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Guy Boivin - One of the best experts on this subject based on the ideXlab platform.

  • hypersusceptibility of human cytomegalovirus to Foscarnet induced by mutations in helices k and p of the viral dna polymerase
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Karima Zarrouk, Van Dung Pham, Jocelyne Piret, Rong Shi, Guy Boivin
    Abstract:

    Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of cytomegalovirus DNA polymerase for susceptibility to Foscarnet. Q579I and K805Q recombinant viruses were hypersusceptible to Foscarnet (respective mean 50% effective concentrations [EC50] of 0.12- and 0.19-fold that of the wild type). Three-dimensional modeling analysis suggested that both mutations favor the closed conformation of the enzyme to which Foscarnet binds with a higher affinity.

  • Herpes simplex virus isolates with reduced adefovir susceptibility selected in vivo by Foscarnet therapy.
    Journal of medical virology, 2002
    Co-Authors: Julie Bestman-smith, Guy Boivin
    Abstract:

    Sequential herpes simplex virus (HSV) isolates from AIDS patients receiving Foscarnet therapy were evaluated for susceptibility to adefovir. Foscarnet-resistant isolates with DNA polymerase mutations in regions II, VI, and between I and VII were also associated with an important decrease in susceptibility to adefovir (mean IC50 increase: 4.6-fold compared to pre-Foscarnet or wild-type isolates) suggesting that adefovir-resistant HSV could be selected in vivo by Foscarnet therapy. J. Med. Virol. 67:88–91, 2002. © 2002 Wiley-Liss, Inc.

  • 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
    The Journal of Infectious Diseases, 1999
    Co-Authors: Isabelle Schmit, Guy Boivin
    Abstract:

    Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients in whom acyclovir and Foscarnet therapy sequentially failed. The 6 postacyclovir (preFoscarnet) HSV isolates were resistant to acyclovir and susceptible to Foscarnet. Of the 9 postFoscarnet isolates, 8 were Foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both drugs. Acyclovir- or Foscarnet-resistant isolates retained susceptibility to cidofovir. The acyclovir-resistant isolates contained single-base substitutions or frameshift mutations in G or C homopolymer nucleotide repeats of the thymidine kinase gene. In contrast, the Foscarnet-resistant strains contained single-base substitutions in conserved (II, III, or VI) or, more rarely, nonconserved (between I and VII) regions of the DNA polymerase (pol) gene. The single isolate exhibiting resistance to acyclovir and Foscarnet contained mutations in both genes. In this study of clinical HSV isolates, DNA pol mutations conferring Foscarnet resistance were not associated with decreased acyclovir or cidofovir susceptibility.

  • effect of Foscarnet on quantities of cytomegalovirus and human immunodeficiency virus in blood of persons with aids
    Antimicrobial Agents and Chemotherapy, 1996
    Co-Authors: Henry H Balfour, Guy Boivin, Courtney V Fletcher, Alejo Erice, W K Henry, Edward P Acosta, S A Smith, M A Holm, D H Shepp
    Abstract:

