July 9, 2002
By now, many physicians will agree that resistance testing is an important tool in the treatment of experienced HIV patients within whom significant resistance to more than one class of drug is expected. In addition to resistance testing, a detailed drug history is crucial to better assist in the selection of the next antiretroviral regimen.
Studies have clearly documented that the fewer genotypic mutations conferring resistance to different antiretroviral drugs one has, the better one's drug susceptibility and virological outcome.
Abacavir is a nucleoside inhibitor of the reverse transcriptase enzyme. Many studies have found abacavir to have a significant effect in controlling viral replication as part of a salvage regimen, but also in intensification strategies. Considering that the genotypic resistance for abacavir is not that much different than for other nucleosides, it is possible that there are other genotypic or phenotypic profiles that may predict which experienced patient is going to respond to an abacavir-containing regimen.
With all these concepts in mind, investigators from Beth Israel Medical Center in New York City tried to determine the factors most strongly associated with a positive virological response in the 24 patients who participated in the abacavir expanded access program. These patients were heavily pretreated with antiretroviral therapy. They all added abacavir and at least one additional drug as a new treatment regimen.
These patients underwent a retrospective genotypic (GT) and phenotypic (PT) testing from stored, baseline plasma samples. Various prognostic factors on virologic response were analyzed and matched to HIV-RNA and CD4 counts at baseline, week eight and week 24.
A Genotypic Sensitivity Score (GSS) was created and defined as the number of significant mutations present on the RT gene. A Phenotypic Susceptibility Score was also created and defined as the number of susceptible drugs in the regimen.
At the short term, a better response to abacavir in those patients highly experienced to antiretroviral therapy was predicted by baseline HIV-RNA, along with GT and PT susceptibility. At 24 weeks, baseline HIV-RNA was not a predictor of the outcome, but rather again baseline GT and PT testing seemed to predict a better response.
Although these findings may be seen by most as expected, I am not convinced that those conclusions can be drawn, at least with the data presented. The sample of patients was very heterogeneous, with other multiple variables along the way on their treatment. The effect of other mutations and the response to other drugs added to the regimen were not investigated. Also, some mutations were counted on the GSS as "one mutation," which may have a more significant impact on susceptibility testing than others, such as the case with multi-drug resistance mutations.
This study, although interesting in design, doesn't add much to the current clinical management of patients with HIV. On the other hand, exploring relationships like this in a more controlled population may result in the discovery of interesting interactions.