Principles of managing antiretroviral drug resistance

The possibility of antiretroviral drug resistance should be considered before commencing any antiretroviral drug regimen, whether initial treatment or subsequent changes in regimen, and if virological suppression is sub-optimal.

When a person is newly infected with HIV, he or she may be infected with a strain that already carries drug-resistance mutations; this is known as transmitted resistance. If available, a baseline drug resistance assay should be done prior to commencing ART, as close as possible to the time of seroconversion, in order to detect transmitted resistance. Over time, mutations that confer drug resistance may not remain detectable in blood cells as wild-type virus becomes the dominant strain. However, these mutations persist in viruses within the viral reservoir and may be selected by subsequently used antiretroviral drugs and re-emerge, leading to virological failure. Drug resistance mutations that are present in low numbers of viruses and not detected by drug resistance assays are said to be “archived”. Testing early in the course of infection is not possible unless infection is detected at seroconversion or shortly afterwards. The possibility of “archived” transmitted and/or selected resistance should be kept in mind, and monitored by validated surrogate markers of treatment response, particularly viral load. If viral load is slow to decrease or does not fall to <200 copies/mL within 6 months of initiating ART, drug resistance should be considered as a possible cause. Ideally, a repeat drug resistance assay will detect resistance at this stage, as long as the viral load is high enough for the assay to be successful (generally ≥1,000 copies/mL). Other possible causes of virological failure should also be considered.

Some patients with long-standing HIV infection may have unrecognised drug-resistant strains, as HIV viral load and drug resistance assays were not available until the 1990s. Treatment history and results of previous viral load testing can identify probable resistance. For example, if a regimen was failing, or if a person with HIV infection was treated with suboptimal ART in the early treatment years.

In the case of a failing regimen, where resistance testing cannot identify the specific resistance mutation/s and other causes have been ruled out, particularly non-adherence, a change of antiretroviral drug regimen should be considered.

The most common indications for genotypic antiretroviral drug resistance tests are:

  • Primary HIV infection
  • Baseline: ART-naïve with established infection
  • Virological failure
    • Collect sample while on failing regimen or add-on testing of stored sample
  • Pregnancy – not on ART
  • ART-treated patient who has ceased therapy (usually due to non-adherence)
    • Restart last effective regimen and assess virological response
    • If the re-initiated ART suppresses viral replication, continue the regimen
    • Repeat resistance testing if the re-initiated ART fails to suppress viral replication.

A common scenario is when the patient lapses from treatment and re-presents months or even years later. Prior to treatment interruption, intermittent adherence or different pharmacokinetic properties of individual drugs in the regimen could lead to the selection of drug-resistant HIV. However, once the patient has stopped drugs for a period of time, the wild-type virus will usually become dominant and drug resistance mutations may not be detected in blood cells, though are archived. Consider whether the components of the regimen have differing durations of action and whether resistance is likely to have emerged, and in that case, consider using an alternative regimen. In these cases, expert advice could reasonably be sought.