A number of observers were puzzled when the FDA recently decided to deny conditional approval of adefovir for treatment of HIV disease due to considerations of toxicity. While no one will dispute that adefovir is a drug with complex and potentially dangerous manifestations, including nephrotoxicity, it is also true that this compound may be able to act effectively in salvage regimens for individuals who have failed all other forms of antiretroviral medication. This may be due in part to the enhanced antiviral activity that adefovir displays against 3TC-resistant HIV variants containing the 184V mutation in RT. In this context, a number of studies have shown that patient responsiveness to adefovir-containing regimens may be more pronounced if the 184V mutation is present as a consequence of 3TC selection pressure. The question is now whether the manufacturer, Gilead Pharmaceuticals, will continue to make adefovir available on an expanded access basis to patients who have few or no alternatives.

The company has understandably been placed in a difficult situation. They would, of course, articulate that adefovir should have been given conditional approval based on the above mentioned considerations. On the other hand, the FDA concern that limited approval of adefovir might lead to inappropriate usage under conditions that did not comply with the conditions of approval, e.g., in patients with earlier stage disease and patients not yet exposed to a full complement of alternative HIV therapies, seems well founded. Clearly, the FDA decided that the potential for toxicity in the latter groups outweighs any potential advantages that adefovir might confer to patients in need of a novel salvage regimen. Of course, the entire issue may became irrelevant, in the event that Gilead succeeds with the development of tenofovir (PMPA), a compound that is structurally similar to adefovir and which has a similar resistance profile in pre-clinical studies. Tenofovir holds the promise of being much less toxic than adefovir. Should this be shown to be the case, then tenofovir may be useful in salvage regimens in much the same fashion as adefovir is now, while its lower toxicity would render it suitable for therapy on a much broader basis, including treatment of previously drug-naive HIV-infected individuals.