contrast the pharmacokinetic profiles, including absorption, distribution, metabolism, and excretion, of tenofovir disoproxil fumarate and tenofovir alafenamide.
• Outline the approved clinical indications, common adverse effects, and major drug interactions associated with tenofovir therapy.
• Analyze special population considerations, including dosing adjustments for renal impairment and use during pregnancy.

Classification

Tenofovir is definitively classified within the broad therapeutic category of antiviral agents. Its specific mechanistic classification is as a nucleoside reverse transcriptase inhibitor (NRTI). NRTIs are analogues of endogenous nucleosides, which upon intracellular activation to their nucleotide forms, compete with natural substrates for incorporation into viral DNA, leading to chain termination.

Chemical Classification and Prodrug Forms

Chemically, tenofovir is an acyclic nucleoside phosphonate analogue of adenosine monophosphate. Its unique acyclic structure confers stability against enzymatic hydrolysis, distinguishing it from traditional nucleoside analogues. A critical pharmacological concept is that tenofovir itself possesses poor oral bioavailability. Consequently, it is administered as lipophilic prodrug esters designed to enhance intestinal absorption and facilitate intracellular delivery.

Two primary prodrug formulations are in clinical use:

• Tenofovir Disoproxil Fumarate (TDF): This is a bis-isopropoxycarbonyloxymethyl ester prodrug of tenofovir. Following oral administration, esterases in the plasma and tissues rapidly hydrolyze the prodrug to release tenofovir. TDF results in high plasma levels of tenofovir, which are then taken up into cells, including target lymphocytes and renal proximal tubule cells, via organic anion transporters.
• Tenofovir Alafenamide (TAF): This is a more recent phosphonoamidate prodrug. TAF is more stable in plasma but is selectively activated within target cells (primarily lymphocytes and hepatocytes) by cathepsin A. This targeted activation allows for significantly lower doses of TAF (typically 25 mg) compared to TDF (300 mg) to achieve equivalent or superior intracellular concentrations of the active metabolite, tenofovir diphosphate, while minimizing systemic exposure to tenofovir.

Both prodrugs are ultimately converted intracellularly by a two-step phosphorylation process, catalyzed by cellular kinases, to the active moiety: tenofovir diphosphate (TFV-DP).

Mechanism of Action

The antiviral activity of tenofovir is mediated exclusively through its diphosphorylated metabolite, tenofovir diphosphate (TFV-DP). This mechanism is characterized by competitive inhibition and obligatory chain termination of viral nucleic acid synthesis.

Molecular and Cellular Pharmacodynamics

TFV-DP acts as an alternative substrate for the viral polymerases. For HIV, the target enzyme is the virally encoded reverse transcriptase (RT). For HBV, the target is the viral DNA polymerase, which also possesses reverse transcriptase activity. The mechanism proceeds through several sequential steps:

1. Competitive Binding: TFV-DP, structurally analogous to the natural substrate deoxyadenosine triphosphate (dATP), competes with dATP for binding to the active site of the viral polymerase.
2. Incorporation: Following binding, the viral polymerase catalyzes the incorporation of TFV-DP into the growing DNA chain. The phosphonate bond in TFV-DP is structurally similar to the phosphate ester bond in natural nucleotides, allowing for this incorporation.
3. Chain Termination: After incorporation, the molecule lacks a 3′-hydroxyl group, which is essential for forming the phosphodiester bond with the next incoming nucleotide. This absence results in the irreversible termination of DNA chain elongation. The incorporated tenofovir monophosphate cannot be excised by the proofreading exonuclease activity of HIV-1 RT, making the termination event permanent.

The primary pharmacodynamic outcome is the inhibition of viral replication. In HIV, this prevents the conversion of viral genomic RNA into proviral DNA, a critical step for integration into the host genome. In HBV, it directly inhibits the reverse transcription step within the viral replication cycle, reducing the production of new viral DNA within the hepatocyte nucleus and cytoplasm.

Pharmacokinetic-Pharmacodynamic Relationship

The antiviral effect correlates with the intracellular concentration and persistence of TFV-DP. TFV-DP has an exceptionally long intracellular half-life (>60 hours in peripheral blood mononuclear cells and several days in certain tissue reservoirs), which permits once-daily dosing. This prolonged intracellular residence time is a key determinant of its potent and sustained antiviral activity, and it also provides a forgiving pharmacokinetic profile, where missed doses are less likely to immediately result in virologic failure compared to drugs with shorter intracellular half-lives.

Pharmacokinetics

The pharmacokinetic profiles of TDF and TAF differ substantially due to their distinct prodrug designs, which directly influence their efficacy and toxicity profiles.

