Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group.

BACKGROUND In patients with human immunodeficiency virus (HIV) infection, combined treatment with several agents may increase the effectiveness of antiviral therapy. We studied the safety and efficacy of saquinavir, an HIV-protease inhibitor, given with one or two nucleoside antiretroviral agents, as compared with the safety and efficacy of a combination of two nucleosides alone. METHODS In this double-blind trial, patients with HIV infection were randomly assigned to receive either saquinavir (1800 mg per day) plus both zidovudine (600 mg per day) and zalcitabine (2.25 mg per day) or zidovudine plus either saquinavir or zalcitabine. The 302 patients enrolled had CD4+ counts of 50 to 300 cells per cubic millimeter and had previously received zidovudine for a median of 27 months. The study lasted 24 weeks, with an optional double-blind extension period of an additional 12 to 32 weeks. RESULTS Ninety-six percent of the patients completed the 24-week study. In all three treatment groups, CD4+ cell counts rose at first and then fell gradually. The normalized area under the curve for the CD4+ count was greater with the three-drug combination than with either saquinavir and zidovudine (P=0.017) or zalcitabine and zidovudine (P<0.001). There were significantly greater reductions in plasma HIV with the three-drug combination than with the other regimens when peripheral-blood mononuclear cells were cultured for HIV and HIV RNA was assessed, and there were greater decreases in serum neopterin and beta2-microglobulin levels. There were no major differences in toxic effects among the three treatments. CONCLUSIONS Treatment with saquinavir, zalcitabine, and zidovudine was well tolerated. This drug combination reduced HIV-1 replication, increased CD4+ cell counts, and decreased levels of activation markers in serum more than did treatment with zidovudine and either saquinavir or zalcitabine. Studies are warranted to evaluate whether the three-drug combination will reduce morbidity and mortality.

[1]  P. Hartigan,et al.  Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS. , 1996, The New England journal of medicine.

[2]  B. Irvine,et al.  Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[3]  H. Burger,et al.  Safety and activity of saquinavir in HIV infection , 1995, The Lancet.

[4]  D. Ho,et al.  Clinical evaluation of branched DNA signal amplification for quantifying HIV type 1 in human plasma. , 1995, AIDS research and human retroviruses.

[5]  S. Yerly,et al.  Response of HIV RNA to didanosine as a predictive marker of survival , 1995, AIDS.

[6]  D. Katzenstein,et al.  Human immunodeficiency virus type 1 quantitative cell microculture as a measure of antiviral efficacy in a multicenter clinical trial. , 1995, The Journal of infectious diseases.

[7]  M. Urdea,et al.  Quantitation of human immunodeficiency virus plasma RNA by branched DNA and reverse transcription coupled polymerase chain reaction assay methods: A critical evaluation of accuracy and reproducibility , 1994 .

[8]  J. Craig,et al.  In vitro anti-HIV and Cytotoxicological Evaluation of the Triple Combination: AZT and ddC with HIV Proteinase Inhibitor Saquinavir (Ro 31-8959) , 1994 .

[9]  R. Dewar,et al.  Application of branched DNA signal amplification to monitor human immunodeficiency virus type 1 burden in human plasma. , 1994, The Journal of infectious diseases.

[10]  M. Winters,et al.  Multicenter evaluation of quantification methods for plasma human immunodeficiency virus type 1 RNA. , 1994, The Journal of infectious diseases.

[11]  S. Vella.  Update on a proteinase inhibitor , 1994 .

[12]  J. Neaton,et al.  A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. The Terry Beirn Community Programs for Clinical Research on AIDS. , 1994, The New England journal of medicine.

[13]  A. Cross,et al.  Didanosine Compared with Continuation of Zidovudine in HIV-infected Patients with Signs of Clinical Deterioration While Receiving Zidovudine , 1994, Annals of Internal Medicine.

[14]  J. Sninsky,et al.  Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection , 1994, Journal of clinical microbiology.

[15]  D. Richman,et al.  Designing phase II studies of chemotherapy for HIV infection using CD4 as an end-point. , 1993, AIDS.

[16]  J. Craig,et al.  Antiviral Synergy between Inhibitors of HIV Proteinase and Reverse Transcriptase , 1993 .

[17]  M. Hirsch,et al.  Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro. , 1992, The Journal of infectious diseases.

[18]  R. Weinstein,et al.  In-Vitro Resistance to Zidovudine and Alpha-interferon in HIV-1 Isolates from Patients: Correlations with Treatment Duration and Response , 1992, Annals of Internal Medicine.

[19]  T. Merigan,et al.  A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. , 1992, The New England journal of medicine.

[20]  J. Bremer,et al.  Standardization of sensitive human immunodeficiency virus coculture procedures and establishment of a multicenter quality assurance program for the AIDS Clinical Trials Group. The NIH/NIAID/DAIDS/ACTG Virology Laboratories , 1992, Journal of clinical microbiology.

[21]  T Creagh-Kirk,et al.  Natural history of advanced HIV disease in patients treated with zidovudine. The Zidovudine Epidemiology Study Group. , 1992, AIDS.

[22]  D. Lambert,et al.  Human immunodeficiency virus type 1 protease inhibitors irreversibly block infectivity of purified virions from chronically infected cells , 1992, Antimicrobial Agents and Chemotherapy.

[23]  Carlo Tomino,et al.  Survival of Zidovudine-Treated Patients With AIDS Compared With That of Contemporary Untreated Patients , 1992 .

[24]  J S Mills,et al.  Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. , 1991, Antiviral research.

[25]  R. Chaisson,et al.  Zidovudine and the natural history of the acquired immunodeficiency syndrome. , 1991, The New England journal of medicine.

[26]  B. Moss,et al.  An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and spread of infection. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Tomi K. Sawyer,et al.  A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation. , 1990, Disease markers.

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

[29]  Robert T. Schooley,et al.  Prolonged Zidovudine Therapy in Patients With AIDS and Advanced AIDS-Related Complex , 1989 .

[30]  R. Schooley,et al.  Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. AZT Collaborative Working Group. , 1989, JAMA.

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

[32]  T Creagh-Kirk,et al.  Survival experience among patients with AIDS receiving zidovudine. Follow-up of patients in a compassionate plea program. , 1988, JAMA.

[33]  M A Fischl,et al.  The efficacy 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.

[34]  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.

[35]  E. Reddy,et al.  HTLV-III gag protein is processed in yeast cells by the virus pol-protease. , 1986, Science.

[36]  A A Tsiatis,et al.  Exact significance testing to establish treatment equivalence with ordered categorical data. , 1984, Biometrics.

[37]  Ann Collier,et al.  Combination and Monotherapy with Zidovudine and Zalcitabine in Patients with Advanced HIV Disease , 1995, Annals of Internal Medicine.