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May 8, 1995

Zidovudine Compared With Didanosine in Patients With Advanced HIV Type I Infection and Little or No Previous Experience With Zidovudine

Raphael Dolin, MD; David A. Amato, PhD; Margaret A. Fischl, MD; et al Carla Pettinelli, MD, PhD; Mohan Beltangady, PhD; Song-heng Liou, MA; Michael J. Brown, PhD; Anne P. Cross, PhD; Martin S. Hirsch, MD; W. David Hardy, MD; Donna Mildvan, MD; Donald C. Blair, MD; William G. Powderly, MD; Michael F. Para, MD; Kenneth H. Fife, MD, PhD; Roy T. Steigbigel, MD; Laurie Smaldone, MD; Clyde S. Crumpacker, MD; Tim Cooley, MD; Ronald T. Mitsuyaso, MD; Ric John; Carsandra Sanders, RPA; Dinah Reitman, MPS; Ross Hewitt, MD; Richard C. Reichman, MD; Lawrence D. Gelb, MD; M. L. McGuire, BSN; Marcella Jones, RN, BSN; Judith L. Neidig, MS, RN; Beth Zwickl, RNC; Paula B. Hartman, RNC; Mary Elizabeth Roarke, BS, RN; Ruth Ann Burk, BS, RN; Jack Fuhrer, MD; Karen A. Somogyi, RN, BA; Kent Sepkowitz, MD; Edward E. Telzak, MD; Vincent J. McAuliffe, MD; Fred T. Valentine, MD; Margarita Vasquez, RN; Thomas C. Merigan, MD; David Katzenstein, MD; Jeffrey Fessell, MD; Diane V. Havlir, MD; Douglas D. Richman, MD; Stephen A. Spector, MD; James O. Kahn, MD; Linda Johnson, RN; Rebecca Coleman, PharmD; Monto Ho, MD; Deborah McMahon, MD; George Pazin, MD; Diana Antoniskis, MD; Bernard McNamara, MD; DeAnn Diamond, RN; Ann C. Collier, MD; Mary A. Paradise, ARNP; Anna Wald, MD; Ann DePaolis-Jones, RN, BSN; Keith Henry, MD; Hetty A. Waskin, MD; Newton E. Hyslop Jr, MD; David M. Mushatt, MD; James A. Zachary, MD; Roy Soeiro, MD; Carol Harris, MD; Barry Zingman, MD; Michael F. Giordano, MD; Sandra Sledz, RN; Henry W. Murray, MD; John T. Carey, MD; Traci L. Davis, RN; Brenda Bagby, MS; Harold A. Kessler, MD; Robert I. Murphy, MD; Robert E. Hirschtick, MD; Sarah H. Cheeseman, MD; Kwan Kew Lai, MD; Patrick G. Fairchild, MD; W. C. Ehmann, MD; J. J. Zurlo, MD; R. Millard, MD; Luigi Troiani, PA; Aline A. Heggen; Charles M. van der Horst, MD; George F. McKinley, MD; Michael H. Grieco, MD; Brenda R. Kolatch, MS; Jonathan C. Goldsmith, MD; Edward D. Gomperts, MD; Lin M. Woods, MN; Louis Grue, RN; Kate Mayjo, RN; Rebecca L. Becker, PA-C; D. T. Jayaweera, MD; Lisa Rolfe, RN, BSN; Joanne Cole, RN; John Jermano, RN, MPH
Author Affiliations

Bethesda, Md; Bethesda; Princeton, NJ.; Harvard University, Boston, Mass; University of California Medical Center—Los Angeles; Beth Israel Medical Center, New York, NY; Mount Sinai Medical Center, New York, NY; SUNY—Buffalo; University of Rochester (NY); Washington University, St Louis, Mo; Ohio State University, Columbus; Indiana University School of Medicine, Indianapolis; SUNY—Stony Brook; Memorial Sloan-Kettering Cancer Center, New York, NY; Bronx (NY) Lebanon Hospital Center; New York (NY) University Medical Center; Stanford (Calif) University; Kaiser-Permanente, Los Angeles, Calif; University of California—San Diego; University of California—San Francisco; University of Pittsburgh (Pa); LAC/USC Medical Center, Los Angeles, Calif; University of Washington, Seattle; St Paul (Minn) Ramsey Medical Center; Duke University Medical Center, Durham, NC; Tulane LSU ACTU, New Orleans, La; Albert Einstein College of Medicine, New York, NY; Cornell University Medical Center, New York, NY; Case Western Reserve University, Cleveland, Ohio; Rush-Presbyterian-St Luke's Medical Center, Northwestern University, Chicago, Ill; University of Massachusetts Medical Center, Boston; Pennsylvania State School of Medicine, Hershey; University of North Carolina, Chapel Hill; St Luke's/Roosevelt Hospital, Columbia University, New York, NY; Children's Hospital of Los Angeles (Calif); The Johns Hopkins University, Baltimore, Md; University of Miami (Fla) School of Medicine; National Institute of Allergy and Infectious Diseases, Bethesda, Md

From the Department of Medicine, University of Rochester (NY) School of Medicine and Dentistry (Dr Dolin); the Harvard School of Public Health, Boston, Mass (Dr Amato and Ms Liou); the Department of Medicine, the University of Miami (Fla) School of Medicine (Dr Fischl); the Division of AIDS, the National Institute of Allergy and Infectious Diseases, Bethesda, Md (Dr Pettinelli); Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Conn (Drs Beltangady, Brown, Cross, and Smaldone); the Infectious Disease Unit, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Hirsch); the Department of Medicine, University of California—Los Angeles Care Center (Dr Hardy); the Division of Infectious Diseases, Beth Israel Medical Center, New York, NY (Dr Mildvan); the Department of Medicine, State University of New York—Syracuse (Dr Blair); the Division of Infectious Diseases, Washington University, St Louis, Mo (Dr Powderly); the Department of Internal Medicine, The Ohio State University College of Medicine, Columbus (Dr Para); the Department of Medicine, Indiana University School of Medicine, Indianapolis (Dr Fife); and the Division of Infectious Diseases, State University of New York— Stony Brook (Dr Steigbigel). Dr Amato is now affiliated with Abt Associates Inc in Cambridge, Mass. A complete list of participants in this study appears on the next page.

Arch Intern Med. 1995;155(9):961-974. doi:10.1001/archinte.1995.00430090111012

Background:  We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine.

Methods:  Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, ≤0.30× 109/L [300/μL]), or asymptomatic HIV (CD4 cell count, ≤0.20× 109/L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival.

Results:  In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d).

Conclusions:  In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.(Arch Intern Med. 1995;155:961-974)

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