The Role of Pharmacogenomics Studies for Precision Medicine Among Ethiopian Patients and Their Clinical Implications: A Scoping Review

Figures & data

Table 1 Summary of Extracted Data and the Main Outcomes

First Author &Year	Study area	Study type	Sample size	Age in year	Patient category	Main Identified Genes	Alleles/Variants/SNP	Clinical implications	Associated Drug(s)
A.H/Wold (2011)^Citation26	AA	Prospective	163	28–42	TB-HIV	ABCB1 CYP2B6, CYP3A5 and UGT2B7	CYP2B6*6, CYP3A5*3, CYP3A5*6, ABCB1 3435C>T and UGT2B7*2 (2327G>A, rs7662029) were 29.7%, 66.9%, 10.6%, 20.9% and 48.1%, respectively CYP2B6*1/*1 and UGT2B7*1/*1	Significant variability between patients was found, partially explained by sex as well as the genotypes of CYP2B6 and UGT2B7. Continuous EFV autoinduction may put patients with the CYP2B6*1/*1 and UGT2B7*1/*1 genotypes at risk for subtherapeutic plasma concentrations. Genotyping is advised to identify patients who are extensive metabolizers, who may be at risk of suboptimal concentration on long-term therapy due to pronounced induction, and slow metabolizers, who, because of high efavirenz concentrations, are susceptible to CNS damage.	Efavirenz
Getnet Yimer (2011)^Citation27	AA	Prospective case-control	373	18–72	TB-HIV	NAT2, CYP2B6 and ABCB1	CYP2B6*6, ABCB1 3435TT and UGT2B7*2/*2	Significant association of DILI with CYP2B6*6 and ABCB1 3435TT genotype. It was observed that the UGT2B7*2/*2 genotype had a nearly significant effect on DILI. In Ethiopia dual infected patients, the genotypes of slow NAT2 acetylators, ABCB1 3435TT as well CYP2B6*6/*6 were found to be pharmacogenetic indicators for the development of ARV and anti-TB DILI.	D4T30/3TC/EFV, CBV/EFV and TDF/3TC/EFV, Isoniazid
Yimer Getnet (2012)^Citation28	AA	Prospective cohort study	285	28–40	HIV	CYP2B6, CYP3A5, ABCB1 and UGT2B7	CYP2B6*6, CYP3A5*3, CYP3A5*6, ABCB1 3435C4T and UGT2B7- 372G4A	Following the start of EFV-based HAART, 15.7% of patients experienced DILI. The onset of DILI was well-predicted by elevated levels of CYP2B6*6, plasma EFV, and common liver enzymes.	D4T30/3TC/EFV D4T40/3TC/ EFV/CBV/EFV TDF/3TC/EFV
Abiy Habtewold (2012)^Citation29	AA	Prospective Cohort	77	30–43	HIV	ABCB1, CYP3A5, CYP2B6, and UGT2B7	ABCB1- 3435C4T, CYP3A5*3, CYP2B6*6, CYP3A5*6, and UGT2B7*2(−327G4A rs7662029) were 21.3, 66.9, 30.6, 10.6, and 46.7%, consecutively.	Up to week 48, CYP3A enzyme induction in HIV patients on long-term EFV-based HAART is sustained. Due to increased plasma efavirenz exposure, patients with the CYP2B6*6/*6 genotype exhibit the most marked CYP3A induction. Variability in plasma EFV exposure among individuals, partially attributed to the CYP2B6 genotype, may impact the degree of variability in CYP3A induction. When CYP3A substrates are used concurrently with EFV, unexpected medication interactions may occur, especially in CYP2B6 slow metabolizers.	Efavirenz
Misgana Ibrahim (2013)^Citation30	AA	Prospective Cohort	29	1 to 15	TB	NAT2 Rapid acetylators	4*/4*, 4*/5*, 4*/6* and 4*/14*. NAT2*5 (341T > C) was the most common SNP, with a frequency of 36.2%; NAT2*6(590G >A) is second, with 27.6%.	Thirteen (45%) of the 29 youngsters were identified as slow acetylators and 16 (55%) as rapid acetylators with a median age of 9 years. This study suggests that among quick acetylators, a 5 mg/kg INH might not be sufficient to produce acceptable plasma levels. Therefore, children should be given a larger dose of INH (mg/kg body weight) based on their acetylator status in order to guarantee that acetylators, especially homozygous ones acquire an appropriate INH plasma concentration as quickly as possible.	Isoniazid
						NAT2 Slow acetylators	5*/5*, 5*/6*, 5*/7* and 6*/7*		Isoniazid
Eliford Ngaimisi (2013)^Citation31	AA	Parallel-Group Prospective Cohort Study	285	28–40	HIV	CYP2B6, and ABCB1	CYP2B6*6, ABCB1 c.4036A/G (rs3842)	Pharmacokinetics of efavirenz were notably predicted by ethnicity, CYP2B6*6, and ABCB1 c.4036A.G (rs3842A.G), which collectively accounted for approximately 20% of patient variability in plasma levels. The extent of EFV auto-induction varies depending on pharmacokinetic and pharmacogenetic differences, which highlights the significance of environment and ethnicity factors in addition to ABCB1 and CYP2B6 when considering an efavirenz dosage optimization strategy.	D4T/3TC/EFV or AZT/3TC/EFV or TDF/3TC/EFV
Abiy Habtewold (2015)^Citation32		Two arm Prospective comparative	493	≥18	TB– HIV	CYP2B6	CYP2B6*6, CYP2B6*1/*1	In weeks 4 and 16, higher EFV plasma concentrations were seen in the RIF-co-treatment group compared to the non-RIF-based anti-TB therapy group, especially in CYP2B6*6 carriers. Nevertheless, there was no difference in the plasma EFV concentration between the two groups at either week in the CYP2B6*1/*1 genotype groups. Patients with TB-HIV coinfection receiving dual therapy for TB and HIV had a significantly greater incidence of DILI/toxicity, mostly because of overlapping toxicity from ARV and anti-TB and disease load (TB and HIV coinfection).	Paradoxically rifampicin increased EFV concentration as a result overlapping hepatotoxicity.
Abiy Habtewold (2016)^Citation33	AA	Prospective, comparative, two-arm	53	28–40	TB– HIV	CYP2B6	CYP2B6*6 CYP2B6*1/*1	Even after adjusting for the influence of either sex or CYP2B6 genotypes, patients’ EFV PK values were unaffected by long-term co-administration of a RIF-based anti-TB treatment. On the other hand, co-administration did considerably raise the PK exposure parameters of the major metabolite, 8-OH-EFV; this impact was more noticeable in females or CYP2B6*6 carriers.	There’s no need to change the daily dosage of EFV from 600 to 800 mg when taken with RIF.
