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Des souches cliniques de virus herpes simplex (VHS) isolees de patients atteints du SIDA et recevant une therapie au foscarnet ont ete evaluees pour leur sensibilite envers l’adefovir. Sequential herpes simplex virus (HSV) isolates from AIDS patients receiving foscarnet therapy were evaluated for their susceptibility to adefovir. Foscarnet, a pyrophosphate analogue that inhibits directly the herpes simplex virus (HSV) DNA polymerase (pol), is the primary alternative treatment for immunocompromised patients with suspected or confirmed acyclovir-resistant HSV infections [Safrin et al., 1991]. We identified previously DNA pol mutations that were associated with resistance to foscarnet in clinical HSV isolates recovered from HIV-infected subjects [Schmit and Boivin, 1999].
For the first five patients (1 to 5), sequential isolates (pre- and post-foscarnet therapy) were available.
ANP compounds are characterized by their long intracellular half-life allowing infrequent dosing and by their large spectrum of antiviral activity [Naesens et al., 1997].
Each foscarnet-resistant virus from this study contained one or two nucleotide substitutions within the conserved regions II, III, VI, and between regions I and VII of the HSV DNA pol gene [Schmit and Boivin, 1999]. Finally, this study did not allow the identification of mutations associated with a significant decrease in susceptibility to cidofovir. To our knowledge, this is the first report in which clinical HSV 1 and 2 isolates resistant to foscarnet were evaluated for their susceptibility to adefovir. Lalezari JP, Drew WL, Glutzer E, Miner D, Safrin S, Owen WF, Jr., Davidson JM, Fisher PE, Jaffe HS. Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Corey L, Drew WL, Boggs J, McGuire B, Jaffe HS, Safrin S. Safrin S, Crumpacker C, Chatis P, Davis R, Hafner R, Rush J, Kessler HA, Landry B, Mills J.
Snoeck R, Andrei G, Gerard M, Silverman A, Hedderman A, Balzarini J, Sadzot-Delvaux C, Tricot G, Clumeck N, De Clercq E. However, a significant level of toxicity may occur following prolonged intravenous foscarnet therapy. In contrast to acyclovir but similar to foscarnet, ANP derivatives do not require a virally-dependent phosphorylation step [Merta et al., 1990] with the potential to inhibit most acyclovir-resistant isolates containing thymidine kinase (TK) mutations.
We now report on susceptibility patterns to adefovir induced by viral DNA pol mutations from the same clinical isolates. Viral susceptibility of those isolates to acyclovir, foscarnet and cidofovir has been previously reported by our group [Schmit and Boivin, 1999]. Such features are particularly interesting when treating immunocompromised patients with several concomitant opportunistic viral infections. Mutations in regions II, VI, and between I and VII were also associated with a valuable decrease in adefovir susceptibility. The post-foscarnet isolate of patient 1 had a moderate (2.7-fold) increase in cidofovir IC50 value when compared to the pre-foscarnet strain. Our results demonstrate that most foscarnet-resistant clinical HSV isolates are also associated with a remarkable decrease in adefovir susceptibility.


Cidofovir-resistant HSV isolates were not selected in our patients receiving prolonged therapy with acyclovir and foscarnet. Susceptibility testing for the latter drugs and adefovir were evaluated using a plaque reduction assay [Safrin et al., 1994].
Clinical histories of the patients as well as genotypic characterization of the HSV strains have been previously reported [Schmit and Boivin, 1999]. Moreover, an oral prodrug of adefovir (adefovir dipivoxil) has been developed and is currently in phase III trial for hepatitis B virus infections [Naesens et al., 1997]. However, since this pre-foscarnet isolate also contained a TK mutation, the relevance of this observation is difficult to interpret.
Similarly, most DNA pol mutations arising from foscarnet therapy in this study did not confer resistance to acyclovir with the possible exception of DNA pol mutations located in conserved region II. Susceptibilities of several drug-resistant herpes simplex virus type 1 strains to alternative antiviral compounds.
Differential susceptibility of several drug-resistant strains of herpes simplex virus type 2 to various antiviral compounds. Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene.
Characterization of drug resistance-associated mutations in the human cytomegalovirus DNA polymerase gene by using recombinant mutant viruses generated from overlapping DNA fragments. Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir.
Herpes simplex virus-specified DNA polymerase is the target for the antiviral action of 9-(2-phosphonylmethoxyethyl)adenine.
Identification of amino acids in herpes simplex virus DNA polymerase involved in substrate and drug recognition.
A point mutation within a distinct conserved region of the herpes simplex virus DNA polymerase gene confers drug resistance. Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. Successful treatment of an acyclovir- and foscarnet-resistant herpes simplex virus type 1 lesion with intravenous cidofovir. Biochemical basis for increased susceptibility to cidofovir of herpes simplex viruses with altered or deficient thymidine kinase activity.
Phosphorylation of acyclic nucleotide analogs HPMPA and PMEA in L1210 mouse leukemia cell extracts.
HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. A controlled trial comparing foscarnet with vidarabine for acyclovir- resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome.


Characterization of the DNA polymerase and thymidine kinase genes of herpes simplex virus isolates from AIDS patients in whom acyclovir and foscarnet therapy sequentially failed.
Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3- hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Properties of a 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-resistant herpes simplex virus type 1 virus mutant. Thus, development of new anti-HSV agents with different mechanisms of action is of high interest.
Ten wild type (wt) (five HSV 1 and five HSV 2) isolates from untreated immunocompetent subjects, and two control strains (MS2 and KOS) were also tested for their susceptibility to the different antivirals. Table I summarizes the mean IC50 values (from three different experiments) to acyclovir, foscarnet, cidofovir, and adefovir for all isolates.
However, further experiments using recombinant viruses are needed to confirm this observation.
Indeed, HSV mutants with deficient or altered TK activity have been reported to be more susceptible to cidofovir in tissue culture than parental strains, probably due to a decreased dCTP pool in infected cells [Mendel et al., 1995].
In conclusion, adefovir would not constitute a valuable alternative treatment for immunocompromised patients developing HSV infections resistant to foscarnet therapy. Characterization of drug-resistant viruses and determination of their patterns of cross-resistance may be useful to clarify the selective mechanism of action for new drugs and may facilitate the management of drug-resistant HSV infections in the clinic. All pre-foscarnet isolates from this study contained a TK mutation responsible for acyclovir resistance [Schmit and Boivin, 1999] and these isolates were indeed found to be slightly more susceptible to cidofovir than wt isolates by a factor of 1.8.
Only the foscarnet-resistant isolate from patient 6 was definitively still susceptible to adefovir (1.2-fold adefovir IC50 increase) whereas the post-foscarnet isolate from patient 4 was associated with a modest decrease in adefovir susceptibility (2-fold IC50 increase). Moreover, foscarnet- and adefovir-resistant isolates were generally more susceptible to cidofovir than wt isolates by a factor of 2.2. On the other hand, susceptibility of foscarnet-resistant isolates to cidofovir was generally unchanged although one isolate from patient 1 had a 2.7-fold increase in cidofovir IC50 value compared with its foscarnet-susceptible counterpart. The availability of wt TK-competent and post-treatment strains isolated from the same patients will thus be important to evaluate more precisely the patterns of resistance to cidofovir. The specific point mutations within the viral DNA pol gene of foscarnet-resistant HSV isolates [Schmit and Boivin, 1999] and the resulting drug phenotypes are summarized in table I.
The only isolate with high level resistance to acyclovir (patient 5) also contained a TK mutation [Schmit and Boivin, 1999].




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