title: Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Multicenter AIDS Cohort Study Group.
abstract: BACKGROUND
  Among patients who begin receiving zidovudine during intermediate-stage human immunodeficiency virus (HIV) infection, it is unclear whether changing to combination therapy (adding didanosine or zalcitabine) or sequential monotherapy (changing to didanosine or zalcitabine) significantly improves survival.
  
  
  OBJECTIVE
  To determine, among patients who began receiving zidovudine during intermediate-stage HIV infection, the differential effects of changing to combination therapy (zidovudine with didanosine or zalcitabine) or sequential monotherapy (with didanosine or zalcitabine) or continuing zidovudine monotherapy.
  
  
  METHODS
  1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed.
  
  
  METHODS
  University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh.
  
  
  METHODS
  Longitudinal cohort study, Treatment groups and important prognostic variables were modeled as time-dependent covariates in Cox proportional hazards models.
  
  
  METHODS
  Progression to AIDS and death.
  
  
  RESULTS
  Compared with patients receiving continued zidovudine monotherapy, patients receiving combination therapy had a 45% improvement in survival (relative risk, 0.55 [95% Cl, 0.41 to 0.74; P < 0.001]) and patients who changed to sequential monotherapy had a 32% improvement in survival (relative risk, 0.68 [Cl, 0.52 to 0.89; P = 0.005]). In the landmark analyses, the median prolongation of survival associated with changing therapy was, at best, 3 to 6 months. Survival curves converged at 3.5 years for the 50 cells/mm3 disease-stage landmark, at 4.4 years for the 100 cells/mm3 landmark and at 4.9 years for the 150 cells/mm3 landmark. Mortality within these periods was 100%, regardless of treatment group or landmark.
  
  
  CONCLUSIONS
  For patients who began receiving zidovudine during intermediate-stage disease, changing to either combination therapy or sequential monotherapy was associated with a statistically significant survival benefit compared with continuation of zidovudine monotherapy. The absolute increase in survival was modest, however, and long-term survival remained poor. Simultaneous time-dependent adjustment for changes in therapy and in important prognostic variables is necessary to derive relatively unbiased estimates of treatment effects in observational studies of HIV infection.
authors.affiliation: Johns Hopkins University School of Hygiene and Public Health, Department of Epidemiology, Baltimore, MD 21205, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Graham
authors.forename: D R
authors.initials: DR
authors.lastname: Hoover
authors.forename: L P
authors.initials: LP
authors.lastname: Park
authors.forename: D S
authors.initials: DS
authors.lastname: Stein
authors.forename: J P
authors.initials: JP
authors.lastname: Phair
authors.forename: J W
authors.initials: JW
authors.lastname: Mellors
authors.forename: R
authors.initials: R
authors.lastname: Detels
authors.forename: A J
authors.initials: AJ
authors.lastname: Saah
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D018791:CD4 Lymphocyte Count; D016049:Didanosine / Q000008:administration & dosage*; D018450:Disease Progression; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D016016:Proportional Hazards Models; D016047:Zalcitabine / Q000008:administration & dosage*; D015215:Zidovudine / Q000008:administration & dosage*
chemical_list: D000998:Antiviral Agents; D015215:Zidovudine; D016047:Zalcitabine; D016049:Didanosine