Survival in HIV-infected patients who have received zidovudine

Comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy

Neil M.H. Graham, Donald Hoover, Lawrence P. Park, Daniel S. Stein, John P. Phair, John W. Mellors, Roger Detels, Alfred J. Saah

Research output: Contribution to journalArticle

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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. Patients: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. Setting: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. Design: Longitudinal cohort study. Treatment groups and important prognostic variables were modeled as timedependent covariates in Cox proportional hazards models. Measurements: 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 timedependent 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.

Original languageEnglish (US)
Pages (from-to)1031-1038
Number of pages8
JournalAnnals of internal medicine
Volume124
Issue number12
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Zidovudine
HIV
Zalcitabine
Didanosine
Survival
Virus Diseases
Acquired Immunodeficiency Syndrome
Therapeutics
Cohort Studies
Baltimore
Los Angeles
Proportional Hazards Models
Observational Studies
Longitudinal Studies
Mortality

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Graham, Neil M.H. ; Hoover, Donald ; Park, Lawrence P. ; Stein, Daniel S. ; Phair, John P. ; Mellors, John W. ; Detels, Roger ; Saah, Alfred J. / Survival in HIV-infected patients who have received zidovudine : Comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. In: Annals of internal medicine. 1996 ; Vol. 124, No. 12. pp. 1031-1038.
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title = "Survival in HIV-infected patients who have received zidovudine: Comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy",
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. Patients: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. Setting: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. Design: Longitudinal cohort study. Treatment groups and important prognostic variables were modeled as timedependent covariates in Cox proportional hazards models. Measurements: 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 timedependent 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.",
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Survival in HIV-infected patients who have received zidovudine : Comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. / Graham, Neil M.H.; Hoover, Donald; Park, Lawrence P.; Stein, Daniel S.; Phair, John P.; Mellors, John W.; Detels, Roger; Saah, Alfred J.

In: Annals of internal medicine, Vol. 124, No. 12, 01.01.1996, p. 1031-1038.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Survival in HIV-infected patients who have received zidovudine

T2 - Comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy

AU - Graham, Neil M.H.

AU - Hoover, Donald

AU - Park, Lawrence P.

AU - Stein, Daniel S.

AU - Phair, John P.

AU - Mellors, John W.

AU - Detels, Roger

AU - Saah, Alfred J.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - 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. Patients: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. Setting: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. Design: Longitudinal cohort study. Treatment groups and important prognostic variables were modeled as timedependent covariates in Cox proportional hazards models. Measurements: 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 timedependent 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.

AB - 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. Patients: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. Setting: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. Design: Longitudinal cohort study. Treatment groups and important prognostic variables were modeled as timedependent covariates in Cox proportional hazards models. Measurements: 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 timedependent 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.

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