Foscarnet Therapy for Ganciclovir-Resistant Cytomegalovirus Retinitis in Patients with AIDS

Abstract

Infections caused by cytomegalovirus (CMV) resistant in vitro to ganciclovir, defined as requiring greater than 6 mumols of ganciclovir for ED50 have developed in some AIDS patients with progressive CMV retinitis despite chronic ganciclovir therapy. Two such patients (CMV isolates ED50, 9.5-14.5 mumols) were treated with foscarnet, an antiviral pyrophosphate analogue to which both patients' isolates demonstrated in vitro susceptibility (ED50, less than or equal to 300 mumols). Each patient had documented retinitis progression, at 2- and 1- to 5-week intervals, respectively, despite high-dose intravenous ganciclovir therapy. Both patients responded to foscarnet therapy with cessation of viral shedding in urine and blood. After foscarnet therapy was started, retinitis stabilized in the two patients for 12 and 25 weeks, respectively, before progression recurred. Therefore, foscarnet may be effective in immunocompromised patients with rapidly progressive CMV retinitis whose CMV isolates have developed in vitro resistance to ganciclovir.

Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis after stem cell transplantation: effective monitoring of CMV infection by quantitative analysis of CMV mRNA

“…However, refractory CMV disease has been reported in association with isolation of ganciclovir-resistant CMV strains. [1][2][3][4] Mutations in CMV UL97 phosphotransferase have been observed in ෂ90% of ganciclovirresistant clinical CMV isolates. 12,13 Since foscarnet is a pyrophosphate analog that does not require phosphorylation for its activity, 5 resistance to foscarnet is not expected to result from mutations in UL97.…”

“…However, the development of resistance to ganciclovir has been reported. [1][2][3][4] Foscarnet (trisodium phosphonoformate, PFA), a pyrophosphate analog, 5 has been used in patients with AIDS, and allogeneic SCT recipients. Because the viral inhibitory mechanism of foscarnet is distinct from that of ganciclovir, foscarnet might be useful in patients with ganciclovir-resistant CMV infection.…”

“…Because the viral inhibitory mechanism of foscarnet is distinct from that of ganciclovir, foscarnet might be useful in patients with ganciclovir-resistant CMV infection. 2,4,6 It usually takes 2 weeks for retinitis to heal on intravenous ganciclovir or foscarnet.…”

In vitro selection of novel RNA ligands that bind human cytomegalovirus and block viral infection

“…Human cytomegalovirus (HCMV) is a ubiquitous herpes virus that causes mild or subclinical diseases in immunocompetent adults but may lead to severe morbidity or mortality in neonates and immunocompromised individuals (Britt & Alford, 1996;Mocarski, 1996)+ Infection by this virus accounts for one of the most common opportunistic diseases (i+e+, CMV retinitis) encountered by AIDS patients+ Very few effective drugs (e+g+, ganciclovir) are currently available and the emergence of drug-resistant strains of HCMV has created a need for the development of new drugs and novel treatment strategies (Jacobson et al+, 1991;Palestine et al+, 1991)+ In vitro selection or SELEX (systematic evolution of ligands by exponential enrichment) procedures (Ellington & Szostak, 1990;Tuerk & Gold, 1990;Joyce, 1992) have been used to isolate oligonucleotide molecules (aptamers) with high affinity to a wide variety of lowmolecular-weight targets and large complexes such as red blood cell membranes (Ellington & Szostak, 1992;Gold et al+, 1995Gold et al+, , 1997Pan et al+, 1995;Morris et al+, 1998;Yang et al+, 1998;Homann & Goringer, 1999)+ This approach has also been used to select RNA aptamers to bind to Rous sarcoma virus (RSV) and African trypanosome, and RNA ligands that inhibited RSV infection were isolated (Pan et al+, 1995;Homann & Goringer, 1999)+ In these procedures, single-stranded oligonucleotide molecules that exhibited the highest affinity to a target were selected from a pool of randomized sequences by reiterative cycles of selection and amplification+ In this study, we employed a modified in vitro selection procedure to isolate ribonucleaseresistant RNA ligands that tightly bind to HCMV infectious particles+ The selected ligands exhibited high HCMV-binding affinity in vitro and effectively inhibited viral infection in tissue culture+ Two of the ligands appeared to block viral entry by interacting with viral surface glycoproteins+ Our study demonstrates the feasibility of using these RNA ligands as a research tool to identify HCMV proteins essential for infectivity and as an antiviral agent to block HCMV infection+ rimidine nucleotides, selection experiments in vitro for the modified RNA molecules that bind to infectious HCMV, and purification and amplification of the selected sequences+ The viral particles were isolated from HCMV-infected human foreskin fibroblasts (HFFs) by gradient ultracentrifugation as described previously (Irmiere & Gibson, 1985;Chen et al+, 1999)+ The infectivity of the purified HCMV was evaluated by titering the particles in human fibroblasts and the intactness of their structures was examined first by obtaining negative staining ima...…”

Intracellular Metabolism of 3′-Azido-3′-Deoxythymidine in the Presence of Ganciclovir or Foscarnet

“…PFA is a pyrophosphate analogue Which directly inhibits the DNA polymerase enzyme from CMV and the reverse transcriptase enzyme of the human immunodeficiency virus (HIV) (Helgstrand et aI., 1978;Oberg 1983;Fletcher et el., 1994;Wagstaff and Bryson, 1994). Both of these drugs are effective antiviral agents and have been used as sole (Collaborative DHPG treatment study group, 1986;Masur et el., 1986;Harris and Mathalone, 1987;Laskin et et., 1987;Palestine et el., 1991;Jacobson et et., 1993;Wagstaff and Bryson, 1994), alternating (Aweeka et el., 1989;Jacobson et et., 1991;Jacobson et et., 1994a) and combination (Jacobson et el., 1994b) therapies for the treatment of CMV infection in AIDS patients.…”