Tuberculosis (TB) has high mortality rate of infectious disease in the world, affecting an estimated ten million people per year in 2019. According to the World Health Organization (WHO), tuberculosis (TB) is one of the top 10 causes of death globally, and in 2020, an estimated 10 million people fell ill with TB and 1.5 million died from the disease [(WHO) World Health Organization, 2020a]. In contrast, atypical mycobacterial infections are generally less severe and less widespread, although they can still cause significant morbidity and mortality in certain populations, such as those with weakened immune systems (Falkinham, 2015; Drummond and Kasperbauer, 2019; Winburn and Sharman, 2022). The reason of the importance to handle the Mycobacterium tuberculosis (Mtb) is based on recent article which highlights the ongoing challenges in TB control and the need for new tools and strategies to combat the disease. This article underscores the continued global burden of TB and the urgent need for new approaches to prevention, diagnosis, and treatment (Esmail et al., 2022).

Most drug-susceptible (DS)-TB patients will have a positive treatment response when treated with the right combination of first-line anti-TB drugs and treatment regimen (duration and dose of the drugs). The World Health Organization (WHO) stated that ensuring access to effective and optimal treatment is a key component to eradicate TB through the End TB Strategy, which includes a priority indicator that 90% or more patients should have a successful treatment outcome (World Health Organization, 2020b). According to WHO, high burden countries for TB are consist of 30 Low- and Middle-Income Countries (LMIC) (World Health Organization, 2021). Ongoing delayed of diagnosis and treatment in LMIC still become problems, worsening prognosis and also continuing TB transmission in the community (Teo et al., 2021). Furthermore, this condition is detrimental to resistance of TB therapy. Resistance to the therapy and risk of drugs adverse effects are the things that could detain to achieve optimal therapy (Pradipta et al., 2018). So, personalized treatment that depends on the individual genetic profile can minimize the risk of toxicity and resistance, thus optimize the treatment. It becomes necessary because of the diversity of drug responses related to the variation in human DNA, such as single-nucleotide polymorphisms (SNPs), which are a single substitution of nucleotides for another (Lander et al., 2001; Subramanian et al., 2001; Kurkó et al., 2013). SNPs that occur in genes related to pharmacokinetics (PK) and pharmacodynamics (PD) processes could affect the response, effectiveness, resistance, and toxicity of drugs (Zastrozhin et al., 2018; Calcagno et al., 2019; Xiang et al., 2020).

Ethambutol (EMB) is a drug widely used for TB treatment. It is used as the first-line anti-TB drug together with rifampicin (RIF), pyrazinamide (PZA), and isoniazid (INH) as a six-month regimen. EMB should not be used alone as monotherapy but rather in tandem with at least one other anti-TB drug. EMB shows a specific effectiveness against the Mtb and atypical/non-tuberculous mycobacteria such as Mycobacterium avium complex bacteria (MAC) that cause pulmonary infection non-tuberculosis and lymphadenitis, but not against other bacteria or other pathogens, such as viruses and fungi (Lee and Nguyen, 2020; Winburn and Sharman, 2022) EMB is also a potential supplementary agent for a treatment regimen of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB (World Health Organization, 2020a). Although as a supplementary agent, EMB is added to the TB regimen as a protection against unrecognized resistance to one of the three core drugs (Horsburgh et al., 2015). However, the WHO recently reported that patients infected with Mtb strain and showing simultaneous resistance to EMB and INH or EMB and RIF had an increased risk of treatment failure and further acquired resistance (Falzon et al., 2011). EMB is a bacteriostatic drug that interferes with the biosynthesis of arabinogalactan in the cell wall of Mtb and inhibits multiplication by bacilli (Palomino and Martin, 2014). However, the exact molecular mechanism of action remains unclear (Schubert et al., 2017). Studies on genetic polymorphisms related to EMB thus far have focused on polymorphisms that occur in the gene of Mtb bacteria (Zenteno-Cuevas et al., 2019). Only a few studies have explored gene polymorphisms in humans that have an impact on the clinical response to EMB, including resistance and toxicity.

In human genetic polymorphism studies of anti-TB, the majority focus on RIF or INH. These studies discussed polymorphisms related to clinical response and toxicity (Baskaran and Sabina, 2017; Bao et al., 2018; Richardson et al., 2018; Yang et al., 2019; Zenteno-Cuevas et al., 2019; Rivière et al., 2020). However, EMB has an important role in the treatment of tuberculosis, such as maintaining the effectiveness of therapeutic regimens (Horsburgh et al., 2015). In addition, the incidence of EMB toxicity is lower than that of other first-line anti-TB drugs, especially in comparison with INH. The toxicity is also thought to be related to polymorphisms in certain drug-metabolizing enzymes (DMEs) (Castro et al., 2015; Sarkar and Ganguly, 2016).

