Zalcitabine

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Donald I Abrams - One of the best experts on this subject based on the ideXlab platform.

  • zidovudine didanosine and Zalcitabine in the treatment of hiv infection meta analyses of the randomised evidence
    The Lancet, 1999
    Co-Authors: Donald I Abrams, William Cameron, Johan N. Bruun, F. Antunes, Clauschristian Carbon, I Chalmers, D Allan, H. Chang, J Chodakewitz
    Abstract:

    Background. To assess the effects of zidovudine, didanosine, and Zalcitabine on HIV disease progression and survival, we undertook mete-analyses of individual patient data and tabular data from all randomised trials that compared these agents.Methods. Individual patient data were available for 7722 participants without AIDS in the nine randomised trials of immediate versus deferred zidovudine, and 7700 participants with or without AIDS in the six trials comparing zidovudine plus didanosine, zidovudine plus Zalcitabine, or zidovudine alone, The main outcomes were mortality and disease progression (new AIDS-defining event or death before any such event).Findings. In the comparison of immediate versus deferred zidovudine, during a median follow-up of 50 months, 1908 individuals progressed, of whom 1351 died. In the deferred group, 61% started antiretroviral therapy (median time to therapy 28 months, which was zidovudine monotherapy in 94%). During the first year of follow-up, immediate zidovudine halved the rate of disease progression (p < 0.0001), increasing the probability of AIDS-free survival at 1 year from 96% to 98%. This early delay did not persist: after 6 years, AIDS-free survival was 54% in both groups. At no time was there any difference in overall survival, which at 6 years was 64% with immediate and 65% with deferred zidovudine (rate ratio 1.04 [95% Cl 0.94-1.15]). In the comparison of zidovudine plus didanosine or Zalcitabine versus zidovudine alone, during a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of didanosine to zidovudine delayed both progression (rate ratio 0.74 [0.67-0.82], p < 0.0001) and death (0.72 [0.64-0.82], p < 0.0001). Similarly, the addition of Zalcitabine to zidovudine also delayed progression (0.86 [0.78-0.94], p = 0.001) and death (0.87 [0.77-0.98], p = 0.02). After 3 years, the estimated percentages alive and without a new AIDS event were 53% for zidovudine plus didanosine, 49% for zidovudine plus Zalcitabine, and 44% for zidovudine alone; the percentages alive were 68%, 63%, and 59%, respectively. Five of the six trials involved randomised comparisons of zidovudine plus didanosine versus zidovudine plus Zalcitabine: in these, the zidovudine plus didanosine regimen had greater effects on disease progression (p = 0.004) and death (p = 0.009).Interpretation. Although immediate use of zidovudine halved disease progression during the first year, this effect was not sustained, and there was no improvement in survival in the short or long term. However, the use of didanosine and, to a lesser extent, Zalcitabine delayed both disease progression and death, at least when added to zidovudine, The comparative effects of these different nucleoside analogues on long-term survival should inform the choice of which to combine with other types of drug, such as protease inhibitors.

  • response of cd4 lymphocytes and clinical consequences of treatment using ddi or ddc in patients with advanced hiv infection
    Journal of Acquired Immune Deficiency Syndromes, 1996
    Co-Authors: Anne Goldman, Cynthia A Launer, Joyce A Korvick, Lawrence R Crane, Bradley P Carlin, Lawrence Deyton, Donald I Abrams
    Abstract:

    The value of CD4 lymphocyte counts as a surrogate marker in persons with advanced human immunodeficiency virus infection during antiretroviral treatment was assessed using longitudinal models and data from the Terry Beirn Community Programs for Clinical Research on AIDS didanosine/Zalcitabine trial of 467 HIV-infected patients. Patients with AIDS or two CD4 counts of < or = 300 who fulfilled specific criteria for zidovudine intolerance or failure were randomized to receive either 500 mg didanosine (ddl) daily or 2.25 mg Zalcitabine (ddC) per day. Absolute CD4 counts were recorded at study entry and at as many as four visits. Patients were followed for clinical disease progression and survival. At 2 months, the difference in mean CD4 count from baseline was +15.4 cells/mm3 in the ddI group but -1.3 cells/mm3 in the ddC group. Patients assigned to ddI had a greater chance of a CD4 response at 2 months than those on ddC, yet only those in the ddC group with a response showed significant improvement in progression of disease or survival compared with ddC nonresponders, ddI responders, and ddI nonresponders (p = 0.03). We conclude that a CD4 response does not necessarily correlate with improved outcome and is therefore not a useful surrogate marker in these patients.