    Four intravenous dosages of Foscarnet given for 10 days were compared with no therapy in persons with AIDS who had asymptomatic cytomegalovirus (CMV) viremia. CMV viremia was quantitated by endpoint cell dilution microcultures, pp65 antigenemia assay, and measurement of CMV DNA in peripheral blood leukocytes by a quantitative-competitive PCR. Human immunodeficiency virus type 1 (HIV-1) viremia was quantitated by endpoint cell dilution microculture, serum p24 antigen assay, and PCR for HIV-1 RNA in plasma. Twenty-seven subjects who had received a median of 22 months of nucleoside antiretroviral therapy were enrolled. Twenty-two subjects received Foscarnet, which was well tolerated and decreased the CMV burden, as reflected by all three indicator assays. During the 10 days of dosing, the level of CMV viremia, as measured by 50 percent tissue culture infective doses, decreased from 117.5 to 12.7 (P = 0.001), the amount of CMV DNA decreased from 20,328 copies to 622 copies per 150,000 leukocytes (P = 0.02), and the level of CMV pp65 antigenemia decreased from 14.9 to 1.6 positive peripheral blood mononuclear cells per 50,000 leukocytes (P = 0.008). A significant pharmacodynamic relationship was found between the peak Foscarnet concentration and a decrease in the level of CMV antigenemia (P < 0.05). Foscarnet had no effect on quantitative HIV-1 microcultures during the 10 days of treatment, but the HIV-1 p24 antigen level in serum decreased significantly, from 454 to 305 pg/ml (P = 0.01). Also, a significant pharmacodynamic relationship was seen between plasma HIV-1 RNA concentrations and both peak Foscarnet concentration (P < 0.01) and the area under the Foscarnet time-concentration curve (P < 0.05). Reductions in the levels of CMV and HIV-1 viremia correlated quantitatively with systemic exposure to Foscarnet, whereas control subjects actually experienced an increase in CMV and HIV-1 burdens. The dual antiviral activity of Foscarnet shown in this trial encourages investigation of its use in combination with other antiretroviral therapies for persons with AIDS.

John Mills - One of the best experts on this subject based on the ideXlab platform.

  • Characterisation of Foscarnet-resistant strains of human immunodeficiency virus type 1.
    Virology, 1995
    Co-Authors: Gilda Tachedjian, Chris Birch, David J. Hooker, Asitha D. Gurusinghe, Hengameh Z. Bazmi, Nicholas J. Deacon, John W. Mellors, John Mills
    Abstract:

    Foscarnet is a broad-spectrum viral DNA polymerase inhibitor active in vitro and in vivo against human immunodeficiency virus type 1 (HIV-1). Strains of HIV-1 resistant to Foscarnet were selected by in vitro passage in increasing concentrations of drug. Reduced susceptibility to Foscarnet was evident at the levels of both HIV-1 replication and reverse transcriptase. Biologically cloned, Foscarnet-resistant strains with distinct genotypes were hypersensitive to zidovudine, azidodeoxyuridine, nevirapine, and R82913 but had unchanged susceptibility to zalcitibine and didanosine. The reverse transcriptase of Foscarnet-resistant strains had unique substitutions Glu89-Lys, Leu92-Ile, or Ser156-Ala, the third being associated with six polymorphic changes. Introduction of these mutations into wild-type HIV-1 by site-directed mutagenesis confirmed their role in Foscarnet resistance. In the three-dimensional structure of the reverse transcriptase enzyme these amino acids are located close to the template strand of the template primer and far away from the putative pyrophosphate binding site, suggesting that the mechanism by which HIV-1 becomes resistant to Foscarnet is indirect. Foscarnet resistance is thus likely to be mediated through an altered interaction of the mutant enzyme with the template strand of the template primer which distorts the geometry of the polymerase active site and thereby decreases Foscarnet binding.

  • correlation between response to acyclovir and Foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus infected patients
    Antimicrobial Agents and Chemotherapy, 1994
    Co-Authors: Sharon Safrin, Joanne Rush, Lienhanh Phan, Tarek Elbeik, Dana Robinson, Ahmed Elbaggari, John Mills
    Abstract:

    In vitro susceptibility testing of herpes simplex virus (HSV) isolates will play an increasingly important role in guiding the clinical management of immunocompromised hosts who have lesions that are poorly responsive to therapy with standard antiviral agents. We assessed the correlation between the in vitro susceptibility result using a plaque reduction assay in Vero cells and the response to antiviral therapy with acyclovir or Foscarnet for 243 clinical isolates of HSV collected from 115 human immunodeficiency virus-infected patients. The in vitro results and clinical responses were highly associated for both acyclovir and Foscarnet (P < 0.001 and P < 0.001, respectively). The predictive values of a susceptible result (50% effective concentrations, < 2 micrograms/ml for acyclovir and < 100 micrograms/ml for Foscarnet) for complete healing of lesions were 62% for acyclovir and 82% for Foscarnet; the predictive values of a resistant result for failure to heal were 95% for acyclovir and 88% for Foscarnet. Thus, in vitro testing has clinical utility in guiding therapy, although the 1 to 2 weeks required to derive a definitive result by the plaque reduction assay is a major limitation.

