What are the side effects of tenofovir and entecavir?

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Last updated: October 3, 2026 • View editorial policy

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Side Effects of Tenofovir and Entecavir

Both tenofovir (TDF) and entecavir have excellent safety profiles, but tenofovir carries specific risks for renal dysfunction and bone abnormalities that require monitoring, while entecavir's most common side effects are mild and include headache, fatigue, dizziness, and nausea.

Entecavir Side Effects

Common Side Effects

According to FDA labeling, the most frequently reported side effects of entecavir include 1:

  • Headache
  • Tiredness/fatigue
  • Dizziness
  • Nausea

These effects are generally mild and well-tolerated. The drug has minimal organ-specific toxicity concerns.

Serious Considerations

  • Lactic acidosis and severe hepatomegaly with steatosis (rare but serious, particularly relevant when stopping therapy)
  • Severe acute exacerbations of hepatitis B can occur if treatment is discontinued 1
  • Drug resistance may develop, especially in patients previously treated with other HBV medications 1

Renal Effects

Entecavir requires dose adjustment in patients with renal impairment, but recent evidence suggests it may actually be associated with decreased eGFR over time. A 2026 study found that ETV treatment showed significantly greater eGFR reduction compared to newer tenofovir formulations at 48 weeks 2. The 2018 AASLD guidelines note no significant differences in renal dysfunction between TDF and entecavir, though individual renal events have been reported 3.

Tenofovir (TDF) Side Effects

Renal Toxicity - The Primary Concern

Tenofovir's most clinically significant side effect is renal dysfunction, which requires systematic monitoring 3:

Required monitoring includes:

  • Serum creatinine
  • Serum phosphorus
  • Urine glucose
  • Urine protein

Monitoring frequency:

  • Before treatment initiation
  • At least annually during treatment
  • More frequently if high-risk features present or preexisting renal dysfunction 3

Specific renal complications reported include:

  • Acute renal failure
  • Hypophosphatemia
  • Fanconi syndrome (proximal tubular dysfunction)
  • Progressive decline in eGFR over time 4

Bone Abnormalities

TDF is associated with decreased bone mineral density 3. However, the 2018 AASLD guidelines state there is insufficient evidence for routine bone mineral density monitoring in the absence of other osteoporosis risk factors 3.

A 2023 study demonstrated that switching from ETV to TAF (a newer tenofovir formulation) resulted in significantly less bone mineral density loss at the lumbar spine and hip compared to continuing ETV 5.

Management of TDF-Related Toxicity

If TDF-associated renal dysfunction or bone disease is suspected, discontinue TDF and substitute with TAF or entecavir, considering any previously known drug resistance 3.

Comparative Safety Evidence

Renal Function

The evidence on comparative renal safety is nuanced:

  • The 2018 AASLD guidelines suggest no preference between entecavir or TDF regarding long-term renal and bone complications, though they acknowledge renal events have been reported with TDF 3

  • TAF (tenofovir alafenamide) is associated with lower rates of bone and renal abnormalities than TDF 3

  • Recent research shows conflicting findings: some studies suggest TDF causes greater eGFR decline 4, while others found no difference between TDF and ETV in post-transplant patients 6

  • A 2026 study found ETV was associated with greater eGFR decline than newer tenofovir formulations (TMF) at 48 weeks 2

Clinical Outcomes

A 2025 nationwide cohort study of 55,885 patients found tenofovir (vs. entecavir) was associated with lower risks of hepatic decompensation, HCC, and major adverse liver-related outcomes, though this relates to efficacy rather than side effects 7.

Critical Monitoring Recommendations

For Tenofovir (TDF) Patients:

  • Baseline: Creatinine, phosphorus, urine glucose, urine protein
  • Ongoing: At least annually, more frequently if high-risk
  • High-risk patients: Those with preexisting renal dysfunction, elderly, diabetes, hypertension, concurrent nephrotoxic medications

For Entecavir Patients:

  • Dose adjustment required for renal impairment based on creatinine clearance 1
  • Monitor for adherence to prevent resistance
  • Watch for hepatitis flares if considering discontinuation

Common Pitfalls to Avoid

  1. Failing to monitor renal function in TDF patients - This is mandatory, not optional
  2. Not adjusting entecavir dose in renal impairment - Dose modification is required per manufacturer recommendations
  3. Abruptly stopping either medication - Can cause severe hepatitis B exacerbations
  4. Ignoring phosphorus levels in TDF patients - Hypophosphatemia is a key marker of tubular dysfunction
  5. Assuming all tenofovir formulations are equal - TAF has superior renal and bone safety compared to TDF

References

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