COVID19 - Pharmacogenetics

Genes affecting Pharmacogenomic recommendations

Gene affecting COVID-19 medication Pharmacogenomic effect Recommendation
G6PD
CYP2D6
IL10
TNF
Gene variants affecting suggested COVID-19 medicines were not detected Dose and/or medicine alterations not required based on pharmacogenomics
G6PD
CYP2D6
IL10
TNF
Potentially decreased tolerance for hydroxychloroquine and elevated risk for adverse effects Hydroxychloroquine use warrants consideration
G6PD Potentially reduced tolerance for chloroquine and hydroxychloroquine and increased risk for hemolytic anemia. Chloroquine and hydroxychloroquine use warrants consideration
SLCO1B1 Potentially decreased tolerance for lopinavir and elevated risk for adverse effects Lopinavir use warrants consideration
IL1 Potentially decreased tolerance for anakinra and elevated risk for adverse effects Anakinra use warrants consideration
G6PD Increased risk for hemolytic anemia Alternative options should be considered for chloroquine

Choloroquine and hydroxychloroquine

Chloroquine is an old malaria medicine first brought into market in the 1930sā€™. It was widely used especially in Asia, but rapidly developed resistance for the most severe form of malaria Malaria Falciparum. Therapeutic window for chloroquine is also narrow, and overdosing may lead to severe poisoning and even death. Today chloroquine has been largely replaced in malaria treatment and prevention by novel medicines with improved efficacy and safety profiles.

Hydroxychloroquine (hydroxychloroquine sulfate) is a chloroquine derivative developed in the 1940sā€™. Today hydroxychloroquine is widely used in the treatment of rheumatoid arthritis and related rheumatoid traits, for example systemic lupus erythematosus. Chloroquine and hydroxychloroquine both are weak bases which elevate intracellular pH. These medicines act as immunomodulators.

Choloroquine and hydroxychloroquine in COVID-19 treatment

Chloroquine and hydroxychloroquine are investigated as potential treatment options against SARS-CoV-2 virus. Their potential mechanism of action in SARS-CoV-2 virus infection is suggested to be the inhibition of intracellular virus release. Animal models have shown that chloroquine and hydroxychloroquine can both inhibit virus transport from endosomes to endolysosomes. This is considered a critical step in intracellular virus release. First human reports of SARS-CoV-2 virus infection have also demonstrated a cytokine storm, with high cytokine concentrations. Hydroxychloroquine as an immunomodulator may reduce this type of inflammatory response, as in rheumatoid arthritis. Anti-inflammatory response may be another mechanism of action for hydroxychloroquine in SARS-CoV-2 virus infection. Currently clinical data on chloroquine and hydroxychloroquine in is SARS-CoV-2 virus infection very limited and based on small trials.

Chloroquine, hydroxychloroquine and G6PD-deficiency

Chloroquine and hydroxychloroquine use call for careful consideration in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD is an enzyme protecting red blood cells against oxidative stress. G6PD-deficiency is a recessive hereditary condition, where G6PD enzyme function is reduced, leading to decreased repair ability in oxidative stress conditions. G6PD-deficiency may lead to hemolysis, a condition where red blood cells are deteriorated by stress response. Hemolysis again may lead to hemolytic anemia, a severe medical condition. Several medicines, including chloroquine and hydroxychloroquine, may induce hemolysis in individuals with G6PD-deficiency.

G6PD gene is located in X-chromosome. Hereditary G6PD-deficiency is rare recessive condition affecting mainly males. Females have two X-chromosomes, and therefore a mutation in one X-chromosome usually does not lead to disease manifestation because the other X-chromosome functions normally. G6PD-deficiency manifestates in females when both X-chromosomes harbour the mutation. Males however have only one X-chromosome, and G6PD-mutation in this only chromosome usually leads to a disease. G6PD-deficiency is most common in the Mediterranean area in Europe, in Middle East, Asia and parts of Africa. In Northern Europe the condition is rare. Globally about 400 million people are affected by G6PD-deficiency.

Chloroquine and hydroxychloroquine use in individuals having genetic mutations in the G6PD gene warrants careful consideration, as these medicines may induce hemolysis and hemolytic anemia. Chloroquine use in not recommended with severe G6PD-deficiency. Hydroxychloroquine is reported to induce hemolysis less than chloroquine.

Genetic variation in IL10, TNF and CYP2D6 influence chloroquine and hydroxychloroquine efficacy and safety

In addition to G6PD-deficiency genetic variation in interleukine-10 (IL10), tumor necrosis factor (TNF) and cytochrome 2D6 (CYP2D6) has been reported to influence safety and/or efficacy of hydroxychloroquine. Altogether three IL10-variants and a TNF-variant have been associated to increased hydroxychloroquine response. Carriers of these gene variants may reach medicine response with reduced medicine dose. Normal recommended dose may lead to increased risk for adverse effects.