Absorption

TDF: The oral bioavailability of tenofovir from TDF, when administered with a meal, is approximately 25%. Administration with a high-fat meal increases the area under the curve (AUC) by approximately 40%. It is rapidly hydrolyzed in plasma to tenofovir.

TAF: TAF demonstrates higher stability in plasma and greater permeability. Its oral bioavailability is estimated to be greater than 80%, with absorption enhanced by food. Less than 1% of TAF is converted to tenofovir in plasma; the majority remains intact for uptake into target cells.

Distribution

Following release from its prodrug, tenofovir is widely distributed into tissues. The volume of distribution at steady-state is large, exceeding total body water, indicating significant tissue binding. Tenofovir distributes into seminal fluid, vaginal secretions, and cerebrospinal fluid, though CSF penetration is relatively low. Plasma protein binding is minimal (<7% for tenofovir and approximately 80% for TAF). The key distinction is that TAF leads to higher intracellular concentrations of TFV-DP in lymphoid cells and hepatocytes while producing plasma tenofovir levels that are over 90% lower than those achieved with TDF.

Metabolism

Tenofovir itself is not metabolized by the hepatic cytochrome P450 enzyme system. The metabolic activation is confined to intracellular phosphorylation. TDF is hydrolyzed by non-specific esterases in the gut, blood, and tissues. TAF is metabolized primarily within cells by cathepsin A and other hydrolases. Neither prodrug is a significant inhibitor, inducer, or substrate of CYP450 enzymes, which minimizes the potential for pharmacokinetic drug interactions mediated through this pathway.

Excretion

Tenofovir is eliminated almost exclusively by the kidneys through a combination of glomerular filtration and active tubular secretion via organic anion transporters (OAT1 and OAT3) in the proximal tubule. Following oral administration of TDF, approximately 70-80% of the dose is recovered unchanged in the urine within 72 hours. The renal clearance of tenofovir exceeds the glomerular filtration rate, confirming active secretion. The elimination half-life (t_1/2) of tenofovir in plasma is approximately 17 hours, but as noted, the intracellular half-life of the active TFV-DP is considerably longer. For TAF, renal excretion of intact prodrug is negligible; its metabolites are excreted renally and fecally.

Dosing Considerations

The standard adult oral dose for HIV treatment is 300 mg once daily for TDF and 25 mg once daily for TAF, both typically administered as part of a fixed-dose combination tablet. For chronic HBV monotherapy, the dose of TDF is also 300 mg daily. The dose of TAF for HBV is 25 mg daily. The profound difference in milligram dose between the two prodrugs, while achieving similar antiviral efficacy, directly reflects the superior targeted delivery and intracellular activation of TAF. Dosing must be adjusted in patients with impaired renal function, particularly for TDF, due to its reliance on renal clearance and association with nephrotoxicity.

Therapeutic Uses/Clinical Applications

Tenofovir is a pivotal agent in antiviral therapy with well-established indications.

Approved Indications

• Treatment of HIV-1 Infection: Both TDF and TAF are approved, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and pediatric patients. They form a backbone component of most recommended initial regimens due to their potency, durability, and high genetic barrier to resistance.
• Treatment of Chronic Hepatitis B Virus (HBV) Infection: TDF and TAF are approved for the treatment of chronic HBV infection in adults and pediatric patients. They are potent inhibitors of HBV replication and are indicated for patients with compensated or decompensated liver disease.
• Pre-Exposure Prophylaxis (PrEP) for HIV: TDF, co-formulated with emtricitabine (FTC/TDF), is approved for HIV PrEP in individuals at high risk of acquiring HIV. TAF co-formulated with emtricitabine (FTC/TAF) is also approved for PrEP, with specific indications based on patient sex and risk factors. PrEP involves the continuous use of antiretrovirals by HIV-negative individuals to reduce the risk of infection.

Off-Label Uses

While the aforementioned are the primary licensed uses, tenofovir may be considered in certain complex scenarios under specialist guidance. These can include its use in multi-drug resistant HIV infections where it retains activity, or in specific post-exposure prophylaxis (PEP) regimens, though other agents are often preferred for standard PEP. Its use for the prevention of mother-to-child transmission of HBV in highly viremic pregnant women is an area of active clinical management, though formal labeling may vary by region.

Adverse Effects

The adverse effect profile differs meaningfully between the two prodrug formulations, largely attributable to the lower systemic tenofovir exposure with TAF.

Common Side Effects

For TDF, common side effects are often gastrointestinal and include nausea, diarrhea, flatulence, and headache. Mild to moderate effects on renal tubular function, manifesting as a small, non-progressive increase in serum creatinine and a decrease in estimated glomerular filtration rate (eGFR), are frequently observed. A decrease in bone mineral density (BMD), particularly at the hip and spine, has been documented in patients receiving TDF-containing regimens.

