September 15, 2003
How can we construct the best, most potent drug regimens for the treatment of HIV? Conventional approaches utilize three-drug regimens that employ two nucleoside reverse transcriptase (NRTI) medications with one other drug -- either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). This two + one approach has dominated therapy since the beginning of the HAART era.
In the search for more and more potent regimens, some researchers have proposed that the addition of a fourth medication to the three-drug regimens might increase treatment potency and lessen the risk of treatment failure and the emergence of drug resistance. This has become important given the general observation that people with very low CD4 cell counts or extremely high viral loads are at greater risk of treatment failure than those with "healthier" numbers.
One approach under exploration is to add an additional NRTI -- a four-drug, or quad approach. The combination triple-nucleoside pill, Trizivir (AZT/3TC/abacavir), permits the simple addition of the third nuke, which is easy from a dosing-restriction and pill-count standpoint -- hence the quad regimen of Trizivir/efavirenz (EFV, Sustiva) could be a twice-daily, low pill-count regimen.
Trizivir/efavirenz was the treatment regimen given to the 55 treatment-naive British patients in this GlaxoSmithKline-sponsored clinical study. The study was open-label (meaning that everyone knew what the patients were taking) and non-comparative (meaning that all the patients took this regimen, there was no other treatment comparison). Importantly, many persons who had the very risk factors for poor response, namely low CD4 count or extremely high viral loads, were included in the study: the average CD4 count of the participants was only 54 and the average viral load was over 250,000.
Patients who did not tolerate efavirenz could have this drug replaced with a different non-nuke -- nevirapine (NFV, Viramune). Such switches were analyzed separately.
After 48 weeks (a research study "year"), over 80 percent of the subjects achieved viral loads less than 50 copies -- a very impressive response rate in this very ill group of patients. If one considers that a switch from efavirenz to nevirapine was a treatment failure, then only 53 percent of the patients had treatment success (indicating that a fair number of these research subjects didn't tolerate efavirenz well). There was also a dramatic ~200 CD4 cell increase over the study period. Three patients (5 percent) withdrew from the study because of abacavir (ABC, Ziagen) hypersensitivity (allergic) reactions. Five others withdrew due to other side effects. There were only small changes in levels of blood cholesterol and triglycerides (lipids).
This study shows that a simple four-drug regimen has significant potency in a people with advanced AIDS. Previous studies in healthier HIV-infected individuals showed similar, encouraging results. This is the first study to examine the role of the Trizivir/efavirenz quad regimen in such ill patients.
Taken together, this and other studies provide the beginnings of support for a strategy of quad-drug therapy for HIV. This study shows that the regimen can be very effective even in patients who are very sick.
This is terrific news for the newly diagnosed who discover that their first CD4 and viral load counts are terrible. There are simple and generally well-tolerated regimens they can use that will still work.
The unanswered question for this group of patients is whether the three- or four-drug regimen is better, and what exactly might be the best combination to use. Would a boosted protease inhibitor work better, as some have suggested? We just don't have this data yet. The ongoing study from the AIDS Clinical Trials Group (ACTG) called 5095 should shed additional light on this question, since it compares the three-drug (Combivir/efavirenz) to the four-drug regimen of Trizivir/efavirenz -- permitting a direct comparison of three drugs versus four. While we try to practice medicine using the best proven science, sometimes clinical medicine forces our hand -- having these clinical trial results gives us scientifically validated support for using the potentially more potent quad regimens for the persons who we worry about the most.
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