  • a comparative trial of didanosine or Zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection
    The New England Journal of Medicine, 1994
    Co-Authors: Donald I Abrams, Cynthia A Launer, Joyce A Korvick, Michael Grodesky, Steven Wakefield, Katherine Muth, Anne I. Goldman, James D. Neaton, Lawrence R Crane, Sandra Kornegay
    Abstract:

    Background Both didanosine and Zalcitabine are commonly used to treat patients with human immunodeficiency virus (HIV) infection who cannot tolerate zidovudine treatment or who have had disease progression despite it. The relative efficacy and safety of these second-line therapies are not well defined. Methods In this multicenter, open-label trial we randomly assigned 467 patients who previously received zidovudine and had 300 or fewer CD4 cells per cubic millimeter or a diagnosis of the acquired immunodeficiency syndrome (AIDS) to treatment with either didanosine (500 mg per day) or Zalcitabine (2.25 mg per day). Results After a median follow-up of 16 months, disease progression or death occurred in 157 of 230 patients assigned to didanosine and 152 of 237 patients assigned to Zalcitabine, for a relative risk of 0.93 for the Zalcitabine group as compared with the didanosine group (P = 0.56), which decreased to 0.84 (P = 0.15) after adjustment for the CD4 count, Karnofsky score, and presence of AIDS at ba...

L. Berrino - One of the best experts on this subject based on the ideXlab platform.

  • cytosine deoxyribonucleoside anti hiv analogues a small chemical substitution allows relevant activities
    International Journal of Antimicrobial Agents, 2012
    Co-Authors: F. Scaglione, L. Berrino
    Abstract:

    The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2',3'-dideoxycytidine (ddC; Zalcitabine), 2',3'-dideoxy-3'-thiacytidine (3TC; lamivudine) and 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance.

  • Cytosine deoxyribonucleoside anti-HIV analogues : a small chemical substitution allows relevant activities
    'Elsevier BV', 2012
    Co-Authors: F. Scaglione, L. Berrino
    Abstract:

    The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2',3'-dideoxycytidine (ddC; Zalcitabine), 2',3'-dideoxy-3'-thiacytidine (3TC; lamivudine) and 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance.The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2\u2032,3\u2032-dideoxycytidine (ddC; Zalcitabine), 2\u2032,3\u2032-dideoxy-3\u2032-thiacytidine (3TC; lamivudine) and 2\u2032,3\u2032-dideoxy-5-fluoro-3\u2032-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance

Alex J Walker - One of the best experts on this subject based on the ideXlab platform.

  • zidovudine azt versus azt plus didanosine ddi versus azt plus Zalcitabine ddc in hiv infected adults
    Cochrane Database of Systematic Reviews, 2000
    Co-Authors: J H Darbyshire, Michael Hughes, M Foulkes, R Peto, W Duncan, A Babiker, Rory Collins, T E A Peto, Alex J Walker
    Abstract:

    BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and Zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus Zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

Michael Hughes - One of the best experts on this subject based on the ideXlab platform.

  • zidovudine azt versus azt plus didanosine ddi versus azt plus Zalcitabine ddc in hiv infected adults
    Cochrane Database of Systematic Reviews, 2000
    Co-Authors: J H Darbyshire, Michael Hughes, M Foulkes, R Peto, W Duncan, A Babiker, Rory Collins, T E A Peto, Alex J Walker
    Abstract:

