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Tenofovir is a nucleotide reverse transcriptase inhibitor (NtRTI) and one of the most commonly prescribed antiretrovirals worldwide for both [[HIV - AIDS (main)|HIV-1]] treatment and pre-exposure prophylaxis ([[HIV post-exposure prophylaxis|PrEP]]). It also has activity against hepatitis B virus (HBV). Tenofovir is available as two distinct prodrugs with different toxicity profiles:<ref name="VireadPI">Viread (tenofovir disoproxil fumarate) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2019.</ref>

*Tenofovir disoproxil fumarate (TDF) — older formulation; higher plasma tenofovir levels; associated with renal toxicity and bone loss
*Tenofovir alafenamide (TAF) — newer formulation; delivers higher intracellular drug with lower plasma levels; improved renal and bone safety but associated with weight gain and lipid elevation

==Administration==
*Type: Nucleotide reverse transcriptase inhibitor (NtRTI); adenosine analog
*Dosage Forms:
**TDF (Viread): 150 mg, 200 mg, 250 mg, 300 mg tablets; 40 mg/g oral powder
**TAF: Available only in fixed-dose combinations (not as a standalone product)
*Routes of Administration: Oral
*Common Trade Names:
**TDF-containing: Viread (TDF alone), Truvada (FTC/TDF), Atripla (EFV/FTC/TDF), Stribild, Complera, Cimduo, Delstrigo, Symfi
**TAF-containing: Descovy (FTC/TAF), Biktarvy, Genvoya, Odefsey, Symtuza

==Adult Dosing==
===TDF===
*HIV treatment: 300 mg PO once daily (with other ARVs)<ref name="VireadPI"/>
*PrEP: 300 mg TDF/200 mg FTC (Truvada) PO once daily
*Chronic HBV: 300 mg PO once daily
*May take with or without food (food increases absorption ~40% but not clinically significant)<ref name="VireadPI"/>

===TAF===
*HIV treatment: 25 mg once daily (in most combinations) or 10 mg once daily (when boosted with cobicistat or ritonavir)
*PrEP: FTC/TAF (Descovy) — approved for PrEP in individuals at risk from receptive anal sex; not approved for receptive vaginal sex
*Available only in fixed-dose combination tablets

==Pediatric Dosing==
*TDF: Approved for ≥2 years and ≥10 kg (HIV); weight-based dosing<ref name="VireadPI"/>
*TAF: Available in pediatric fixed-dose combinations; consult prescribing information
*TDF associated with decreased bone mineral density in children — TAF or abacavir preferred in growing children (particularly pre-pubertal)<ref name="NIHPeds">Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Tenofovir Disoproxil Fumarate. NIH Guidelines. Accessed 2025.</ref>

==Special Populations==
===[[Drug pregnancy categories|Pregnancy Rating]]===
*TDF: Extensively studied in pregnancy; no increased birth defect risk in APR data. Preferred NRTI backbone (as TDF/FTC) in pregnancy<ref name="VireadPI"/>
*TAF: Less pregnancy data than TDF; lower tenofovir plasma levels raise theoretical concern about placental transfer and efficacy. TDF is generally preferred over TAF in pregnancy
*Antiretroviral Pregnancy Registry: 1-800-258-4263

===Lactation risk===
*Tenofovir present in human milk at low levels; women with HIV should discuss risks and benefits of breastfeeding with their provider<ref name="VireadPI"/>

===Renal Dosing===
*Adult TDF (primarily renally eliminated; dose interval adjustment required):<ref name="VireadPI"/>
**CrCl ≥50 mL/min: 300 mg PO once daily (no adjustment)
**CrCl 30–49 mL/min: 300 mg PO every 48 hours
**CrCl 10–29 mL/min: 300 mg PO every 72–96 hours
**Hemodialysis: 300 mg PO every 7 days (administer after dialysis session); tenofovir is efficiently removed by hemodialysis (~54% extraction coefficient)
*Adult TAF: Not recommended if CrCl <15 mL/min (unless on hemodialysis, per some combination labels); no adjustment needed for CrCl ≥15
*Pediatric: No specific TDF dose adjustment data for renal impairment

===Hepatic Dosing===
*Adult: No dose adjustment for TDF or TAF (tenofovir is not hepatically metabolized)<ref name="VireadPI"/>
*Pediatric: No adjustment needed

==Contraindications==
*Allergy to class/drug
*TDF-specific: Not recommended with concurrent or recent use of nephrotoxic agents when alternatives exist<ref name="VireadPI"/>