  • a controlled trial comparing Foscarnet with vidarabine for acyclovir resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome
    The New England Journal of Medicine, 1991
    Co-Authors: Sharon Safrin, Clyde S Crumpacker, Pam Chatis, Roger B Davis, Richard Hafner, Joanne Rush, Harold A Kessler, Bernard Landry, John Mills
    Abstract:

    Abstract Background and Methods. Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both Foscarnet and vidarabine. We conducted a randomized trial to compare Foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either Foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to Foscarnet and vidarabine. Results. The lesions in all eight patients assigned to Foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01),...

  • A Controlled Trial Comparing Foscarnet with Vidarabine for Acyclovir-Resistant Mucocutaneous Herpes Simplex in the Acquired Immunodeficiency Syndrome
    The New England journal of medicine, 1991
    Co-Authors: Sharon Safrin, Clyde S Crumpacker, Pam Chatis, Richard Hafner, Joanne Rush, Harold A Kessler, Bernard Landry, Roger J. Davis, John Mills
    Abstract:

    Background and methods Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both Foscarnet and vidarabine. We conducted a randomized trial to compare Foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either Foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to Foscarnet and vidarabine. Results The lesions in all eight patients assigned to Foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to Foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued Foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after Foscarnet was discontinued. Conclusions For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, Foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.

Sharon Safrin - One of the best experts on this subject based on the ideXlab platform.

  • correlation between response to acyclovir and Foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus infected patients
    Antimicrobial Agents and Chemotherapy, 1994
    Co-Authors: Sharon Safrin, Joanne Rush, Lienhanh Phan, Tarek Elbeik, Dana Robinson, Ahmed Elbaggari, John Mills
    Abstract:

    In vitro susceptibility testing of herpes simplex virus (HSV) isolates will play an increasingly important role in guiding the clinical management of immunocompromised hosts who have lesions that are poorly responsive to therapy with standard antiviral agents. We assessed the correlation between the in vitro susceptibility result using a plaque reduction assay in Vero cells and the response to antiviral therapy with acyclovir or Foscarnet for 243 clinical isolates of HSV collected from 115 human immunodeficiency virus-infected patients. The in vitro results and clinical responses were highly associated for both acyclovir and Foscarnet (P < 0.001 and P < 0.001, respectively). The predictive values of a susceptible result (50% effective concentrations, < 2 micrograms/ml for acyclovir and < 100 micrograms/ml for Foscarnet) for complete healing of lesions were 62% for acyclovir and 82% for Foscarnet; the predictive values of a resistant result for failure to heal were 95% for acyclovir and 88% for Foscarnet. Thus, in vitro testing has clinical utility in guiding therapy, although the 1 to 2 weeks required to derive a definitive result by the plaque reduction assay is a major limitation.

  • Foscarnet-Resistant Herpes Simplex Virus Infection in Patients with AIDS
    The Journal of infectious diseases, 1994
    Co-Authors: Sharon Safrin, Sandra Kemmerly, Betsy Plotkin, Timothy Smith, Nancy Weissbach, Denise De Veranez, Lienhanh Phan, David L. Cohn
    Abstract:

    Six human immunodeficiency virus-infected patients had clinical lesions of herpes simplex virus (HSV) type 2 that showed in vitro resistance to Foscarnet. In each patient, lesions were unresponsive to Foscarnet therapy or developed during daily suppressive Foscarnet. Five patients had a history of intermittent or chronic Foscarnet use for the management of acyclovir-resistant HSV infection, and 1 was receiving daily Foscarnet for suppression of cytomegalovirus retinitis. Seven of 10 Foscarnet-resistant isolates from 6 patients were susceptible to acyclovir in vitro, and 1 was of borderline susceptibility. In 3 patients, the administration of acyclovir, either alone or in combination with Foscarnet, resulted in healing. Clinically significant resistance to Foscarnet may occur in immunosuppressed patients with prior Foscarnet exposure. Addition or substitution of acyclovir to Foscarnet therapy may be a useful strategy for patients in whom Foscarnet resistance is suspected, pending the results of in vitro susceptibility testing.