The relatively low toxicity and low incidence of resistance are the reasons why EMB is widely used in both sensitive and resistant TB. Personalized medicine practices are highly recommended to maintain and obtain the optimal therapeutic effect of EMB, but human studies of polymorphisms related to EMB clinical response, which is the basis for personalized medicine-based therapy, are scarce. Mapping out all the polymorphisms that have an impact on EMB efficacy, risk of toxicity, and risk of resistance can help us maintain the effectiveness of EMB as one of the TB drugs for sensitive and resistant TB. This article summarizes the genetic polymorphisms associated with alterations in the pharmacokinetic profile, resistance incidence, and susceptibility to EMB toxicity.

This review summarizes the results of several studies related to the effects of polymorphisms on the EMB clinical response (effectivity, pharmacokinetics, resistance, and susceptibility to toxicity). It includes studies from the PubMed database identified using the keywords “genetic polymorphism” and “ethambutol”. Furthermore, research communications, thesis manuscript, reviews, expert opinions, non-English studies, and unrelated studies were excluded (Figure 1). The thesis manuscript that we have found is the manuscript who have not already been published, and article reviews that were excluded are articles in the form of narrative reviews or mini-reviews that do not contain statistically new conclusions.

A total of 131 reports of human studies were collected; among them, 91 studies of Mtb polymorphism, 11 review studies, 4 thesis publications, and 8 unrelated studies, which discuss genetic polymorphism related to susceptibility of TB, were excluded. Hence, a total of 17 articles were included in this study. Most of the articles discussed the effect of gene polymorphisms on the therapeutic outcome, i.e., effectiveness, resistance to EMB, and side effects or toxicity.

From this study we got only eight studies (42.1%) that held in the LMIC, while the rest is research conducted in developed countries with high incomes. In contrast, globally more than 90% of reported tuberculosis infections occur in LMIC. Despite a cumulative reduction in global tuberculosis-related deaths, global progress is still far away from the targets set by the WHO on End TB Strategy and the United Nations on Sustainable Development Strategy. Goals on tuberculosis (SDG 3.3) (WHO, 2015; 2020; UN, 2022), efforts are needed to increase the optimization of tuberculosis therapy, especially in LMIC.

EMB is widely used in both sensitive TB and resistant TB (Lee and Nguyen, 2020) cases. A global systematic and meta-analysis stated that the resistance and the increasing risk of toxicity were a trend towards increase risk of MDR-TB (Pradipta et al., 2018). It is well known that resistance and risk to toxicity might be affected by the genetic polymorphism. Although only a few studies have explored the association between human genetic polymorphisms and EMB clinical response, we hypothesize that genetic polymorphisms influence the clinical response to EMB by two mechanisms: 1) alteration of the pharmacokinetic profile leads to ineffective therapy due to resistance and an increased risk of drug toxicity, and 2) alteration of the expression or activity of mitochondrial-related genes may lead to an increased risk of EMB optic toxicity. EMB is included in the category of TB drugs with mild adverse effects (World Health Organization, 2020a). The toxicity of EMB is mainly reversible optical nerve degradation, but as a regiment, EMB might also play a role in hepatotoxicity. Some studies have shown that EMB has a hepatotoxic effect, but others have not. It is dose-related; more than 40% of adults develop ototoxicity at doses greater than 50 mg/kg (Donald et al., 2006). EMB binds to TetR, a transcriptional regulator that enhances the INH sensitivity of the inhA gene and leads to increases in the killing effect of INH, thus increasing INH toxicity (Zhu et al., 2019). Genetic polymorphisms in drug metabolic enzyme-encoded genes, such as GST, CYP, and UGT, could affect the risk of EMB hepatotoxicity (Li et al., 2013; Richardson et al., 2018; Sun et al., 2019). Meta-analysis study which conducted on various middle-and high income countries prove that there are significant association between RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene to the hepatotoxicity (Richardson et al., 2018). The results of a study on the GSTM1 gene polymorphism (null genotype) showed that the polymorphism was associated with hepatotoxic risk in the EMB-containing regimen, while the non-EMB-containing regimen showed insignificant results. In the GSTT1 gene polymorphism, the null genotype was associated with hepatotoxic risk in the regimen without EMB. However, previous studies have shown that EMB as monotherapy causes rare or no liver toxicity (Richardson et al., 2018). Another study from China resulted in the possibility that EMB induces/increases the risk of hepatotoxicity when used together with other anti-TB drugs. Unfortunately, the study was only conducted on Chinese people with a small number of samples (Peng et al., 2021). However, this information may add to the evidence that the toxicity of EMB to the liver needs to be considered.

