July 14, 2003
There continues to be a large number of studies describing switches among patients who are well suppressed on protease inhibitor (PI)-based regimens (see discussion of Poster 543). These studies fall into two groups. The first selects patients based on side effects -- most often elevated lipids, but some include lipodystrophy/lipoatrophy. The second type takes all comers. The studies are most often observational or single armed. The most useful, such as the NEFA study, randomize patients to different switch studies.
There are now four drugs that are the focus of switch studies: nevirapine (NVP, Viramune), efavirenz (EFV, Sustiva), abacavir (ABC or ABV, Ziagen) and, most recently, atazanavir (ATV, Reyataz). This study focuses on nevirapine and confirms the efficacy and beneficial lipid effects of switching.
This study from Madrid was a prospective observation of a group of patients successfully suppressed on PI-based therapy who switched to nevirapine-based therapy for clinical reasons. The most common reason was treatment simplification (43 percent) followed by lipid abnormalities or lipodystrophy (32.5 percent) and kidney abnormalities (24.5 percent).
One hundred and ten patients were enrolled; about half were treatment naive when they started their PI-based regimen. Nine were lost to follow-up. Slightly more than 91 percent maintained viral load suppression below the limits of detection. CD4 counts continued to increase, averaging almost 150 cells/mL. The drops in cholesterol and triglycerides were impressive. Mean cholesterol decreased from 306 mg/dL to 230 and mean triglycerides from 1390 to 470. Kidney function improved, predominantly among patients who had been on indinavir (IDV, Crixivan). Nevirapine side effects were seen in 16 patients.
The impressive size of the drop in cholesterol was somewhat greater than in other nevirapine-switching studies and substantially greater than in most other switching studies. Reasons for this include selecting for patients with significant PI-induced worsening who might have been expected to benefit and the longer than average follow-up. Follow-up was longer than 30 months for 68 patients.
Still, this study confirms findings from a number of other studies focusing on switching from PIs to non-nucleosides, and extends the follow-up to show that the benefits are lasting. In fact, in another study (Poster 591), a group from a different Madrid hospital presented the results from a non-randomized study of switching from a PI to a once-daily regimen of ddI (didanosine, Videx), 3TC (lamivudine, Epivir) and either nevirapine or efavirenz. The primary purpose of this study was to show that simplification improved adherence and that, once again, the switch strategy to non-nucleoside-based regimens was effective at maintaining viral load suppression and improving adherence.
Taking all of the switch studies together, a few generalizations can be made. In general, switching maintains viral suppression in most patients, with most regimens, in the range of 90 percent after one year. The worst results were when simplifying to Trizivir (AZT + 3TC + ABV) among patients with prior nucleoside therapy. That approach is best avoided, but Trizivir switching was effective for those who had been on their first PI-based regimen. All of the strategies pursued have resulted in lower cholesterol and lipid levels. There are few head-to-head, well-controlled comparisons, but it appears that the lipid benefits are best with nevirapine, if one looks at both total cholesterol and HDL cholesterol, but efavirenz fares very well, and the choice can be individualized. Switching to atazanavir is also effective, but more studies need to be done.
Simple, well-tolerated regimens clearly improve the experience of people on therapy. The still unanswered question is whether it is better to start with a very potent regimen with a high genetic barrier -- such as a PI-based regimen -- and then simplify if lipid or fat problems develop? Or is it preferable to start initially with a non-nucleoside regimen. Stay tuned for some trials over the next few years to try and answer these long-term strategy questions. In the meantime, it will give the experts, the traveling speakers and the marketers food for some interesting debates.
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