July 14, 2003
Induction maintenance is a simple concept that theoretically makes a great deal of sense. The idea is to start therapy with an extremely potent regimen when the patient's viral load is high but his/her immune control of HIV may be low and very few naturally occurring resistance mutations are likely to be present -- the induction phase. Then, when the patient's viral load has been suppressed, HIV reservoirs have been decreased and immune function has improved, it might be possible to control the virus with a simpler regimen -- the maintenance phase. As we have learned more about the potential risks of long-term therapy (high lipids, lipodystrophy, etc.), it has become more attractive to consider simpler maintenance regimens.
There are several practical problems however. It is unclear how long the induction phase should last or what the measure of success should be before switching to maintenance. It is also unclear what would make the best induction regimen -- use NNRTIs for their potency and tolerability but low genetic barrier, or use protease inhibitors (PIs) with their high genetic barrier. In addition, it is uncertain how much is "enough" for maintenance therapy. To date, studies of induction maintenance have tested going from three drugs to one or two and failed to maintain control (Trilege, ACTG 343), or have used poorly tolerated regimens (Trizivir [abacavir + 3TC + AZT] plus amprenavir [APV, Agenerase]).
ESS40013 is a study that should help add some clarity to these questions. The study design is straightforward. Antiretroviral-naive patients with more than 5,000 copies/mL of HIV RNA are treated with Trizivir and efavirenz (EFV, Sustiva). This four-drug regimen requires only three pills a day. If patients are suppressed for one year and their viral loads remain below 50 copies/mL, they will be randomized to a simplified regimen of Trizivir, or stay on the four-drug regimen.
At this meeting, results were only presented on the induction phase. Thus, it was a chance to see whether the four-drug regimen was successful and well tolerated.
The study has enrolled 448 patients, most with fairly advanced disease. The median viral load was greater than 100,000 copies/mL and the CD4 count was 210 cells/mm3. About 12 percent of the enrolled patients have dropped out for adverse events, 5 percent for viral failure and 20 percent for a variety of reasons. By strict intent-to-treat (ITT) analysis, 61 percent had less than 50 copies/mL at one year, and the response was not different among those with higher viral loads or lower CD4 cell counts. Side effects were what would be expected with these drugs: 7 percent had hypersensitivity reaction, 6 percent had rash, and efavirenz-associated neurological symptoms were common but tended not to be severe. Nevirapine (NVP, Viramune) could be substituted if efavirenz-associated symptoms persisted.
So where does this leave us? It does not yet tell us anything about maintenance. We will have to wait another year for that. The regimen was effective and well tolerated, but the ITT results are not as good as in some trials of three-drug regimens. This may be due to waning interest in the trial as much as anything else, or the increased availability of treatment outside of the study. Luckily, enough people are continuing on in the study that we will hopefully learn whether the maintenance strategy can work. I still hold out hope for the strategy, but we have yet to see proof that it works.
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