  • a controlled trial comparing Foscarnet with vidarabine for acyclovir resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome
    The New England Journal of Medicine, 1991
    Co-Authors: Sharon Safrin, Clyde S Crumpacker, Pam Chatis, Roger B Davis, Richard Hafner, Joanne Rush, Harold A Kessler, Bernard Landry, John Mills
    Abstract:

    Abstract Background and Methods. Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both Foscarnet and vidarabine. We conducted a randomized trial to compare Foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either Foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to Foscarnet and vidarabine. Results. The lesions in all eight patients assigned to Foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01),...

  • A Controlled Trial Comparing Foscarnet with Vidarabine for Acyclovir-Resistant Mucocutaneous Herpes Simplex in the Acquired Immunodeficiency Syndrome
    The New England journal of medicine, 1991
    Co-Authors: Sharon Safrin, Clyde S Crumpacker, Pam Chatis, Richard Hafner, Joanne Rush, Harold A Kessler, Bernard Landry, Roger J. Davis, John Mills
    Abstract:

    Background and methods Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both Foscarnet and vidarabine. We conducted a randomized trial to compare Foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either Foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to Foscarnet and vidarabine. Results The lesions in all eight patients assigned to Foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to Foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued Foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after Foscarnet was discontinued. Conclusions For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, Foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.

Douglas A. Jabs - One of the best experts on this subject based on the ideXlab platform.

  • mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis
    The Journal of Infectious Diseases, 2001
    Co-Authors: Douglas A. Jabs, Barbara K Martin, Michael Forman, James P Dunn, Janet L Davis, David V Weinberg, Karen K Biron, Fausto Baldanti
    Abstract:

    The clinical significance of cytomegalovirus (CMV) Foscarnet resistance was studied in patients with acquired immunodeficiency syndrome and CMV retinitis. Sequencing of the CMV pol gene was performed in 30 isolates. Phenotypic resistance was characterized by the DNA hybridization assay (DHA) in 30 isolates and by plaque-reduction assay (PRA) in 18 isolates. Nine isolates had Foscarnet resistance mutations, including V787L and E756Q that were confirmed by marker transfer experiments. Seven of 9 isolates with a 50% inhibitory concentration (IC(50)) >600 microM by DHA had genotypic resistance, compared with 2 of 21 with an IC(50) 400 microM and genotypic resistance, whereas only 1 of 13 susceptible isolates had genotypic resistance (P=.0007). Sixteen of 18 isolates had concordant PRA and DHA phenotypes. Among 44 patients treated with Foscarnet, drug resistance increased the risk of retinitis progression (odds ratio, 14; P=.016). The incidence of Foscarnet resistance after 6, 9, and 12 months of therapy was 13%, 24%, and 37%, respectively.

  • Morbidity and Toxic Effects Associated With Ganciclovir or Foscarnet Therapy in a Randomized Cytomegalovirus Retinitis Trial
    Archives of Internal Medicine, 1995
    Co-Authors: Richard A. Lewis, Douglas A. Jabs, Pamela Clogston, Victor Fainstein, Ronald Gross, Tobias Samo, Colette Tuttle, Linda Apuzzo, John G. Bartlett, Laura Coleson
    Abstract:

    Background: The Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial compared the use of either ganciclovir or Foscarnet for the initial treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. We previously reported that patients treated with Foscarnet lived longer but were more likely to have their treatment switched, the latter suggesting Foscarnet may not have been as well tolerated as ganciclovir. This study compared the morbidity and toxic reactions reported during the trial. Methods: Two hundred thirty-four patients with the acquired immunodeficiency syndrome and previously untreated cytomegalovirus retinitis at 11 university centers were randomly assigned to receive intravenously either Foscarnet (n=107) or ganciclovir (n=127). Medical histories, laboratory tests, and drug treatment histories during the first 6 months of treatment were analyzed. Results: Neutropenia was more common in patients assigned to ganciclovir than to Foscarnet (34% vs 14%;P=.001). Patients assigned to Foscarnet reported more infusion-related symptoms (58% vs 24%;P .001); they also experienced a trend toward more nephrotoxic effects (13% vs 6%;P=.082) and electrolyte abnormalities. The incidence of seizures was similar in both groups (Foscarnet, 12%; ganciclovir, 9%;P=.511). Patients assigned to Foscarnet were more likely to be switched to the alternative treatment (Foscarnet to ganciclovir, 46%; ganciclovir to Foscarnet, 11%;P Conclusions: Compared with ganciclovir, the use of Foscarnet was more frequently limited by the occurrence of toxic reactions. However, these toxic reactions rarely had long-term sequelae. In light of the previously reported survival benefit seen in patients treated with Foscarnet, these data support the use of Foscarnet for the initial treatment of cytomegalovirus retinitis. (Arch Intern Med. 1995;155:65-74)

  • Controversies in the treatment of cytomegalovirus retinitis: Foscarnet versus ganciclovir.
    Infectious agents and disease, 1995
    Co-Authors: Douglas A. Jabs
    Abstract:

    Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with AIDS. Untreated, CMV retinitis is a binding disease. Ganciclovir, a nucleoside analog, and Foscarnet, a pyrophosphate analog, are both effective in controlling CMV retinitis. A randomized, controlled, comparative trial of Foscarnet and ganciclovir demonstrated that they were equivalent in terms of controlling CMV retinits, but that Foscarnet was associated with a longer survival, possibly due to an antiretroviral effect of Foscarnet. However, Foscarnet was less well tolerated than ganciclovir, primarily due to the nature of its side effects. Because Foscarnet and ganciclovir have different side effects, initial treatment of CMV retinitis should be individualized. Newer technological developments, including oral ganciclovir and the ganciclovir intraocular device, may influence the choice of initial treatment, particularly because of their effect on the quality of life when compared to chronic intravenous therapy. The occurrence of relapse and the development of resistance remain long-term concerns, which may alter the use of anti-CMV drugs over time.

Mark A. Jacobson - One of the best experts on this subject based on the ideXlab platform.

  • Is there a pharmacokinetic interaction between Foscarnet and zalcitabine during concomitant administration
    Clinical therapeutics, 1998
    Co-Authors: Francesca T. Aweeka, Mark A. Jacobson, Suzanne R. Brody, Kim Botwin, Sarah Martin-munley
    Abstract:

    Foscarnet, an antiviral agent used in the treatment of cytomegalovirus infection, and zalcitabine, an antiretroviral nucleoside analogue used in the treatment of human immunodeficiency virus infection, are commonly used concomitantly. Foscarnet and zalcitabine may interact pharmacokinetically, as both compounds are partially eliminated by renal tubular secretion. Owing to dose-related toxicities associated with these two drugs, it is essential that we have data regarding their pharmacokinetic disposition during concomitant therapy. Twelve patients randomly received either Foscarnet (four doses) or zalcitabine (five doses) (Phase 1), followed by concomitant Foscarnet (four doses) and zalcitabine (six doses) (Phase 2), followed by dosing with the drug not received in Phase 1 (Phase 3). Following the last dose in each phase of the study, serial plasma samples were collected over 8 hours for zalcitabine and over 12 hours for Foscarnet to determine the pharmacokinetics of each drug using noncompartmental analysis. Foscarnet plasma and urine levels were determined using high-performance liquid chromatography, and zalcitabine levels were determined using radioimmunoassay. No clinically significant alterations in the pharmacokinetics of Foscarnet or zalcitabine occurred in this study. Thus despite the potential for Foscarnet and zalcitabine to compete for renal tubular secretion, no apparent pharmacokinetic interaction exists between these two drugs at the clinically relevant doses studied.

