RISK ASSESSMENT OF FIRST-LINE TREATMENT FAILURE IN UNTREATED HIV PATIENTS IN NORTHWESTERN FEDERAL DISTRICT OF THE RUSSIAN FEDERATION


Cite item

Full Text

Abstract

The HIV infection epidemic in Russia continues to evolve, and HIV infection cases have been registered in all territorial entities of the Russian Federation. 2021 Treatment coverage was 82.2% and 56.4% individuals under dispensary observation and living with diagnosed HIV infection. 79.9% receiving ART subjects were shown to achieve undetectable viral load.

Highly active antiretroviral therapy (HAART) currently represents a combination of three (less frequently four) antiretroviral drugs targeting pathways involved in various stages of HIV replication in vivo. Treatment failure is a problem facing doctors and patients using HAART. The most common cause of therapeutic failure is the development of HIV drug resistance. The emergence of resistance is associated with processes involving mutation occurring in the viral genome influenced by evolutionary factors.

Therefore, it is important clinically and programmatically to learn more about the rate of first-line treatment failure, the rate of switching to a second-line ART regimen, and to identify patients at risk to develop strategies for preventing development of further failure cases.

The study was aimed at analyzing ineffectiveness of first-line ART therapy in patients in Northwestern Federal District of the Russian Federation.

Materials and methods

Sequencing reactions were performed using the AmpliSens HIV Resist-Seq. Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE software. Isolate genotyping was performed using the MEGA-X software with the Neighbor-joining algorithm.

Results

The HIV pol genes in 239 patients with first-line ART failure and 100 naïve patients were sequenced; all sequences genotyped as HIV-1 sub-subtype A6. According to analysis, 82% of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. In total, we encountered 87 different drug resistance mutations.

Conclusion

We have shown increased proportion of patients with first-line ART failure among all patients with treatment failure. The main cause for such changes is probably related to the prevalence of primary drug resistance, estimated here at 8%. Specific differences were found between drug resistance mutation profiles in patients without suppressed viral load and patients with virological breakthrough. The overall results of the study indicate a need to diagnose and characterize HIV drug resistance prior to initiation of therapy in order to avoid ineffective first-line antiretroviral treatment.

Full Text

Introduction

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS), which is responsible for the deaths of over 38 million people [18, 33]. Because there is no cure for HIV, patients are subject to life-long therapy, yet when the first HIV drugs were introduced, resistance evolved in nearly all treated individuals in the first 6 months of treatment, sometimes within weeks [13, 27]. This drug resistance (DR), often encoded by single mutations conferring strong resistance, led to rebounding viral popula-tions and treatment failure [9, 14].

  Highly active antiretroviral therapy (HAART), introduced in 1995, was expected to prevent the evolution of drug resistance and subsequent treatment failure [10]. However, while triple-drug combination therapies have saved many lives, HIV has continued to evolve drug resistance all the way up to the present [11, 15, 24, 35]. The high mutation rate of HIV is critical for its survival during drug therapies. The virus can obtain drug re-sistance mutations, and they are one of the major challenges for effective HAART. Some drug-resistant viruses are also capable of being transmitted, and consequently these strains can increase in prevalence as described below [2, 4, 17, 36]. Adhering to the ART regimen is crucial to achieve and maintain viral suppression as well as to prevent further HIV transmission and the progression of HIV infection [1, 3]. Furthermore, close adher-ence to ART (over 95% of the time) is required to achieve full viral load suppression. When patients fail to attain the required adherence level, they may experience a poorer progno-sis, higher morbidity/mortality, or the development of resistance to ART [12, 21].

  The HIV infection epidemic in Russia continues to evolve [32], and HIV infection cases have been registered in all territorial entities of the Russian Federation. The number of Russian regions with a high prevalence of HIV infection (more than 0.5% of the popula-tion) reached 34 in 2018. In the first half of 2020, 38,126 individuals with antibodies to HIV-1 were newly identified in Russia. By the end of the first half of 2020, 1,094,050 Rus-sians with laboratory-diagnosed HIV infection were known to be living in the country [6]. The number of patients receiving antiretroviral therapy was 660,821 in 2021. Treatment coverage in 2021 was 82.2% of the number of those under dispensary observation and 56.4% of the number of those living with a diagnosis of HIV infection. In 527,705 patients, 79.9% of those receiving ART, an undetectable viral load was achieved [7].

