ndomized Study of Didanosine Monotherapy and Combination Therapy With Zidovudine in Hemophilic and Nonhemophilic Subjects With Asymptomatic Human Immunodeficiency Virus-l Infection

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-l (HIV-1) infection, we conducted an open-label, phase 1/11 study in 126 asymptomatic HIV-l-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddl 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects ( P = .008), but there were no differences in toxicity between treatment arms ( P = ,511, nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median

[1]  Carolyn Pillers Dobler,et al.  Mathematical Statistics , 2002 .

[2]  P. Volberding,et al.  Combination Therapy with Zidovudine and Didanosine Compared with Zidovudine Alone in HIV-1 Infection , 1993, Annals of Internal Medicine.

[3]  C. Kessler,et al.  Three-year randomised study of high-purity or intermediate-purity factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status , 1993, The Lancet.

[4]  J. Gatell,et al.  Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter , 1993 .

[5]  Robert Schooley,et al.  CD4+ Lymphocytes Are an Incomplete Surrogate Marker for Clinical Progression in Persons with Asymptomatic HIV Infection Taking Zidovudine , 1993, Annals of Internal Medicine.

[6]  J. Aboulker,et al.  Preliminary analysis of the Concorde trial , 1993, The Lancet.

[7]  D. Katzenstein,et al.  Measurement of HIV virus load and genotypic resistance by gene amplification in asymptomatic subjects treated with combination therapy. , 1993, Journal of acquired immune deficiency syndromes.

[8]  T. Merigan,et al.  Alternating and Intermittent Regimens of Zidovudine and Dideoxycytidine in Patients with AIDS or AIDS-Related Complex , 1993, Annals of Internal Medicine.

[9]  C. Birch,et al.  Incidence of zidovudine-resistant human immunodeficiency virus isolated from patients before, during, and after therapy. , 1992, The Journal of infectious diseases.

[10]  S D Kemp,et al.  Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. , 1991, Science.

[11]  T. Merigan,et al.  Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. NHF-ACTG 036 Study Group. , 1991, Blood.

[12]  H. Mitsuya,et al.  Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex , 1990, The Lancet.

[13]  R. Detels,et al.  A simple method for improved assay demonstrates that HIV p24 antigen is present as immune complexes in most sera from HIV-infected individuals. , 1990, The Journal of infectious diseases.

[14]  T. Merigan,et al.  Alternating and intermittent regimens of zidovudine (3'-azido-3'-deoxythymidine) and dideoxycytidine (2',3'-dideoxycytidine) in the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. , 1990, The American journal of medicine.

[15]  C. Pettinelli,et al.  2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. , 1990, The New England journal of medicine.

[16]  S D Kemp,et al.  Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). , 1989, Science.

[17]  H. Mitsuya,et al.  Clinical pharmacology of 3'-azido-2',3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. , 1989, The New England journal of medicine.

[18]  H. Mitsuya,et al.  In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. , 1989, Science.

[19]  D. Brettler,et al.  Factor VIII:C concentrate purified from plasma using monoclonal antibodies: human studies. , 1989, Blood.

[20]  D. Richman,et al.  HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. , 1989, Science.

[21]  J. Molina,et al.  Inhibition of bone marrow myelopoiesis and erythropoiesis in vitro by anti‐retroviral nucleoside derivatives , 1988, British journal of haematology.

[22]  M A Fischl,et al.  The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. , 1987, The New England journal of medicine.

[23]  R. Prescott,et al.  HUMAN T-LYMPHOTROPIC VIRUS TYPE III (HTLV-III) INFECTION IN SERONEGATIVE HAEMOPHILIACS AFTER TRANSFUSION OF FACTOR VIII , 1985, The Lancet.

[24]  J. Gitlin,et al.  Diminished helper/suppressor lymphocyte ratios and natural killer activity in recipients of repeated blood transfusions. , 1984, Blood.

[25]  N. Zoumbos,et al.  Immunologic abnormalities in patients receiving multiple blood transfusions. , 1984, Annals of internal medicine.

[26]  Marcello Pagano,et al.  An Algorithm for Finding the Exact Significance Levels of r × c Contingency Tables , 1981 .

[27]  M Zelen,et al.  The randomization and stratification of patients to clinical trials. , 1974, Journal of chronic diseases.

[28]  N. Mantel.  Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[29]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[30]  S. Steinberg,et al.  A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. , 1994, The Journal of infectious diseases.

[31]  S. Lagakos,et al.  Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. , 1990, Journal of acquired immune deficiency syndromes.

[32]  S. Lagakos,et al.  Safety and Efficacy of zidovudine in asymptomatic HIV infected individuals withless than 500 CD4+ cells/mm3. , 1990 .

[33]  Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. , 1987, MMWR supplements.