Safety and effectiveness concerns of lopinavir/ritonavir in COVID-19 affected patients: a retrospective series

Abstract

Context Originally developed for treatment of human immunodeficiency virus (HIV), the antiviral combination lopinavir/ritonavir (LPV/r) is being repurposed for treating the novel coronavirus disease (COVID-19) despite minimal experience in this markedly different population and an in-vitro derived EC50 against SARS-CoV-2 several hundred-fold greater than for HIV. We present a case series including a case of severe hyponatremia and a 32-fold overdose raising safety and effectiveness concerns in COVID-19 patients. Methods We measured LPV trough concentrations in 12 patients and reviewed their clinical charts for side effects known to occur in HIV patients. Findings Compared to established LPV trough concentrations in HIV patients, concentrations in COVID-19 patients were 3-fold greater (19.37 ± 10.12 mcg/mL versus 6.25 mcg/mL). In addition, cholestasis and dyslipidemia toxicity thresholds were exceeded in 12/12 and 11/12 patients respectively. No patients achieved the presumed therapeutic concentration. Side effects included gastrointestinal symptoms (5/12), electrolyte imbalances (4/12), liver enzyme disturbances (5/12) and triglyceride elevations (2/12). Conclusion No patients reached presumed therapeutic LPV concentrations despite experiencing side effects and exceeding cholestasis and dyslipidemia toxicity thresholds. This raises concerns for the safety and effectiveness of LPV/r. Clinicians should consider closely monitoring for side effects and not necessarily attribute them to COVID-19.

Effectiveness of Remdesivir, Lopinavir/Ritonavir, and Favipiravir for COVID-19 Treatment: A Systematic Review

“…Additionally, lopinavir/ritonavir inhibits CYP enzyme binding, which in turn causes adverse drug reactions and increases the frequency and severity of other potential complications. 42 Lopinavir/ritonavir also affects the body’s immunoregulation which causes the initial growth of the virus to increase due to decreased immune function. 43…”

“…Additionally, lopinavir/ritonavir inhibits CYP enzyme binding, which in turn causes adverse drug reactions and increases the frequency and severity of other potential complications. 42 Lopinavir/ritonavir also affects the body's immunoregulation which causes the initial growth of the virus to increase due to decreased immune function. 43 In a study conducted by Grimaldi et al, there was a higher incidence of acute kidney injury and the need for renal replacement therapy in patients receiving lopinavir/ritonavir, which raised doubts about its safety profile.…”

Clinical Efficacy and Safety of Antiviral Drugs in the Extended Use against COVID-19: What We Know So Far

“…In this study, LPV/RTV did not improve clinical outcomes by minimizing hospital stay, mechanical ventilation, or mortality rate. A retrospective study was conducted to observe whether the conventional dose of LPV/RTV used for HIV can be used in COVID-19 patients; it turns out dose tampering is a mandatory act to use the drug for the latter purpose [89]. Cao et al [74] conducted a randomized, controlled, open-label clinical trial (ChiCTR2000029308) on 199 patients (LPV/RTV = 99 and SOC = 100).…”

“…A comparative randomized clinical trial between sofosbuvir/daclatasvir (SFV/DCV) and LPV/RTV was carried out where only the discharge rate was better in the LPV/RTV group; better survival rate and fewer complications were shown in the SFV/DCV group [125]. Similarly, Lepage et al [89] and Schneider et al [90] conducted retrospective studies and found several preliminary results that warrant well-designed and more extensive randomized controlled clinical trials.…”

Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021

“…However, a retrospective case-series study raised concerns about the safety of lopinavir-ritonavir use in COVID-19 patients based on the possibility of causing serious adverse events even before reaching the presumed therapeutic concentration for COVID-19 treatment. Moreover, WHO reported the recommendation of Solidarity trial regarding immediate discontinuation of this combination in COVID-19 patients due to ineffectiveness and safety concerns on July 4, 2020 ( Lepage et al, 2021 ). Again, a large retrospective, multicenter study involving 8,553 COVID-19 patients found no overall advantage of lopinavir-ritonavir administration in early COVID-19 patients ( Lora-Tamayo et al, 2021 ).…”