  Therefore, surveillance of the HIV epidemic and HIV DR is strongly needed in the re-gion since increased ART coverage and a subsequent increase in HIV DR to those drugs used can significantly worsen therapeutic effectiveness or make it impossible to achieve the goals of the 90-90-90 initiative [34]. With this intended rapid scaling up of detection and therapy, it is also important to sustain treatment success with undetectable viral loads in patients on first-line ART. Otherwise, failure on first-line regimens can lead to a complicated, less tolerable, and more expensive second-line ART regimen with fewer drug options if drug related toxicities develop.

  Therefore, it is important clinically and programmatically to learn more about the rate of first-line treatment failure, the rate of switching to a second-line ART regimen, and to identify which patients are at risk in order to develop strategies to prevent development of further failure cases.

 

Aim

The aim of the work was to analyze ineffectiveness of first-line therapy in patients in Russia's Northwestern Federal District.

 

Materials and Methods

The study was approved by the Ethics Committee of the Saint Petersburg Pasteur In-stitute. It included analysis of HIV samples obtained from: 239 patients with first-line ART failure who contacted the Northwestern Federal District AIDS Center for diagnostic clari-fication of drug resistance status in the period 2014-2018; and from 100 patients without any history of ART.

  Quantitative analysis of HIV RNA was carried out with the AmpliSens® HIV-Monitor-FRT commercial kit (Central Research Institute of Epidemiology, Russia), with a sensitivity threshold of 500 copies/ml. Samples with a detectable viral load (VL) were analyzed using RT-PCR and Sanger sequencing. For reverse transcription and am-plification of HIV RNA, the RT-PCR-kit-Pro/Rev and PCR-kit-Pro/Rev commercial kits (Central Research Institute of Epidemiology, Russia) were used. Sequencing reactions were performed using the AmpliSens® HIVResist-Seq kit (Central Research Institute of Epidemiology, Russia) according to manufacturer instructions, as described earlier [26]. Sequencing was carried out using Applied Biosystems 3500 genetic analyzers according to instructions.

  Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE software [22, 8, 25]. The consensus sequence included a 1302 nt region of the polymerase (pol) gene encoding protease (PR) and a part of reverse transcriptase (RT/OT) in the 2253–3554 nt region; coordinates are given for HIV HXB2 in the GenBank database (K03455.1). The resulting sequences were analyzed for the presence of drug resistance mutations using the Stanford database [31]. Sample genotyping was performed using the REGA HIV-1 Subtyping Tool 3.0 [23].

The statistical significance of differences was determined using the chi-square test (χ2). The level of significance (p) adopted in this work was 0.05 (or 5.0%). Confidence in-tervals were determined by the method of Klopper-Pearson.

 

Results

Study patients contacted the Northwestern Federal District AIDS Center for diagnostic clarification of drug resistance status over the 2014-2018 period. The proportion of pa-tients with first-line ART failure (among all patients with ART failure) was not the same across years (Fig. 1).

The HIV pol genes of 239 patients with first-line ART failure were sequenced; all sequences gen-otyped as HIV-1 sub-subtype A6. According to analysis, 82% (82% NRTI, 72% NNRTI) of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. In total, we encountered 87 different drug resistance mutations (49 NRTI, 38 NNRTI). The most common mutations in patients are presented in Table 1.

The HIV pol genes of 100 patients with no history of ART were sequenced; all se-quences genotyped as HIV-1 sub-subtype A6. Viral genomes from 8 subjects (8%, 95% CI 3.52% - 15.16%) were found to harbor resistance-conferring mutations to NRTIs. Four of these were found to harbor mutations associated with zidovudine resistance. All signifi-cant drug resistance mutations encountered were found in single cases: K70E; K70R; D67N; L74; and M184V (in combination with NNRTI-related resistance mutations V106M and G190S). An isolated amino acid substitution, D67N, was found in one sample; it is associated with resistance to zidovudine only in combination with other re-sistance-conferring mutations (i.e., M41L, K70R, and T215Y). A62V (n=4) was identified by itself (3 samples) and once in combination with an NNRTI resistance mutation, V179D (1 sample).

 

Discussion

We draw attention here to the fact of an increase in the number of patients experienc-ing ineffectiveness with 1st line ART. Federal AIDS Center reports also point to the insuffi-cient effectiveness of ART. In only 80% of those receiving ART was an undetectable viral load achieved [7]. This trend is likely associated with an increase in the prevalence of primary HIV drug resistance in Russia, which is 5-7% according to various estimates [16].

