Replication of the HIV-1 virus is error-prone, resulting in millions of mutations each day.1,2 When mutations occur in virus proteins that are the targets of antiretroviral (ARV) drugs, drug resistance can occur.3

Durable virologic suppression, which helps to prevent the development of resistance, has driven the shift from monotherapy to triple therapy over time.4 Today, DHHS Guidelines recommend INSTI-based triple-therapy regimens (INSTI + 2 NRTIs) as initial regimens for most people with HIV.5

TYPES OF DRUG
RESISTANCE

There are two types of drug resistance: treatment-emergent (also called therapy-emergent) and transmitted.6

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 and help prevent resistance from developing.6-8

How ARV drug resistance develops

The likelihood of developing drug resistance is dependent on the level of ARVs in the plasma while the HIV virus is replicating.6-8

Chart showing the probability of resistance in relation to antiviral drug levels

The main factors that contribute to suboptimal ARV plasma levels include:

  • Poor treatment adherence9-11
  • Food effects9
  • Drug-drug interactions10,11

In the presence of suboptimal drug levels, drug-resistant mutations can develop.6-8 Mutations such as M184V, which is among the most common mutations in patients failing antiretroviral therapy (ART), alter viral enzymes and their susceptibility to a drug.12-14

Transmitted drug resistance occurs when a drug-resistant virus is transmitted from one person to another.6,7

Prevalence of transmitted drug resistance in the US by ARV class, 2013-2016 (N=36,288)15


Chart showing the prevalence of transmitted drug resistance in the US by ARV class

Adapted from McClung RP, Ocfemia CB, Saduvala N, et al. Poster presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA.

  • About 19% of treatment-naive people in the US had resistance mutations to ≥1 ARV during 2013-201615

  • According to DHHS, transmitted drug-resistant HIV is generally either NNRTI- or NRTI-resistant5

  • According to DHHS, transmitted PI resistance is much less common than either NNRTI or NRTI resistance and, to date, INSTI resistance is rare5

SELECTING A REGIMEN WITH A HIGH BARRIER TO RESISTANCE

An ARV's barrier to resistance refers to the threshold above which clinically meaningful resistance develops (or the ease with which resistance develops) to a given drug (and in some cases, to other drugs in the same class). Resistance barriers for specific ARVs vary from low to high, based on the interplay among key contributing factors16,17:

  • Relative ARV genetic barriers16
    • The number of critical mutations needed to make a treatment ineffective
  • Susceptibility and/or viral fitness of the drug-resistant HIV8,16
    • Pre-existing resistance can impact viral replication and the efficacy of the drug being used to varying levels

There is essentially no cross-resistance among ARV drug classes (ie, resistance to one class does not impact the activity of other classes of unused ARVs).18

Barrier to resistance may vary depending on an ARV’s pharmacokinetics17,19

(ie, how the drug is absorbed, distributed, metabolized, and eliminated from the body)

Chart illustrating the relationship between an ARV's pharmacokinetics and its barrier to resistance

Adherence is a key factor in maintaining durable suppression over time. Early-era HAART studies demonstrated the need for ≥95% adherence to achieve and sustain HIV suppression.20 Longer drug plasma half-life may be a factor in delaying virologic failure during times of suboptimal adherence.19,20

HIV DRUG-RESISTANCE TESTING

The main types of tests used to detect drug-resistant HIV viral strains include genotypic, phenotypic, and proviral DNA.5

Genotypic resistance assay predicts drug susceptibility by comparing a patient’s viral DNA sequence and a wild-type reference sequence. Results take 1-2 weeks.5

Phenotypic resistance assay exposes a sample of the patient’s HIV to all available ARVs at different concentrations and measures the virus’ ability to replicate. The test can determine which drugs will work and which no longer respond to the current ARV regimen. Results are available in 2-3 weeks, at a higher cost than genotypic assays.5

Proviral DNA is a newer 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

Proviral DNA testing may not detect all hidden resistance mutations.5 For example, in a recent study (N=87), proviral DNA failed to detect existing M184V/I mutations in about half of participants.21

All prior and current drug-resistance test results, if available, should be considered when constructing a new regimen for a patient.5

DHHS GUIDANCE: RESISTANCE TESTING IN TREATMENT-NAIVE ADULTS5

  • Early treatment initiation: 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, ART initiation should not be delayed while awaiting resistance test results; the HIV regimen can be modified once results are reported5
  • Baseline resistance testing: Recommended for persons with HIV at entry into care to guide selection of the initial ART5
  • 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 gene5

In cases of early treatment initiation, ART should not be delayed while awaiting resistance test results.5*

*It’s important to educate patients regarding ART and adherence. Treatment may be deferred on a case-by-case basis as clinically appropriate.

DHHS GUIDANCE: RESISTANCE TESTING IN ART-EXPERIENCED ADULTS5

In cases of virologic failure5

  • HIV drug-resistance testing should be performed to aid in selection of active drugs when switching ART regimens in:
    • People with virologic failure and HIV RNA levels >1,000 copies/mL
    • People with suboptimal viral load reduction
  • 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 therapy
  • When a person experiences virologic failure while receiving an INSTI-based regimen, genotypic testing for INSTI resistance should be requested

In cases of virologic suppression5

(ie, switches due to adverse events, drug-drug or drug-food interactions, pill burden, pregnancy, cost, or the desire for regimen simplification)5

  • 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 recommended

Genotypic resistance testing is preferred over phenotypic resistance testing in people with suboptimal virologic response or virologic failure while on first- or second-line regimens and in persons with known resistance patterns or whose resistance patterns are not expected to be complex.5


DHHS, Department of Health and Human Services; HAART, highly active antiretroviral therapy; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TDRM, Transmitted drug resistance-associated mutations.

REFERENCES:

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