The recently held Conference on Retroviruses and Opportunistic Infections was a disappointment in terms of the amount of information presented on new nucleosides. This may have been due, in part, to toxicity problems relating to a number of products that are or were in various stages of pre-clinical and clinical development.

One drug which did receive reasonable attention is DAPD, a novel dioxolane guanosine analog that is deaminated in vivoby cellular adenosine deaminase to yield DXG. Both DAPD triphosphate and DXG triphosphate are potent chain terminators of HIV reverse transcriptase (RT). DAPD, when administered as monotherapy, seems to be safe and to possess excellent pharmacokinetics over a 14-day period during which plasma concentrations of both DAPD and DXG could be easily detected (Abstract 103). Furthermore, DAPD did not select for altered genotypes in 18 subjects who participated in this study. Drops in viral load of between 0.45 and 1.45 log₁₀ copies/mL were recorded in a dose-ranging study in which bid dosing with DAPD ranged between 25-300 mg (Abstract 668).

Another new drug that was reported on is tenofovir disoproxil fumarate (DF; formerly PMPA prodrug), which was studied in treatment-experienced patients in a placebo-controlled, double-blind dose-ranging trial in the context of stable background antiretroviral therapy (Abstract 740). The results of viral load testing showed reductions between 0.40-0.75 log₁₀ copies/mL over 24 weeks. Mutations occurring in the RT gene may have been related to the patients' drug history, since many of these individuals developed (or had at baseline) either a variety of thymidine analog-associated substitutions or the K65R, M184V, or L74V substitutions. These individuals had previously taken ddI, 3TC, abacavir, AZT, and/or d4T. Further analysis will be required to determine whether tenofovir DF can directly select for the K65R mutation in vivo, as it has been shown to do in tissue culture studies.

One additional compound that was studied is 3'-fluoro-3'-deoxythymidine (FLT), which was tested in vitroagainst a variety of drug-resistant mutated HIV-1 strains (Abstract 742). Viruses that possessed resistance to AZT remained sensitive to FLT and selection for resistance to FLT using wild-type virus occurred very slowly and did not reach high levels. FLT also retained activity against viruses containing any of the 151M, 184V, and 210W substitutions and against viruses containing either insertions or deletions in the fingers region of RT, which have been associated with multiple drug resistance. These findings establish a rationale for the possible use of FLT in salvage therapy regimens. Although FLT, like AZT, is a thymidine analog, its success in these studies may relate to its novel structure.

Finally, a number of alkylglycerol analogs of forscarnet (PFA) were shown to be more active than PFA in vitroand one of these, MB-PFA was highly synergistic with AZT in tissue culture studies (Abstract 666). Interestingly, these analogs seem to be well absorbed when given orally to animals. Two of these compounds, MB-PFA and EB-PFA, were active against viruses that displayed resistance to AZT, 3TC, and a variety of NNRTIs, but had less potency against viruses containing the K65R substitution, which also encodes resistance to PFA. These drugs may therefore have important roles in future salvage regimens for the treatment of HIV disease.