  A similar prevalence of primary drug resistance was obtained in this study. Moreo-ver, the most common DR mutations in naive patients are multiple drug resistance to drugs of the NRTI and NNRTI classes, which are most often the main first-line ART. The pattern of DR mutations among patients with first-line ART failure is consistent with the most common resistance mutations described in the literature [29, 19].

  However, there is significant heterogeneity in the occurrence of some mutations within the study group. Conventionally, the group can be divided into two subgroups: the first - patients who did not achieve viral load suppression (N=124); and the second - pa-tients in whom the viral load was suppressed, after which there was a virological break-through, i.e., a growth in viral load (N = 115). Comparison of these subgroups revealed a difference in the occurrence of some significant drug resistance mutations (Fig. 2). For in-dividual mutations, differences in occurrence reached statistical significance (p<0.05) (Ta-ble 2).

The most characteristic mutations for patients in the first group (inadequate suppres-sion) were K65R, Y181C, and Y115F. In the second group (inadequate suppression with breakthrough), they were M184V, D67N, K103N, and T215Y. Accordingly, for patients who experienced a virological breakthrough after long-term use of one ART regimen, thy-midine analogue resistance mutations (TAM) were more common, as well as the K103N NNRTI resistance mutation. For patients who initially failed therapy, mutations to non-thymidine nucleoside analogues and NNRTI resistance mutation Y181C were seen.

  It is interesting that M184V (the most common mutation both in the study group and in patients with HIV DR generally) was significantly more common among patients who have experienced a virological breakthrough. Apparently, mutations causing DR were obtained mainly before initiation of treatment in the first group. In such cases (before treatment), probably only those mutations that are least associated with impaired replica-tion remain in the viral genome. In the absence of selective drug pressure, mutations which negatively affect replication have no competitive advantage and likely self-eliminate in the viral population. With ART, however, their ability to confer resistance and permit replication at all likely outweighs their detriment to replication.

  However, this assumption casts doubt on the fact that TAM and the M184V mutation were also detected among naive patients in this study. In this light, additional studies are required to establish the causes of differences in the mutation profiles in the studied sub-groups. It is worth noting differences in the occurrence of the A62V mutation in the differ-ent study groups. Among naive patients, the occurrence of this mutation was 4%, yet among patients with ART failure, it reached 15%. At the same time, in ART failure sub-groups 1 and 2, the prevalence of this mutation was also different: 12% and 22%, respec-tively. This difference does not reach statistical significance (χ2 (Yates) = 3.319, p = 0.069), but it closely approaches it.

  HIV-1 reverse transcriptase (RT), the enzyme responsible for converting the sin-gle-stranded viral RNA genome into its double-stranded DNA counterpart, can acquire an A62V amino acid substitution. This is known to be associated with multi-drug resistance, but is not a resistance-conferring mutation by itself [30, 28]. It is known that the A62V mutation alone can significantly increase viral mutation frequency [5, 20], while nega-tively impacting replicative capacity and viral fitness in the absence or presence of AZT. The fact that differences in A62V occurrence did not reach significance may be due to in-sufficient sample sizes. Nevertheless, the current trend may suggest that presence of this mutation is associated with an increased risk of virological breakthrough in patients and subsequent higher mortality rates.

 

Conclusion

We have shown an increase in the proportion of patients with first-line ART failure among all patients with treatment failure. The main reason for these changes is probably the prevalence of primary drug resistance, estimated in this paper at 8%. Specific differ-ences were found between drug resistance mutation profiles in patients without viral load suppression and patients with virological breakthrough. A possible connection between the A62V mutation and the likelihood of a virological breakthrough was found. The over-all results of the work indicate the need to diagnose and characterize HIV drug resistance before initiation of therapy in order to avoid ineffective first-line antiretroviral treatment.

 

×

About the authors

Alexandr Nikolaevich Shchemelev

Saint-Petersburg Pasteur Institute

Email: tvildorm@gmail.com
ORCID iD: 0000-0002-3139-3674

Junior Researcher, Laboratory of Virology and Immunology HIV Infection

Russian Federation

Yulia Vladimrovna Ostankova

Saint Petersburg Pasteur Institute

Email: shenna1@yandex.ru
ORCID iD: 0000-0003-2270-8897
SPIN-code: 5294-8768

PhD (Biology), Senior Researcher at the Laboratory of Molecular Immunology St. Petersburg Pasteur Institute, St. Petersburg, Russian Federation.

