What are the guidelines for renal dose modification of Tenofovir Disoproxil Fumarate (TDF) in patients with impaired renal function?

Renal Dose Modification of Tenofovir Disoproxil Fumarate (TDF)

For patients with impaired renal function, TDF requires dose-interval adjustment based on creatinine clearance: 300 mg every 48 hours for CrCl 30-49 mL/min, every 72-96 hours for CrCl 10-29 mL/min, and weekly dosing for hemodialysis patients, though TDF should ideally be avoided entirely when CrCl falls below 60 mL/min due to significant nephrotoxicity risk. 1, 2

Specific Dosing Adjustments by Creatinine Clearance

The dose-interval modifications are clearly defined in current guidelines:

• CrCl ≥50 mL/min: TDF 300 mg every 24 hours (standard dosing) 1, 2
• CrCl 30-49 mL/min: TDF 300 mg every 48 hours 1, 2
• CrCl 10-29 mL/min: TDF 300 mg every 72-96 hours 1, 2
• CrCl <10 mL/min with hemodialysis: TDF 300 mg every 7 days (or after approximately 12 hours total dialysis time), administered following completion of dialysis 1, 2
• CrCl <10 mL/min without dialysis: TDF is not recommended due to lack of safety data 1, 2

Critical Safety Threshold: Avoid TDF When CrCl <60 mL/min

The most important clinical consideration is that TDF should ideally be avoided entirely in patients with baseline eGFR <60 mL/min, as this population experiences accelerated renal decline and increased nephrotoxicity risk. 1, 3 The 2022 Korean Association for the Study of the Liver (KASL) guidelines explicitly recommend avoiding TDF in patients with risk factors for renal dysfunction including baseline eGFR <60 mL/min, proteinuria, albuminuria (urine albumin:creatinine ratio >30 mg/g), hypophosphatemia (<2.5 mg/dL), uncontrolled diabetes, or hypertension. 1

In patients with any renal risk factors, tenofovir alafenamide (TAF), entecavir, or besifovir are strongly preferred over TDF. 1 TAF demonstrates significantly superior renal safety, with median eGFR decline of only -0.3 mL/min compared to -5.0 mL/min with TDF over 96 weeks in patients with renal risk factors. 1

Mandatory Monitoring Protocol

If TDF must be continued in patients with renal impairment, intensive monitoring is essential:

• Baseline assessment: Serum creatinine, estimated creatinine clearance, urine glucose, urine protein, and serum phosphorus (in patients with chronic kidney disease) 2
• Initial monitoring: Every 3 months during the first year 1
• Ongoing monitoring: Every 6 months thereafter if stable 1
• Enhanced monitoring: More frequent assessment (every 3 months) if CrCl <60 mL/min or serum phosphate <2 mg/dL develops 1

The monitoring should specifically assess for proximal tubular dysfunction, including euglycemic glycosuria and urinary phosphate wasting, which are hallmarks of TDF-associated Fanconi syndrome. 2, 4

Absolute Contraindications and Drug Interactions

TDF must be avoided with concurrent or recent use of nephrotoxic agents, particularly NSAIDs. 2 Cases of acute renal failure requiring hospitalization and renal replacement therapy have been reported in HIV-infected patients with baseline renal dysfunction who received high-dose or multiple NSAIDs while on TDF. 2 Alternative analgesics should be used in patients at risk for renal dysfunction. 2

TDF is also not recommended when CrCl is below 15 mL/min without renal replacement therapy. 1

When Dose Adjustment Fails: Switching Strategy

If renal function worsens despite dose adjustment, or if proximal tubular dysfunction develops (evidenced by persistent bone pain, pain in extremities, fractures, muscular pain or weakness, hypophosphatemia, or glycosuria), TDF should be discontinued and switched to TAF, entecavir, or besifovir. 1

Switching from TDF to TAF results in significant renal recovery: patients who switched showed median eGFR improvement of +0.94 mL/min versus continued decline of -2.74 mL/min in those remaining on TDF at 48 weeks. 1 Bone mineral density also recovers after switching, with improvements of +1.74% in spine and +0.66% in hip compared to continued losses with TDF. 1

Special Populations

For hemodialysis patients: TDF 300 mg should be administered once weekly following completion of a dialysis session, assuming three hemodialysis sessions of approximately 4 hours duration per week. 1, 2 High-flux hemodialysis efficiently removes tenofovir with an extraction coefficient of 54%. 5

For patients with hepatitis B co-infection: Dose adjustment follows the same creatinine clearance-based algorithm, but the decision to continue TDF versus switching to TAF or entecavir must weigh the need for HBV suppression against renal safety. 1

Common Pitfall to Avoid

The most frequent error in clinical practice is failure to dose-adjust TDF when CrCl falls below 50 mL/min. 6 A retrospective study found that HIV clinic providers often failed to adjust TDF doses appropriately, though patients who received proper dose adjustments stayed on their TDF-based regimens 21 months longer and had greater CD4 cell count gains. 6 However, the better approach is to switch to a safer alternative (TAF, entecavir, or besifovir) rather than continuing dose-adjusted TDF in patients with renal impairment. 1, 3