Foscarnet in the Treatment of Cytomegalovirus Retinitis in Acquired Immune Deficiency Syndrome

LeHoang, Phuc; Girard, B.; Robinet, M; Marcel, Patricia; Zazoun, Lydie; Matheron, Sophie; Rozenbaum, Willy; Katlama, Christine; Morer, I.; Lernestedt, J.-O.; Saraux, H; Pouliquen, Y.; Gentilini, M; Roussélie, F

doi:10.1016/s0161-6420(89)32824-7

Cited by 114 publications

(16 citation statements)

References 40 publications

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“…Our PCR method allowed reproducible amplification of 15 the evaluation of the effectiveness of antiviral treatment; and (iii) to evaluate the decrease in viral DNAs in both blood and aqueous humor after foscarnet IT. The chi-square test was used to evaluate the level of the viral load versus the persistence or disappearance of HCMV in blood PMNL, and, finally, the coefficient of correlation was determined to verify whether a correlation existed between levels of viral DNA in blood and those in aqueous humor.…”

Section: Methodsmentioning

confidence: 99%

Effect of foscarnet induction treatment on quantitation of human cytomegalovirus (HCMV) DNA in peripheral blood polymorphonuclear leukocytes and aqueous humor of AIDS patients with HCMV retinitis. The Italian Foscarnet Study Group

Gerna

Baldanti

Sarasini

et al. 1994

Antimicrob Agents Chemother

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The aim of this study was to investigate peripheral blood polymorphonuclear leukocytes and, whenever possible, aqueous humor from 65 AIDS patients with ophthalmoscopically diagnosed human cytomegalovirus (HCMV) retinitis to determine (i) whether patients consistently carry viral DNA and (ii) to what extent foscarnet induction treatment decreases viral DNA levels. HCMV DNA was quantified by PCR using densitometric analysis of hybridization products obtained from external standards and a standard curve from which the number of genome equivalents of test samples, normalized by using an internal amplification control, was interpolated. Results showed that 56 of 65 patients (86.1%) were positive for HCMV DNA prior to induction treatment. Of 41 of the 56 patients (73.2%) whose blood had become DNA negative after induction, only 5 had a high viral load (>5,000 genome equivalents per 2 x 10i polymorphonuclear leukocytes) prior to induction, whereas as many as 13 of the 15 (26.8%) patients remaining DNA positive after induction had a high viral load prior to induction. Finally, of the nine patients (13.8%) with DNA-negative blood prior to induction treatment, three were shifted to foscarnet from ganciclovir, while six were erroneously enrolled in the study. Pre-and postinduction aqueous humor samples were obtained from 12 patients; all of these were DNA positive prior to induction, whereas after induction, 4 became negative, 6 showed a marked decrease in viral DNA, and 2 had neariy stable low DNA levels. In conclusion, PCR is a valuable tool for etiologic diagnosis and monitoring of HCMV retinitis treatment in AIDS patients. HCMV DNA is consistently present in the blood and aqueous humor of all patients with HCMV retinitis. Foscarnet induction treatment is highly effective in suppressing or reducing DNA levels in both blood leukocytes and aqueous humor.Induction regimens of both foscarnet and ganciclovir have been shown to be highly effective in halting progression of human cytomegalovirus (HCMV) retinitis in patients with AIDS (2, 4, 10-15, 17, 21

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Section: Methodsmentioning

confidence: 99%

Effect of foscarnet induction treatment on quantitation of human cytomegalovirus (HCMV) DNA in peripheral blood polymorphonuclear leukocytes and aqueous humor of AIDS patients with HCMV retinitis. The Italian Foscarnet Study Group

Gerna

Baldanti

Sarasini

et al. 1994

Antimicrob Agents Chemother

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“…Previous studies have shown that 3'-azido-3'-deoxythymidine (AZT), phosphonoformate (PFA), and 2',3'-dideoxythymidine (ddT) each inhibit HIV-1 replication in vitro (18)(19)(20). PFA has also been shown to be effective in treating cytomegalovirus retinitis in patients with AIDS (17). It is generally assumed that reverse transcriptase (RT) is the common target of AZT, PFA, and ddT.…”

mentioning

confidence: 99%

Synergistic inhibition of human immunodeficiency virus type 1 replication in vitro by two-drug and three-drug combinations of 3'-azido-3'-deoxythymidine, phosphonoformate, and 2',3'-dideoxythymidine

