Renal Fanconi syndrome and myopathy after liver transplantation: Drug‐related mitochondrial cytopathy?

Bayrakçı, Umut Selda; Baskın, Esra; Özçay, Figen; Özdemir, Binnaz Handan; Karakayalı, H.; Haberal, Mehmet

doi:10.1111/j.1399-3046.2007.00839.x

Cited by 15 publications

(12 citation statements)

References 23 publications

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“…Polymerase γ is unique among the cellular replicative DNA polymerases as it is highly sensitive to inhibition by nucleoside analogues used in the treatment of human immunodeficiency virus and chronic hepatitis B and C infections 18, 19. Likewise, evidence of mitochondrial dysfunctions has also been reported with other drugs used to treat hepatitis B, such as lamivudine, telbivudine, and fialuridine5, 20–25 Thus, it is not surprising that clevudine could also produce mitochondrial toxicity.…”

Section: Discussionmentioning

confidence: 99%

Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA

Seok

Lee

et al. 2009

Hepatology

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Clevudine (Revovir), a pyrimidine nucleoside analogue, is a recently introduced antiviral drug. Clinical trials have demonstrated potent, sustained antiviral activity against hepatitis B virus without specific adverse events. The lack of cytotoxicity and absence of an effect on mitochondrial function have been considered the reasons for the fewer adverse events. However, it came to our attention that several hepatitis B patients developed myopathy during clevudine therapy.Our study was aimed to analyze the clinical and pathological features of patients with clevudineinduced myopathy with some consideration of its pathogenetic mechanism. Seven hepatitis B patients who developed severe skeletal myopathy during clevudine therapy were examined in this study. The demographic data, clinical features, pathological findings, and molecular studies of these patients were analyzed with speculation about the underlying pathogenic mechanisms. All seven patients were treated with clevudine for more than 8 months (8-13 months). In all, the main symptom was slowly progressive proximal muscular weakness over several months. A markedly elevated creatine kinase level and myopathic patterns on electromyography were found. Muscle biopsies revealed severe myonecrosis associated with numerous ragged red fibers, cytochrome c oxidase-negative fibers, and predominant type II fiber atrophy. Molecular studies using quantitative polymerase chain reaction showed a depletion of the mitochondrial DNA in the patients' skeletal muscle. Conclusion: To the best of our knowledge, this is the first report of myopathy associated with clevudine therapy. This study has clearly shown that long-term clevudine therapy can induce the depletion of mitochondrial DNA and lead to mitochondrial myopathy associated with myonecrosis. Careful clinical and laboratory attention should be paid to patients on long-term clevudine therapy for this skeletal muscle dysfunction. (HEPATOLOGY 2009; 49:2080-2086 H epatitis B virus (HBV) is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. As carriers of HBV serve as reservoirs for vertical and horizontal transmissions, the prevalence of carriers and the number of acute and chronic liver diseases place HBV infection among the most frequent and important transmissible diseases of the hepatobiliary system. Appropriate therapeutic agents are required in order to prevent its irreversible sequelae.Currently, the use of oral antiviral drugs is considered a milestone of chronic hepatitis B therapy. The majority of these are nucleoside and nucleotide analogues that interfere primarily with viral replication by inhibition of the viral DNA polymerase. However, their therapeutic effects are limited because of the development of drug resistance, 1,2 relapse following cessation of treatment, 3,4 and possible toxicity. 5 Mitochondrial cytotoxicity is a wellknown side effect of nucleoside analogues and is most frequently associated with therapy using nucleoside re-

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Section: Discussionmentioning

confidence: 99%

Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA

Seok

Lee

et al. 2009

Hepatology

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“…Over the years, rare reports of reversible myopathy, neuropathy, pancreatitis, and Fanconi syndrome have been reported with lamivudine treatment in patients with HBV and HIV coinfection 30–34. In addition, patients with HIV infection receiving higher daily doses of lamivudine may develop lipoatrophy and asymptomatic macrocytosis 35.…”

Section: Lamivudinementioning

confidence: 99%

Side effects of long-term oral antiviral therapy for hepatitis B

2009

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The aim of this review is to summarize the safety profile of the five approved oral nucleoside analogs used to treat chronic hepatitis B virus (HBV) infection, focusing on both the class adverse effects and those that have been reported with individual agents, as well as their safety in pregnancy. All nucleoside analogs have a "Black Box" warning because of their potential for inhibition of human DNA polymerase gamma involved in mitochondrial DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying clinical manifestations of mitochondrial toxicity (i.e., neuropathy, myopathy, lactic acidosis), but these side effects are rarely reported with the oral antiviral agents active against HBV. Adefovir and tenofovir are associated with a dose-dependent but usually reversible proximal renal tubular toxicity. For these reasons, patients receiving these agents should be monitored for renal toxicity and the dose modified for renal insufficiency. Prolonged use of tenofovir has also been reported to lead to reduced bone mineral density in patients with human immunodeficiency virus infection, but prospective studies in patients with HBV infection are lacking. Telbivudine treatment is associated with moderate serum creatine phosphokinase elevations in up to 12% of patients. There have been few prospective studies on the safety of nucleoside analogs during pregnancy. According to the Antiretroviral Pregnancy Registry, the incidence of birth defects associated with lamivudine and tenofovir use during pregnancy is not increased. Studies on the safety of long-term therapy with the nucleoside analogs, alone and in combination, are needed as are further studies of children, the elderly, pregnant women, and patients with renal insufficiency. (HEPATOLOGY 2009;49: S185-S195.)

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“…Although rare cases of lactic acidosis and Fanconi‐like syndrome have been reported following LAM treatment of patients with HBV and HIV coinfection , dose‐adjusted lamivudine treatment is considered safe in patients with CHB and renal insufficiency . The safety of ETV, in terms of renal insufficiency, has not been well studied.…”

Section: Introductionmentioning

confidence: 99%

Telbivudine protects renal function in patients with chronic hepatitisBinfection in conjunction with adefovir‐based combination therapy

Lee

et al. 2013

Journal of Viral Hepatitis

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Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV-based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed-effects model. HBV DNA levels were also compared between the five groups during the 96-week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P < 0.001 for each group compared with baseline eGFR). In patients with a baseline eGFR between 50 and 90 mL/min, the change in eGFR was the most significant in the ADV + LdT group (+0.641 mL/min; P < 0.001). Age, gender, baseline eGFR and treatment option were significant predictive factors for eGFR changes. In conclusion, our results suggest that the combination therapy of LdT and ADV is significantly associated with renoprotective effects in CHB patients when compared with other ADV-based combination or single therapies.

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Renal Fanconi syndrome and myopathy after liver transplantation: Drug‐related mitochondrial cytopathy?

Cited by 15 publications

References 23 publications

Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA

Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA

Side effects of long-term oral antiviral therapy for hepatitis B

Telbivudine protects renal function in patients with chronic hepatitisBinfection in conjunction with adefovir‐based combination therapy

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