# Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?
## 5 Chloroquine and Hydroxychloroquine
[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. Lower levels of desethyl HCQ in individuals with _CYP2D6*4_ (AA) were found to be associated with a significantlyhigher 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 prodrug that are activated by CYP2D6 (codeine and tramadol) [72; 73]. In addition, _CYP2C8*2_ (rs11572103) and _CYP2C8*3_ (rs11572080) display a markedly decreased activity in vitro [74]. The study including malaria-infected patients found that low-activity alleles of _CYP2C8_ (i.e., *2, *3, and *4) were associated with a worse decrease in gametocytaemia than wild-type alleles one day after chloroquine/primaquine treatment (\(-\)2.21 vs. \(-\)11.18 gametocytes/uL, \(p\) = 0.007, respectively), while individuals with variant alleles of _SLCOIA2_ and _SLCOIB1_ had reduced gametocytaemia clearance compared to the wild-type alleles (\(p\) = 0.018 and 0.024, respectively) [69; 75]. It confirms that variations within these drug transporters may be crucial in the pharmacogenetics of chloroquine [76]. Hydroxy chloroquine and chloroquine are substrates of organic anion transporting polypeptides (OATP), influx cellular membrane transporters encoded by _SLCO14_. Since genes involved in the pharmacokinetics of these two drugs are considered \"very important pharmacogenes (VITs)\" by the PharmGKB, the variations within them may markedly affect the outcome of treatment [40]. Patients with known glucose-6 phosphate dehydrogenase deficiency should receive a reduced dose due to the risk of hemolysis and hemolytic anaemia [77]. High individual and ethnical dissimilarities in G6 PD activity are related to genetic variations within its gene. For example, the deficiency of enzymatic activity was found to be frequent in Europe, the Mediterranean area, the Middle East, Asia, as well as in some regions of Africa [78]. The results of studies have indicated that as much as 39% of COVID-19 patients suffering from lupus were intolerant to HCQ or failed to respond to the treatment [10; 79]. 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]. Long-term chloroquine and hydroxychloroquine treatment was found to induce retinal toxicity, while hydroxychloroquine alone can cause drug-related retinopathy which endures even following the cessation of therapy, as well as ocular toxicity and visual disturbances (retinal and macular toxicity) [82; 83]. Retinopathy occurs more frequently in case of prolonged, high-dose treatment with hydroxychloroquine and chloroquine [84].