Toxicological Effects of Antituberculosic Chemotherapy in Adults: An Integrative Literature

Objective: To analyze the toxicological effects of anti national and international literature in the period from 2015 to 2020. Review Article -65, 2021; Article no.JPRI.67009


INTRODUCTION
Tuberculosis (TB) is an infectious and contagious disease caused by Mycobacterium tuberculosis (MT), considered a public health problem due to its high incidence and prevalence, in addition to affecting more frequently populations that present low economic level, social inequality, malnutrition, alcoholism, smoking, pathologies and other conditions that reduce the immune capacity [1].
The treatment of TB, consisting of isoniazid, rifampicin, ethambutol and pyrazinamide, has great efficacy when associated with the correct doses and use for a sufficient time, aiming to avoid bacterial persistence, the development of drug resistance, ensuring the patient's cure [2]. However, it can cause undesirable side effects, either by the active ingredient itself or by its metabolites, such as the occurrence of toxicity in the patient [3].
Toxicological effects are the most recurrent adverse reactions associated with anti-TBs, which can lead to interruptions in treatment with resulting poor outcomes, including the risk of drug resistance. There are risk factors for the onset of these effects, such as patients with liver abnormalities, such as the chronic hepatitis B virus and the hepatitis C virus (HCV), disseminated tuberculosis, Asian ethnicity, female sex, significant use of alcohol, administration simultaneous use of other hepatotoxic drugs, being elderly and malnourished [4].
Side effects, especially the most serious ones, are related to a higher rate of treatment abandonment, resulting in longer therapy time and a greater number of hospitalizations and outpatient and home visits. In addition, changes in the therapeutic regimen resulting from these adverse effects lead to the inclusion of one or more less potent and more toxic drugs, an increased risk of treatment failure, recurrence of the disease and an increase in the duration of treatment [2].
Given the above, the present study aimed to analyze the toxicological effects of antituberculosis chemotherapy in adults in national and international literature in the period from 2015 to 2020.

METHODOLOGY
This is a descriptive, qualitative research, such as Integrative Literature Review (ILR). The ILR is a research method that aims to conduct a comprehensive and systematic analysis of the literature. Thus, the ILR must be carried out in six stages, namely: 1) identification of the theme and selection of the research question; 2) delimitation of the eligibility criteria and identification of studies in the main banks and databases; 3) evaluation of the chosen studies and critical analysis; 4) categorization of the study; 5) evaluation and description of the results and 6) presentation of the results in an integrative review structure [5]. From the object of study, the following guiding question was developed: What are the toxicological effects of anti-tuberculosis chemotherapy in adults in national and international scientific research?
The collection of scientific material was carried out through online access in the following databases: VHL Regional Portal, PubMed / Medline (National Library of Medicine and National Institutes of Health / Medical Literature Analyzes Sand Retrieval System Online), Ark, Web of Science, Microsoft Academic Library and Cochrane. In order to improve, refine and guarantee the direction of all works relevant to the search for the theme, the choice of articles occurred from the combination of four descriptors DeCS/MeSH (Health Sciences Descriptors), respectively: "Toxicity"; "Antituberculosis", "Adult" and "Chemotherapy" mediated by the Boolean operator "AND", in order to add restrictions to the number of studies.
The inclusion criteria determined for the selection of documents were: scientific articles published in the period from 2015 to 2020, free full text in Portuguese or English, and which address the topic of study. Studies outside the defined period, editorials, letters to the editor, incomplete articles, paid articles, reflective studies and those that did not address the theme suggested by the authors were excluded.
The articles were categorized based on the level of evidence by type of study, but levels 8 and 9 were not included in this study. The levels of evidence are divided into nine levels according to the type of study. At level 1, the evidence is named for systematic reviews; level 2, evidence from a randomized clinical trial; level 3, evidence obtained from a cohort study; level 4, evidence from case-control studies; level 5, evidence derived from cross-sectional study; level 6, evidence derived from case series research; level 7, evidence from a case report being an opinion and / or report; level 8, evidence from animal research and level 9 are evidence based on laboratory research [6].
After the critical analysis and the grouping of the selected studies, the articles were analyzed using the IRaMuTeQ software (Interface of R pour les Analyzes Multidimensionnelles de Textes et de Questionnaires), as it provides a more complex analysis of the articles researched by the author, having class formation according to the repetition of the words in the text. In addition, it is a tool that allows multiple forms of statistical analysis on the textual corpus and or the word tables in which this analysis is \anchored in software R. This program was developed in France by Pierre Ratinaud [7].
For the analysis of the data obtained through the IRaMuTeQ software, the text corpus was developed through the results and conclusion of the selected articles. Thus, we opted for the Descending Hierarchical Classification (DHC) method, which has the purpose of obtaining the formation of classes of text segments in different colors and may be with words similar to each other and also distinct from the segments of other textual classes [8].
At the end of the data collection, a total of 1105 articles were obtained in the referred databases. After this phase, the articles underwent an evaluation regarding the title and abstract, and of this total, 308 were excluded from the screening process. The assessment during this phase had the purpose of discarding articles that did not meet the eligibility criteria. At the end of the screening process, the final sample emerged from the reading of the full text composed of 36 articles that were evaluated regarding the title of the article, country, authors, year of publication and database, types of study, level of evidence, objective and synthesis of the results and those that answered the research question. The selection process for the selected articles is shown in the search flowchart below Fig. 1.