For TAF, the spectrum shifts. Gastrointestinal effects are less frequent. The most commonly reported adverse effects with TAF-containing regimens include headache and fatigue. Weight gain has been observed more commonly in patients initiating therapy with TAF-based regimens compared to TDF-based regimens, though the etiology is multifactorial and not fully attributed to TAF alone.

Serious and Rare Adverse Reactions

• Renal Toxicity: TDF is associated with a risk of acute renal failure, Fanconi syndrome (a generalized dysfunction of the proximal renal tubules leading to glycosuria, aminoaciduria, phosphaturia, and bicarbonate wasting), and acute tubular necrosis. These events are less common with TAF but monitoring remains essential.
• Bone Effects: TDF use is associated with a higher risk of osteomalacia and fractures due to its impact on renal phosphate handling and vitamin D metabolism. TAF has a markedly reduced effect on BMD.
• Lactic Acidosis and Severe Hepatomegaly: As a class effect of NRTIs, lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported rarely. This is thought to be related to mitochondrial toxicity from inhibition of mitochondrial DNA polymerase-γ.
• Exacerbations of Hepatitis B: Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-HBV therapy, including tenofovir. This underscores the necessity for close clinical and laboratory monitoring for several months after stopping therapy in patients co-infected with HIV and HBV, and the critical importance of not using tenofovir for HIV PrEP in individuals with untreated HBV infection.

Black Box Warnings

Tenofovir prodrugs carry several boxed warnings, the most stringent safety labeling required by regulatory authorities:

1. Lactic Acidosis/Severe Hepatomegaly: A warning for lactic acidosis and severe hepatomegaly with steatosis, which can be fatal.
2. Exacerbation of Hepatitis B upon Discontinuation: A warning that discontinuation of anti-hepatitis B therapy, including tenofovir, may result in severe acute exacerbations of hepatitis B. For patients co-infected with HIV and HBV, this warning emphasizes that tenofovir should only be discontinued under a healthcare provider’s guidance, and that HIV therapy must be continued with alternative agents effective against HIV.
3. Risk of Drug Resistance with PrEP in Undiagnosed HIV: For the PrEP indication, a warning that FTC/TDF or FTC/TAF must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiation and at least every 3 months during use. Use in individuals with undiagnosed acute HIV infection can lead to the development of drug-resistant HIV.

Drug Interactions

While tenofovir is not a CYP450 substrate, inhibitor, or inducer, significant drug interactions occur primarily through competition for renal elimination pathways.

Major Drug-Drug Interactions

• Nephrotoxic Agents: Concurrent administration of drugs with known nephrotoxic potential (e.g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, high-dose or multiple non-steroidal anti-inflammatory drugs) may increase the risk of renal impairment with TDF. Caution is advised, and renal function should be monitored closely.
• Drugs that Reduce Renal Function: Any agent that reduces renal function (e.g., certain antiretroviral protease inhibitors like atazanavir or lopinavir/ritonavir when given with TDF) can increase tenofovir plasma concentrations. The mechanism involves inhibition of P-glycoprotein and/or renal transporters, potentially increasing TDF exposure and nephrotoxicity risk.
• Drugs Competing for Renal Tubular Secretion: Coadministration of drugs that are also actively secreted by the renal organic anion transporter system (e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir) may increase serum concentrations of either tenofovir or the co-administered drug by competing for excretion.
• Didanosine (ddI): Coadministration of TDF with didanosine is not recommended due to pharmacokinetic interactions that increase didanosine exposure, potentially increasing the risk of didanosine-associated adverse effects, including pancreatitis and neuropathy.

Contraindications

Tenofovir formulations are contraindicated in patients with a history of clinically significant hypersensitivity to any component of the product. A specific and critical contraindication exists for the use of tenofovir for HIV PrEP in individuals with unknown or positive HIV-1 status, due to the risk of developing drug-resistant virus. The presence of severe renal impairment (e.g., creatinine clearance <30 mL/min for TDF, <15 mL/min for TAF) is a contraindication to use without appropriate dose adjustment or alternative therapy.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy: Tenofovir is classified as Pregnancy Category B for TDF and TAF. Extensive data from the Antiretroviral Pregnancy Registry and clinical trials indicate no increased risk of major congenital malformations associated with first-trimester exposure compared to the general population. TDF is a preferred NRTI component in antiretroviral regimens for pregnant persons living with HIV due to its potency and favorable safety profile. For pregnant individuals with chronic HBV and high viral load, tenofovir is also recommended to reduce the risk of mother-to-child transmission. The benefits of therapy generally outweigh potential risks.