CYP2D6 gene variants have also been suggested to affect hydroxychloroquine safety and efficacy. Liver enzyme CYP2D6 cleaves (metabolizes) several medicines in the liver. High hydroxychloroquine concentrations have been observed in individuals who are poor or intermediate CYP2D6 metabolizers (CYP2D6*4 ja CYP2D6*10). Unlike with several other medicines, there is no established clinical guidance related to CYP2D6 gene variants in chloroquine or hydroxychloroquine use.

Lopinavir and ritonavir

Lopinavir and ritonavir are used in the treatment of Human Immunodeficiency virus (HIV) infection. Lopinavir is a HIV protease inhibitor. Lopinavir inhibits HIV protease, an enzyme cleaving viral proteins. Protease inhibition leads to formation of dysmorphic provirions, and to inhibition of viral replication.

Ritonavir acts as an enhancer for lopinavir effect. Ritonavir is a potent liver CYP-blocker, especially effecting CYP3A4 enzyme. CYP enzymes have a key role in the metabolism of several medicines in the liver. When CYP enzymes are blocked, the metabolism of these medicines is reduced or inhibited. This leads to increased medicine concentration, with poor medicine clearance from the body. By clocking CYP3A4 enzyme, ritonavir is enhancing the effect and concentrations of the medicines usually metabolized by CYP3A4, including lopinavir.

Lopinavir and ritonavir in COVID-19 infection

Lopinavir/ritonavir combination has been previously been suggested as a potential medicine in MERS and SARS infections. MERS and SARS belong to the same virus family with the current SARS-CoV-2 virus. In animal models lopinavir/ritonavir has shown efficacy against MERS virus infection. In humans in SARS-CoV-2 infection lopinavir/ritonavir combination has been tested in small patient series, so far with conflicting results.

Lopinavir pharmacogenetics

SLCO1B1 gene variants have been linked with individual lopinavir concentrations. There are no established clinical treatment recommendtion on lopinavir pharmacogenetics. Gene variants affecting to ritonavir concentrations have not been reported.

Interleukin inhibitors

Interleukins belong to cytokines together with other molecules such as chemokines and interferons. Cytokines are involved in body immune and inflammatory response. Increased cytokine concentrations are seen in many inflammatory diseases, for example in rheumatoid conditions and some asthma subtypes. Interleukins are involved in white blood cell signaling and act as modulators of immune and inflammatory response.

Anakinra is a biologic medicine used in the treatment of rheumatoid arthritis and other related conditions in combination with methotrexate. Anakinra is an interleukin inhibitor. Anakinra acts as a competitive interleukin 1 receptor inhibitor. Increased IL1 is seen is plasma and synovial fluid of the patients with rheumatoid arthritis. By binding to IL1a and IL1b receptors, anakinra neutralizes the biologic activity of IL1a and IL1b. Several different cell types secrete interleukin 1 (IL1). IL1 then activates and stimulates immune cells and causes fever and increased endothelial adhesion.

Another interleukin inhibitor tocilizumab targets to the inhibition of interleukin 6 (IL6) receptors. IL6. T- and B-lymphocytes and macrophages produce IL6. IL6 is involved in B-cell differentiation and stimulation of acute phase proteins. Tocilizumab is a IL6 inhibitor, which blocks IL6 receptor and decreases inflammatory response of IL6 cytokines. Tocilizumab is approved for the treatment of rheumatoid arthritis and other related conditions.

Interleukin inhibitors in COVID-19 treatment

First human reports of SARS-CoV-2 virus infection have also demonstrated a cytokine storm, with high cytokine concentrations. The potential mechanism of action of anakinra and tocilizumab SARS-CoV-2 virus infection are based on their ability to decrease cytokine burden. Tocilizumab targets IL6 receptor inhibition. Up to three-fold IL6 concentrations have been described in patients with severe SARS-CoV-2 virus.

Anakinra prescribing information https://www.medicines.org.uk/emc/product/559/smpc


Note

The decision on medication is made by a physician. Use medicines only as directed by your physician. Medication should always be based on the careful judgement of the physician. Medication should not be initiated or the dosage of the current drug be changed without physicians consideration. There is no known drug for the prevention of Covid-19 disease. The best way to protect yourself from a viral infection is to take care of good hand hygiene and avoid contacts.

Negen COVID19 - PGx panel is included in following genomic analysis products:

Negen 360 Negen MyData - COVID19

Literature

Davila L1, Ranganathan P. Pharmacogenetics: implications for therapy in rheumatic diseases. Nat Rev Rheumatol. 2011 Aug 9;7(9):537-50.

Liu J et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020; 6: 16.

Cao B et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18.

Liu F et al. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int J Infect Dis. 2020 Mar 12.

Peters and Van Noorden. Glucose-6-phosphate Dehydrogenase Deficiency and Malaria: Cytochemical Detection of Heterozygous G6PD Deficiency in Women. J Histochem Cytochem. 2009 Nov; 57(11): 1003ā€“1011.

Kupferschmidt et al. Race to find COVID-19 treatments accelerates. Science 2020. https://science.sciencemag.org/content/367/6485/1412.long