A new method of drug resistance testing may allow resistance mutations to be detected even where viral load levels are low. This is the finding of researchers at Imperial College, London, who presented their work at the 6th International Congress on Drug Therapy in HIV Infection in Glasgow today.
Given the frequency with which antiretroviral treatment failure is associated with drug resistance, and the impact of resistance mutations on the outcome of replacement drug regimens, testing for drug resistance when changing from a failing combination has become commonplace. In fact, current practice guidelines indicate that the selection of replacement regimens should always be informed by the expert interpretation of results from a drug resistance test.
The accuracy of resistance test results is maximised where tests are performed on samples drawn whilst the failing regimen is still being taken, and where viral load is above 1,000-2,000 copies. At lower viral load levels, standard resistance tests lack sensitivity, and in the absence of drug pressure, fitter, drug-sensitive viruses will likely be out-grown by less-fit, drug-resistant viruses. These minority drug-resistant viruses may then be missed by the resistance test.
Whilst the ‘best’ time to change therapy is not clearly established, there’s evidence that continuing on a regimen which is failing to suppress viral load leads to the accumulation of resistance mutations. This suggests that the risk of resistance will be minimised if a failing regimen is changed sooner rather than later.
Clearly these competing clinical pressures pose a dilemma for HIV patients and physicians – if therapy is failing to suppress viral replication, do you wait to change until the viral load is high enough to provide an accurate resistance test result, even though by waiting you may be encouraging resistance to develop?
The ideal scenario, of course, is for resistance tests to be available which provide an accurate assessment of drug resistance even where viral load levels are low, and new data presented by St Mary’s Hospital and the Jefferiss Wing Laboratories at Imperial College, suggest this option may be in reach of HIV clinical care settings before too long.
The Mary’s team modified an existing Advanced Biosystems (ABI) genotyping assay with additional primers in order to improve its sensitivity. Samples were taken from 62 HAART recipients who had viral loads below 1,000 copies; the usual sensitivity break-point for the ABI test. Of these, seven samples failed to amplify, two of which had viral load levels below 50 copies. Primary resistance mutations were detected in 39 of the remaining 55 samples (71%).Thirty-nine had primary mutations in the reverse transcriptase (RT) gene; 28 had at least one secondary RT mutation; nine had a primary protease gene mutation; and 50 had polymorphisms associated with protease inhibitor resistance.
Interestingly, two individuals who underwent serial genotyping were found to accumulate resistance mutations, despite having modest viral load levels and stable CD4 counts.
NAM’s award-winning patient information booklet on Resistance can be downloaded in pdf format here at aidsmap.com.
Mackie NE et al. Determination of drug-resistant mutations at viral loads of less than 1000 HIV-1 RNA copies/ml in plasma samples from HIV-1 infected patients on highly active antiretroviral therapy (HAART). 6th International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P196, 2002.