# Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?
## 5 Chloroquine and Hydroxychloroquine  
Chloroquine (CQ) and hydroxychloroquine (HCQ) are drugs used to treat and as prophylaxis for malaria and autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Additionally, chloroquine has been used to treat amebiasis and hydroxychloroquine has been used to prevent thrombosis among patients with anti-phospholipid antibody syndrome [2; 61; 62]. According to studies, chloroquine and hydroxychloroquine inhibit the expressions of major histocompatibility complex (MHC) class II, limit the formation of IL-1, IFN\(\alpha\), and TNF, as well as impair the activity of cyclic GMP-AMP synthase partly via the accumulation of phagocytic cells in lysosomes and autophagosomes and altering local pH concentrations [63]. Chloroquine and hydroxychloroquine were among the most frequently administered repurposed therapeutic agents during the first stages of the pandemic [25]. They are the first antiviral drugs formally designated for COVID-19 treatment as FDA Emergency Use Authorization was issued on 28 March 2020 [3]. However, later on, new data which suggested that these drugs' potential benefits may not outweigh their identified potential risks were published [63]. The clinical trials assessing the efficacy and safety of these drugs are still ongoing. In the treatment of COVID-19, CQ is administered orally at a dose of 300 mg (adults), twice a day for a maximum of 10 days, while in the case of HCQ, the loading dose of 400 mg twice a day during the first day and then 200 mg bid (10 days average) is used [3]. The results of studies indicated that CQ and HCQ were effective in the fight against SARS-CoV-2 [64]. These two drugs hamper virus entry by targeting the endosomal pathway. They are capable of increasing the pH of endosomes and inhibiting membrane fusion [17]. Moreover, both drugs inhibit the glycosylation of host receptors and proteolytic processing thus blocking viral entry [65]. The immunomodulatory effects of these drugs have been suggested to facilitate the management of the cytokine storm associated with advanced COVID-19 disease [40]. In addition, their impact on hampering autophagy/lysosomal activity has been described [65; 66]. SARS-CoV-2 virus during the invasion of the host body uses ACE2 receptors expressed on host epithelial cells as well as cofactor transmembrane protease, serine 2 (TMPRSS2). It has been suggested that some variants in _ACE2_ (e.g., rs762890235 and rs1316056737) may prevent the interaction with the S protein and affect the clinical efficacy of HCQ or CQ [3]. One of the studies revealed that the ACE2 variant rs41303171 may stimulate the activation of TMPRSS2 and facilitate subsequent viral entry [67]. It is possible that HCQ and CQ may only be effective in the treatment of TMPRSS2-deficient patients who are infected by SARS-CoV-2, while such treatment exerts lower or no effect in those with wild-type TMPRSS2 [3]. Both drugs are broadly metabolized in the liver by CYP2C8, CYP3A4, CYP3A5, and, to a lesser extent, CYP2D6 [2; 68]. The results of studies indicated that polymorphisms within these genes could affect malaria treatment with chloroquine. Carriers of _CYP2C8*4_ (missense mutation) have lower enzyme activity which translates into lower treatment efficacy compared to wild-type allele *1 A [69]. In turn, the allele _CYP2D6*10_ was found to be associated with the hydroxychloroquine metabolic ratio [70]. Patients with systemic lupus erythematosus demonstrated a \(\sim\)20% increased ratio of the active metabolite of hydroxychloroquine metabolism to its parent drug in individuals carrying variants in CYP2D6 (rs1135840: CC vs. GG was 0.90 vs. 0.69, respectively, \(p<0.01\)) [70]. 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]. [PERSON] et al.