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The Body PRO Covers: The XIV International AIDS Conference

Strategies to Prevent Loss of CD4+ and Onset of Resistance During Treatment Interruptions

July 11, 2002

  • Strategies to Prevent Loss of CD4+ and Onset of Resistance During Treatment Interruptions (LbPeB9025)
    Authored by Franco Lori, Renato Maserati, Andrea Foli, Lina Tomasoni, Marco Migliorino, Franco Maggiolo, Angelo Pan, Stefania Paolucci, Carmine Tinelli, Richard D'Aquila, Julianna Lisziewicz
    View the original abstract


Use of hydroxyurea (HU) as an adjunct to antiretroviral therapy has declined due to concerns over toxicity, especially when given with ddI. However, some interest in its use remains, both as a means of increasing drug potency and potentially reducing CD4+ activation, therefore protecting vulnerable CD4+ cells from HIV-related elimination. This study looks at a hydroxyurea-containing regimen as part of a treatment interruption strategy.

Beginning in September 2000, 60 antiretroviral-naive HIV-infected patients were randomized to receive either a standard triple-therapy regimen of ddI/d4T/indinavir or to ddI/d4T/hydroxyurea. After 12 weeks of treatment, a second randomization occurred, either to continuous therapy for an additional 24 weeks or to an STI arm consisting of three-weeks-on three-weeks-off therapy. At the end of 36 weeks, all medications were discontinued.

Viral load reductions were similar in both arms, with declines in HIV RNA of 2.89 and 2.73 log for the indinavir and hydroxyurea arms, respectively. As has been reported previously, the hydroxyurea-treated arm experienced a blunting of the CD4+ response; the continuous indinavir arm had an increase of over 128 cells, while continuous hydroxyurea had a fall of 5 cells, a statistically significant difference.

During the treatment interruptions, the indinavir-treated patients experienced the typical rise in viral load and fall in CD4+ cell counts that have been seen in numerous prior studies. In the hydroxyurea interruption group, however, there was an unusual pattern of virologic rebound during interruptions accompanied by a smooth, constant increase in CD4+ cells, leading to a gain of 110 cells by week 36.

After all therapy was discontinued, there was a sharp rebound of viral load and fall in CD4+ for all treatment arms that occurred three weeks post cessation. A resistance analysis found only one patient (treated with continuous indinavir) developed an important new resistance mutation, and this subject had three resistance mutations at baseline. In this short study, there were no significant differences in toxicity between the study arms, although there were two cases of neuropathy and one of pancreatitis in the hydroxyurea group.

As part of a strategy of treatment interruption, considerable excitement with the use of hydroxyurea originally arose from the widely reported "Berlin patient," who maintained virologic suppression despite coming off medications after being treated with a combination of indinavir, ddI, and hydroxyurea during acute HIV infection. Here, the paradoxical rise of CD4+ cells during treatment interruptions in the hydroxyurea arm partially offsets the suppressive effect of hydroxyurea during therapy, and confirms that hydroxyurea is immunologically and/or virologically active in ways that differ from typical antiretroviral therapy. However, given the proven excess toxicity seen in other published trials and cohort studies, the use of hydroxyurea should be limited to the research setting.


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This article was provided by TheBodyPRO.com. It is a part of the publication The XIV International AIDS Conference.
 



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