Kong

Zhu

Ruprecht

et al. 1991

Antimicrob Agents Chemother

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The effects of 3'-azido-3'-deoxythymidine (AZT), phosphonoformate (PFA), and 2',3'-dideoxythymidine (ddT) and their combinations on human immunodeficiency type 1 (HIV-1) replication were studied by measuring the HIV-1 p24 antigen expression and reverse transcriptase (RT) release in HIV-1-infected MT4 cells in vitro. RT activity was also measured in a cell-free system by using poly(rA)-oligo(dT) as the primer-template, and cell growth inhibition was measured in noninfected MT4 cells. The interactions of these two-and three-drug combinations were evaluated by the combination index (CI) method and isobologram techniques. The 50% effective concentrations (EC50s) of AZT, PFA, and ddT were 0.014 to 0.005, 9.4 to 8.8, and 8.4 to 2.5 ,uM, respectively, for p24 enzyme-linked immunosorbent assays (ELISAs) and 0.0055 to 0.0034, 1.43 to 1.37, and 2.87 to 2.83 ,uM, respectively, for RT activity in vitro; for RT activity in the cell-free system, the EC50s were 0.00019 to 0.00024, 0.012 to 0.02, and 0.00074 to 0.0005 ,uM, for AZT-5'-triphosphate, PFA, and ddT-5'-triphosphate, respectively. AZT in combination with PFA (1:200) or ddT (1:5) as well as the combination of these three drugs (1:200:5) synergistically inhibited HIV-1 replication and RT activity in the cell-free system over a wide range of drug concentrations, with the CIs ranging from 0.5 to 0.9, in which CIs of <1, 1, and >1 indicate synergism, additive effect, and antagonism, respectively. Three-and two-drug combinations of AZT, PFA, and ddT showed similar degrees of synergism against HIV-1 replication in p24 assays and RT release assays, whereas the combination of AZT and ddT was found to be the most selective in terms of its anti-HIV-1 effect versus cytotoxicity. Dose reduction indices calculated from both HIV-1 replication inhibition, as measured by p24 ELISA and by RT activity in the cell-free system, indicated that two-and three-drug combinations at high effect levels and the selected combination ratios allow 2-to 240-fold dose reduction over the single drug alone in terms of their anti-HIV-1 effects. The three-drug combination showed the highest dose reduction index. These findings suggest that increased efficacy and reduced toxicity may be achieved in AIDS therapy by using AZT, PFA, and ddT in two-or three-drug combinations.

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“…Vision stabilized or improved in 80 to 100% of patients, but maintenance therapy was required, and even so, 70% or more relapsed (134,224,274,336,495). The potential advantage of foscarnet in this setting is that it has less bone marrow toxicity than ganciclovir, and it may be possible to use it in conjunction with zidovudine.…”

Section: Foscarnetmentioning

confidence: 99%

Antiviral therapy: current concepts and practices

Bean

1992

Clin Microbiol Rev

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Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

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Foscarnet in the Treatment of Cytomegalovirus Retinitis in Acquired Immune Deficiency Syndrome

Cited by 114 publications

References 40 publications

Effect of foscarnet induction treatment on quantitation of human cytomegalovirus (HCMV) DNA in peripheral blood polymorphonuclear leukocytes and aqueous humor of AIDS patients with HCMV retinitis. The Italian Foscarnet Study Group

Effect of foscarnet induction treatment on quantitation of human cytomegalovirus (HCMV) DNA in peripheral blood polymorphonuclear leukocytes and aqueous humor of AIDS patients with HCMV retinitis. The Italian Foscarnet Study Group

Synergistic inhibition of human immunodeficiency virus type 1 replication in vitro by two-drug and three-drug combinations of 3'-azido-3'-deoxythymidine, phosphonoformate, and 2',3'-dideoxythymidine

Antiviral therapy: current concepts and practices

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