HIV drug resistance: molecular mechanisms, clinical significance, and current approaches to adjusting antiretroviral therapy (literature review)

Stasyuk G. E.¹
scientific company operator;
ORCID: 0009-0000-8131

1Federal State Budgetary Military Educational Institution of Higher Education «S. M. Kirov Military Medical Academy», Saint Petersburg, Russia

Stasyuk Gleb Evgenevich; e-mail: virko-viktor@mail.ru

The study had no sponsorship.

The authors declare no conflict of interest.

26.05.2026

14.08.2026

Introduction. Drug resistance of the human immunodeficiency virus (HIV) remains one of the key challenges in modern infectious diseases, significantly affecting the effectiveness of antiretroviral therapy and long-term disease prognosis. The high genetic variability of HIV contributes to the rapid emergence of resistance mutations and complicates the selection of effective treatment regimens. Objective. To analyze current data on the molecular mechanisms of HIV drug resistance, evaluate their clinical significance, and review modern approaches to the diagnosis and optimization of antiretroviral therapy. Materials and methods. A review of Russian and international scientific publications on HIV drug resistance mechanisms published in recent years was performed using specialized medical databases. The analysis included data from clinical and experimental studies, systematic reviews, and clinical guidelines focusing on resistance mutations, diagnostics, and treatment of HIV infection. Results and discussion. Drug resistance development is associated with the accumulation of mutations in genes encoding reverse transcriptase, protease, and integrase, as well as with the impact of viral genetic variability and subtype diversity. Cross-resistance and compensatory mutations play an important role in maintaining viral replicative capacity. Modern diagnostic methods, including genotypic and phenotypic testing as well as next-generation sequencing technologies, allow detection of minor viral variants and improve the prediction of treatment efficacy. Clinical evidence indicates that both transmitted and acquired resistance significantly influence the risk of virological failure and the choice of treatment regimens. Conclusion. Genetic variability of HIV and the emergence of resistance mutations are key factors determining the effectiveness of antiretroviral therapy. The use of advanced diagnostic methods and personalized treatment approaches can improve therapeutic outcomes and reduce the spread of drug-resistant HIV strains.

HIV, drug resistance, antiretroviral therapy, mutations, genotyping, virological failure

10.29234/2308-9113-2026-14-3-150-165

1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. NIH; 2023.

2. Wensing A.M., Calvez V., Ceccherini-Silberstein F. et al. 2022 update of the drug resistance mutations in HIV-1. Topics in Antiviral Medicine. 2022; 30(4): 559–574.

3. Menéndez-Arias L. Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Research. 2010; 85(1): 210–231. DOI: https://doi.org/10.1016/j.antiviral.2009.07.006

4. Tao K., Rhee S.Y., Chu C. et al. Treatment-emergent dolutegravir resistance mutations in individuals naïve to HIV-1 integrase inhibitors. Viruses. 2023; 15(9): 1932. DOI: https://doi.org/10.3390/v15091932

5. Carr A., Mackie N.E., Paredes R., Ruxrungtham K. HIV drug resistance in the era of contemporary antiretroviral therapy: a clinical perspective. Antiviral Therapy. 2023; 28(5). DOI: https://doi.org/10.1177/13596535231201162

6. World Health Organization. HIV drug resistance report 2021. Geneva: WHO; 2021.

7. Emel'yanov V.N., Kuzin A.A., Virko V.A. et al. Osnovy obshchey epidemiologii. Epidemiologicheskaya diagnostika [Fundamentals of general epidemiology. Epidemiological diagnostics]. Saint Petersburg: Voenno-meditsinskaya akademiya imeni S.M. Kirova; 2025. 94 p. (In Russ.)

8. Emel'yanov V.N., Kuzin A.A., Virko V.A. et al. Epidemiologicheskaya diagnostika. Epidemiologicheskoe obsledovanie ochagov [Epidemiological diagnostics. Investigation of epidemiological foci]. Saint Petersburg: Voenno-meditsinskaya akademiya imeni S.M. Kirova; 2025. 96 p. (In Russ.)

9. World Health Organization. HIV drug resistance fact sheet. Geneva: WHO; 2025.

10. Kuzin A.A., Emel'yanov V.N., Bolekhan V.N. et al. Epidemiologiya sotsial'no znachimykh zabolevaniy [Epidemiology of socially significant diseases]. Saint Petersburg: Voenno-meditsinskaya akademiya imeni S.M. Kirova; 2025. 93 p. (In Russ.)

