The SMART Study Group
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, email@example.com.
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.
; Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy: A Randomized Trial. Ann Intern Med. 2008;149:289-299. doi: 10.7326/0003-4819-149-5-200809020-00003
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Published: Ann Intern Med. 2008;149(5):289-299.
The SMART (Strategies for Management of Anti-Retroviral Therapy) study was designed to assess whether the risks associated with long-term use of antiretroviral therapy could be reduced through the episodic use of antiretroviral therapy guided by CD4+ cell counts. This treatment interruption strategy (episodic antiretroviral therapy or drug conservation strategy) was compared with the current practice of continuous antiretroviral therapy (viral suppression strategy). As previously reported, the episodic treatment strategy caused an excess risk for opportunistic diseases or death (the primary end point), an excess risk for serious nonopportunistic diseases, and inferior quality of life compared with the continuous antiretroviral therapy strategy (1–4). The excess risk for opportunistic disease or death due to any cause in the drug conservation group was largely attributable to lower CD4+ cell counts and higher HIV RNA levels during follow-up compared with those in the viral suppression group (1, 5). The episodic treatment strategy was discontinued on 11 January 2006, and all participants assigned to the drug conservation group were advised to reinitiate antiretroviral therapy, except for some who had remained antiretroviral therapy–naive. All participants, including those who were still antiretroviral therapy–naive, were then followed for an additional 18 months.
Samir K. Gupta
Indiana University School of Medicine
September 25, 2008
Renal Outcomes in SMART
TO THE EDITOR: In the recent analysis by the SMART Study Group (1), resumption of continuous antiretroviral therapy after a structured treatment interruption did not fully abrogate the increased risk of serious adverse events and mortality associated with initial assignment to the drug conservation arm of the trial. This suggests that even short periods of untreated HIV infection may confer a greater overall risk of major complications than that posed by the antiretroviral treatments themselves. However, there was a significant interaction between the study period (pre-modification vs. post-modification) and the treatment group assignment (continuous virologic suppression vs. drug conservation) for renal disease events. Although the renal event rates were quite low, this result implies that longer-term, continuous antiretroviral therapy may eventually lead to a higher rate of nephropathy.
It would be of interest to describe more fully the medical and antiretroviral treatment histories, including that of the potentially nephrotoxic antiretroviral drug tenofovir disoproxil fumarate, received by those study participants who developed renal disease and compare them to matched control groups, from both study periods, of those who did not develop such complications. Such an analysis from this well-characterized cohort would be of great value in identifying potential risk factors for renal disease in HIV-infected patients.
1. The SMART Study Group. Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy. Ann Intern Med. 2008;149:289-299.
Dr. Gupta reports having received advisory and speaking fees from Gilead Sciences, Inc. (the manufacturer of tenofovir disoproxil fumarate) and is the Principal Investigator of a phase IV study, sponsored by Gilead Sciences, Inc., studying renal toxicities associated with antiretroviral therapies.
James D. Neaton
University of Minnesota
October 22, 2008
Re: Renal Outcomes in SMART
We concur with Dr. Gupta that the renal outcomes before and after the protocol modification in SMART are interesting and require further study. The interaction p-value corresponding to the treatment hazard ratio comparison before and after the protocol change was significant (p=0.014);however, the number of participants with renal events, defined in SMART as death from renal disease or end stage renal disease (ESRD), was too small (a total of 18 across both treatment groups) to reliably study predictors (1). A careful study of risk factors for renal disease in the SMART study requires more events. Thus, we are exploring the possibility of using stored plasma samples to measure creatinine on SMART participants over the entire follow-up period. With these data, an expanded renal outcome (e.g., death due to renal failure, end stage renal disease or large decline in estimated glomular filtration rate) would result in more events and would allow reliable assessment of risk factors for renal disease as Dr. Gupta suggests.
Our finding that treatment interruption increases risk of renal progression is supported by another recent investigation in SMART (2,3). Stored samples were used to measure cystatin C, a marker of renal function, during the first year of the study, but before the protocol change. Cystatin C levels increased significantly in the treatment interruption group compared to those randomly assigned to receive continuous antiretroviral therapy (3).
Ultimately, we think that the risk and benefits of antiretroviral treatment are best assessed in a randomized trial of early therapy instead of a treatment interruption study like SMART. A trial called the Strategic Timing of AntiRetroviral Therapy (START) study is scheduled to begin next year and is designed to investigate the risk/benefit of early antiretroviral treatment on clinical outcomes, including renal disease, as well as other serious non-AIDS conditions such as cardiovascular disease, liver disease and malignancies.
1. The SMART Study Group. Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy. Ann Intern Med 2008; 149:289-299.
2. The SMART Study Group. CD4+ count-guided interruption of antiretroviral therapy. NEJM 2006; 255:2283-2296.
3. Mocroft A, Wyatt C, Szczech L, Neuhaus J, El-Sadr W, et al. Interruption of antiretroviral therapy is associated with increased plasma cystatin C: results from the SMART study. AIDS (in press).
James D. Neaton for the INSIGHT SMART Study Group
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