Severe rhabdomyolysis-induced acute kidney injury following concomitant use of Genvoya® (EVG/COBI/FTC/TAF) and simvastatin; a case report

Abstract

Background Genvoya® (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) is a recent single regimen for the treatment of Human Immunodeficiency Virus (HIV). However, because of its complexity, it is difficult to predict drug interactions, especially when associated with HMG-CoA reductase inhibitors and/or in the setting of other comorbidities. We discuss the mechanisms of these potential drug interactions as the cause of rhabdomyolysis and acute kidney injury in the context of prior and current medication therapy with possible underlying liver and kidney dysfunction. Case presentation We describe the case of a 54-year-old man diagnosed with HIV who developed severe rhabdomyolysis-induced anuric acute kidney injury (AKI) requiring renal replacement therapy following introduction of Genvoya® concomitantly with simvastatin, in the context of recently diagnosed hepatitis C and hepatitis A. Haemodialysis was continued over 5 weeks followed by progressive clinical and biological improvements. Five months later, a new antiretroviral regimen was started and has been well tolerated. Conclusion Simvastatin, as well as lovastatin, because of their CYP3A4 metabolism, and to a lesser extent atorvastatin, which is only partially metabolized by CYP3A4, are the HMG-CoA reductase inhibitors with the greatest risk of drug interactions and should not be used in patients under HIV-therapy. Patients receiving HMG-CoA reductase inhibitors should be monitored regularly for the occurrence of muscular adverse effects and drug interactions should be considered with each new prescription or change in clinical status. There are many online tools that enable clinicians to rapidly check for drug interactions. We recommend the one from the University of Liverpool for patients under HIV-therapy ( https://www.hiv-druginteractions.org/checker ), while for patients under hepatitis C-therapy, we advise to consult http://www.hep-druginteractions.org/ . This case illustrates the importance of multidisciplinary collaboration in the treatment of HIV-positive patients because of their complexity, associated comorbidities and the potential of multiple drug-drug interactions potentially exacerbated by underlying liver and/or kidney dysfunction.

Recommendations for the Management of Drug–Drug Interactions Between the COVID‐19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications

“… 16 Indeed, a patient treated with the strong CYP3A4 pharmacokinetic booster cobicistat developed a severe rhabdomyolysis‐induced kidney failure 10 days after initiation of simvastatin. 17 Given the high risk of harm, simvastatin is contraindicated with nirmatrelvir/ritonavir. Thus, simvastatin has to be paused to enable treatment with nirmatrelvir/ritonavir.…”

“…For instance, ritonavir is predicted to increase simvastatin (metabolized 100% by CYP3A4) concentrations by 100‐fold, thereby exposing an individual to the risk of a deleterious adverse event 16 . Indeed, a patient treated with the strong CYP3A4 pharmacokinetic booster cobicistat developed a severe rhabdomyolysis‐induced kidney failure 10 days after initiation of simvastatin 17 . Given the high risk of harm, simvastatin is contraindicated with nirmatrelvir/ritonavir.…”

A suspected case of hyponatraemia induced rhabdomyolysis: a case report

“…Several previous case reports have implicated combined anti-retroviral therapy (cART) with the onset of rhabdomyolysis [ 18 – 24 ]. The cART regimen used to treat HIV infection in our patient consisted of dolutegravir, an integrase inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs).…”

Overdose of the HIV Medicine Genvoya® in Two Auto-Intoxications

“…Cobicistat, which is added to the HAART medication as a pharmacokinetic enhancer, is an inhibitor of the metabolising enzyme CYP2D6, a substrate and inhibitor of CYP3A4 and an inhibitor of the P-glycoprotein (P-gp). Drug-drug interactions (DDI) with co-medication of the patient could occur, leading to elevated serum levels of the latter and more pronounced side-and toxic effects (6). Besides Genvoya®, the Case 1 patient was prescribed a number of other pharmaceuticals for his psychiatric illnesses; valproic acid, venlafaxine, quetiapine, trazodone, lorazepam, olanzapine and alprazolam.…”