Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Birkuš, Gabriel; Hitchcock, Michael; Cihlář, Tomáš

doi:10.1128/aac.46.3.716-723.2002

Cited by 392 publications

(279 citation statements)

References 44 publications

Supporting

Mentioning

252

Contrasting

Unclassified

Order By: Relevance

“…Although TDF is similar to other nucleotide analogues in its affinity for hOAT-1, in vitro data suggest that TDF is substantially less toxic to renal proximal tubule epithelial cells than cidofovir [16,17]. Also, no significant changes in mitochondrial DNA levels were observed in renal proximal tubule epithelial cells exposed to TDF concentrations ranging from 3 to 300 mM [18]. Furthermore, evidence of renal toxicity in animals was observed at TDF exposures 2-20 times greater than those used in humans [19].…”

Section: Discussionmentioning

confidence: 80%

Incidence of and risk factors for tenofovir‐induced nephrotoxicity: a retrospective cohort study

et al. 2005

View full text Add to dashboard Cite

ObjectivesDespite the recent publication of case reports describing various manifestations of tenofovir-related nephrotoxicity, data regarding the incidence of and risk factors for this adverse effect are currently lacking. MethodsA retrospective cohort study of patients from four centres in Toronto, Canada, enrolled in the tenofovir expanded access programme with a minimum of 3 months follow up, was carried out. ResultsA total of 172 patients receiving tenofovir disoproxil fumarate (TDF) for a median of 16 months (range 3-25 months) were included in the study. Seven (4%) patients developed grade 1 (444 mmol/ L from baseline) increases in serum creatinine (SCr) during follow up; no patient developed grade 2 or higher nephrotoxicity. Fifteen (8.7%) patients had an increase in SCr of greater than 1.5 times baseline values during follow up. Four (2.3%) patients discontinued TDF because of an increase in SCr and/or abnormal urinalysis. Of 62 patients with a urinalysis, grade 1 or higher proteinuria (o 3 g/L) was observed in 27 (43%) patients. Only baseline SCr [odds ratio (OR) 5 0.51 per 10 mmol/L increase; P 5 0.0005] and baseline creatinine clearance (1.26 per 10 mL/min increase; P 5 0.01) were significantly associated with ever having a 1.5-fold increase in serum creatinine. Twenty-eight (16%) and 11 (6%) patients developed grade 1 (serum phosphorus 0.71 mmol/L) and grade 2 (serum phosphorus 0.61 mmol/L) hypophosphataemia during follow-up, respectively. ConclusionsAlthough slight increases in SCr did occur after starting TDF, clinically significant nephrotoxicity was rare. The clinical significance of TDF-related hypophosphataemia and proteinuria requires further study.Keywords: adverse effects, anti-HIV agents, creatinine, kidney, tenofovir IntroductionTenofovir disoproxil fumarate (TDF) is the only nucleotide analogue currently available for the management of HIV infection. The efficacy of TDF was initially established in two clinical trials with antiretroviral (ARV)-experienced patients, in which the addition of TDF to stable background therapy resulted in a significant decrease in viral load relative to placebo, with a similar incidence of adverse effects [1]. In addition, study GS-903 established TDF as a comparable alternative to stavudine when used in combination with lamivudine and efavirenz in ARV-naive patients, while eliciting less mitochondrial and metabolic toxicity [2]. The convenience of once-daily administration coupled with a favourable toxicity profile has rendered TDF a welcome addition to the ARV arsenal. Importantly, unlike structurally related nucleotide analogues such as cidofovir and adefovir, clinically significant nephrotoxicity did not emerge as a treatment-limiting adverse effect of TDF in the clinical trials. Furthermore, the renal safety profile of TDF was similar to that of stavudine over 144 weeks of followup in study However, post-marketing experience with TDF has raised the possibility that nephrotoxicity may be an uncommon but important adverse effect of this agent. Several c...

