In a patient with impaired renal function (elevated serum creatinine), how should tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) be dosed based on creatinine clearance?

Tenofovir Dosing in Patients with Elevated Creatinine

For tenofovir disoproxil fumarate (TDF), dose adjustment is mandatory when creatinine clearance falls below 50 mL/min: give 300 mg every 48 hours for CrCl 30-49 mL/min, every 72 hours for CrCl 10-29 mL/min, and every 7 days (after dialysis) for hemodialysis patients. 1, 2 Tenofovir alafenamide (TAF) requires no dose adjustment for CrCl ≥30 mL/min but lacks safety data below this threshold. 1

Critical Distinction Between TDF and TAF

The two formulations have fundamentally different renal safety profiles that determine their use in renal impairment:

• TDF carries significantly higher nephrotoxic risk due to elevated plasma tenofovir concentrations, causing proximal tubular dysfunction, eGFR decline, and potential Fanconi syndrome 3, 4
• TAF demonstrates superior renal safety with 92% less impact on kidney function—in clinical trials, eGFR declined only 0.6-1.8 mL/min with TAF versus 4.8-5.4 mL/min with TDF (p<0.004) 3
• TAF is preferred over TDF for patients with existing renal impairment or risk factors for kidney disease 3

Specific Dosing Recommendations for TDF

Based on Creatinine Clearance (Cockcroft-Gault Formula):

• CrCl ≥50 mL/min: No adjustment needed—standard 300 mg once daily 1, 2
• CrCl 30-49 mL/min: 300 mg every 48 hours 1, 2
• CrCl 10-29 mL/min: 300 mg every 72 hours 1, 2
• Hemodialysis patients: 300 mg every 7 days after dialysis session 1, 2
• Peritoneal dialysis: Use with caution—insufficient data 1

Important Caveat:

The fixed-dose combination emtricitabine/tenofovir should not be used when CrCl <30 mL/min because the combination tablet cannot be dose-adjusted appropriately 1

TAF Dosing in Renal Impairment

• CrCl 30-80 mL/min: No dose adjustment required—use standard dosing 1
• CrCl <30 mL/min: Safety and efficacy not established; avoid use 1
• Post-kidney transplant: TAF-based regimens can be safely used, whereas interferon-based therapy should be avoided due to rejection risk 1

Monitoring Requirements

Baseline Assessment:

• Calculate creatinine clearance using Cockcroft-Gault formula before initiating tenofovir 1, 2
• Obtain baseline urinalysis to screen for proteinuria, especially in high-risk patients (Black patients, CD4 <200 cells/µL, diabetes, hypertension, HCV coinfection) 1

Ongoing Monitoring:

• Recheck creatinine clearance at 1-3 months after TDF initiation, then every 6-12 months if stable 4
• More frequent monitoring (every 3-6 months) is required for patients with established CKD (eGFR <50 mL/min) or risk factors 4
• Monitor serum phosphate in patients on TDF to detect tubular dysfunction 3

When to Switch or Discontinue

Indications for Switching from TDF to TAF:

• Rapid decline in kidney function: eGFR drops >25% and decreases to <50 mL/min from baseline 4
• New onset or worsening proteinuria/albuminuria 4
• **Development of eGFR <60 mL/min/1.73m²** or rapid eGFR decline (>3-5 mL/min/1.73m² per year) 3

Evidence for Improvement After Switching:

Real-world data shows that 76% of patients with eGFR <60 mL/min who experienced renal deterioration on TDF reversed to eGFR increase after one year on TAF (p=0.009) 5

Risk Factors Requiring Enhanced Vigilance

Patients at highest risk for TDF-related nephrotoxicity include those with:

• Age ≥40 years (OR 3.79 for developing eGFR <70 mL/min) 6
• Baseline eGFR <90 mL/min (OR 9.59 for further decline) 6
• Concomitant ritonavir-boosted protease inhibitors or cobicistat, which increase tenofovir exposure 3
• Comorbid hypertension, diabetes, or HCV coinfection 4

Practical Clinical Algorithm

1. Calculate baseline CrCl using Cockcroft-Gault formula 1, 2

2. If CrCl ≥50 mL/min:

   • TAF-based regimen preferred (no dose adjustment needed) 3
   • TDF acceptable if TAF unavailable (standard 300 mg daily) 1, 2

3. If CrCl 30-49 mL/min:

   • TAF strongly preferred (no dose adjustment) 3
   • If TDF necessary: 300 mg every 48 hours 1, 2

4. If CrCl <30 mL/min:

   • Avoid TAF (insufficient safety data) 1
   • TDF: 300 mg every 72 hours (CrCl 10-29) or weekly for hemodialysis 1, 2
   • Consider alternative NRTI backbone (abacavir if HLA-B*5701 negative, or dose-adjusted zidovudine) 4

5. Monitor response at 1-3 months, then every 6-12 months 4

Common Pitfalls to Avoid

• Do not use the fixed-dose combination tablet (emtricitabine/tenofovir) when dose adjustment is needed—it cannot be split 1
• Do not rely on serum creatinine alone—always calculate CrCl or eGFR, as creatinine may be falsely reassuring in patients with low muscle mass 1
• Remember that cobicistat and dolutegravir increase serum creatinine through inhibition of tubular secretion without affecting actual renal function 1
• Hemodialysis efficiently removes tenofovir (54% extraction coefficient), necessitating post-dialysis dosing 2, 7