Research of Russian physicians’ opinions on tuberculosis pharmacogenetics

1. Introduction

According to the World Health Organization (WHO), tuberculosis is the most widespread socially significant disease worldwide. The annual mortality rate from tuberculosis is 1.2 million people [1]. The efficacy of tuberculosis treatment both in Russia and worldwide is rather low and amounts to 69.6% abacillation and 61.4% of destruction closure [2]. Poor drug tolerance from the high incidence of adverse reactions (ADRs) during treatment with TB drugs is a factor affecting such outcomes. However, about 20–60% of patients stop taking one or more TB drugs on their own, which contributes to relapse, continued bacterial excretion, collapse of lung tissue and increased spread of resistant mycobacteria strains.

Emerging ADRs can lead to disability and death if it is not identified and handled immediately [3,4]. The negative effect of ADRs on tuberculosis prognosis is associated with both a direct threat to patients’ health and life as well as an increased risk of treatment failure [5], which has worldwide importance.

One effective approach for dealing with this problem is through the implementation of PGx methods, which allow for both the consideration of individual patient characteristics and reduce the incidence of drug intolerance. Over than 5 million clinical annotations of medicines are already available on the website pharm.gkb.org, as well as 188 clinical recommendations for dosage based on PGx, including TB drugs.

The use of PGx methods in patients with tuberculosis may safely (the study is conducted in vitro) provide personalization of drug treatment and dosage, reduce the risk of ADRs, increase treatment tolerance, improve patient quality of life and the efficacy of TB treatments. Global healthcare could minimize the economic burden of tuberculosis treatment by decreasing the frequency of ADRs and the additional financial costs associated with them, which shows the obvious benefits associated with implementation of this approach.

However, there is currently no widespread implementation of PGx methods in the practice of phthisiology service, which may be due to the low awareness of specialists about the goals and capabilities of PGx methods. The authors’ belief that experienced phthisiologists and novice specialists have different levels of understanding about PGx’s goals and objectives formed the basis of the study’s hypothesis. The objective of the study was to examine the level of awareness and willingness of phthisiologists, both experienced and novice specialists - residents and post-graduate students of the Russian Medical Academy of Continuing Postgraduate Education (RMACPE), to implement PGx - testing methods in their work to improve treatment safety, predict the occurrence of ADRs and personalize patient therapy.

2. Materials and methods

3. Results

A total of 499 specialists from 21 cities of the Russian Federation participated in the survey (Table 1). According to the study design and the data presented in Table 1, the participants were divided into specialists working in the phthisiology service who had sufficient work experience - n = 314 (62.92%) - and novice specialists without experience who were enrolled in post-graduate and residency education at RMACPE - n = 185 (37.08%).

Among phthisiologists, there were 252 (19.74%) women and 62 (80,25%) men. The respondents were primarily over 45 (221; 70.38%) and had a total work experience of more than 10 years (n = 241; 76.75%).

In terms of gender, there were 56 (30.3%) men and 129 (69.7%) women among novice specialists without prior work experience. 129 (69.7%) of the respondents in this group were specialists under the age of 30.

4. Discussion

A questionnaire developed by the authors was used to survey specialists, both those with work experience in the phthisiology service and post-graduate students and residents of RMACPE, in order to assess the opinion of Russian physicians in the field of PGx tuberculosis.

The authors’ primary hypothesis was that experienced phthisiologists and novice specialists vary in their knowledge of the goals and objectives of PGx. This hypothesis was kind of confirmed during the research process. For example, the researchers found that 252 (80.25%) phthisiologists and more than 168 (90.9%) graduate and post-graduate students and residents of RMACPE, believed that patient genetic features could influence their individual response to drug therapy in terms of efficacy and safety (Q7). In response to question Q9, novice specialists were more confident than experienced phthisiologists that a bioinformatics course should be included as a required subject in the curricula of medical educational institutions.

The majority of respondents who answered positively to question Q15, whether the pharmacogenetic approach can help in choosing the regimen and dosage of medications used in patients, also prevailed in the group of individuals studying at RMACPE.

Residents and post-graduate students seemed to have a statistically significant higher amount of positive responses to the question Q17 about whether PGx can help in choosing the regimen and dose of drugs used in patients.

The authors assumed that the predominance of older age group representatives (70.38%) among phthisiatricians and the absence of PGx subjects during their higher education can account for such statistically significant differences in the answers to these questions. While currently, PGx learning is being more and more integrated into the basic and varied modules of university educational programs.

We could not identify any available publications in the literature on a survey of phthisiology service specialists about the goals and objectives of PGx. A similar survey of physicians in the field of cardiovascular disease (CVD) PGx was conducted in the Russian Federation [6]. The authors discovered that a significant number of Russian physicians support PGx testing for prescribing cardiac drugs. Among the key factors preventing the implementation of PGx tests in clinical practice were physicians’ lack of awareness of PGx, the absence of PGx tests in clinical guidelines and treatment standards, and a lack of economic justification for the use of PGx methods [6].

