Tenofovir

Tenofovir is a nucleotide reverse transcriptase inhibitor (NtRTI) and one of the most commonly prescribed antiretrovirals worldwide for both HIV-1 treatment and pre-exposure prophylaxis (PrEP). It also has activity against hepatitis B virus (HBV). Tenofovir is available as two distinct prodrugs with different toxicity profiles:[1]

  • 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)[1]
  • 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)[1]

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[1]
  • 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)[2]

Special Populations

Pregnancy Rating

  • TDF: Extensively studied in pregnancy; no increased birth defect risk in APR data. Preferred NRTI backbone (as TDF/FTC) in pregnancy[1]
  • 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[1]

Renal Dosing

  • Adult TDF (primarily renally eliminated; dose interval adjustment required):[1]
    • 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)[1]
  • Pediatric: No adjustment needed

Contraindications

  • Allergy to class/drug
  • TDF-specific: Not recommended with concurrent or recent use of nephrotoxic agents when alternatives exist[1]

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[1]
  • 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[1]
  • Lactic acidosis with hepatic steatosis (NRTI class effect; including fatal cases)[1]
  • Decreased bone mineral density (TDF > TAF): Osteomalacia, osteoporosis, pathologic fractures. TDF inhibits bone mineralization[1]
  • Immune reconstitution inflammatory syndrome (IRIS)

Common

  • Nausea, diarrhea, headache, fatigue, dizziness[1]
  • Elevated creatinine (TDF — represents actual renal tubular injury, unlike 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)[1]
  • 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[1]
  • Excretion: ~70–80% unchanged in urine via glomerular filtration and active tubular secretion[1]

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.[1]

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)[1]
  • 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[1]
  • Hepatitis B flare on discontinuation: Identical to emtricitabine and 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[1]
  • 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)[1]
  • Overdose: Supportive care. Tenofovir is efficiently removed by hemodialysis (~54% extraction). Monitor renal function and serum phosphorus[1]

See Also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 Viread (tenofovir disoproxil fumarate) [prescribing information]. Foster City, CA: Gilead Sciences, Inc.; 2019.
  2. ↑ Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Tenofovir Disoproxil Fumarate. NIH Guidelines. Accessed 2025.
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