RESULTS AND DISCUSSION
At the end of this stage, the final sample emerged, consisting of 36 studies, which met the established criteria, as shown in the following table Table 1.
Based on the end of the sample, the analysis was performed using IRaMuTeQ software. The content analysis was done through the Descending Hierarchical Classification (DHC), which has the formation of classes, divided and identified, by colors and percentages. Class 1 (Red) corresponds to 35.34% of the words in the corpus, class 2 (Green) corresponds to 20.3% of the words, Class 3 (blue) corresponds to 20.3% of the word association in the corpus and class 4 (Purple) corresponds to 24.6% of the word association in the corpus.
Through the formation of the classes through the CHD, the IRaMuTeQ software provided information that would provide subsidies to build the filogram from the dendogram of the classes obtained from the text corpus. For the construction of the filogram, the words that obtained a frequency equal to or higher than the registered average were used, with the frequency (f) and the chi-square (x²) of the most repeated words being placed, being organized into classes by the most significant words. After analyzing the identification of textual domains and interpretation, we sought to name their respective meanings in the classes described below: 1) Association between hepatotoxicity and the appearance of liver damage; 2) The incidence of adverse events related to antituberculin therapy; 3) Risk factors of regular consumption of antituberculins; 4) Intensive renal treatment for patients with nephrotoxicity. The class filogram is shown below Fig. 2.

Class 1-Association of Hepatotoxicity and Appearance of Liver Disease
From the results, it was analyzed that the assessment of the risk of occurrence of hepatotoxicity in patients undergoing TB treatment becomes necessary, given the effects of the drugs used in anti-tuberculosis chemotherapy. Hepatotoxicity induced by antituberculosis drugs (ATDH) is one of the main complications resulting from antituberculin therapy with an incidence of 2% to 28%, being responsible for the increase in substantial morbidity and mortality and decrease in the effectiveness of the treatment due to its interruption. It may have different factors that contribute to its development, such as old age, female gender, malnutrition, HIVinfection and pre-existing liver disease [9,10].  Retrospective descriptive study. Level 3.
Identify the incidence of Acute Kidney Injury (AKI) and the results of our management of AKI induced by anti-TB drugs in a single TB treatment center in the past 10 years.
Rifampicin is the main cause of AKI. Levofloxacin can be an alternative to rifampicin thanks to its safety and potency. Restarting anti-TB treatment without rifampin and steroid administration in the short term may be a viable management for AKI. The results of this study suggest that approximately half of all drug-induced liver injury cases occur within the first month, while 60% of (IHA) cases occur within 2 months. Elevated total bilirubin, aspartate aminotransferase, leukocyte count, pre-existing hepatitis and low platelet count are independent risk factors for the development of anti-TB drug-induced IHA.
It was analyzed that advanced age as a risk factor for hepatoxicity and found that patients over 60 years old had a prevalence in these cases, due to physiological changes and increased risk of drug toxicity [23]. In turn, it was assessed that the risk of hepatotoxicity in HIVcoinfected patients, concluding that advanced age (over 45 years), HIV / AIDS status and regular alcohol consumption were identified as factors that aggravate the occurrence of hepatotoxicity when taking TB medications [33].
The study showed that the decrease in the immune status of patients with HIV may be related to the increased risk of liver toxicity, indicating an acceleration of liver enzymes and progression to cirrhosis in coinfected patients compared to controls. In addition, these patients have a constant state of malnutrition, due to the depletion of glutathione reserves, making them vulnerable to oxidation and, therefore, to oxidative stress that is a mediator of hepatotoxicity [12].

