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SOME ASPECTS OF THE RESISTANCE OF HIV INFECTION TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
Rakhimova Visolakhon Shavkatovna, associate professor, Department of Infectious Diseases, Tashkent Institute of Postgraduate Medical Education,
Republic of Uzbekistan E-mail: [email protected]
SOME ASPECTS OF THE RESISTANCE OF HIV INFECTION TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
Abstract: The results showed that the most common mutation ofM184V does not in itselflead to pharmacological resistance of HIV, and among the complexes of thymidanalogous mutations, M41L and D67N dominated leading to the development of low-level resistance to all nucleoside reverse transcriptase inhibitors. Keywords: HIV infection, nucleoside reverse transcriptase inhibitors.
The widespread prevalence of HIV infection worldwide causes the enormous social, economic and demographic significance of this disease. The number of HIV-infected people in the world according to WHO data for 2017 exceeds 30 million people.
Currently, HIV infection is a priority health care issue. The number of HIV-infected patients with clinical manifestations of the disease requiring specific treatment increases annually.
The history of antiretroviral therapy for HIV began in 1987, when the first drug that suppressed viral replication, azidothymidine, was approved. In subsequent years, a number of drugs of the same pharmacological group were developed -nucleoside reverse transcriptase inhibitors (NRTIs). However, after a certain time, it was found that treatment with one or two drugs does not produce the desired effect due to the rapid emergence of mutant forms of the virus with reduced sensitivity to antiretroviral drugs (ARVs). HIV replication. The combination of three or four drugs (the so-called highly active antiretroviral therapy - HAART) made it possible in many cases to suppress the multiplication of the virus. The use of HAART has contributed to a significant reduction in mortality among HIV-infected patients, but it did not eliminate the problem of resistance of the human immunodeficiency virus [1; 3; 5; 9].
And in most cases, the ineffectiveness of therapy is associated with the development of HIV resistance to antiretroviral drugs. Highly active antiretroviral therapy, which should be given to a patient for life, may not be effective due to the development of resistance to antiretroviral drugs. Due to the high degree of genetic variability of HIV, the active replication of the virus and the need for long-term use of ARV drugs, the emergence of HIV resistance is inevitable. Resistance potentially develops to all ARV drugs and may manifest as early as 14-28 days after administration of the drug. The spread of HIV resistance to ARV drugs leads to a decrease in the effec-
tiveness of therapy, an increase in mortality from HIV / AIDS and an increase in the cost of antiretroviral therapy [2; 5; 9].
Studying the level of HIV resistance to ARVP is an important and integral component in the provision of quality care for HIV-infected patients. Detection of resistance is necessary to analyze the transmitted resistance of the virus in order to minimize its spread, as well as timely planning and taking measures to prevent the circulation of resistant strains [2; 5].
A complex has been undertaken in the country to limit the effects of the negative effect of virus resistance on the patient's body.
Analyzing the data of HIV-infected patients receiving various treatment regimens, taking into account resistance to antiretroviral drugs, may clarify some still unclear issues in the management of such patients, optimize the strategy of antiretroviral therapy and increase its effectiveness.
Purpose of the study. Determination of resistance to reverse transcriptase inhibitors.
Material and methods. Analyzed 200 plasma samples of HIV-positive patients. The study included patients with the experience of receiving ART for at least a year. Studies on the identification of mutations associated with HIV resistance to ARVP included the determination of nucleotide sequences of the human immunodeficiency virus genome. Processing of sequencing data, obtaining a consensus sequence and further analysis was carried out using the Stanford University database (http: // hivdb. Stanford. Edu) to determine the mutation profile of HIV resistance to various ARVs.
The results of the study. Analyzed 83 samples of patients in whose blood the HIV viral load was detected. The analysis showed that in the study group, mutations of resistance to nucleoside reverse transcriptase inhibitors (NRTI resistance mutations) contained a number of mutations.
The analysis of resistance to individual drugs showed that the average and high degree of resistance to most drugs from the group of nucleoside reverse transcriptase inhibitors was de-
Section 2. Medical science
tected with approximately the same frequency. So, sensitivity to tenafovir was maintained in 49(59%) patients, in 16(19.2%) patients there was a low level of resistance to this drug. The average degree of resistance was found in 8(9.6%) of the blood samples examined, despite the fact that these patients did not take a regimen containing tenafovir. And only in 10 (12%) patients, in the AVR scheme of which tenafovir was obtained, the results indicated a high resistance of HIV to the drug.
In 5 samples in the highly resistant group, a K65R mutation was found associated with a decrease in sensitivity to tenafovir and didanosine (3-4 times). Patients who found this mutation had low rates of DM 4 cells that did not exceed 110 copies / ml, a high level of HIV-RNA (OR [95% CI] and the duration of the first-line regimen (lamivudine, tenafovir, efavi-renz) for more than 12 months In studies [4; 7], it was shown that with the introduction of tenofovir into clinical practice, the K65R mutation causing resistance to this drug became the subject of close attention. However, taking tenofovir in combination with didanosine and abacavir significantly increased the likelihood veniya mutation (especially while receiving three drugs), whereas the joint receiving zidovudine and lamivudine reduced the risk of this phenomenon [6; 10; 11].
In the samples we studied, a sensitivity analysis to emtric-itabine was also carried out, despite the fact that this drug is not used in the country. So, in 65(78.3%) samples from 83 studied patients receiving therapy for at least a year, full sensitivity was found, in 3(3.6%) patients a moderate degree of resistance was found and in 5(6.0%) samples a high degree of resistance. In this
group, a large percentage ofM184V mutations was observed in almost all patients (70%). M184V is the most common mutation in the reverse transcriptase gene that overcomes the effects of emtricitabine and lamivudine. M184V also slows down the onset of resistance and increases susceptibility to zidovudine, tenafivir. Also in the group with high resistance to emricitabine, there were found complexes of timidin-tax mutations (TAM), which are non-polymorphic mutations - D67N, K70R. They reduce susceptibility to the entire group of NNIOT, contributing to the unblocking of the primer (for example, removal of nucleotides, pyrophosphorolysis) [8; 9; 11].
Zidovudine sensitivity has also been investigated. This drug has been used in the country since 2006 and is the most commonly used in AVT schemes. So full sensitivity was found in 70 (84.3%) patients from 83 examined. Only 3 had a low degree of resistance, 6 had a medium resistance, and 3 had a high degree of resistance. In samples with a high degree of resistance to zidovudine, TAM mutations were identified: M41L D67N T215Y. Together, M41L and T215Y provide high resistance to zidovudine and stavudine, as well as low to medium resistance to abacavir, didanosine, and tenafovir. D67N reduces susceptibility mainly to zidovudine and stavudine [4; 9; 11].
Conclusion. On average, each patient identified 1.35 mutations of HIV mutations. The most common mutation was M184V, which was not isolated pharmacologically resistant to HIV. Among TAM Thus, the results suggest that among patients receiving ARV therapy for at least a year, a number of mutations occur, which need to be studied as clinically significant.
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