    BACKGROUND: Zidovudine (AZT) monotherapy was the first antiretroviral drug to be tested widely. The next two drugs to be developed were didanosine (ddI) and Zalcitabine (ddC). OBJECTIVES: To assess the effects of zidovudine (AZT), zidovudine plus didanosine (ddI) and zidovudine plus Zalcitabine (ddC) on HIV disease progression and survival. SEARCH STRATEGY: Investigators and pharmaceutical companies were contacted, and MEDLINE searches were supplemented by searching conference abstracts. SELECTION CRITERIA: Randomised controlled trials comparing any two of AZT plus ddI, AZT plus ddC or AZT alone in participants with or without AIDS which collected information on deaths and new AIDS events. DATA COLLECTION AND ANALYSIS: Individual patient data with, wherever possible, follow-up obtained beyond that previously published were obtained and checked for internal consistency and consistency with any published reports; any apparent discrepancies were resolved with the trialists. Time to death and to disease progression (defined as a new AIDS-defining event or prior death) were analysed on an intention to treat basis, stratified to avoid direct comparisons between participants in different trials. MAIN RESULTS: Six trials were included in the meta-analysis. During a median follow-up of 29 months, 2904 individuals progressed, of whom 1850 died. The addition of ddI to AZT delayed both progression (RR 0.74; 95% CI 0.67 to 0.82, P<0.0001) and death (RR 0.72; 95% CI 0.64 to 0.82, P<0.0001). Likewise, the addition of ddC to AZT also delayed progression (RR 0. 86; 95% CI 0.78 to 0.94, P=0.001) and death (RR 0.87; 95% CI 0.77 to 0.98, P=0.02). After 3 years the estimated percentages alive and without a new AIDS event were 53% for AZT+ddI, 49% for AZT+ddC and 44% for AZT alone; the percentages alive were 68%, 63% and 59% respectively. Five of the six trials involved randomised comparisons of AZT+ddI versus AZT+ddC: in these, the AZT+ddI regimen had greater effects on disease progression (P=0.004) and death (P=0.009). REVIEWER'S CONCLUSIONS: The use of ddI and, to a lesser extent, ddC delayed both HIV disease progression and death, at least when added to AZT.

  • a trial comparing nucleoside monotherapy with combination therapy in hiv infected adults with cd4 cell counts from 200 to 500 per cubic millimeter
    The New England Journal of Medicine, 1996
    Co-Authors: Scott M Hammer, Robert T. Schooley, David Katzenstein, Michael Hughes, Holly Gundacker, Richard Haubrich, Keith W Henry, Michael M Lederman, John P Phair, Manette T Niu
    Abstract:

    Background This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter. Methods We randomly assigned 2467 HIV-1–infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of Zalcitabine; or 400 mg of didanosine. The primary end point was a >50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death. Results Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus Zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative ...

  • the relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in hiv infected adults with 200 to 500 cd4 cells per cubic millimeter
    The New England Journal of Medicine, 1996
    Co-Authors: David Katzenstein, Scott M Hammer, Michael Hughes, Holly Gundacker, Brooks J Jackson, Susan A Fiscus, Suraiya Rasheed, Tarek Elbeik, Richard C Reichman, Anthony J Japour
    Abstract:

    Background We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175. Methods The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus Zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype. Results After eight weeks, the mean (±SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26±0.06 for patients treated with zidovudine alone, 0.65±0....

F. Scaglione - One of the best experts on this subject based on the ideXlab platform.

  • cytosine deoxyribonucleoside anti hiv analogues a small chemical substitution allows relevant activities
    International Journal of Antimicrobial Agents, 2012
    Co-Authors: F. Scaglione, L. Berrino
    Abstract:

    The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2',3'-dideoxycytidine (ddC; Zalcitabine), 2',3'-dideoxy-3'-thiacytidine (3TC; lamivudine) and 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance.

  • Cytosine deoxyribonucleoside anti-HIV analogues : a small chemical substitution allows relevant activities
    'Elsevier BV', 2012
    Co-Authors: F. Scaglione, L. Berrino
    Abstract:

    The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2',3'-dideoxycytidine (ddC; Zalcitabine), 2',3'-dideoxy-3'-thiacytidine (3TC; lamivudine) and 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance.The search for new nucleoside analogue compounds targeting the virally encoded reverse transcriptase was developed by modifying the nucleoside structure to create inhibitor compounds. In this review, the structure-activity relationship of antiviral compounds synthesised from the naturally existing cytosine deoxyribonucleoside (dC) was evaluated. The line of research starting from dC led to the synthesis of 2\u2032,3\u2032-dideoxycytidine (ddC; Zalcitabine), 2\u2032,3\u2032-dideoxy-3\u2032-thiacytidine (3TC; lamivudine) and 2\u2032,3\u2032-dideoxy-5-fluoro-3\u2032-thiacytidine (FTC; emtricitabine) and looks very interesting because each product comes from a single small change in the chemical structure of the former compound, resulting in a progressive improvement in terms of activity, pharmacokinetics, tolerability and emergence of resistance