A high barrier to drug resistance should be a major consideration
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.1-3
Types of drug resistance
There are two types of drug resistance: transmitted and treatment-emergent (also called therapy-emergent) resistance.4
Transmitted drug resistance occurs when a drug-resistant virus is transmitted from one person to another.4 According to the DHHS guidelines:
- Transmitted drug-resistant HIV is generally either NNRTI- or NRTI-resistant5
- Transmitted PI resistance is much less common than either NNRTI or NRTI resistance and, to date, INSTI resistance is rare5
In an analysis of HIV sequences reported to the National HIV Surveillance System from 2014 to 2018 (n=50,747):
ALMOST 10,000 TREATMENT-NAÏVE PATIENTS had transmitted resistance mutations to ≥1 class of ARVs6
Treatment-emergent drug resistance
Treatment-emergent drug resistance occurs when the HIV-1 virus replicates in the presence of suboptimal or inconsistent levels of ARVs. Adherence to a prescribed ARV regimen is necessary to maintain virologic suppression.4,5,7
Consider the impact of suboptimal drug levels4,7,8
The main factors that contribute to suboptimal ARV plasma levels include:
HIV drug resistance testing
Genotypic, phenotypic, and proviral DNA tests are used to detect drug-resistant HIV viral strains.5
Genotypic resistance assay predicts drug susceptibility by comparing a patient’s viral DNA sequence and a wild-type reference sequence.5
Phenotypic resistance assay exposes a sample of the patient’s HIV to all available ARVs at different concentrations and measures the virus’s ability to replicate. The test can determine which drugs will work and which no longer respond to the current ARV regimen.5
Proviral DNA assay is a genotypic resistance assay designed to provide drug resistance data in virologically suppressed patients (ie, HIV below the limit of detection). It can provide information for NRTIs, NNRTIs, INSTIs, and PIs when standard resistance testing cannot be performed due to inadequate plasma viral load.5
An HIV-1 proviral DNA test in host cells is now commercially available. This test is intended to detect archived resistance mutations in patients with HIV RNA below the limit of detection or with low-level viremia.5
Consider prior and current drug resistance test results when evaluating comprehensive therapies for your patients.5
Resistance testing in treatment-naïve adults5
Resistance testing in ART-experienced adults
- 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 regimen5
- Within-class and between-class switches can usually maintain viral suppression, provided there is no viral resistance to the ARV agents in the new regimen5
- 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 recommended5
ART, antiretroviral therapy; DHHS, US Department of Health and Human Services; INSTI, integrase strand transfer inhibitor; NNRTI, non- nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RNA, ribonucleic acid; TDRM, transmitted drug resistance-associated mutations.
- 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.
- 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.
- AIDSMap. Resistance mutations. Updated July 2019. Accessed February 1, 2022. https://www.aidsmap.com/about-hiv/resistance-anti-hiv-drugs
- Tang MW, Shafer RW. HIV-1 antiretroviral resistance: scientific principles and clinical applications. Drugs. 2012;72(9):e1-e25.
- 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 January 20, 2022. Accessed January 31, 2022. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/guidelines-adult-adolescent-arv.pdf
- 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.
- 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.
- HIVinfo.NIH.gov. HIV treatment: drug resistance. Updated August 4, 2021. Accessed February 1, 2022. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/drug-resistance
- 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.
- Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2(4):a007161.
- 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.
- Luber AD. Genetic barriers to resistance and impact on clinical response. MedGenMed. 2005;7(3):69.
- Zdanowicz MM. The pharmacology of HIV drug resistance. Am J Pharm Educ. 2006;70(5):100.
- Clutter DS, Jordan MR, Bertagnolio S, Shafer RW. HIV-1 drug resistance and resistance testing. Infect Genet Evol. 2016;46:292-307.
- Pau AK, George JM. Antiretroviral therapy: current drugs. Infect Dis Clin North Am. 2014;28(3):371-402.