July 9, 2002
At this meeting protease inhibitors are taking a big hit as first-line agents in the treatment of antiretroviral-naive patients. The most important predictors of the virologic success of a given antiretroviral regimen are a combination of the potency of the regimen and its durability. Several studies have shown that NNRTI-based regimens (mainly efavirenz) are very potent and durable, and they compared favorably to PI-based regimens in almost every single study that has been presented so far.
The results of ACTG 384 will be presented later during this conference and commented on in more detail in another review. That study was a head-to-head comparison between efavirenz (EFV) and nelfinavir (NVP) in combination with d4T and ddI or AZT and 3TC (or both). Efavirenz clearly won in this confrontation. And so did AZT + 3TC. However, this was not the first time this has happened. Efavirenz had also won a previous confrontation when compared against indinavir as part of the pivotal trial, DMP-006. Critics liked to point out that DMP-006 was not a blinded study and that the design favored efavirenz. There is some value in these criticisms, but the trial reproduced real-life experiences with this drug. There won't be too many questions about the results of ACTG 384: it was blinded, with all drugs administered two times a day -- and again EFV-based regimens were significantly superior.
In this study from Madrid, the authors examined the durability rather than the potency of PI-based regimens when compared to NNRTI-based regimens. They retrospectively compared the outcomes of 256 naive patients who started HAART between April 1998 (when nelfinavir and nevirapine first became available) and October 2000. The main limitations of the study are that it is retrospective and the two groups are not very well matched. Patients on PI-based regimens tended to have higher viral loads and lower CD4+ cell counts than the patients on NNRTI-based regimens.
The authors looked at the durability of a patient's first regimen and noticed that it was much more likely that patients on NNRTI-based regimens would remain on their initial regimen longer than patients who were started on a PI-based regimen (924 days versus 629 days). When they controlled for viral load, CD4 and prior AIDS diagnosis using a Cox model, they still found that the use of NNRTI-based regimens was more durable than PI-based regimens.
Another group from Madrid (J.R. Arribas, TuOrB1187) presented another retrospective study asking whether PI-based regimens are more potent than NNRTI-based regimens in patients with low CD4+ cell counts (less than 100 copies per ml). Again the NNRTI-based regimens (efavirenz) were the winners. And this is a population in which many clinicians feel compelled to use PIs.
There is a growing body of evidence that suggests NNRTI-based regimens (mainly efavirenz) are more potent, more durable and less toxic than PI-based regimens as first-line therapy. However, this is something that clinicians had already decided a couple of years ago. Now the data to support the prevailing approach is here. However, current antiretroviral guidelines still place PI- and NNRTI-based regimens at the same level for first-line therapies. They might have to be rewritten after all this new evidence is "digested." For some patients with very specific issues it may be necessary to have them start therapy on a PI-based regimen, but clearly -- for the majority of naive patients -- NNRTI-based regimens are the most reasonable option.
However, the future may bring back PIs as first-line therapy. The growing frequency with which primary resistant NNRTI isolates are found in individuals who are naive to therapy (in some regions of the country up to 20 percent) might make it necessary to start protease inhibitors in a significant number of patients and certainly warrants using sensitivity testing in all cases prior to the initiation of therapy. And last, but not least, we are still missing a comparative trial of efavirenz vs. lopinavir, the most potent of the currently available protease inhibitors. However, I have the feeling that even if both regimens are equally potent, the high frequency of lipid abnormalities associated with the use of lopinavir will still lead most clinicians to use efavirenz as first-line therapy.
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