2.4.1. AdefovirDipivoxil (PMEA, PTeveonTM)
Adefovir is a nucleotide analogue with activity against a broad spectrum ofretroviruses and herpes simplex virus 1 and 2, cytomegalovirus, and HIV-1 and HIV-2. It is a potent inhibitor of retroviral reverse transcriptase. The active metabolite, which is adefovir diphosphate, inhibits HIV reverse transcriptase and terminates the growing DNA chain, specifically replacing deoxy-adenosine triphosphate.35 A double-blind, randomized, placebo-controlled study in adults is evaluating the effect of treatment on viral load and CD4 count in adults when adefovir dipivoxil is added to an existing regimen of highly treatment-experienced patients. Enrollment was closed in May 1997 with 442 patients. A prospective virology cohort of 142 of the 442 patients enrolled in the study was analyzed to determine the effect of baseline genotype on the reduction of HIV RNA at 24 weeks. The baseline characteristics and prior treatment experience of the virology cohort was consistent with those of the overall trial. Upon entering the trial more than 90% of the patients were zidovudine-experienced, almost 80% were lamivudine-experienced, and approximately 65% were stavudine-experienced. What is interesting about these results is that at 24 weeks, the lamivudine-associated M184V mutation appears to confer greater susceptibility to adefovir di-pivoxil than wild-type strains. A trial is currently underway which is assessing adefovir dipivoxil in children, ages 3 months to 16 years, using two dose levels in combination with nelfinavir and an NRTI. There appears to be adefovir dipivoxil-related nephrotoxicity characterized by type II renal tubular acidosis with phosphate wasting, requiring regular monitoring of serum phosphate and renal function. The use of adefovir dipivoxil as a treatment option for protease inhibitor failures is being evaluated.
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