==Adverse Reactions==
===Serious===
*Nephrotoxicity (TDF — major distinguishing toxicity): Acute renal failure, Fanconi syndrome (proximal renal tubular injury with hypophosphatemia, glycosuria, proteinuria, metabolic acidosis), acute tubular necrosis. Risk increased with pre-existing renal disease, concomitant nephrotoxins (NSAIDs, aminoglycosides, acyclovir/valacyclovir), and ritonavir/cobicistat boosting<ref name="VireadPI"/>
*'''Hepatitis B flare (Boxed Warning — both TDF and TAF):''' Severe, acute HBV exacerbations (including hepatic decompensation and failure) after discontinuing tenofovir in HIV/HBV co-infected patients<ref name="VireadPI"/>
*'''Lactic acidosis with hepatic steatosis''' (NRTI class effect; including fatal cases)<ref name="VireadPI"/>
*Decreased bone mineral density (TDF > TAF): Osteomalacia, osteoporosis, pathologic fractures. TDF inhibits bone mineralization<ref name="VireadPI"/>
*[[Immune reconstitution syndrome|Immune reconstitution inflammatory syndrome (IRIS)]]

===Common===
*Nausea, diarrhea, headache, fatigue, dizziness<ref name="VireadPI"/>
*Elevated creatinine (TDF — represents actual renal tubular injury, unlike [[Dolutegravir|dolutegravir]] which is benign OCT2 inhibition)
*TAF-specific: Weight gain, elevated LDL cholesterol and triglycerides (more than TDF)

==Pharmacology==
*Half-life: ~17 hours (plasma tenofovir after TDF); intracellular tenofovir diphosphate half-life ~150 hours in PBMCs (supports once-daily dosing)<ref name="VireadPI"/>
*Bioavailability: ~25% fasted (TDF); TAF achieves higher intracellular levels at much lower plasma concentrations
*Metabolism: TDF is hydrolyzed to tenofovir (not CYP450-metabolized). TDF is a P-gp and BCRP substrate<ref name="VireadPI"/>
*Excretion: ~70–80% unchanged in urine via glomerular filtration and active tubular secretion<ref name="VireadPI"/>

==Mechanism of Action==
Tenofovir is an acyclic nucleotide analog of adenosine monophosphate. Both TDF and TAF are prodrugs that are converted intracellularly to the active metabolite tenofovir diphosphate. Tenofovir diphosphate competes with the natural substrate deoxyadenosine 5'-triphosphate for incorporation by HIV-1 reverse transcriptase and HBV polymerase. Once incorporated, it terminates the growing DNA chain. Unlike nucleoside analogs, tenofovir already contains one phosphate group and requires only two additional phosphorylation steps for activation.<ref name="VireadPI"/>

==Comments==
*TDF vs. TAF — the key distinction:
**TDF = higher plasma tenofovir → renal toxicity and bone loss but lipid-neutral and more pregnancy data
**TAF = lower plasma tenofovir → less renal/bone toxicity but weight gain and dyslipidemia
**Knowing which formulation a patient is on helps the ED physician assess risk when evaluating AKI or metabolic complaints
*TDF nephrotoxicity pearl: If a patient on a TDF-containing regimen (Truvada, Atripla, Stribild, Complera, etc.) presents with AKI, check a urinalysis for glycosuria with normoglycemia and low serum phosphorus — these point to proximal tubular injury (Fanconi syndrome) rather than prerenal azotemia. Standard dipstick may miss tubular proteinuria (it primarily detects albumin)<ref name="VireadPI"/>
*NSAID caution: Avoid frequent or prolonged NSAID use in patients on TDF — multiple cases of acute renal failure requiring hospitalization and dialysis reported after NSAID initiation in TDF patients with renal risk factors<ref name="VireadPI"/>
*Hepatitis B flare on discontinuation: Identical to [[Emtricitabine|emtricitabine]] and [[Lamivudine|lamivudine]] — tenofovir has anti-HBV activity. Stopping any tenofovir-containing regimen in an HIV/HBV co-infected patient risks severe HBV reactivation. This is especially dangerous in patients with advanced liver disease<ref name="VireadPI"/>
*PrEP formulation matters: Truvada (TDF/FTC) is approved for PrEP via all sexual exposure routes. Descovy (TAF/FTC) is not approved for receptive vaginal sex PrEP due to lack of study data in that population
*'''Low drug interaction profile:''' Tenofovir is not CYP450-metabolized. However, drugs that decrease renal function or compete for tubular secretion increase tenofovir levels (e.g., acyclovir, ganciclovir, aminoglycosides, high-dose NSAIDs). Didanosine is contraindicated with TDF (increases ddI toxicity)<ref name="VireadPI"/>
*Overdose: Supportive care. Tenofovir is efficiently removed by hemodialysis (~54% extraction). Monitor renal function and serum phosphorus<ref name="VireadPI"/>

==See Also==
*[[HIV - AIDS (main)]]
*[[HIV post-exposure prophylaxis]]
*[[Immune reconstitution syndrome]]
*[[Emtricitabine/tenofovir]]
*[[Emtricitabine]]

==References==
{{reflist|2}}
[[Category:Pharmacology]]