show abstract

Section: Discussionmentioning

confidence: 80%

Incidence of and risk factors for tenofovir‐induced nephrotoxicity: a retrospective cohort study

et al. 2005

View full text Add to dashboard Cite

show abstract

“…45,46 The results for ApoC3 -455 were also not consistent with those of the Italian cohort, which showed an association of the 4 Kruskal-Wallis test. 5 The first measurement after patients started antiretroviral therapy. 6 The last measurement of the observation period.…”

Section: Discussionmentioning

confidence: 99%

“…Many mechanisms have been suggested, including mitochondrial toxicity by nucleoside reverse transcriptase inhibitors (NRTIs), inhibition of adipocyte differentiation by protease inhibitors (PIs), increased levels of inflammatory cytokines, and HIV itself. [5][6][7] Mitochondrial toxicity has been clearly shown to play a pivotal role; in particular, thymidine analogs are strong inhibitors of DNA polymerase-c and lead to mitochondrial depletion and dysfunction 8 ; mainly stavudine (d4T), but also zidovudine (AZT) and didanosine (ddI) are strongly related to LA. 9,10 In previous in vitro and clinical studies, newer nucleoside and nucleotide agents, such as lamivudine (3TC), emtricitabine, abacavir, and tenofovir, appear to be much weaker inhibitors of mitochondrial DNA polymerase-c or other mitochondrial functions, and appear to be associated with a lower risk of events thought to be related to mitochondrial toxicity.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms inFasGene Is Associated with HIV-Related Lipoatrophy in Thai Patients

Likanonsakul

Rattanatham

Feangvad

et al. 2013

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

The present study aimed to evaluate the role of genetic polymorphisms in the emergence of lipoatrophy or lipodystrophy in HIV-infected patients with antiretroviral therapy (ART) in Thailand. Position 455 upstream of the Apolipoprotein C3 gene (ApoC3 T-455C, rs2854116), codon 64 of the Beta3 adrenergic receptor gene (ARb3 Tcod64C, rs4994), and position 670 upstream of the Fas gene (Fas A-670G, rs1800682) were genotyped in 829 HIV-infected Thai patients who had started ART. Crude and adjusted incidence rate ratios (IRR) were calculated using Poisson regression. The serum levels of cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were also analyzed. Multivariate analysis revealed an association between the Fas -670AA genotype, but not the ApoC3 -455 or ARb3 cod64 genotypes, with the incidence of lipoatrophy after adjusting for gender and stavudine (d4T)-containing regimens (IRR = 1.72, 95% CI = 1.20-2.45, p = 0.003). However, ApoC3 -455C homozygous patients showed elevated serum levels of triglycerides, while this genotype did not affect serum total cholesterol, HDL, or LDL levels in patients with lipoatrophy or lipodystrophy. In contrast, the ARb3 cod64 genotype did not show any significant association with the serum levels of cholesterol, triglycerides, HDL, or LDL. In conclusion, Fas -670AA affected the incidence of lipoatrophy in HIV-1-infected Thai patients, while the ApoC3 -455C allele affected the serum levels of triglycerides. These results confirmed the role of genetics in the development of ART-related metabolic disorders.

show abstract

“…Mitochondrial toxicity due to NRTI use in HIV-infected adults has been reported most often in patients taking zidovudine, lamivudine, stavudine, and didanosine. In vitro, the potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (no longer available in US)>didanosine>stavudine> zidovudine>lamivudine=abacavir=tenofovir [66].…”

Section: Hyperlactatemia and Lactic Acidosismentioning

confidence: 99%

A Review of the Toxicity of HIV Medications

et al. 2013

View full text Add to dashboard Cite

Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

show abstract

Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

Cited by 392 publications

References 44 publications

Incidence of and risk factors for tenofovir‐induced nephrotoxicity: a retrospective cohort study

Incidence of and risk factors for tenofovir‐induced nephrotoxicity: a retrospective cohort study

Polymorphisms inFasGene Is Associated with HIV-Related Lipoatrophy in Thai Patients

A Review of the Toxicity of HIV Medications

Contact Info

Product

Resources

About