Zelalem Petros (2016)^Citation34	AA	Prospective Cohort, GWAS	646	18–72	TB-HIV	6(24,967,240)	A/G (A), rs10946737	ATD-induced liver toxicity, which accounts for 11.6% of ATDILI, may be linked to potential genetic variants.	Rifampicin, Isoniazid, Pyrazinamide
Zelalem Petros (2017)^Citation35	AA	Prospective Cohort, GWAS	719	≥18	TB-HIV, ARV-Group	17(62,121,526) 7(116,857,547), 17 (61,770,954)	T/C (T), rs199650082, A/C (A), rs7804397, T/C (T), rs16947045	Developed DIH by ARV or ARV-ATD drugs are identified.	ARV Drugs
					ARV-ATD Group	12(79,201,073)10(21,292,923), 5 (115,050,362)	T/C (C), rs4842407 A/G (A), rs11012476 A/C (A), rs251891	Developed DIH by ARV or ARV-ATD drugs are identified.	Both ARV and ATB Drugs
Zelalem Petros (2017)^Citation36	AA	Case-control comparative study	495	≥18	TB-HIV	HLA-B	HLA-B*57, HLA-B*14	Anti-TB and ARV medication-induced liver injury is more likely to occur in patients with HLA-B57:03 and HLA-B57:02 variant alleles, namely in situations of cholestatic liver injury and mild DILI.	Anti-TB and ARV drugs
Abiy Habtewold (2017)^Citation37	AA	Prospective cohort	313	≥18	TB-HIV	CYP2B6	CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6	Three genotypes were found: CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6. This study confirmed that CYP2B6 genotype-derived dose optimization of EFV is necessary.	EFV
Eugenia Lo (2019)^Citation38	Regions	Prospective cohort	344	All	Malaria	G6PD	G267+119C/T (rs782000110, C→T), A376G (rs1050829, A→G) and G1116A (rs2230036, G→A)	Among feverish patients throughout Ethiopia, G6PD deficiency is mildly prevalent. Therefore, before giving patients with Plasmodium vivax an extreme treatment, G6PD deficiency testing is advised.	Primaquine
Jemal Hussien Ahmed (2019)^Citation39	AA	Prospective cohort study	285	≥18	Breast Cancer	CYP2J2, CYP2C9, CYP2B6, ABCB1, CYP2C19, CYP3A5, POR	CYP2B6* 6, CYP2C9* 2, CYP2C9* 3, CYP2C19* 2, CYP2C19* 3, CYP3A5* 3, CYP2J2* 7, POR* 28, and ABCB1 rs3842G variant alleles were identified	In Ethiopian breast cancer patients, CYP2J2*7 was found to be a new pharmacogenetic risk factor for hematopoietic damage caused by chemotherapy. There was an association of hematologic toxicities among breast cancer caring CYP2C9 and CYP2J2 genotype. However, no significant hematologic toxicity risk between CYP2B6, CYP2C19, or POR* 28 and ABCB1 genotype. Neutroponic toxicity (50.2%) was the predominant manifestation of a higher prevalence of either grade 3 or 4 blood toxicities (51%). Conversely, low CYP2C9 enzyme activity and incorrect CYP2C9 variant alleles provide protection against the development of blood toxicity.	CPA
Jemal Hussien Ahmed (2020)^Citation40	AA	Prospective cohort study	267	33–48	Breast Cancer	CYP3A5, CYP2C9, POR	CYP3A5*3 or *6, CYP3A5*1/*1, CYP2C9 *2 or *3, CYP2C9 *2 or *3	In Ethiopian breast cancer patients, a single compartment model describes the PK profile of CPA. Wide variations in BSA, BMI, CYP3A5, and CYP2C9 genotypes, as well as CPA dosing regimens, all contribute to the 54.5% patient variability in CPA clearance. CYP3A5 activity was discovered to be altered by POR. Exposure to CPA plasma is predictive of neutropenic damage related to chemotherapy.	CPA
Eleni Aklilu (2020)^Citation41	AA	Prospective cohort study	102	30–55	TB-HIV	ABCB1, CYP3A5, CYP2B6, SLCO1B1 and UGT2B7	Allele frequencies overall: CYP3A5*1, CYP2B6*6, CYP3A5*3, CYP3A5*6, ABCB1c. 4036 A>G, ABCB1c. 3435C>T, SLCO1B1c.388A>G (*1B, UGT2B7-327G>A (*2), SLCO1B1 c.521T>C*5)* were documented.	Patients receiving concurrent rifampicin-based anti-TB therapy are more likely than those receiving EFV-based ART alone to experience unexpected medication interactions with CYP3A substrates. This research verified the minimal possibility of CYP3A-mediated medication interaction between EFV and RIF. The risk of death can be decreased by starting ART and TB medications together as soon as a patient is diagnosed with TB and HIV co-infection.	EFV and RIF
Sabina Mugusi (2020)^Citation42	AA	Prospective multicenter Parallel comparative	481	≥18	TB-HIV	CYP2B6	In general, long-term co-treatment with RIF raised the concentration of EFV in plasma in Ethiopians with CYP2B6*6/*6 > *1/*6 > *1/*1.	The effects of efavirenz auto-induction, pharmacokinetics, and immunologic outcomes are all influenced by the CYP2B6 genotype, anti-TB co-medication, and demographic variance. Regardless of demographic variance or co-treatment with anti-tuberculosis medication, the CYP2B6 genotyping is a stronger predictor of EFV plasma concentration. Optimizing the dosage of efavirenz requires considering variations in CYP2B6 genotype, population, and geography.	EFV and RIF
Adugna Chala (2021)^Citation43	Oromia, SNNP	Prospective Cohort	111	3–16	HIV	CYP2B6 and ABCB1	CYP2B6*6, CYP2B6*1/*1 and ABCB1c.3435 C>T	CYP2B6 genotype-based dose adjustments may be more significant in determining the ideal pediatric efavirenz dose.	EFV
Wondmagegn Tamiru (2022)^Citation44	AA	Case-control comparative study	240	≥18	HIV & Diabetes	CYP3A4, CYP3A5, CYP2B6, and ABCB1	CYP2B6*6 and CYP3A5*6 (3A4*1B/ 3A5*3/*3A5*6)	The haplotype combination of 3A5*3/3A4*1B/*3A5*6 and the defective functional CYP3A5*6 allele were the predominant independent predictors of the total GMDs, IFG and IR. Captivatingly, the CYP2B6*6 genotype was a strong predictor of DM incidence (higher risk) on long-term EFV-based cART.	EFV

