GMHC Treatment Issues, Vol. 10, No. 2; February 1996
Theo Smart

Adefovir (and PMPA, a new derivative now entering clinical studies -- see December's Treatment Issues, page 3) is a nucleotide analog that is similar to nucleoside analogs such as ddI but does not need to undergo as much processing within cells to become active.

Both nucleotide and nucleoside analogs attack reverse transcriptase, so HIV resistance can cover drugs in both classes at once. In particular, HIV mutations that confer a ten-fold loss of susceptibility to adefovir in the test tube also reduce susceptibility to ddI and ddC by four fold and to 3TC by 40 fold. These laboratory derived mutations have not been observed yet in any patients treated with adefovir.

Data from a twelve week placebo-controlled study of adefovir, at 125 or 250 mg per day, were presented during the Retrovirus Conference. Both doses reduced viral load by 70 percent, (roughly equivalent to the effect of AZT), and viral load rebounded when treatment stopped. The CD4 cell response was greater on the lower dose, a boost of 57 versus 27 for the high dose. CD4 counts decreased by 41 in those on placebo. Side effects, mostly nausea and diarrhea, happened more frequently in the high-dose arm.

Researchers at one study site found that adefovir treatment reduced levels of CMV in the semen by more than 50 percent in four out of seven patients. In test tube studies, adefovir is as active against CMV as ganciclovir, while it is much more bioavailable in people than oral ganciclovir. Gilead Sciences plans to look at adefovir both for HIV and CMV in upcoming large phase 3 studies.

Ironically, broad spectrum antiviral drugs like adefovir are a cause of concern for some researchers. They fear that those who take drugs like adefovir for HIV disease risk developing breakthrough CMV infections cross-resistant to adefovir and other CMV medications as well. As of yet, there is no data on whether CMV can evolve resistance to adefovir, but it would be surprising if it could not, especially should the drug enter widespread use. If CMV-resistance to adefovir confers cross-resistance to the other CMV treatments, it might be best to limit CMV's exposure to the drug by reserving adefovir for those needing CMV prophylaxis.

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