Russian Federation, 197101, St. Petersburg, st. Mira, 14

Diana Eduardovna Valutite

Saint Petersburg Pasteur Institute

Email: dianavalutite008@gmail.com
ORCID iD: 0000-0002-0931-102X

clinical laboratory diagnostics doctor at department of diagnostics of HIV infection and AIDS-associated diseases St. Petersburg Pasteur Institute, St. Petersburg, Russian Federation

Russian Federation, 197101, St. Petersburg, st. Mira, 14

Elena Nikolaevna Serikova

St. Petersburg Pasteur Institute

Email: elena.donetsk.serikova@mail.ru
ORCID iD: 0000-0002-0547-3945

Researcher, Laboratory of Virology and Immunology HIV Infection, Postgraduate Student St. Petersburg Pasteur Institute, St. Petersburg

Russian Federation, 197101, St. Petersburg, st. Mira, 14

Elena Borisovna Zueva

St. Petersburg Pasteur Institute

Email: ezueva75@mail.ru
ORCID iD: 0000-0002-0579-110X

PhD, Biologist at the department of diagnostics of HIV infection and AIDS-associated diseases St. Petersburg Pasteur Institute

Russian Federation, 197101, St. Petersburg, st. Mira, 14

Alexandr Vladimirovich Semenov

Ekaterinburg Research Institute of Viral Infections SRC VB Vector

Email: alexvsemenov@yahoo.com
ORCID iD: 0000-0003-3223-8219

PhD, BD (Biology), Ekaterinburg Research Institute of Viral Infections SRC VB Vector, Director, Ekaterinburg, Russian Federation

Russian Federation, г. Екатеринбург, ул. Летняя, 23

Areg Artemovich Totolian

St. Petersburg Pasteur Institute

Author for correspondence.
Email: totolian@pasteurorg.ru
ORCID iD: 0000-0003-4571-8799

Academician of the Russian Academy of Sciences, PhD, MD (Medicine), Professor, Head at the Laboratory of Molecular Immunology, Director of the St. Petersburg Pasteur Institute; head Department of Immunology, First St. Petersburg State Medical University named after Academician I.P. Pavlov.

