December 18, 2001
In the area of treatment interruption, the area with the greatest promise for immunologic (as opposed to cost and toxicity) benefit is in applying this strategy to those with acute HIV infection. As shown by Drs. Rosenberg and Walker, treatment of patients with acute HIV infection appears to preserve their HIV-specific CD4 responses, and some of these patients have been able to remain off therapy now for a prolonged period of time after a variable number of treatment interruptions. This clinical study from Spain reviews preliminary experience with structured treatment interruption in a group of recently infected patients.
The study design calls for 14 such patients to receive d4T, 3TC, and indinavir for 12 months, followed by four treatment interruption cycles consisting of two months off treatment followed by two to four months on treatment. Only those patients with an HIV RNA <20 copies, a CD4 cell count >500, and a normal CD4:CD8 ratio are eligible. After the four cycles of treatment, those with CD4 cell counts >500 and an HIV RNA <5,000 are to remain off treatment.
Thus far, 12 patients (10 men, 2 women) have been enrolled, none with genotypic resistance to antiretroviral agents. Importantly, most of the patients were diagnosed after resolution of symptoms of acute HIV, and after seroconversion, with a mean time from acute HIV symptoms to starting antiretroviral therapy of nine weeks. As a result, while the mean viral load was relatively high at 286,306 copies/mL, there was a wide range, as clearly some of the patients had already begun to reach their virologic set point prior to starting therapy.
Perhaps due to the relatively late treatment of these newly-infected patients compared with those in the Rosenberg study, these patients did not achieve as strong an HIV-proliferative CD4 response. Cessation of therapy was associated with a viral load rebound to on average 4.89 log on first cessation, and 3.89 on the second. Both treatment interruptions also led to significant declines in CD4 cell counts (296 and 93 cells, respectively), although since these patients all started with high CD4 cell counts, they were in no danger of opportunistic infections. Four patients had virologic rebounds that were <5,000 copies/mL, yet based on the protocol they resumed therapy, at least for now.
Stopping treatment also led to a strengthening of the HIV-specific CD8 T-cell response, and a diminution of the CD4 T-cell response -- findings previously reported elsewhere. No resistance mutations have emerged during the study, and patients resuming therapy had a quick virologic response with no treatment failures.
While the results presented here are preliminary, they raise the question of the goals of these treatment strategies. Is it to improve the immunologic profile of patients on treatment? Or is it simply to reduce overall drug exposure, thereby reducing cost and toxicity? If the latter, patients treated soon after acquiring HIV may well benefit the most from intermittent therapy simply because they have high enough CD4 cell counts to withstand the inevitable declines that occur off treatment. Such a "pulse" therapy strategy, while immunologically less exciting than concepts such as "autoimmunization," is being investigated in multiple other studies.
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