We read with interest the retrospective study on renal tubular dysfunction (RTD) during nucleotide analogue (NA) therapy in chronic hepatitis B (CHB).[1] RTD was diagnosed by a new definition, but all seven patients developed previously evaluated renal dysfunction markers, such as creatinine clearance (CrCl) <60 mL/min (<50 in five cases) and hypohosphataemia ≤2.3 mg/dL (≤2.0 in four cases).

The authors concluded that RTD develops in 15% of CHB patients treated with adefovir/tenofovir for 2–9 years, which is questionable, at least for tenofovir, for several reasons. First, most patients (47/51) started with adefovir, while only 4 started with tenofovir and 5 additional cases switched from adefovir to tenofovir. Similar probabilities of CrCl decrease have been reported for adefovir,[2, 3] whereas large 5-year phase III (n = 490) and 2.5-year real-life cohort (n = 302) studies have reported minimal (<2%) rates of CrCl <50 mL/min and/or hypophosphataemia <2 mg/dL in tenofovir-treated naive CHB patients.[4, 5] Given the small number of tenofovir-treated patients in the study, the confidence intervals for RTD rates are impressively wide (0–49%). Second, the small total patient number (possible type II error) might have hidden an influence of comorbidities reported in 57% and 39% of patients with and without RTD. Third, the authors did not report any adefovir/tenofovir dose modification in case of RTD signs and therefore cannot comment on the outcome of such a strategy. Finally, the probability of clinical bone effects from hypophosphataemia remains unclear, as mild alkaline phosphatase increases were reported in three patients and no bone biopsy was performed.

In conclusion, we agree that appropriate renal monitoring is required for all CHB patients treated with NAs, as suggested by recent guidelines,[6] but we believe that there is still no clear evidence on the probability of tenofovir nephrotoxicity in CHB. Results from large and well-designed long-term studies are awaited.


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  2. Acknowledgements
  3. References

Declaration of personal interests: Spilios Manolakopoulos has served as a speaker, a consultant and an advisory board member for Bristol-Myers Squibb, Gilead, Merck, Novartis and Roche, and has received research funding from Bristol-Myers Squibb and Roche. Athanasia Striki has nothing to disclose. George Papatheodoridis has served as a speaker, a consultant and an advisory board member for Bristol-Myers Squibb, Gilead, Merck, Novartis and Roche, and has received research funding from Bristol-Myers Squibb, Gilead and Roche. None of the authors is an employee of any pharmaceutical company, owns stocks and shares in any pharmaceutical company or owns any patent. Declaration of funding interests: None.


  1. Top of page
  2. Acknowledgements
  3. References
  • 1
    Gara N, Zhao X, Collins MT, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012; 35: 131725.
  • 2
    Manolakopoulos S, Striki A, Deutch M, et al. Long-term adefovir plus lamivudine therapy does not decrease creatinine clearance in HBeAg-negative chronic hepatitis B patients. Liver Int 2011; 31: 152532.
  • 3
    Ha NB, Ha NB, Garcia RT, et al. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil. Hepatology 2009; 50: 72734.
  • 4
    Marcellin P, Buti M, Gane EJ, et al. Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis. Hepatology 2011; 54(Suppl.): 1011A2A.
  • 5
    Lampertico P, Soffredini R, Vigaro M, et al. Tenofovir monotherapy for naive patients with chronic hepatitis B: a multicenter European study in clinical practice in 302 patients followed for 30 months. J Hepatol 2012; 56(Suppl. 2): S208.
  • 6
    European Association for the Study of the Liver. EASL Clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 57: 16785.