Abbreviations: AA, Addis Ababa; ABCB1, ATP-binding cassette subfamily-B member-1; ADRs, adverse drug reactions; AZT/3TC/EFV, Zidovudine, Lamivudine, Efavirenz; ATDILI, anti-tuberculosis drug-induced liver injury; CYP450, cytochrome P450; DILI, Drug induced liver injury; DNA, Deoxyribonucleic acid; D4T/3TC/EFV, Stavudine/Lamivudine/Efavirenz; G6DP, Glucose 6-phosphate dehydrogenase; GWAS, Genome wide association study; HAART, Highly active antiretroviral therapy HIV, Human Immunodeficiency Virus; HLA, human leukocyte antigen; INH, isoniazid; NAT2, N-acetyl transferase 2; PZA, pyrazinamide; RIF, rifampicin; NA, not available; SNP, single nucleotide Polymorphism; SLCO1B1, solute carrier organic anion transporter family member-1B1; D4T, stavudine; RCT, randomized clinical trial; SNNP, South Nation Nationality People; TDF, Tenofovir; TB, tuberculosis; UGT1A1, Uridine diphosphate glucuronosyltransferase.

Figure 1 Flow diagram for study selection.

Figure 2 Distributions of research undertaken in Ethiopia on pharmacogenomics by study area.

Figure 3 Frequency distribution of diseases category.

Figure 4 The major genes identified among Ethiopian patients.

Figure 5 Studied drugs distributions in association with identified genes.

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