According to a survey conducted in the United States, more than 97% of nonphthisiology physicians believe that genetic factors may impact individual response to pharmacotherapy [7]. According to studies conducted in the United Arab Emirates, Egypt, Zimbabwe, and Kuwait, survey participants (doctors, pharmacists, and students) showed a lower awareness of PGx researches, ranging from 41.7% to 56% [8–11].

The lack of specialized knowledge and skills, the lack of necessary equipment, limited funding, and the ethical component of research (violation of confidentiality and discrimination based on ethnicity) are among the main reasons that make it difficult to implement PGx in clinical practice in these countries.

According to the results of this research, the key reasons preventing widespread implementation of PGx in clinical guidelines and treatment standards are the lack of pharmacogenetic testing in clinical guidelines and treatment standards, the lack of large-scale randomized clinical trials, physicians’ lack of pharmacogenetic knowledge, and the lack of economic justification for the use of PGx (Fig. 1).

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Fig. 1.

Respondents’ opinions on the problems preventing the implementation of PGx in real clinical practice.

The majority of respondents, including both experienced specialists and novice physicians, said they were unaware of the pharmgkb.org website, according to the researchers’ findings. Moreover, this database offers the results of large-scale randomized clinical trials, with validation of pharmaceutical doses determined by the genetic features of patients. The use of this service might significantly improve TB therapy quality, patient compliance, and reduce the amount of ADRs.

Despite the fact that the majority of respondents rated their knowledge of PGx from 1 to 6 points (on a 10-point scale), 38 (12.11%) phthisiologists and 30 (16.2%) RMACPE residents and post-graduate students have worked with pharmacogenetic testing. The ability to use PGx in the apparent lack of obvious clinical experience among postgraduate students and residents has seemed to be explained by the continuous work of the RMACPE winter and summer schools of young scientists on pharmacogenetics and personalized medicine under the guidance of RAS Academician D.A. Sychev, the presence of a science-intensive base at the RMACPE Institute of molecular and personalized medicine, and the extensive experience in teaching PGx at professional retraining and continuing education cycles.

In the authors’ opinion, the fact that a large majority of respondents believed that PGx testing should go along with the prescription of new, combined drugs rather than first-line medications is important. Furthermore, more than half of the respondents assume that PGx can prevent ADRs during pharmacotherapy and subsequently minimize the economic burden by saving money for their treatment. According to the Federal Clinical Guidelines for the Diagnosis and Treatment of Tuberculosis of the Respiratory System (2022), Order of the Ministry of Health No. 951 of December 29, 2014 “On approval of methodological recommendations for improving the diagnosis and treatment of tuberculosis of the respiratory system,” the main TB drugs of the 1st line are used for chemotherapy in primary drug-sensitive tuberculosis. The prevalence of ADRs is observed in every second patient when first-line TB drugs are used [12].

Since PGx prescribing is strictly regulated at the federal level, phthisiologists may believe that their variability of choice is limited. However, knowledge of individual PGx features of TB drugs could allow phthisiologists to individually adjust the prescription of chemotherapy drugs, increase the safety of such treatment for patients, and reduce the frequency of ADRs without violating federal clinical guidelines. Therefore, it is necessary not only to raise awareness of PGx capabilities and the pharmgkb.org resource, but also to develop guidelines for interpreting these results in the form of a decision-making system.

It seems that the following factors must be present for the successful implementation of PGx tests in the practical healthcare of the Russian Federation and, in particular, in the phthisiology service:

closer integration of clinical experience with modern, knowledge-intensive PGx knowledge, which is only possible with ongoing advancement of expert professional training;

In order to increase the safety of pharmacotherapy, a survey was carried out in the Russian Federation among experienced phthisiologists, post-graduate students, and residents of RMACPE about knowledge and potential of PGx use in patients with TB. According to a survey, experienced phthisiologists and novice specialists are not equally aware of the PGx’s goals and objectives. The authors found that the majority of responders recognize the importance of PGx testing and are motivated to use the tests in clinical practice. All respondents, however, showed a low level of awareness on possibilities of PGx and the pharmgkb.org website, which provides the results of large-scale randomized clinical trials, with validation of drug doses determined by genetic patient features. The implementation of this service could significantly increase patient compliance, lower ADRs, and enhance TB therapy quality.

We hope that after gaining specialized knowledge about the prospects and benefits of PGx, the development of patient-specific decision-making systems, the inclusion of PGx in federal clinical guidelines, and the implementation of PGx methods in psychiatric services in Russia as well as worldwide will become more evident, which will improve the situation with low TB treatment efficacy.