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• W2049455568 abstract "Despite the potential benefit of telaprevir (TVR) in HIV/hepatitis C virus (HCV)-coinfected patients, there is a concern about possible clinically significant antiretroviral drug interactions, and real-life experience in this clinical setting is lacking. We report the case of a 51-year-old HIV/HCV-coinfected patient receiving tenofovir (TDF), emtricitabine, and ritonavir-boosted atazanavir (ATVr), who started therapy with TVR and developed acute renal failure and liver toxicity. The patient had been on stable TDF therapy for 2 years. A few weeks after starting TVR, the patient experienced a progressive deterioration in renal function (Table 1). At week 2, TDF/emtricitabine was changed to abacavir/lamivudine to avoid TDF-related nephrotoxicity. At week 4, the patient was hospitalized for severe nausea vomits and dehydration. Hepatic function was abnormally elevated, with no apparent explanation. ATV overexposure was suspected as the cause of liver injury, and ATV plasma concentration was found to be abnormally elevated (2.7 μg/ml) at 60 h after the last dose. HCV double therapy was reintroduced on the fifth day of hospitalization, and both HIV and HCV viral loads remained undetectable at week 12.Table 1: Laboratory findings.In the clinical setting, a significant estimated glomerular filtration rate decrease during TVR treatment was recently reported, particularly in patients with risk factors for renal impairment [1,2]. TVR has shown in-vitro inhibition of drug transporters expressed in the kidney [3]. The inhibition of organic cation transporter 2 (OCT2) by telaprevir has been suggested as the mechanism responsible for elevations in plasma creatinine during TVR therapy [4], and this may have contributed to the initial rise on creatinine plasma level in our patient. Tenofovir has been clearly related to renal toxicity, mainly because of tubular dysfunction. The combination of ATV and TDF results in an increase in TDF exposure that could lead to a higher risk of nephrotoxicity [5]. Several antiretroviral drugs have proven to be substrates of OCT1 and OCT2, which suggests that drug interactions related to the OCTs may be relevant for antiretroviral therapy, in particular, by affecting hepatic or renal elimination [6]. In this line, this journal has recently published the case of a patient on TDF-based regimen who suffered rapid deterioration of renal function after starting TVR and presented increased TDF plasma trough concentrations by 300%; the authors suggested that TDF elimination could have been reduced by the inhibition of renal drug transporters by TVR [7]. In our case, a major role of TDF in renal impairment does not seem probable since TDF withdrawal did not restore kidney function. Nevertheless, TDF plasma level was not measured and therefore we can not rule out an accumulation of TDF thorough renal drug transporters inhibition by TVR. Telaprevir is mainly metabolized by the CYP3A4, acting as both a substrate and an inhibitor. This is of particular importance for the treatment of HIV patients, as the use of ritonavir-boosted HIV protease inhibitors (HIV-IPr) is sometimes indispensable. Currently, the only HIV-PIr recommended for coadministration with TVR is ATVr. An increase in the ATV minimum concentration by 85% was seen when ATV and TVR were combined in healthy volunteers, which led to an increased risk of symptomatic hyperbilirubinemia [8]. In our case, TVR initiation probably led to a rise in ATV concentrations since an unexpected, abnormally high plasma ATV level was seen 60 h after the last dose, at a value similar to the maximum concentration described for the drug [5]. This fact had its clinical and laboratory correlation in the form of nausea, vomits, a rise in hepatic enzymes, and hyperbilirubinemia, which ultimately contributed to renal failure through intravascular volume depletion and dehydration. To the best of our knowledge, an unexpected plasma ATV elevation leading to such a major side effect of the drug has not been described previously, and its mechanism is uncertain, since it might not be attributed only to CYP3A4 mediation. A hypothetical reduction in ATV renal excretion by inhibition of renal drug transporters in the presence of TVR might have been involved in the overexposure to this drug seen in our patient. In conclusion, even though major drug–drug interactions between ATV and TVR have not been seen in clinical trials, we report a serious adverse event that was likely related to a major rise in plasma ATV concentration in the presence of TVR. Various mechanisms that are currently incompletely defined may have been implicated in this unexpected drug–drug interaction. It seems advisable to closely monitor patients on TVR therapy, particularly if additional risk factors or co-medications are present. The effect of TVR on renal and hepatic drug transporters and its related clinical implications deserve further investigation. Conflicts of interest Daniel Podzamczer has received research grants and/or honoraria for advisories and/or conferences from Boehringer Ingelheim, GSK, Viiv, Pfizer, BMS, Abbott, Gilead, Janssen and Merck; Elena Ferrer and Eva Van den Eynde have received honoraria for lectures from Boehringer Ingelheim, GSK, Viiv, Pfizer, BMS, Abbott, Gilead, Janssen and Merck." @default.
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• W2049455568 title "Acute renal failure and liver toxicity in an HIV/hepatitis C coinfected patient receiving telaprevir and boosted atazanavir" @default.
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