July 15, 2004
"Induction maintenance" is a treatment strategy that uses a more potent regimen initially and drops back to a less potent (and hopefully less toxic) regimen after the initial response. It is modeled on cancer chemotherapy, which has been established as the best approach to treating many cancers.
It is generally held that induction maintenance is not a successful HIV treatment strategy. This seems clear when the induction regimen consists of 3 drugs, and the maintenance regimen is a dual nucleoside regimen. But dropping back from a 4-drug regimen ("quad therapy") to a simpler 3-drug regimen would seem to hold promise. The quad therapy could bring a patient through the early phase of treatment faster. In theory, because there is drug present during substantial HIV replication during this phase, this is a vulnerable period for developing resistance mutations. It might be that it takes less potency to "keep HIV in the undetectability box" than it does to get it there. This would permit the use of less potent regimens, such as zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir), that also have less potential for long-term toxicity.
Past induction-maintenance trials have not, however, supported the strategy. Patients on the more potent regimen who achieve HIV undetectability are randomized to continue it or switch to the maintenance regimen. The failure of the maintenance arm may be in part due to a subtlety in the way the outcome is scored. The patient who breaks through (that is, whose HIV becomes detectable) is deemed a failure even if reintensification re-establishes HIV undetectability. But if prompt reintensification usually returns the HIV to undetectability at a low enough risk of HIV mutation, it still might be a good strategy. It could be, for instance, that 80% of patients could get to a less toxic, easier-to-take regimen with little harm done to the 20% of patients who cannot.
Zidovudine/lamivudine/abacavir recently suffered a setback when the ACTG 5095 trial deemed it generally undesirable as a starting regimen. However, that study did not establish that patients who have undetectable HIV RNA on zidovudine/lamivudine/abacavir should have their regimen changed, or that regimen reduction to zidovudine/lamivudine/abacavir alone is inappropriate.
This study is the most recent induction-maintenance trial. It speaks to the general strategy and provides useful information about zidovudine/lamivudine/abacavir as sole HIV therapy.
Details of This Study
Markowitz et al started 448 antiretroviral-naive patients on zidovudine/lamivudine/abacavir and efavirenz (EFV, Stocrin, Sustiva). After a year, 282 patients had HIV RNA <50 copies/mL and were willing to be randomized to continuing the quad therapy or switching to zidovudine/lamivudine/abacavir alone. The relatively long induction phase was chosen to deplete cellular HIV reservoirs, which may take longer than it does to achieve plasma HIV undetectability.
At the end of 96 weeks (a year after randomization), 79% of the zidovudine/lamivudine/abacavir plus efavirenz patients had HIV RNA <50 copies/mL, and 77% of the zidovudine/lamivudine/abacavir patients had HIV RNA <50 copies/mL (P = .70). Non-inferiority of the zidovudine/lamivudine/abacavir switch was established with a 95% confidence interval of -8.6% to -5.7%.
Drug-related adverse events, including fatigue and dreams, were more common in the zidovudine/lamivudine/abacavir plus efavirenz patients (15% vs. 6%). HIV resistance mutations in patients breaking through treatment in both arms were the expected M184V and K103N. Cholesterol levels were lower in the zidovudine/lamivudine/abacavir patients, and there was a trend toward better adherence in those patients (80% vs. 89%, P = .057).
Significance for Patients and Clinicians
This important study will require more revelation than a 10-minute presentation allows before we can fully assimilate it. It is unfortunate that so many patients dropped out during the induction phase, as the study lost power as a result. It is also unfortunate that adherence rates, while good, were less than zidovudine/lamivudine/abacavir may require to best gain its lower long-term toxicity benefit. Nevertheless, the study provides support for maintenance treatment with zidovudine/lamivudine/abacavir alone.
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