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Survival Benefit of Initiating Antiretroviral Therapy in HIV-Infected Persons in Different CD4⁺ Cell Strata

Frank J. Palella, Jr., MD; Maria Deloria-Knoll, PhD; Joan S. Chmiel, PhD; Anne C. Moorman, BSN, MPH; Kathleen C. Wood, BSN; Alan E. Greenberg, MD, MPH; Scott D. Holmberg, MD, MPH, the HIV Outpatient Study (HOPS) Investigators*

15 April 2003 | Volume 138 Issue 8 | Pages 620-626

Background: Optimal timing of antiretroviral therapy (ART) initiation for HIV-infected persons remains unclear.

Objective: To assess survival benefit of initiating ART at different CD4⁺ cell counts.

Design: Prospective observational study.

Setting: U.S. clinics in the HIV Outpatient Study (HOPS).

Patients: HIV-infected patients with CD4⁺ cell counts, plasma HIV RNA viral load, and ART use recorded from January 1994 through March 2002.

Measurements: Before initiation of ART, patients were grouped by their CD4⁺ cell counts into three subgroups: 0.201 to 0.350 x 10⁹ cells/L (n = 399), 0.351 to 0.500 x 10⁹ cells/L (n = 327), and 0.501 to 0.750 x 10⁹ cells/L (n = 122). We compared mortality rates for each CD4⁺ subgroup among patients who initiated ART and patients who delayed ART until reaching a lower CD4⁺ subgroup.

Results: Mortality rates for 340 patients who initiated ART and 59 who delayed ART in the CD4⁺ subgroup of 0.201 to 0.350 x 10⁹ cells/L were 15.4 and 56.4 deaths per 1000 person-years, respectively (rate ratio, 0.27 [95% CI, 0.14 to 0.55]; P < 0.001). For the CD4⁺ subgroup of 0.351 to 0.500 x 10⁹ cells/L, mortality rates for 240 patients who initiated ART and 887 who delayed ART were 10.0 and 16.6 deaths per 1000 person-years, respectively (rate ratio, 0.61 [CI, 0.22 to 1.67]; P = 0.17). For the CD4⁺ subgroup of 0.501 to 0.750 x 10⁹ cells/L, mortality rates in 55 patients who initiated ART and 67 who delayed ART were 7.5 and 3.1 deaths per 1000 person-years, respectively (rate ratio, 1.20 [CI, 0.17 to 8.53]; P > 0.2). Patients in the 0.201 to 0.350 x 10⁹ cells/L and 0.351 to 0.500 x 10⁹ cells/L CD4⁺ subgroups who initiated ART were more likely than those who delayed ART to achieve an undetectable HIV viral load (P = 0.03 and 0.04, respectively).

Conclusions: Among HIV-infected persons with CD4⁺ cell counts of 0.201 to 0.350 x 10⁹ cells/L, initiating ART is associated with reduced mortality compared with delaying such therapy. Survival benefits of earlier ART initiation (at CD4⁺ cell counts of 0.351 to 0.500 x 10⁹ cells/L) are possible.

*For the HOPS Investigators, see Appendix.

Editors' Notes Context When to start antiretroviral therapy (ART) for HIV infection is controversial. Starting too early exposes patients to side effects and uncertain benefits. Starting too late deprives patients of benefits. Contribution In this cohort study, HIV-infected patients with baseline CD4+ cell counts between 0.201 and 0.350 x 109 cells/L who began ART immediately had lower mortality rates than those who started therapy after their CD4+ cell count decreased to less than 0.201 x 109 cells/L. Optimal timing of therapy is unclear when the CD4+ cell count is greater than 0.350 x 109 cells/L. Cautions A randomized, controlled trial is the best way to identify the optimal timing of ART. –The Editors

 

Author and Article Information

From Northwestern University, Chicago, Illinois; National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; and APACHE Medical Systems, Cerner Corporation, Vienna, Virginia.

Acknowledgment: The authors thank John P. Phair, MD, Professor Emeritus of Medicine, The Feinberg School of Medicine, Northwestern University, for his ongoing support, insight, and sage advice.

Grant Support: By the Centers for Disease Control and Prevention (contract 200-2001-00133), Atlanta, Georgia.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Frank J. Palella Jr., MD, Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, 676 North Saint Clair, Suite 200, Chicago, IL 60611; e-mail, f-palella{at}northwestern.edu.

Current Author Addresses: Dr. Palella: Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, 676 North Saint Clair, Suite 200, Chicago, IL 60611.

Drs. Deloria-Knoll and Chmiel: Department of Preventive Medicine, The Feinberg School of Medicine, Northwestern University, 680 North Lake Shore Drive, Suite 1102, Chicago, IL 60611.

Ms. Moorman, Dr. Greenberg, and Dr. Holmberg: Centers for Disease Control and Prevention, Mailstop E-45, 1600 Clifton Road, Atlanta, GA 30333.

Ms. Wood: Cerner Corporation, 2800 Rockcreek Parkway, Kansas City, MO 64117.

Author Contributions: Conception and design: F.J. Palella, M. Deloria-Knoll, J.S. Chmiel, A.C. Moorman, S.D. Holmberg.

Analysis and interpretation of the data: F.J. Palella, M. Deloria-Knoll, J.S. Chmiel, A.C. Moorman, A.E. Greenberg, S.D. Holmberg.

Drafting of the article: F.J. Palella.

Critical revision of the article for important intellectual content: F.J. Palella, M. Deloria-Knoll, J.S. Chmiel, A.C. Moorman, A.E. Greenberg, S.D. Holmberg.

Final approval of the article: F.J. Palella, M. Deloria-Knoll, J.S. Chmiel, A.C. Moorman, K.C. Wood, A.E. Greenberg, S.D. Holmberg.

Provision of study materials or patients: F.J. Palella.

Statistical expertise: M. Deloria-Knoll, J.S. Chmiel.

Obtaining of funding: K.C. Wood.

Administrative, technical, or logistic support: F.J. Palella, A.C. Moorman, K.C. Wood, S.D. Holmberg.

Collection and assembly of data: F.J. Palella, A.C. Moorman, K.C. Wood, S.D. Holmberg.

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