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High Barrier to Resistance

High Barrier to Resistance

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A high barrier to resistance is important for long-term success with treatment1

How does drug resistance occur?

Replication of the HIV-1 virus is error-prone, resulting in millions of mutations each day. When mutations occur in virus proteins that are the targets of antiretroviral (ARV) drugs, drug resistance can occur. There are two types of drug resistance: transmitted and treatment-emergent resistance.2-4

Transmitted resistance

  • Occurs when a drug-resistant virus is transmitted from one person to another5
  • Is generally either NNRTI- or NRTI-resistant1
  • Transmitted PI resistance is much less common than either NNRTI or NRTI resistance and, to date, INSTI resistance is rare1,6

Treatment-emergent resistance1,5,7

The likelihood of developing drug resistance is dependent on:

  • When the HIV-1 virus replicates in the presence of suboptimal or inconsistent levels of ARVs
  • Strict adherence to a prescribed HIV regimen helps reduce this risk by achieving and maintaining virologic suppression
  • Lack of adherence or intermittent access to a prescribed ART may result in treatment failure and the emergence of drug resistance mutations, which may jeopardize future treatment options
Main factors that may contribute to suboptimal ARV plasma levels include:

Suboptimal HIV treatment adherence8-10

Food effects8

Drug-drug interactions9,10

A high barrier to resistance may help address the threat that drug resistance poses to individuals and communities.11,12

HIV drug resistance testing1

Consider prior and current drug resistance test results when evaluating comprehensive therapies for your patients. Genotypic, phenotypic, and proviral DNA tests are used to detect drug-resistant HIV viral strains.

DHHS recommended resistance testing in treatment-naïve adults1

  • ART initiation should not be delayed while awaiting resistance test results; the HIV regimen can be modified once results are reported. In persons with acute or recent (early) HIV infection, in pregnant people with HIV, or in people who will initiate ART on the day of or soon after diagnosis, treatment initiation should not be delayed pending resistance
  • Baseline resistance testing: recommended for people with HIV at entry into care to guide selection of the initial ART
  • Standard genotypic testing: involves testing for mutations of the reverse transcriptase (RT) and protease (PR) genes. If transmitted INSTI resistance is a concern, providers should ensure that testing also includes the integrase gene

DHHS recommended resistance testing in ART-experienced adults1

In cases of virologic failure:

  • HIV drug-resistance testing should be performed to aid in selection of active drugs when changing ART regimens in:
    • People with virologic failure and HIV RNA levels >200 copies/mL (AI for >1,000 copies/mL, AIII for 501-1,000 copies/mL, CIII for confirmed HIV RNA 201-500 copies/mL). For people with confirmed HIV RNA levels >200 copies/mL but <500 copies/mL, drug-resistance testing may be unsuccessful but should still be considered
    • People with suboptimal viral load reduction (All)
  • In cases of virologic failure, perform HIV drug-resistance testing while the person is taking prescribed ARVs, or if that is not possible, within 4 weeks after discontinuing a non-long-acting ARV regimen
  • When a person experiences virologic failure while receiving an INSTI-based regimen, genotypic testing for INSTI resistance should be requested

In cases of optimizing ARV therapy in the setting of viral suppression:

  • It is critical to review a patient’s full ARV history, including virologic responses, past ARV-associated toxicities and intolerances, and cumulative resistance test results before selecting a new ART regimen
  • Within-class and between-class switches can usually maintain viral suppression, provided there is no viral resistance to the ARV agents in the new regimen
  • Monotherapy with either a boosted PI or an INSTI has been associated with unacceptable rates of virologic failure and the development of resistance; therefore, monotherapy as a switching strategy is not recommended

Mutations related to resistance may jeopardize future treatment options.1

Having a high barrier to resistance is one of the most important attributes in a regimen1

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People featured are compensated by Gilead.

When selecting an ART, remember that not all HIV treatments offer a high barrier to resistance.1

Opportunities to assess your patient’s regimen for high barrier to resistance

There are many opportunities to consider assessing your patient’s HIV regimen for high barrier to resistance. These include at treatment initiation, if your patient experiences virologic failure, or if your patient needs to restart treatment.1,13 Per DHHS guidelines, ART selection should be based on the regimen’s virologic efficacy, potential adverse effects, pill burden, dosing frequency, potential drug-drug interactions, cost, access, resistance test results, and the patient's comorbid condition(s).1

Safety & Tolerability

A regimen’s safety and tolerability profile may help support people with HIV through all stages of life.1

Consider safety and tolerability

ART, antiretroviral therapy; ARV, antiretroviral; DNA, deoxyribonucleic acid; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RNA, ribonucleic acid.

References:
  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. US Department of Health and Human Services. Updated September 12, 2024. Accessed January 8, 2025. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf
  2. Soriano V, Perelson AS, Zoulim F. Why are there different dynamics in the selection of drug resistance in HIV and hepatitis B and C viruses? J Antimicrob Chemother. 2008;62(1):1-4.
  3. Cromer D, Schlub TE, Smyth RP, et al. HIV-1 mutation and recombination rates are different in macrophages and T-cells. Viruses. 2016;8(4):118-132.
  4. AIDSMap. Resistance to anti-HIV drugs. Updated July 2019. Accessed December 10, 2024. https://www.aidsmap.com/about-hiv/resistance-anti-hiv-drugs
  5. Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012;72(9):e1-e25.
  6. 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.
  7. Gardner EM, Burman WJ, Skteiner JF, Anderson PL, Bangsberg DR. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23(9):1035-1046.
  8. Atkinson MJ, Petrozzino JJ. An evidence-based review of treatment-related determinants of patients' nonadherence to HIV medications. AIDS Patient Care STDs. 2009;23(11):903-914.
  9. Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2(4):a007161.
  10. Gonzalez-Serna A, Swenson LC, Watson B, et al. A single untimed plasma drug concentration measurement during low-level HIV viremia predicts virologic failure. Clin Microbiol Infect. 2016;22(12):1004.e9-1004.e16.
  11. Beyrer C, Pozniak A. HIV drug resistance—an emerging threat to epidemic control. New Engl J Med. 2017;377(17):1605-1607.
  12. Akinsola O, Folayan T, Ibidoja I, Okunola D, Adepoju LA. Drug resistance in anti-viral medications: a case study of human immunodeficiency virus. Journal of Disease and Global Health. 2025;18(1):59-73.
  13. Coffey S, Bacon O. Immediate ART Initiation & Restart: Guide for Clinicians. AETC National Coordinating Resource Center. March 17, 2023. Accessed February 28, 2025. https://aidsetc.org/sites/default/files/media/document/2023-06/ncrc-rapid-art-full.pdf
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