Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy

A Randomized Trial

2 September 2008 | Volume 149 Issue 5 | Pages 289-299

Background: Episodic use of antiretroviral therapy guided by CD4⁺ cell counts is inferior to continuous antiretroviral therapy.

Objective: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death.

Design: Randomized, controlled trial.

Setting: Sites in 33 countries.

Patients: 5472 HIV-infected individuals with CD4⁺ cell counts greater than 0.350 x 10⁹ cells/L enrolled from January 2002 to January 2006.

Intervention: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment.

Measurements: Opportunistic disease or death was the primary outcome.

Results: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4⁺ cell counts were 0.152 x 10⁹ cells/L (95% CI, 0.136 to 0.167 x 10⁹ cells/L) less in participants previously assigned to episodic treatment (P < 0.001). The proportion of follow-up time spent with CD4⁺ cell counts of 0.500 x 10⁹ cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels 400 copies/mL after 6 months), but CD4⁺ cell counts after 6 months remained 0.140 x 10⁹ cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4⁺ cell counts for those who reinitiated therapy.

Limitation: Follow-up was too short to assess the full effect of switching from episodic to continuous antiretroviral therapy.

Conclusion: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.

Editors' Notes Context Continuous antiretroviral therapy improves outcomes for patients with HIV compared with episodic, CD4+ cell count–guided therapy. Contribution This long-term follow-up of clinical trial participants demonstrates that the increased hazard of opportunistic disease and death decreases, but is not eliminated, with resumption of continuous antiretroviral therapy in participants initially assigned to episodic therapy. Caution An 18-month follow-up may have been too short to assess true changes in hazard. Implication Patients who receive episodic antiretroviral therapy decrease but do not eliminate their excess risk for disease when they resume continuous treatment. —The Editors

 

Author and Article Information

From Harlem Hospital Center, Columbia University, New York, New York; University of Minnesota, Minneapolis, Minnesota; Community Research Initiative of New England, Boston, Massachusetts; Medical Research Council, Clinical Trials Unit, London, United Kingdom; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; and Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.

Writing Group: W.M. El-Sadr, B. Grund, J. Neuhaus, A. Babiker, C.J. Cohen, J. Darbyshire, S. Emery, J.D. Lundgren, A. Phillips, and J.D. Neaton.

Grant Support: By the National Institute of Allergy and Infectious Disease, National Institutes of Health (grants U01AI042170, U01AI46362, and U01AI068641).

Potential Financial Conflicts of Interest: Consultancies: C.J. Cohen (GlaxoSmithKline, Bristol-Meyers Squibb, Abbott, Merck, Pfizer, Gilead, Johnson & Johnson), S. Emery (Tibotec, Bristol-Meyers Squibb, Gilead), J.D. Lundgren (Abbott, Bristol-Meyers Squibb, Merck, GlaxoSmithKline, Gilead, Tibotec, Pfizer, Roche). Honoraria: C.J. Cohen (Johnson & Johnson, Gilead, Pfizer, Merck, Abbott, Bristol-Meyers Squibb, GlaxoSmithKline), J.D. Lundgren (Abbott, Bristol-Meyers Squibb, Merck, GlaxoSmithKline, Gilead, Tibotec, Pfizer, Roche). Grants received: C.J. Cohen (GlaxoSmithKline, Bristol-Meyers Squibb, Abbott, Merck, Pfizer, Gilead, Johnson & Johnson), S. Emery (Gilead Sciences, Bristol-Meyers Squibb, GlaxoSmithKline, Roche, Abbott, Abbott Laboratories, MRL), J.D. Lundgren (Roche, Pfizer, Tibotec, Gilead, GlaxoSmithKline, Merck, Bristol-Meyers Squibb, Abbott).

Reproducible Research Statement: Study protocol: Available at http://www.insight-trial.org. Statistical code and data set: Not available.

Requests for Single Reprints: James D. Neaton, PhD, Division of Biostatistics, School of Public Health, University of Minnesota, 2221 University Avenue Southeast, Room 200, Minneapolis, MN 55414; e-mail, jim{at}ccbr.umn.edu.

Current Author Addresses: Dr. El-Sadr: Harlem Hospital Center, Division of Infectious Diseases/Medicine, 506 Lenox Avenue, Suite 3101A, New York, NY 10037.

Drs. Grund and Neaton and Ms. Neuhaus: Division of Biostatistics, School of Public Health, University of Minnesota, 2221 University Avenue Southeast, Suite 200, Minneapolis, MN 55414-3080.

Dr. Cohen: Community Research Initiative of New England, 23 Miner Street, Boston, MA 02215.

Drs. Darbyshire and Babiker: Medical Research Council, Clinical Trials Unit, 222 Euston Road, London NW1 2DA, United Kingdom.

Dr. Emery: National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, University of New South Wales, Sydney, New South Wales 2010, Australia.

Dr. Lundgren: Rigshospitalet and University of Copenhagen, Copenhagen HIV Programme, Panum Institute (21.1), Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Dr. Phillips: Royal Free and University College Medical School, Department of Primary Care and Population Sciences, HIV Epidemiology & Biostatistics Group, University College London (Hampstead Campus), Rowland Hill Street, London NW3 2PF, United Kingdom.

Author Contributions: Conception and design: W.M. El-Sadr, C.J. Cohen, S. Emery, J.D. Lundgren, J.D. Neaton.

Analysis and interpretation of the data: W.M. El-Sadr, B. Grund, J. Neuhaus, C.J. Cohen, S. Emery, A. Phillips, J.D. Neaton.

Drafting of the article: W.M. El-Sadr, B. Grund, J. Neuhaus, J.D. Neaton.

Critical revision of the article for important intellectual content: W.M. El-Sadr, B. Grund, A. Babiker, C.J. Cohen, J. Darbyshire, S. Emery, J.D. Lundgren, A. Phillips, J.D. Neaton.

Final approval of the article: W.M. El-Sadr, B. Grund, J. Neuhaus, A. Babiker, C.J. Cohen, J. Darbyshire, S. Emery, J.D. Lundgren, A. Phillips, J.D. Neaton.

Provision of study materials or patients: W.M. El-Sadr, C.J. Cohen, J.D. Lundgren.

Statistical expertise: B. Grund, A. Babiker, J. Darbyshire, A. Phillips, J.D. Neaton.

Obtaining of funding: J.D. Neaton.

Administrative, technical, or logistic support: A. Babiker, J. Darbyshire, S. Emery, J.D. Neaton.

Collection and assembly of data: A. Babiker, J. Darbyshire, S. Emery, J.D. Lundgren, J.D. Neaton.

ClinicalTrials.gov registration number: NCT00027352.

^* For writing group members, see end of article; for investigators in the SMART Study Group, see the Appendix.

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