11. Ntamatungiro A.J., Kagura J., Weisser M., Francis J.M. Pre-treatment HIV-1 drug resistance in antiretroviral therapy-naive adults. Journal of Antimicrobial Chemotherapy. 2022; 77(12): 3231–3241. DOI: https://doi.org/10.1093/jac/dkac338

12. Takem E.N., Coox C., Shang J. et al. The association between HIV pretreatment drug resistance and virological outcomes. PLoS One. 2024; 19(4): e0300456. DOI: https://doi.org/10.1371/journal.pone.0300456

13. Hemelaar J. The origin and diversity of the HIV-1 pandemic. Trends in Molecular Medicine. 2012; 18(3): 182–192. DOI: https://doi.org/10.1016/j.molmed.2011.12.001

14. Zanini F., Puller V., Brodin J., Albert J., Neher R.A. In vivo mutation rates and the landscape of fitness costs of HIV-1. Virus Evolution. 2017; 3(1): vex003. DOI: https://doi.org/10.1093/ve/vex003

15. Hemelaar J., Gouws E., Ghys P.D., Osmanov S. Global distribution of HIV-1 subtypes. AIDS. 2006; 20(16): W13–W23. DOI: https://doi.org/10.1097/01.aids.0000247564.73009.bc

16. Kantor R., Katzenstein D. Drug resistance in non-subtype B HIV-1. Journal of Clinical Virology. 2004; 29(3): 152–159. DOI: https://doi.org/10.1016/S1386-6532(03)00115-X

17. Rhee S.Y., Jordan M.R., Raizes E. et al. HIV-1 drug resistance mutations. PLoS One. 2015; 10(12): e0145772. DOI: https://doi.org/10.1371/journal.pone.0145772

18. Blanco-Arévalo J.L., García-Deltoro M., Torralba M. et al. HIV-1 resistance to integrase inhibitors. AIDS Reviews. 2024; 26(2): 67–79. DOI: https://doi.org/10.24875/AIDSRev.24000011

19. Singh A.K., Das K. Insights into HIV-1 reverse transcriptase inhibition. Viruses. 2022; 14(5): 1027. DOI: https://doi.org/10.3390/v14051027

20. Obasa A.E., Mikasi S.G., Brado D. et al. Drug resistance mutations in HIV-1. Frontiers in Microbiology. 2020; 11: 438. DOI: https://doi.org/10.3389/fmicb.2020.00438

21. Bokharaei-Salim F., Esghaei M., Khanaliha K. et al. HIV-1 RT and protease mutations. PLoS One. 2020; 15(3): e0229275. DOI: https://doi.org/10.1371/journal.pone.0229275

22. Yu F., Li Q., Wang L. et al. Drug resistance to HIV-1 integrase inhibitors. Pharmacogenomics and Personalized Medicine. 2022; 15: 195–203. DOI: https://doi.org/10.2147/PGPM.S345797

23. Kagan R.M., Baxter J.D., Kim T. et al. HIV-1 drug resistance trends in the era of modern antiretrovirals. Open Forum Infectious Diseases. 2025; 12(8): ofaf446. DOI: https://doi.org/10.1093/ofid/ofaf446

24. Lu X., Li Y., Liu M. et al. Drug resistance mutations in newly diagnosed HIV-1 infections. Frontiers in Cellular and Infection Microbiology. 2025; 15: 1510916. DOI: https://doi.org/10.3389/fcimb.2025.1510916

25. Liu S., Yuan D., Zhou Y. et al. Resistance to second-generation integrase inhibitors. International Journal of Antimicrobial Agents. 2024; 64(3): 107294. DOI: https://doi.org/10.1016/j.ijantimicag.2024.107294

26. Fokam J., Anim-Keng T.T., Pokam B.T. et al. Acquired HIV-1 drug resistance. AIDS Research and Therapy. 2025; 22: 97. DOI: https://doi.org/10.1186/s12981-025-00775-z

27. Flieller R., Garcia-Morales C., Brasesco M. et al. HIV drug resistance survey. Viruses. 2023; 15(2): 490. DOI: https://doi.org/10.3390/v15020490

28. Lu X., Kang X., Chen S. et al. HIV-1 genetic diversity and resistance. AIDS Research and Human Retroviruses. 2015; 31(10): 1038–1045. DOI: https://doi.org/10.1089/AID.2015.0160

29. Gupta R.K., Gregson J., Parkin N. et al. HIV-1 drug resistance before ART. Lancet Infectious Diseases. 2018; 18(3): 346–355. DOI: https://doi.org/10.1016/S1473-3099(17)30702-8

30. Ermak T.N., Kravchenko A.V. Lekarstvennaya ustoychivost' VICh v Rossiyskoy Federatsii [HIV drug resistance in the Russian Federation]. Infektsionnye bolezni [Infectious Diseases]. 2020; 18(2): 45–52. (In Russ.)

31. World Health Organization. Guidelines on HIV drug resistance. Geneva: WHO; 2019.

32. Phillips A.N., Cambiano V., Nakagawa F. et al. Viral load monitoring. Lancet HIV. 2017; 4(1): e16–e25. DOI: https://doi.org/10.1016/S2352-3018(16)30077-2

33. Pokrovskiy V.V., Ladnaya N.N., Sokolova E.V. VICh-infektsiya v Rossiyskoy Federatsii [HIV infection in the Russian Federation]. Epidemiologiya i infektsionnye bolezni [Epidemiology and Infectious Diseases]. 2022; 27(3): 5–15. (In Russ.)