For optical toxicity, the mitochondrial genome plays a role in the majority. Mitochondria, important cell organelles, generate most of the chemical energy needed to power the biochemical reactions of the cell (William Gahl, 2021). The health and survival of mitochondria are maintained through fission and fusion mechanisms, which are mediated by MFN1 and MFN2 on the outer mitochondrial membrane and OPA1 on the inner mitochondrial membrane (Liesa et al., 2009; Chen, Liu and Dorn 2nd, 2011). Genetic disorders due to mitochondrial dysfunction are not uncommon, and the majority of these patients will have eye-related manifestations, including visual loss from the optic nerve and retinal disease, that could be irreversible. Defects in mitochondrial genes such as MFN and OPA1 could cause mitochondrial dysfunction that leads to impaired mitochondrial energy production and oxidative stress (Yu-Wai-Man and Newman, 2017). In addition, mt-ND, which is a gene on mitochondrial DNA that functions to code for the NADH dehydrogenase protein, is predicted as an epigenetic factor of LHON in patients with a primary LHON mutation. Some case-report studies on Italy and Korea stated that they believe that their patient had ethambutol optic neuropathy. It cannot be excluded that the heteroplasmic DNA mutation of LHON may have predisposed the patient to toxic neuropathy (De Marinis, 2001; Seo et al., 2010). Several studies and case reports conducted in Italy, England, and United States of America have shown that the risk and susceptibility of ototoxicity-related EMB may be related to genetic polymorphisms of these genes (Guillet et al., 2010; Fonkem et al., 2013). Unfortunately, the authors have not found studies related to mt-DNA, MFN, and OPA1 conducted in LMIC. Hence, need further pharmacogenetic study on these genes in patients with EMB therapy in LMIC.

Genetic polymorphisms related to pharmacokinetic mechanisms could affect drug exposure and efficacy and lead to drug resistance. In brief, the pharmacokinetic mechanism is divided into four stages: absorption, distribution, metabolism, and excretion. Transporter proteins, such as ABC transporters and SLC transporters, work on the efflux and influx/uptake of drugs into cells. Polymorphism of the genes that encode these proteins affect the absorption, distribution, and excretion of the drugs (Parvez et al., 2017; Pontual et al., 2017). Genetic polymorphisms in DMEs, such as CYP, GST, and UGT, affect drug metabolism. All of these genes play a role in altering the pharmacokinetic rate and affect drug concentration exposure at the target site. Hence, it leads to under-treatment if the concentration is below the therapeutic dose or increases the risk of toxicity/adverse effects if the concentration is higher and enters the toxic dose (Fatiguso et al., 2016; Sundell et al., 2020). Long-term effects and under-treatment or non-optimal therapeutic doses increase the risk of drug resistance (Pontual et al., 2017). In addition, the rate of drug clearance, excretion, or detoxification could affect the increased risk of toxicity (Parvez et al., 2017; Richardson et al., 2018; Sun et al., 2019). Individual variations in the clinical response to therapy are known to be influenced by gene polymorphisms, so studies in this regard should be supported and developed. In addition, the practice of personalized medicine, which aims to minimize the rate of resistance, minimize the incidence of toxicity, and increase the effectiveness of treatment, should be recommended for all diseases, especially TB, given that the key to successful treatment of TB is optimal and effective treatment (World Health Organization, 2020b).

The articles included in this review were not limited in period of time due to the limited number of related studies. This review is subject to slight potential bias, including the influence of the personal viewpoints of the author, gaps in literature searching, and selection methods, which may lead to the omission of relevant research.

Genetic polymorphisms that occur related to the pharmacokinetics process could alter gene expression or its activities that alter drug concentration (decreased or increased). Therefore, this might be related to the treatment outcome (efficacy and safety/toxicity). Susceptibility to the optic toxicity of EMB could be affected by mitochondrial genetic polymorphism. Personalized medicine is an effort to provide individual therapy based on genetic profiles. Personalized medicine can provide a better and more effective treatment for TB that is efficacious, safe, and prevents drug resistance.