Adefovir Dipivoxil (bis-POM PMEA), an oral prodrug of adefovir (PMEA), a nucleotide analogue with inhibitory activity against HIV and various herpes viruses (HSV, CMV) and hepatitis B is presently being studied in several large Phase II-III clinical trials. One of the pivotal trials sponsored by the manufacturers of adefovir, Gilead Sciences is comparing the drug to placebo in antiretroviral experienced patients with HIV infection with CD4 counts > 200 cells/mm3. Preliminary data on the genotypic resistance patterns of HIV-1 variants isolated from 38 patients who have completed 6 months or longer of adefovir therapy was presented at the 4th National Conference on Human Retroviruses and Opportunistic Infections in Washington, D.C. In vitro studies had demonstrated that a K65R or K70E HIV reverse transcriptase mutation could be selected in the presence of adefovir which confers approximately a 10 fold decrease in susceptibility. The median viral load reduction during the first 6 months of adefovir therapy was 0.6 logs. During the initial 12 weeks of therapy, none of 20 patients who received 125 mg of adefovir monotherapy developed codon mutations which confer resistance to adefovir. Of 16 patients analyzed after another 6 months of adefovir maintenance therapy however, RT mutations were observed in only 5 patients. Four of these patients were receiving concomitant therapy and had a decrease in HIV RNA of greater or equal to 0.5 logs. During the 12 weeks of monotherapy 5 of 20 patients who had AZT-resistance mutations at codons 41 or 215 showed no decrease in viral RNA. However 4 of 5 patients with AZT resistance mutations showed a 0.5 log reduction in RNA during the 6 month maintenance phase of the study, including one patient who was not receiving concomitant antiretroviral therapy. These data suggest that HIV codon mutations associated with adefovir dipivoxil resistance do not arise readily during prolonged therapy and that the drug may be active in patients who have prior resistance to other nucleoside analogues. The main side effects of adefovir, which occurs rarely is hepatic inflammation. A large clinical endpoint trial exploring the potential benefit of adefovir in an advanced population of AIDS patients with CD4 counts < 100 cells/mm3 is being conducted by the Community Program for Clinical Research on AIDS (CPCRA). This trial will explore the potential beneficial effects of adefovir on HIV disease progression and preventive effects against cytomegalovirus.