Russian Federation, 197101, St. Petersburg, st. Mira, 14

References

  1. Bartlett J.A. Addressing the challenges of adherence. // J Acquir Immune Defic Syndr (1999) 2002;29(Suppl 1):S2–10. https://doi.org/10.1097/00126334-200202011-00002.
  2. Brenner B., Wainberg M.A., Salomon H., Rouleau D,; Dascal A., Spira B., Sekaly R.P., Conway B., Routy J.P. Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Investigators of the Quebec Primary Infection Study. // Int. J. Antimicrob. Agents 2000, 16, 429–434. https://doi.org/10.1016/S0924-8579(00)00270-3
  3. Bunnell R., Ekwaru J.P., Solberg P., Wamai N., Bikaako-Kajura W., Were W., Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. // AIDS (London, England) 2006;20:85–92. https://doi.org/10.1097/01.aids.0000196566.40702.28.
  4. D’Aquila R.T., Schapiro J.M., Brun-Vezinet F., Clotet B., Conway B., Demeter L.M., Grant R.M., Johnson V.A., Kuritzkes D.R., Loveday C. Drug resistance mutations in HIV-1. // Top HIV Med. 2003, 11, 92–96. https://pubmed.ncbi.nlm.nih.gov/12717052/
  5. Dapp M.J., Heineman R.H., Mansky L.M. Interrelationship between HIV-1 fitness and mutation rate. // J. Mol. Biol. 2013;425:41–53.. https://doi.org/10.1016/j.jmb.2012.10.009
  6. Fact sheets. HIV infection in the Russian Federation as of December 31, 2020 (In Russian) http://www.hivrussia.info/wp-content/uploads/2021/03/VICH-infektsiya-v-Rossijskoj-Federatsii-na-31.12.2020-..pdf
  7. Fact sheets. HIV infection in the Russian Federation as of December 31, 2021 (In Russian) http://www.hivrussia.info/wp-content/uploads/2022/03/Spravka-VICH-v-Rossii-na-31.12.2021-g..pdf
  8. Golosova O., Henderson R., Vaskin Y., Gabrielian A., Grekhov G., Nagarajan V., Oler A.J., Quiñones M., Hurt D., Fursov M., Huyen Y. Unipro UGENE NGS pipelines and components for variant calling, RNA-seq and ChIP-seq data analyses. // Peer J 2014 2:e644. https://doi.org/10.7717/peerj.644;
  9. Günthard H.F., Calvez V., Paredes R., Pillay D., Shafer R.W., Wensing A.M., Jacobsen D.M., Richman D.D. Human immunodeficiency virus drug resistance: 2018 recommendations of the international antiviral Society-USA panel. // Clinical Infectious Diseases. 2019;68:177–187. https://doi.org/10.1093/cid/ciy463.
  10. Hammer S.M., Squires K.E., Hughes M.D., Grimes J.M., Demeter L.M., Currier J.S., Eron J.J., Feinberg J.E., Balfour H.H., Deyton L.R., Chodakewitz J.A., Fischl M.A., for the AIDS clinical trials group 320 study team A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. // New England Journal of Medicine. 1997;337:725–733. https://doi.org/10.1056/NEJM199709113371101.
  11. Hogg R.S., Yip B., Kully C., Craib K.J., Schechter M.T., Montaner J.S., Montaner J.S. Improved survival among HIV-infected patients after initiation of triple-drug antiretroviral regimens. // CMAJ. 1999;160:659–665. https://pubmed.ncbi.nlm.nih.gov/10102000/
  12. Iacob S.A., Iacob D.G., Jugulete G. Improving the adherence to antiretroviral therapy, a difficult but essential task for a successful HIV treatment-clinical points of view and practical considerations. // Front Pharmacol. 2017;8:831. https://doi.org/10.3389/fphar.2017.00831.
  13. Larder B.A., Darby G., Richman D.D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. // Science. 1989;243:1731–1734. https://doi.org/10.1126/science.2467383.
  14. Larder B.A., Kemp S.D. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT) // Science. 1989;246:1155–1158. https://doi.org/10.1126/science.2479983.
  15. Lee F.J., Amin J., Carr A. Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks' follow-up. // PLOS ONE. 2014;9:e97482. https://doi.org/10.1371/journal.pone.0097482.
  16. Level and structure of HIV drug resistance among naive patients in the Russian Federation (In Russian) http://www.hivrussia.info/wp-content/uploads/2020/12/2020-Rossijskaya-baza-dannyh-LU-VICH-u-naivnyh-patsientov.pdf
  17. Louie M., Hogan C., Di Mascio M., Hurley A., Simon V., Rooney J., Ruiz N., Brun S., Sun E., Perelson A.S., Determining the relative efficacy of highly active antiretroviral therapy. // J. Infect. Dis. 2003, 187, 896–900. https://doi.org/10.1086/368164
  18. Lucas S., Nelson A.M. HIV and the spectrum of human disease. // J. Pathol. 2015, 235, 229–241. https://doi.org/10.1002/path.4449
  19. Maksimenko L.V., Totmenin A.V., Gashnikova M.P., Astakhova E.M., Skudarnov S.E., Ostapova T.S., Yaschenko S.V., Meshkov I.O., Bocharov E.F., Maksyutov R.А., Gashnikova N.M. Genetic Diversity of HIV-1 in Krasnoyarsk Krai: Area with High Levels of HIV-1 Recombination in Russia. // Biomed Res Int. 2020 Sep 10;2020:9057541. https://doi.org/10.1155/2020/9057541.
