Abstract
Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to analyze the association between osteomalacia and genetic variants in 51 drug transporters genes. Clinical and follow-up data of the ADV-treated patients were collected. Target capture sequencing was used to identify genetic variations of 51 drug transporter genes. A total of 193 hepatitis B patients treated with ADV were enrolled, of whom 140 had osteomalacia. The other 53 without osteomalacia were included in the control group. The median duration of ADV treatment before the onset of osteomalacia was 6.5 years (range:1.5–7 years). We found that most patients with osteomalacia had hypophosphatemia, high serum alkaline phosphatase levels, hypouricemia, nondiabetic glycosuria, proteinuria. Stopping ADV administration, supplementing calcitriol and calcium were effective treatments. During 3–6 months of follow-up, the clinical symptoms and biochemical indicators of patients with osteomalacia have been significantly improved. There was no significant difference in duration of adefovir treatment in patients with or without osteomalacia (p = 0.791). Through regression analysis, we found that age was a risk factor for osteomalacia [per 1 year, odds ratio (OR), 1.053; 95% confidence interval (95% CI), 1.020–1.087; p = 0.015]. 1992 single nucleotide variants were found using target capture sequencing. However, the associations of genetic variants of 51 drug transporter genes and the risk of osteomalacia were negligible. Osteomalacia is prone to occur in patients with chronic hepatitis B treated with long-term ADV at a therapeutic dose. After standard treatment, the prognosis is mostly good. We failed to find genetic variants that can predict the risk of ADV-induced osteomalacia.
Highlights
Adefovir dipivoxil (ADV), a type of nucleotide analogue developed in 2002, is widely used for chronic hepatitis B therapy (Hadziyannis et al, 2003; Marcellin et al, 2003; Han, 2006; Chen an Ju, 2012)
There was no significant difference in sex ratio, duration of chronic hepatitis B, and duration of adefovir treatment in patients with or without osteomalacia (p values were 0.070, 0.367, 0.791, respectively), and patients with osteomalacia were older than patients without (p 0.001)
Prospective studies have shown that dosedependent nephrotoxicity is associated with ADV, while ADV 10 mg/d is relatively safe for the treatment of chronic hepatitis B (Izzedine et al, 2004)
Summary
Adefovir dipivoxil (ADV), a type of nucleotide analogue developed in 2002, is widely used for chronic hepatitis B therapy (Hadziyannis et al, 2003; Marcellin et al, 2003; Han, 2006; Chen an Ju, 2012). Several side effects associated with ADV are reported, including acute renal failure and Fanconi syndrome (Izzedine et al, 2009; Jung et al, 2010; Girgis et al, 2011). These side effects have been well known to occur at a dose of 60 mg/d or 120 mg/d when treating human immunodeficiency virus (Earle et al, 2004; Izzedine et al, 2004; Hadziyannis et al, 2006; Izzedine et al, 2009). The State Food and Drug Supervision and Administration has warned that attention should be paid to the risk of ADV-induced osteomalacia (Zhu et al, 2018)
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