What are the safety considerations for using TAF (tenofovir alafenamide) and Entecavir in patients with Chronic Kidney Disease (CKD)?

Safety of TAF and Entecavir in CKD

Both TAF and entecavir are safe first-line options for chronic hepatitis B patients with CKD, with TAF demonstrating superior renal safety compared to tenofovir DF and entecavir showing broader dosing flexibility in severe renal impairment (eGFR <15 mL/min). 1, 2

Drug Selection Algorithm Based on Renal Function

For Treatment-Naïve Patients with eGFR ≥15 mL/min

• TAF is generally preferred due to superior renal safety profile, particularly in patients with risk factors for renal dysfunction 1, 3
• Entecavir remains an excellent alternative with minimal renal effects 1
• Both agents require dose adjustment when creatinine clearance falls below 50 mL/min for entecavir and 15 mL/min for TAF 1, 2

For Treatment-Naïve Patients with eGFR <15 mL/min (Without Dialysis)

• Entecavir is the only first-line option as TAF is not recommended in this population 1, 2
• Entecavir can be dose-adjusted down to <10 mL/min and for hemodialysis patients 1, 2

For Patients on Dialysis (eGFR <15 mL/min)

• Both entecavir (with dose adjustment) and TAF (25 mg q24h) can be used 2, 4

TAF Renal Safety Profile

Superior Safety Compared to Tenofovir DF

• TAF causes significantly less eGFR decline than tenofovir DF: median changes of -0.3 mL/min vs. -5.0 mL/min over 96 weeks in patients with renal risk factors 1
• In HBeAg-positive patients, eGFR decline was 0.6 mL/min with TAF vs. 5.4 mL/min with TDF (p<0.0001) 1, 3
• In HBeAg-negative patients, eGFR decline was 1.8 mL/min with TAF vs. 4.8 mL/min with TDF (p=0.004) 1, 3

Mechanism of Improved Safety

• TAF achieves 90% lower plasma tenofovir concentrations than TDF while maintaining intracellular efficacy 3
• This results in less proximal tubular dysfunction, reduced risk of Fanconi syndrome, and minimal impact on bone mineral density 1, 3

Real-World Evidence of Renal Improvement

• Switching from other NAs to TAF improves renal function in CKD patients: eGFR improvement coefficient of 21.7 mL/min/1.73 m² over 96 weeks (p<0.001) 5
• 76% of patients with eGFR <60 mL/min who had renal deterioration on TDF showed eGFR increase after one year of TAF (p=0.009) 6
• Peak eGFR improvement occurs between weeks 24-48 after switching to TAF 5

Entecavir Renal Safety Profile

Minimal Renal Effects

• Entecavir has less effect on renal function and bone metabolism compared to tenofovir DF 1
• Long-term entecavir therapy shows minimal rates of renal function decline 1

Recent Comparative Data with TAF

• One 2022 study suggested higher risk of CKD progression with entecavir vs. TAF (19.9 vs. 5.1 per 1000 person-years; adjusted HR 4.05,95% CI 2.14-7.68) 7
• However, a larger 2025 nationwide analysis found no significant difference in CKD or ESRD incidence between TAF and entecavir after propensity score matching (CKD IRR 1.20,95% CI 0.69-2.10; ESRD IRR 1.49,95% CI 0.81-2.75) 8
• The most recent and largest study supports equivalent renal safety between the two agents 8

Specific Risk Factors Favoring TAF Over Tenofovir DF

Avoid tenofovir DF and prefer TAF or entecavir in patients with: 1

• Baseline eGFR <60 mL/min/1.73 m²
• Proteinuria or albuminuria (urine albumin:creatinine ratio >30 mg/g)
• Hypophosphatemia (<2.5 mg/dL)
• Uncontrolled diabetes or hypertension
• Age >50-60 years
• Osteopenia or osteoporosis
• Chronic steroid use or medications affecting bone density
• History of fragility fracture

Dose Adjustments for Entecavir in CKD

Treatment-Naïve Patients (0.5 mg standard dose): 1

• CrCl ≥50 mL/min: 0.5 mg q24h
• CrCl 30-49 mL/min: 0.25 mg q24h or 0.5 mg q48h
• CrCl 10-29 mL/min: 0.15 mg q24h or 0.5 mg q72h
• CrCl <10 mL/min or hemodialysis: 0.05 mg q24h or 0.5 mg q7 days

Lamivudine-Resistant Patients (1 mg standard dose): 1

• CrCl ≥50 mL/min: 1 mg q24h
• CrCl 30-49 mL/min: 0.5 mg q24h or 1 mg q48h
• CrCl 10-29 mL/min: 0.3 mg q24h or 1 mg q72h
• CrCl <10 mL/min or hemodialysis: 0.1 mg q24h or 1 mg q7 days

TAF Dosing in Renal Impairment

• Standard dose of 25 mg daily is maintained until eGFR <15 mL/min 1, 4
• TAF is not recommended when CrCl <15 mL/min without renal replacement therapy 1
• For patients on hemodialysis, TAF 25 mg q24h can be used 2, 4

Monitoring Requirements

Baseline Assessment: 1

• Serum creatinine and estimated creatinine clearance
• Urine glucose and protein
• Serum phosphate (especially if considering tenofovir DF)
• In CKD patients, also assess serum phosphorus

During Treatment: 1

• Liver function tests every 3-4 months during first year, then every 6 months
• Serum HBV DNA every 3-4 months during first year, then every 6-12 months
• Renal monitoring (eGFR, serum phosphate) on clinically appropriate schedule for all patients on any NA 1, 4
• More frequent monitoring for patients at high renal risk

Critical Safety Warnings for TAF

Postmarketing Renal Events

• Cases of acute renal failure, proximal renal tubulopathy, and Fanconi syndrome have been reported with TAF-containing products, though most had confounding factors 4
• Patients with impaired renal function and those on nephrotoxic agents (including NSAIDs) are at increased risk 4

Management of Renal Decline

• Discontinue TAF if clinically significant decreases in renal function or evidence of Fanconi syndrome develop 4
• Monitor for lactic acidosis and hepatomegaly with steatosis, though rare 4

Common Pitfalls to Avoid

• Do not use tenofovir DF in patients with eGFR <60 mL/min or other renal risk factors when TAF or entecavir are available 1
• Do not forget dose adjustment for entecavir when CrCl <50 mL/min 1, 2
• Do not assume TAF can be used in severe renal impairment (eGFR <15 mL/min) without dialysis 1, 2
• Do not overlook concomitant nephrotoxic medications (NSAIDs, aminoglycosides, contrast agents) that increase risk 4
• In treatment-experienced patients with prior lamivudine exposure, TAF may be preferred over entecavir due to maintained high barrier to resistance 1, 2