Genotypic resistance tests determine what changes have taken place in HIV's structure that may alter the way it makes key proteins (like protease and reverse transcriptase). These changes are called mutations. The other approach -- phenotypic testing -- presents a more direct measure of resistance. It examines the amount of drug needed to stop the replication of the virus -- grown from a person's blood -- in a laboratory setting.
Resistant HIV requires higher levels of the same drug to get a level of suppression equal to that of a non-resistant virus. When the amount of drug needed is roughly four or more times the amount needed to suppress the original form of the virus, treatment with most drugs become impractical. Doses high enough to suppress the virus at that point may be too toxic.
Results from two studies illustrate the benefits of genotypic resistance testing. First, the French Viradapt study followed 108 people, all of whom previously used anti-HIV therapies and had viral loads over 10,000 copies HIV RNA. Upon entering the study, half of the participants received the best available therapy as estimated by their previous treatment history. The other half received the best available therapy as determined by considering the results from a resistance test.
At six months, those whose treatment assignments were based on resistance tests experienced a 1.15 log (14-times) reduction in viral load. Those not getting the same guidance only experienced a 0.67 log (4.7-times) reduction in viral load. Moreover, 32% of the participants who had resistance testing guidance achieved viral load suppression to below 200 copies HIV RNA, compared to only 14% of those who did not. This clearly suggests that using resistance tests to guide treatment decisions results in a more useful regimen.
After six months, everyone in the study received a resistance test and accompanying results. Some certainly altered their anti-HIV regimen based on the test results. The benefits of resistance testing further emerged at the end of one year, where viral load results were nearly indistinguishable between the two groups. In the group with initial resistance testing, pre-study viral load reduction remained 1.15 logs (14-times). The other group realized improved viral suppression to 0.98 log (9.5-times).
The second study, known as the GART study, showed very similar results. The GART study included 153 people with a median viral load of about 28,000 copies and median CD4+ cell counts of 230. All volunteers experienced a return of measurable viral load while on three-drug (a protease inhibitor and two nucleoside analogues) regimens prior to enrollment. At study entry, half received therapy based on resistance test results, with expert interpretation. The other half received therapy based on previous anti-HIV therapy history.
After twelve weeks, there was about a half log (2.8-times) difference in viral load between the two groups, with the group which received resistance test results having the better anti-HIV response. One interesting observation found an average 0.37 log (2.3 times) reduction occurred in viral load for each drug that a person used and was not previously resistant to. For each drug used in a combination that a person was resistant to, a 0.17 log (1.5 times) reduction still occurred in viral load. This suggests that even when genotypic resistance testing detects some measurable level of resistance to a given drug, it does not mean that the drug is rendered completely useless.
Resistance testing will play a major role in guiding anti-HIV therapy treatment decisions. Such tests will also likely be used to determine if someone was initially infected with a drug-resistant virus and to select anti-HIV therapies for use in a combination regimen.
The success reported in these initial studies may be somewhat dependent upon finding a number of drugs to which each person was not yet resistant. Whether similar results can be expected in people who show resistance to all currently available therapies remains to be seen.
Resistance tests are becoming more widely available as some third party payers begin to reimburse for them. Because of this, and study results showing the benefits of resistance testing, many laboratories now perform genotypic and/or phenotypic resistance tests. It is important to select a reputable laboratory as not all labs or all tests are the same. They differ in quality control, quality assurance, test sensitivity, test accuracy and the interpretation of the results. For more information on resistance testing, call Project Inform's National HIV/AIDS Treatment Hotline and ask for the Geno-/Phenotypic Resistance Test Quick Sheet.