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More Trouble for Adefovir

April 1999

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The 2nd International Workshop on Salvage Therapy was also the setting for a complete report on ACTG 359, the first randomized and controlled large rescue therapy trial. The study enrolled 277 volunteers (17% women) who had taken indinavir for more than six months (median of 14 months). Their viral loads ranged from 2,000 to 200,000 copies/ml (median of 32,000), and their median initial CD4 count was 229/mm3. Essentially no previous treatment with other protease inhibitors, NNRTIs or adefovir was allowed. Six salvage regimens were compared over a 16 week period: Fortovase (saquinavir soft gel capsules) plus either ritonavir or nelfinavir for the protease inhibitor component and delavirdine, adefovir or the two together as reverse transcriptase inhibitors. None of the traditional nucleoside analogs were used in this trial, whose participants had extensive past use of these agents.

Overall, only 30% of participants had viral loads below 500 copies/ml after 16 weeks. There was no significant difference between nelfinavir and ritonavir as the second protease inhibitor (though the pill burden and dosing schedule was much more onerous for nelfinavir/Fortovase combination than for ritonavir/Fortovase). When looking at the effectiveness of adefovir and/or delavirdine, the investigators found that the adefovir alone performed demonstrably worse than either the delavirdine or the two together. Only about 18% of those on adefovir had viral loads below 500 copies/ml. At first glance, delavirdine seems to be a more potent agent than adefovir under the conditions of ACTG 359.

But there is more to the story: Delavirdine reduces the liver's extraction of protease inhibitors from the blood, making them more effective. Combining adefovir and delavirdine in two of the ACTG 359 regimens greatly reduced blood levels of delavirdine and the blood levels of the protease inhibitors, especially saquinavir. According to Roy Gulick, M.D., of Cornell Medical School, who presented the study at the Workshop, "Adefovir cuts the levels of delavirdine by half, and this resulted in the levels of saquinavir going down by half, too."

But the audience was not convinced that reduced delavirdine levels were the sole cause of the loss of saquinavir. The trial regimens that contained adefovir without delavirdine also yielded seriously eroded saquinavir levels and had the poorest outcomes. Several members of the audience pressed Gilead Sciences, adefovir's sponsor, to conduct further studies to detail the interactions between adefovir and protease inhibitors as well as nonnucleoside reverse transcriptase inhibitors like delavirdine.

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The trial results represent another setback for Gilead Sciences. Adefovir already has had problems with comparatively low antiviral efficacy and, especially, kidney toxicities that last year caused Gilead to halve the set dose. The company has been heading toward an FDA New Drug Application for adefovir that features the drug's use as a rescue agent. Its strong suit in this role is that 3TC-resistant HIV shows somewhat increased sensitivity to adefovir, at least initially. In another Workshop presentation, Michael Miller, Ph.D., of Gilead, argued that adefovir-containing rescue combinations should include 3TC to maintain 3TC resistance and enhance adefovir's activity. This suggestion failed to warm Workshop attendees to adefovir's potential. Workshop co-chair John Mellors, M.D., commented after Dr. Miller's presentation, "This is good hypothesis-generating data. Now we need a good controlled clinical trial." Additional trials will further retard adefovir's advance to the market, if their results don't derail it altogether.


Back to the GMHC Treatment Issues April 1999 contents page.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 
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