Risk of Resistance
HIV drug resistance may develop depending on a medicine's barrier to resistance and during periods when drug levels are suboptimal2
HIV is one of the fastest-mutating pathogens and can mutate millions of times per day3-6
Mutations can affect ARV target proteins, resulting in potential drug resistance7
According
to the DHHS Guidelines
- Drug resistance is cumulative, meaning that once a mutation is detected in a resistance assay, it should be considered present in that patient’s HIV thereafter1
One particular concern is cross-resistance, caused by HIV mutations that confer resistance to drugs in the same ARV class, rendering them ineffective—thus limiting treatment options.1
A Treatment With a High Barrier to Resistance Is Key1
It is important to consider a regimen's barrier to resistance when selecting a HIV treatment option for initial therapy1
In an analysis of HIV sequences reported to NHSS from 2014 to 2018,
1 IN 5 TREATMENT-NAÏVE PATIENTS IN THE US (n=9616/50747) DEMONSTRATED RESISTANCE TO ≥1 ARV CLASS8
Preexisting resistance is a critical consideration when switching ART in virologically suppressed PWH1
Longer duration of ART is a factor associated with developing resistance.9 In a 2023 survey that included PWH over the age of 50 or living with HIV for more than 15 years (N=673), the reported average number of years on ART was 23.10
M184V/I is one of the most common resistance mutations associated with treatment failure11:
The M184V/I resistance mutation was present in 31% of samples with any drug resistance mutation in a 2017 analysis from a large US database.11,*
M184V/I reduces susceptibility to some NRTIs >200-fold and increases susceptibility to other NRTIs.12,13
*The analysis for 2017 included about 10,000 samples. The number of samples with any drug resistance mutation was not provided.
According
to the DHHS Guidelines
- For regimen optimization in the setting of NRTI resistance, if an NRTI is to be included in the new regimen, two NRTIs should be included in the regimen with a fully active, high-resistance barrier drug.1,†
†Please see DHHS guidelines for specific recommended antiretrovirals.
The Potential of Undetected Resistance Mutations May Impact Virologic Suppression1
Commercial resistance assays may fail to detect a mutation if it constitutes less than 20% of circulating virus.1 Genotypic identification of resistance mutations, including M184V/I, may be complicated by the reemergence of wild-type virus in the absence of selective pressure from HIV treatment.1,14 Drug resistance mutations can be present in the HIV reservoir and not detected in your patient’s most recent drug-resistance test.1
Before switching therapy in the setting of virologic suppression, it's important to consider underlying resistance and review full ART history, including virologic response, and cumulative resistance test results.1
How important is resistance to your treatment decisions?
Early clinical developments working to achieve viral suppression often had their own challenges. Resistance was top among them, and it remains a crucial concern when treating patients living with HIV.
ART, antiretroviral therapy; ARV, antiretroviral; DHHS, US Department of Health and Human Services; NHSS, National HIV Surveillance System; NRTI, nucleotide reverse transcriptase inhibitor; PWH, people with HIV.
References: 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Updated September 12, 2024. Accessed September 24, 2024. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf 2. Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23(9):1035-1046. 3. Sanjuán R, Domingo-Calap P. Mechanisms of viral mutation. Cell Mol Life Sci. 2016;73(23):4433-4448. 4. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350(10):1023-1035. 5. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996;271(5255):1582-1586. 6. Perelson AS. Modelling viral and immune system dynamics. Nat Rev Immunol. 2002;2(1):28-36. 7. Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2022 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2022;30(4):559-574. 8. McClung RP, Oster AM, Ocfemia MCB, et al. Transmitted drug resistance among human immunodeficiency virus (HIV)-1 diagnoses in the United States, 2014-2018. Clin Infect Dis. 2022;74(6):1055-1062. 9. Pennings PS. HIV drug resistance: problems and perspectives. Infect Dis Rep. 2013;5(Supp 1):e5. 10. Health HIV. State of Aging with HIV Third Annual National Survey. Accessed June 27, 2024. https://healthhiv.org/stateof/agingwithhiv/ 11. Kagan RM, Dunn KJ, Snell GP, et al. Trends in HIV-1 drug resistance mutations from a U.S. reference laboratory from 2006 to 2017. AIDS Res Hum Retroviruses. 2019;35(8):698-709. 12. Stanford University Drug Resistance Database. NRTI resistance notes. Updated October 25, 2023. Accessed June 27, 2024. https://hivdb.stanford.edu/dr-summary/resistance-notes/NRTI/ 13. Geretti AM, Blanco JL, Marcelin AG, et al. HIV DNA sequencing to detect archived antiretroviral drug resistance. Infect Dis Ther. 2022;11(5):1793-1803. 14. Boettiger DC, Kiertiburanakul S, Sungkanuparph S, et al. The impact of wild-type reversion on transmitted resistance surveillance. Antivir Ther. 2014;19(7):719-722.