  20. Maldonado J.O., Mansky L.M. The HIV-1 Reverse Transcriptase A62V Mutation Influences Replication Fidelity and Viral Fitness in the Context of Multi-Drug-Resistant Mutations. // Viruses. 2018 Jul 19;10(7):376. https://doi.org/10.3390/v10070376.
  21. Nachega J.B., Marconi V.C., van Zyl G.U., Gardner E.M., Preiser W., Hong S.Y. HIV treatment adherence, drug resistance, virologic failure: evolving concepts. // Infect Disorders Drug Targets. 2011;11(2):167–174. https://doi.org/10.2174/187152611795589663.
  22. Okonechnikov K., Golosova O., Fursov M., the UGENE team. Unipro UGENE: a unified bioinformatics toolkit. // Bioinformatics 2012 28:1166-1167. doi: 10.1093/bioinformatics/bts091
  23. Peña A.C.P., Faria N.R., Imbrechts S., Libin P., Abecasis A.B., Deforche K., Gomez A., Camacho R.J., de Oliveira T., Vandamme A.M. Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: Performance evaluation of the new REGA version 3 and seven other tools. // Infectious Genetics and Evolution 2013; 19:337-48. doi: 10.1016/j.meegid.2013.04.032
  24. Rocheleau G., Brumme C.J., Shoveller J., Lima V.D., Harrigan P.R. Longitudinal trends of HIV drug resistance in a large canadian cohort, 1996-2016. // Clinical Microbiology and Infection. 2018;24:185–191. https://doi.org/10.1016/j.cmi.2017.06.014.
  25. Rose R., Golosova O., Sukhomlinov D., Tiunov A., Prosperi M. Flexible design of multiple metagenomics classification pipelines with UGENE. // Bioinformatics, bty901, 2018/10/25. https://doi.org/10.1093/bioinformatics/bty901
  26. Schemelev A.N., Ostankova Yu.V., Zueva E.B., Khanh T.H., Semenov A.V. Genotypic and pharmacoresistant HIV characteristics in patients in the Socialist Republic of Vietnam. // HIV Infection and Immunosuppressive Disorders 2020;12(2):56-68. https://doi.org/10.22328/2077-9828-2020-12-2-56-68
  27. Schuurman R., Nijhuis M., van Leeuwen R., Schipper P., de Jong D., Collis P., Danner S.A., Mulder J., Loveday C., Christopherson C. Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC) // Journal of Infectious Diseases. 1995;171:1411–1419. https://doi.org/10.1093/infdis/171.6.1411.
  28. Shafer R.W., Kozal M.J., Winters M.A., Iversen A.K.N., Katzenstein D.A., Ragni M.V., Meyer W.A., Gupta P., Rasheed S., Coombs R., et al. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. // J. Infect. Dis. 1994;169:722–729. https://doi.org/10.1093/infdis/169.4.722.
  29. Shchemelev A.N., Semenov A.V., Ostankova Yu.V., Zueva E.B., Valutite D.E., Semenova D.A., Davydenko V.S., Totolian A.A. Genetic diversity and drug resistance mutations of HIV-1 in Leningrad Region. // Journal of microbiology, epidemiology and immunobiology 2022; 99(1):28–37. https://doi.org/10.36233/0372-9311-216
  30. Shirasaka T., Kavlick M.F., Ueno T., Gao W.Y., Kojima E., Alcaide M.L., Chokekijchai S., Roy B.M., Arnold E., Yarchoan R. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. // Proc. Natl. Acad. Sci. USA. 1995;92:2398–2402. https://doi.org/10.1073/pnas.92.6.2398.
  31. Soo-Yon Rhee, Matthew J. Gonzales, Rami Kantor, Bradley J. Betts, Jaideep Ravela, and Robert W. Shafer Human immunodeficiency virus reverse transcriptase and protease sequence database. // Nucleic Acids Research, 2003, 31(1), 298-303 https://doi.org/10.1093/nar/gkg100
  32. UNAIDS DATA 2017. Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS; 2017. https://www.unaids.org/sites/default/files/media_asset/20170720_Data_book_2017_en.pdf
  33. UNAIDS data 2020 https://www.unaids.org/en/resources/documents/2020/unaids-data
  34. UNAIDS DATA, 2017. https://www.unaids.org/en/resources/documents/2017/2017_data_book.
  35. Walensky R.P., Paltiel A.D., Losina E., Mercincavage L.M., Schackman B.R., Sax P.E., Weinstein M.C., Freedberg K.A. The survival benefits of AIDS treatment in the united states. // The Journal of Infectious Diseases. 2006;194:11–19. https://doi.org/10.1086/505147.
  36. Walsh J.C., Pozniak A.L., Nelson M.R., Mandalia S., Gazzard B.G., Virologic rebound on HAART in the context of low treatment adherence is associated with a low prevalence of antiretroviral drug resistance. // JAIDS, J. Acquired Immune Defic. Syndr. 2002, 30, 278–287. https://doi.org/10.1097/00126334-200207010-00003

Supplementary files

There are no supplementary files to display.


Copyright (c) Shchemelev A.N., Ostankova Y.V., Valutite D.E., Serikova E.N., Zueva E.B., Semenov A.V., Totolian A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies