CYP2D6 and CYP3A4 variants influence the risk and outcome of COVID-19 infection among rheumatoid arthritis patients maintained on hydroxychloroquine

Abstract

Objectives Hydroxychloroquine (HCQ) has been used as an off label for the management of coronavirus disease (Covid-19) infection with other drugs. However, different genetic variants can affect the metabolism of HCQ leading to inter-individual differences in its efficacy. In this study, we investigated the effects of variants in CYP2D6, CYP3A4 and CYP3A5 on the risk of Covid-19 infection among patients receiving HCQ for controlling rheumatoid arthritis (RA). Methods A total of 60 patients were genotyped for CYP2D6*2XN, CYP2D6*4, CYP3A4*1B and CYP3A5*2. They were receiving HCQ for the treatment of RA. The patients were evaluated clinically for fever and dry cough, radiologically via chest computed tomography (CT) and immunologically via anti-Covid-19 IgG and IgM titers. Results Variants in CYP2D6 significantly affected the grade of ground glass (CYP2D6*4 AA carriers showed the higher risk for grade 3) and the risk of positive anti-Covid-19 IgM (CYP2D6*2XN CC and CYP3A4*1B AA had the lowest risk), the duration of HCQ, the use of corticosteroids or gender did not affect the Covid-19 status significantly. Conclusions In general, the outcome of the studied patients receiving HCQ was good (no deaths, no intubation needed). CYP2D6 variants could affect the outcome of Covid-19 infection.

Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?

“…In carriers of CYP2D6*4 (AA), HCQ is poorly metabolized which results in reduced formation of desethyl HCQ, thus probably diminishing the efficiency of HCQ in preventing COVID-19 viruses from entering cells. Lower levels of desethyl HCQ in individuals with CYP2D6*4 (AA) were found to be associated with a significantly higher grade of ground-glass opacities in the chest CT compared to wild and heterozygous carriers (but the p-value was >0.05) [15]. Due to the fact that both CQ and HCQ were found to inhibit CYP2D6 activity, they may not only potentiate the effects of other CYP2D6 substrates, including carvedilol and labetalol but also reduce the effectiveness of prodrugs that are activated by CYP2D6 (codeine and tramadol) [72,73].…”

“…The authors suggested that the occurrence of CYP polymorphisms may explain the wide variation in this drug levels in the blood. In turn, individuals with the CYP2D6*4 (rs3892097) variant have hardly any or even no CYP2D6 activity as a result of a splicing defect in an intron (between the third and fourth exon) [15,71]. Hareedy et al [15] hypothesized that desethyl HCQ could be primarily responsible for the actions of HCQ, therefore the rate of its formation via CYP2D6 and other CYP enzymes could modify COVID-19 status among HCQ receivers for rheumatoid arthritis.…”

“…In turn, individuals with the CYP2D6*4 (rs3892097) variant have hardly any or even no CYP2D6 activity as a result of a splicing defect in an intron (between the third and fourth exon) [15,71]. Hareedy et al [15] hypothesized that desethyl HCQ could be primarily responsible for the actions of HCQ, therefore the rate of its formation via CYP2D6 and other CYP enzymes could modify COVID-19 status among HCQ receivers for rheumatoid arthritis. In carriers of CYP2D6*4 (AA), HCQ is poorly metabolized which results in reduced formation of desethyl HCQ, thus probably diminishing the efficiency of HCQ in preventing COVID-19 viruses from entering cells.…”

“…The most severe complications associated with HCQ and CQ treatment include QTc prolongation and ventricular arrhythmias which can be highly dangerous, especially for critically ill patients [80]. HCQ has a better safety profile compared to chloroquine [15]. The results of a large retrospective study of hospitalized patients with COVID-19 conducted in the New York metropolitan region revealed that patients treated with hydroxychloroquine and azithromycin had a higher prevalence of cardiac arrest and possibly higher mortality [81].…”

“…Despite being less time-consuming, the repurposing still requires clinical trials to confirm the efficiency and safety in a different target group of patients. No definitive drugs or vaccines for the treatment or prevention of COVID-19 have been approved in 2021, available therapies only obtained 'conditional approval' [15]. Drug repurposing is a cost-and time-saving approach to managing COVID-19 [12][13][14]; however, limitations such as low success rate and the possibility of adverse side effects cannot be overlooked [13][14][15][16][17].…”