HIV drug resistance testing is an important part of treatment planning because HIV can develop genetic changes that make some antiretroviral medicines less effective. Resistance can be present when HIV is first diagnosed or can develop later during treatment. Modern resistance testing helps healthcare professionals identify resistance-associated mutations and select medicines that are more likely to suppress HIV effectively. Current U.S. HIV guidelines recommend resistance testing at entry into care and emphasize using the results together with treatment history, viral-load measurements, and other clinical information.
HIV drug resistance occurs when genetic changes in HIV allow the virus to continue reproducing despite the presence of an antiretroviral medicine.
Resistance can affect different classes of HIV medicines, including:
A mutation that reduces sensitivity to one medicine can sometimes affect other medicines in the same class. This is known as cross-resistance.
HIV reproduces rapidly and can acquire genetic mutations during replication.
When antiretroviral therapy does not completely suppress viral replication, resistant variants can sometimes become more prominent.
Factors that can contribute to resistance include:
Resistance is not always caused by adherence problems. Some people acquire HIV that is already resistant to one or more antiretroviral medicines.
Resistance testing provides information that can help clinicians select an effective treatment regimen.
The NIH recommends HIV drug-resistance testing for people entering HIV care to help guide initial antiretroviral therapy. A genotypic resistance test is generally preferred for initial treatment planning.
The results can help determine:
Genotypic testing looks for specific genetic mutations associated with HIV drug resistance.
Standard testing commonly examines the HIV reverse transcriptase and protease genes.
When integrase resistance is a concern, the integrase gene can also be tested. This can be particularly important for people who have previously used an integrase inhibitor or long-acting cabotegravir.
Genotypic testing is generally favored because it is faster, less expensive, and easier to interpret than phenotypic testing in many clinical situations.
Phenotypic testing measures how well HIV grows in the presence of different antiretroviral medicines.
The result can indicate how much drug concentration is required to inhibit the virus compared with a reference strain.
Phenotypic testing can be useful when resistance patterns are complicated, particularly in people with extensive treatment histories.
However, it is generally more expensive and can take longer than genotypic testing.
Resistance testing can be used at several points during HIV care.
Resistance testing is recommended when a person enters HIV care to help select the initial treatment regimen.
Treatment should generally not be delayed while waiting for resistance results when immediate treatment is appropriate. Once results become available, the regimen can be modified if necessary.
Resistance testing is particularly important when HIV viral load remains detectable or increases despite treatment.
Current NIH guidance recommends resistance testing for confirmed virologic failure when HIV RNA is repeatedly above 200 copies/mL, with stronger recommendations at higher viral-load levels.
Testing can also help when viral load does not decline as expected after starting or changing therapy.
The results may help determine whether resistance is contributing to inadequate viral suppression.
Timing can affect the usefulness of a resistance test.
For people experiencing virologic failure, testing should ideally be performed while the person is still taking the failing regimen or within four weeks after stopping a non-long-acting regimen.
If more time has passed, testing may still provide useful information, but some previously selected mutations may no longer be detectable because the drug pressure has been removed.
This is why previous resistance-test results are important.
A current resistance test does not necessarily reveal every resistance mutation that HIV has developed in the past.
Some resistant variants can become less detectable after a treatment regimen is stopped.
For this reason, NIH guidance recommends reviewing all previous and current resistance tests when designing a new regimen.
A complete treatment history can therefore be just as important as the newest laboratory result.
For some people with very low or undetectable HIV RNA, conventional plasma-based resistance testing may not work.
A next-generation sequencing test that examines HIV proviral DNA can sometimes provide additional information about archived resistance mutations.
However, these tests can miss some previously existing mutations and should be interpreted cautiously.
They may be considered in selected people with extensive treatment histories, multiple previous treatment failures, or situations where conventional resistance testing cannot be performed successfully.
Integrase strand transfer inhibitors are an important part of modern HIV treatment.
When resistance to this class is possible, additional integrase genotypic testing may be necessary.
NIH guidance specifically highlights the importance of integrase resistance testing for people with previous exposure to long-acting cabotegravir for HIV prevention, people who have received an integrase-based post-exposure regimen, and people experiencing treatment failure while receiving an integrase inhibitor.
Long-acting cabotegravir and rilpivirine require special attention because both medicines remain in the body for a prolonged period.
People who experience virologic failure after receiving long-acting cabotegravir and rilpivirine should undergo resistance testing, including integrase testing, regardless of the time since the last injection.
This is important because resistance mutations affecting both integrase inhibitors and NNRTIs can emerge during treatment failure.
Resistance testing does not automatically determine a complete treatment regimen.
Clinicians consider the results alongside:
The goal is generally to construct a regimen containing enough fully active medicines to achieve and maintain viral suppression.
Viral load measures the amount of HIV RNA in the blood.
It is one of the primary laboratory measurements used to monitor whether treatment is working. CD4 testing provides information about immune function.
A detectable or rising viral load does not automatically mean drug resistance.
Other possibilities can include:
Resistance testing helps determine whether resistant HIV is contributing to the problem.
Taking HIV medication consistently is important because incomplete treatment can allow HIV to replicate while exposed to antiretroviral drugs.
However, adherence should be discussed without assuming that treatment failure is caused by missed doses.
Healthcare professionals may review:
Addressing these issues can be an important part of treatment planning.
Some medications can change the concentration of antiretroviral drugs in the body.
Interactions can involve:
A medication review can help identify interactions that could reduce treatment effectiveness or increase adverse effects.
Hepatitis B status is particularly important when selecting HIV treatment.
Some antiretroviral medicines are active against both HIV and hepatitis B.
Changing an HIV regimen without considering hepatitis B treatment can create problems, including hepatitis B reactivation or worsening in some circumstances.
Treatment planning should therefore include appropriate hepatitis B testing