Lactation: Tenofovir is excreted in human milk in low concentrations. The Centers for Disease Control and Prevention in the United States recommend that individuals with HIV in the United States should not breastfeed due to the risk of postnatal HIV transmission, regardless of maternal viral load or antiretroviral therapy. For HIV-negative individuals using tenofovir for HBV treatment or PrEP, a risk-benefit assessment should be conducted, though data on effects on the nursing infant are limited.

Pediatric and Geriatric Considerations

Pediatrics: Both TDF and TAF are approved for use in pediatric patients of specific age and weight ranges. Formulations include oral powder and lower-strength tablets. Dosing is based on body weight and body surface area. Careful monitoring of renal function and bone health is particularly important in growing children.

Geriatrics: Clinical studies of tenofovir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy in this population. Renal function must be assessed prior to and during therapy, with dose adjustments made per prescribing guidelines.

Renal and Hepatic Impairment

Renal Impairment: This is the most critical pharmacokinetic consideration. Tenofovir clearance is linearly related to renal function. For TDF, dosing interval adjustment (e.g., every 48 hours or twice weekly) is required for patients with creatinine clearance (CrCl) <50 mL/min. It is not recommended when CrCl is <10 mL/min and not dialyzable. For TAF, due to its different elimination pathway, no dose adjustment is required for patients with CrCl ≥15 mL/min. For patients with end-stage renal disease (CrCl <15 mL/min) not on dialysis, TAF is not recommended. For patients on hemodialysis, TAF can be administered after dialysis sessions on dialysis days. Regular monitoring of serum creatinine, estimated CrCl, serum phosphorus, and urine glucose/protein is mandatory for all patients.

Hepatic Impairment: The pharmacokinetics of tenofovir are not significantly altered in patients with mild to moderate hepatic impairment. No dose adjustment is required. Studies in severe hepatic impairment are limited, but significant changes are not anticipated as tenofovir is not hepatically metabolized. However, in patients with HBV and decompensated liver disease, tenofovir is a recommended first-line agent, and careful monitoring for hepatic flares and renal function is essential.

Summary/Key Points

• Tenofovir is a nucleoside reverse transcriptase inhibitor (NRTI) administered as prodrugs (TDF and TAF) to overcome poor oral bioavailability. TAF provides more efficient intracellular delivery, allowing for lower doses and reduced systemic exposure compared to TDF.
• The active metabolite, tenofovir diphosphate (TFV-DP), competitively inhibits viral reverse transcriptase/DNA polymerase and acts as an obligatory chain terminator, halting viral DNA synthesis in both HIV and HBV.
• Key pharmacokinetic differences exist: TDF yields high plasma tenofovir levels, is renally cleared, and requires dose adjustment in renal impairment. TAF yields low plasma tenofovir but high intracellular TFV-DP, has less renal dependence, and a different dosing adjustment schedule for severe renal disease.
• Approved indications include treatment of HIV-1 infection (in combination), treatment of chronic HBV infection, and HIV pre-exposure prophylaxis (PrEP).
• The adverse effect profile is prodrug-dependent. TDF is associated with greater risks of nephrotoxicity (including Fanconi syndrome) and bone mineral density loss. TAF is associated with a more favorable renal and bone safety profile but may be linked to weight gain.
• Black box warnings address lactic acidosis/hepatomegaly, severe hepatitis B flare upon discontinuation, and the risk of drug-resistant HIV if used for PrEP in undiagnosed individuals.
• Major drug interactions are primarily mediated through competition for renal tubular secretion (e.g., with other nephrotoxic agents or drugs secreted by OAT transporters).
• Tenofovir is a preferred agent in pregnancy for HIV and HBV. Dose adjustment is critical in renal impairment, especially for TDF. No dose adjustment is typically needed for hepatic impairment.

Clinical Pearls

• Before initiating a TDF- or TAF-containing regimen, assess baseline renal function (serum creatinine, eGFR, urinalysis) and consider bone density screening in patients with risk factors for osteoporosis.
• For PrEP, confirm a negative HIV-1 test immediately before starting and at minimum every 3 months thereafter. Also test for HBV and renal function at baseline.
• In patients with HIV/HBV co-infection, discontinuation of tenofovir can precipitate a severe and potentially fatal hepatitis flare. Antiretroviral therapy must be continued with agents active against HIV if tenofovir is stopped.
• When switching a virologically suppressed patient from TDF to TAF, monitor for potential weight gain and lipid profile changes, while expecting stabilization or improvement in renal and bone parameters.
• The choice between TDF and TAF involves a personalized risk-benefit assessment, weighing factors such as pre-existing renal or bone disease, cardiovascular risk, cost, and formulary availability.

References

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