  • Effect of Foscarnet therapy on human immunodeficiency virus p24 antigen levels in AIDS patients with cytomegalovirus retinitis.
    The Journal of infectious diseases, 1992
    Co-Authors: Mohan M. Reddy, Roger B Davis, Michael H. Grieco, George Mckinley, Dennis M. Causey, Charles Van Der Horst, David M. Parenti, Thomas M. Hooton, Mark A. Jacobson
    Abstract:

    Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured in 22 AIDS patients who had detectable serum antigen at baseline after induction and maintenance therapy of Foscarnet for cytomegalovirus retinitis in phase I/II multicenter trials. The HIV p24 antigen levels decreased from a baseline value of 199 +/- 236 (mean +/- SD) and 140 pg/mL (median) to 106 +/- 218 and 28 pg/mL after 14 days of Foscarnet induction therapy (60 mg/kg every 8 h). During chronic Foscarnet maintenance, there was a sustained decrease in mean HIV p24 antigen levels below pre-Foscarnet therapy baseline concentrations for a median of 16 weeks after Foscarnet induction. These results provide evidence for a sustained clinical antiretroviral effect of chronic Foscarnet maintenance therapy, consistent with a recent report that Foscarnet-treated AIDS patients live longer than ganciclovir-treated patients.

  • Maintenance therapy for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome: Foscarnet
    The American Journal of Medicine, 1992
    Co-Authors: Mark A. Jacobson
    Abstract:

    The use of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) is limited by marrow toxicity and by the development of resistance to this agent in CMV strains capable of causing progressive disease. Foscarnet retains activity against ganciclovir-resistant CMV and has an adverse effect profile different from that of ganciclovir. Preliminary data from studies conducted under the AIDS Clinical Trials Group (ACTG) program indicate that intravenous Foscarnet maintenance therapy at 60, 90, and 120 mg/kg/day in AIDS patients with CMV retinitis successfully completing Foscarnet induction therapy is associated with median times to retinitis progression of 90, 95, and greater than 123 days, respectively. An ACTG trial of Foscarnet in patients failing ganciclovir therapy has been initiated, as has a trial jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases comparing the safety and efficacy of Foscarnet and ganciclovir. Also underway is a trial evaluating the effects of combination and alternating regimens of these two agents.

  • Foscarnet Therapy for Ganciclovir-Resistant Cytomegalovirus Retinitis in Patients with AIDS
    The Journal of infectious diseases, 1991
    Co-Authors: Mark A. Jacobson, W L Drew, Judith Feinberg, James J. O'donnell, P V Whitmore, R D Miner, David M. Parenti
    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-Induced Hypocalcemia and Effects of Foscarnet on Calcium Metabolism
    The Journal of clinical endocrinology and metabolism, 1991
    Co-Authors: Mark A. Jacobson, Dennis M. Causey, Francesca T. Aweeka, John G Gambertoglio, Anthony A. Portale
    Abstract:

    Foscarnet (trisodium phosphonoformate), an investigational pyrophosphate analog increasingly used to treat refractory cytomegalovirus retinitis and mucocutaneous herpes simplex virus infections in immunocompromised patients, has been reported to cause abnormalities in serum calcium and phosphate, including cases of fatal hypocalcemia. To further elucidate the magnitude and mechanism of these abnormalities in humans treated with Foscarnet for opportunistic herpes virus infections, we analyzed anaerobic serum specimens and 24-h urine samples before and after single and multiple doses of iv Foscarnet and performed a series of in vitro experiments with normal human serum and plasma. Plasma ionized calcium concentrations acutely decreased by a mean 0.17 mmol/L in the 6 individuals who received a 90 mg/kg dose of Foscarnet and by a mean 0.28 mmol/L in the 11 individuals who recieved a 120 mg/ kg dose (P = 0.016, 90 vs. 120 mg/kg dose). Results of in vitro experiments showed a highly significant inverse linear r...