July 9, 2002
When comparing initial therapies with highly active therapy, there are several types of questions that can be asked. Most studies focus on which drug is most effective and best tolerated as the third drug, the role usually filled by a protease inhibitor or an NNRTI. Some look at the so-called backbone of nucleosides. Very few studies ask the important question of what will work the best, not during the initial one year, but over the long term and includes who will do best when second-line therapy is used. Since the object of treatment is to help people live well for decades, not months, these trials are the ones that are beginning to get at these key questions. The Atlantic study was one of the first of these studies. A new crop is underway and beginning to give results.
John Bartlett from Duke presented early results (48 weeks) from the CLASS study, a study of sequencing in patients starting their first regimen. The CLASS study is unusual in several ways. It uses an unusual backbone of abacavir (Ziagen) and 3TC (Epivir). It initially compares three different types of regimens -- an NNRTI-based with efavirenz (Sustiva) (ABC/3TC/EFV), a boosted protease regimen using amprenavir (Agenerase)/ritonavir (ABC/3TC/APV/r) and a triple nucleoside regimen using stavudine (d4T, Zerit) (ABC/3TC/d4T). Perhaps most important is that it is a strategy or sequencing trial, where patients who have initial failure are switched to a preplanned regimen and followed for at least two years. The so-called primary endpoint is the number of patients with undetectable viral loads (less than 400) at two years. Additional studies will look at lipid and body shape changes.
These early results are more conventional, but interesting. About 300 patients in multiple countries entered the trial. At entry, the median viral load was just under five log or 100,000 copies and the median CD4+ count was about 300. Thus, the patients are representative of the typical person who would start with today's guidelines.
The proportion of patients with less than 400 copies by intent-to-treat analysis on the original regimen was highest in the efavirenz arm (90 percent vs. 80 percent for the PI regimen vs. 81 percent on the triple nucleoside). Because this study really aimed to ask who was doing best whether they were on the first or second regimen, an important analysis is the proportion with less than 50 copies regardless of regimen (ITT observed) -- once again efavirenz was favored (93 percent vs. 73 percent vs. 73 percent). The triple nucleoside regimen was the best tolerated, amprenavir/ritonavir the least well, perhaps due to the use of ritonavir and the current Agenerase formulation. Central nervous system side effects were the primary problem with efavirenz. Hypersensitivity reactions occurred in 6 percent.
As in several previous studies, the NNRTI-containing regimen for initial therapy was as least as effective as other approaches with better tolerability. The main concern remains the issue of whether the usefulness of NNRTIs for salvage therapy means they should be saved for later regimens. This study will not answer that question.
The use of the new "backbone" was very effective and well tolerated, and may become popular if it proves to avoid the resistance problems and mitochondrial problems that can emerge after long term use of AZT and d4T, both thymidine analogues. Fat wasting may at least in part be related to long-term use of thymidine.
The most important results of this trial will come in another year, as the long term outcome and the response to switching are reported. Long-term examination of resistance, body shape changes, and lipids will add a great deal. Similar strategy trials are underway with other regimens, including the large ACTG 384 trial.
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