Class 2-The Incidence of Adverse Events Related to Antituberculin Therapy
In the case of drugs most associated with hepatotoxicity [21], it was observed that Pyrazinamide has a well-recognized toxicity profile. The occurrence of hepatotoxicity and arthralgia are among the most common events and these are often reported to have side effects. The study by [34] showed the association of Isoniazid with the risk of occurrence of hepatotoxicity, leading to treatment interruption in 26 of the 60 cases, in addition to a decrease in efficacy in the others.
When assessing the incidence of hepatotoxicity in patients undergoing TB treatment, the literature shows a steady growth in which it is identified that the incidence of drug-induced hepatotoxicity (HDHD) in patients on antituberculosis therapy, with 24.6% of the patients having toxicity, being associated with the combined form of anti-TB drugs, genetic factors and peak plasma levels [12]. In turn, it was found in the study that among 108 patients who developed HDDH, 73 patients (67.5%) had hepatotoxicity within 30 days, emphasizing that monitoring of liver function during the first week in patients with extrapulmonary tuberculosis and function abnormal liver disease at baseline may be useful for very early detection of HDHD and better prognosis [13].
It is also observed that the incidence of symptomatic hepatotoxicity can vary from 15% to 18% in hospitalized patients, resulting in the prolongation of the individual and decrease in the effectiveness of the treatment, increasing the risk of being affected by morbidities and mortality rates [26].

Class 3-Risk Factors of Regular
Consumption of Antituberculins It appears that the success rate of TB treatment in patients with hepatotoxicity is lower compared to the group that does not have hepatotoxicity.
The difference seems to be attributed to a higher mortality rate from all causes in the group, as it presents the largest number of elderly patients and / or with comorbidities, which may have negatively impacted treatment outcomes and mortality [9,38].
Early detection of the risk of hepatotoxicity in patients undergoing TB treatment is clinically important for several reasons, especially its association with decreased mortality and severe hepatotoxicity. In addition, early detection can allow for a shorter recovery time, from occurrence to normalization of AST, ALT and bilirubin, as the resolution of abnormal liver function tests is likely to be faster [13,10].
Therefore, monitoring liver function earlier in patients undergoing anti-tuberculosis treatment allows the identification of toxicological effects in patients associated with the completion of treatment with first-line anti-tuberculosis drugs, resulting in treatment efficacy and reduction of data caused by drug therapy [26].

Class 4-Intensive Renal Treatment for Patients with Nephrotoxicity and Toxicity
The occurrence of drug-induced nephrotoxicity for antituberculosis treatment is not yet well defined, but authors state that hepatotoxicity occurs in the first month, considered the intensive treatment phase. Thus, early detection of ADIH is extremely important for the maintenance of treatment, so it is recommended that a test be carried out on all users who use antituberculosis therapy, 2 weeks after the start of treatment [13,21].
Nephrotoxicity, identified in patients, is something that occurs in patients who use second-line injectable antituberculous drugs, being aminoglycosides and capreomycin. The adverse events caused by minoglycoside medications are: acute tubular necrosis, activation of the renin-angiotensin systems and decreased glomerular filtration. This nephrotoxicity reveals renal failure that does not have a decrease in urine production. Thus, patients in the intensive phase of treatment for tuberculosis develop nephrotoxicity due to the long period of treatment. [20,38].
Ototoxicity is another adverse effect caused by second-line medications for the treatment of multidrug-resistant tuberculosis, which is why in the studies it is reported about the importance of being monitored through an evaluation, using the audiogram, vestibular test, Romberg test and measurement of serum creatinine, considering that it is also necessary to carry out a questionnaire on hearing symptoms in order to minimize the most severe hearing loss [26,20]. Fig. 1.

CONCLUSION
The treatment regimen for tuberculosis, despite being effective, can generate undesirable side effects for users due to the daily use of the four components of the drugs (isoniazid, rifampicin, ethambutol and pyrazinamide). In our review, we identified that elderly people, HIV positive and alcohol users are more likely to have toxicological effects during treatment, which can lead to a possible abandonment of treatment.
Given this, it is necessary for health professionals to be attentive and monitor the progress of therapy in order to identify these adverse effects early in order to intervene as soon as possible in the case and thereby reduce the patient's discomfort and increase the chances that he will complete the procedure treatment.

CONSENT
It is not applicable.