34. Hamers R.L., Sigaloff K.C., Kityo C. et al. HIV drug resistance after ART failure. Lancet Infectious Diseases. 2012; 12(4): 307–317. DOI: https://doi.org/10.1016/S1473-3099(11)70276-9

35. Kravchenko A.V., Ermak T.N. Sovremennye podkhody k terapii VICh [Modern approaches to HIV therapy]. Infektsionnye bolezni [Infectious Diseases]. 2021; 19(1): 30–38. (In Russ.)

36. Ministry of Health of the Russian Federation. VICh-infektsiya u vzroslykh: klinicheskie rekomendatsii [HIV infection in adults: clinical guidelines]. Moscow; 2023. (In Russ.)

37. Ladnaya N.N., Pokrovskiy V.V. Epidemiologiya VICh-infektsii [Epidemiology of HIV infection]. Zhurnal mikrobiologii, epidemiologii i immunobiologii [Journal of Microbiology, Epidemiology and Immunobiology]. 2021; 98(4): 12–20. (In Russ.)

38. Stanford University. HIV Drug Resistance Database. Available at: https://hivdb.stanford.edu (accessed: 2025).

39. Mbunkah H.A., Marzel A., Schmutz S. et al. Low-abundance HIV drug-resistant variants. Journal of Antimicrobial Chemotherapy. 2020; 75(10): 2905–2914. DOI: https://doi.org/10.1093/jac/dkaa257

40. Noguera-Julian M., Edgil D., Harrigan P.R. et al. Next-generation sequencing for HIV drug resistance. Journal of Infectious Diseases. 2017; 216(S9): S829–S833. DOI: https://doi.org/10.1093/infdis/jix411

41. Paredes R., Marconi V.C., Lockman S. et al. Impact of HIV drug resistance testing. Clinical Infectious Diseases. 2016; 63(5): 655–662. DOI: https://doi.org/10.1093/cid/ciw324

42. Günthard H.F., Calvez V., Paredes R. et al. HIV drug resistance testing recommendations. Lancet Infectious Diseases. 2019; 19(4): e121–e132. DOI: https://doi.org/10.1016/S1473-3099(18)30673-9

43. World Health Organization. Consolidated guidelines on HIV. Geneva: WHO; 2021.

44. Günthard H.F., Saag M.S., Benson C.A. et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults. JAMA. 2016; 316(2): 191–210. DOI: https://doi.org/10.1001/jama.2016.8900

45. Stellbrink H.J., Arribas J.R., Stephens J.L. et al. Bictegravir study. Lancet HIV. 2019; 6(6): e364–e372. DOI: https://doi.org/10.1016/S2352-3018(19)30080-3

46. Cahn P., Madero J.S., Arribas J.R. et al. Dolutegravir plus lamivudine. Lancet. 2019; 393: 143–155. DOI: https://doi.org/10.1016/S0140-6736(18)32462-0

47. Orkin C., Arasteh K., Hernández-Mora M.G. et al. Long-acting ART. New England Journal of Medicine. 2020; 382(12): 1124–1135. DOI: https://doi.org/10.1056/NEJMoa1909512

48. Gandhi R.T., Landovitz R.J., Sax P.E. et al. IAS-USA recommendations. JAMA. 2025; 333(7): 609–628. DOI: https://doi.org/10.1001/jama.2024.24543

49. Emel'yanov V.N., Kuzin A.A., Panin I.S., Kulemin M.E. Epidemiologicheskiy monitoring pokazateley zabolevaemosti, smertnosti i dostovernost' ucheta germinogennykh opukholey yaichka [Epidemiological monitoring of morbidity and mortality indicators and reliability of testicular germ cell tumor registration]. Vestnik Rossiyskoy Voenno-meditsinskoy akademii [Bulletin of the Russian Military Medical Academy]. 2025; 27(1): 115–124. (In Russ.) DOI: https://doi.org/10.17816/brmma632060

50. Kim Y.S. Long-acting injectable antiretroviral agents. Infection & Chemotherapy. 2021; 53(4): 686–695. DOI: https://doi.org/10.3947/ic.2021.0136

51. Deeks S.G., Overbaugh J., Phillips A., Buchbinder S. HIV infection. Nature Reviews Disease Primers. 2015; 1: 15035. DOI: https://doi.org/10.1038/nrdp.2015.35

52. Chopra A., Bedi S., Verma S. et al. HIV capsid inhibitors. Drugs. 2022; 82(2): 123–138. DOI: https://doi.org/10.1007/s40265-021-01636-9

53. Swindells S., Andrade-Villanueva J.F., Richmond G.J. et al. Long-acting cabotegravir and rilpivirine. New England Journal of Medicine. 2020; 382(12): 1112–1123. DOI: https://doi.org/10.1056/NEJMoa1909512