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Fanconi Syndrome Associated with Long-term Adefovir and Subsequent Tenofovir Therapy for Chronic Hepatitis B Infection

174 Copyrightc 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 2016. 3. 29 Revised: 2016. 6. 30 Accepted: 2016. 7. 7


CASE REPORT
At presentation, the patient had normal liver function, except a mildly increased ALP level, as assessed in laboratory tests done every 6 months, and well-controlled CHB with an 8-month TDF regimen. Her most recent liver ultrasound showed a slight- Although she appeared to be recovering, the biochemical abnormalities had not fully normalized (Table 1).

DISCUSSION
We report a case of Fanconi syndrome with adverse effects in a patient with CHB treated with long-term ADV followed by TDF. In the absence of any drug history, besides the use of HBV antiviral agents, it was thought that prolonged ADV and TDF therapy were contributing to renal insufficiency. A renal -177 -biopsy was not performed because the patient had distinct clinical features and normal renal function.
In this case study, Fanconi syndrome, which is associated with the use of multiple medications and chemicals [2], was most likely drug-induced. Several drugs, including aminoglycosides, ifosfamide, cisplatin, streptozocin, mercaptopurine, tetracycline, and valproate, have been found to be associated with Fanconi syndrome [2].
ADV, at doses ranging from 60-120 mg/day, can cause nephrotoxicity when used as an adjuvant to antiretroviral therapy for HIV infection [3]. ADV does not appear to produce clinically significant nephrotoxicity at lower doses (10 mg/day for 48 weeks). A long-term (144 weeks) safety and efficacy study showed that only four patients (3%) had increased serum creatinine levels [4]. The more recently developed TDF therapy has been favored due to its excellent safety profile and, in particular, its lack of nephrotoxicity [5]. In patients with HIV treated with TDF, nephrotoxicity is uncommon and has been reported in only 1-2% of patients [6]. In CHB monoinfection, nephrotoxicity and decreased eGFR are less evident and TDF therapy is well tolerated. TDF at 300 mg daily is rarely associated with nephrotoxicity, at least when used for 1-2 years [7]. However, several case reports have described Fanconi syndrome with prolonged, low-dose ADV therapy [2] in HIV or CHB patients treated with TDF [8]. Therefore, ADV and TDF might be associated with rare instances of proximal renal tubular dysfunction, and nephrotoxicity can be affected by the treatment duration and dose.
The risk factors for this complication appear to be greater age and pre-existing renal function in HIV-infected patients [1,5] In TDF-based therapy, prolonged renal dysfunction has been found to last as long as 18 months [9]. A shorter duration of drug administration prior to discontinuation is associated with a greater likelihood of renal recovery. At the time of drug discontinuation, mild proteinuria was also a favorable indicator for eventual renal function recovery [10]. Despite the relatively short TDF maintenance period (9 months) in the present case, complete biochemical recovery was not achieved at 12 months after antiviral drug cessation, due to the 42-month course of ADV treatment. At the time of TDF discontinuation, severe proteinuria was likely to be associated with a poor prognosis.
Therefore, a degree of renal dysfunction might persist and even be irreversible, after drug cessation.
Nucleotide analogues appear to cause Fanconi syndrome in a proportion of patients without obvious risk factors, and may be observed at varying times after therapy initiation. Therefore, patients with CHB who undergo prolonged nucleotide analogue treatment, even without symptoms, should be regularly monitored for levels of serum creatinine, electrolytes, phosphorus, uric acid, and calcium. Regular laboratory monitoring may lead to decreased morbidity and mortality associated with Fanconi syndrome, an easily reversible condition.