0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Articles |

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

The SMART Study Group
[+] Article and Author Information

ClinicalTrials.gov registration number: NCT00027352.

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


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@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.


Ann Intern Med. 2008;149(5):289-299. doi:10.7326/0003-4819-149-5-200809020-00003
Text Size: A A A

As a consequence of the recommendation to initiate antiretroviral therapy for treatment-experienced participants in the drug conservation group, excess risk for opportunistic disease or death statistically significantly decreased during the 18 months after study modification compared with the period before study modification. Treatment HRs for other major outcomes also decreased. However, residual excess risk remained at study closure. We attribute the residual excess risk for opportunistic disease or death to lower CD4+ cell counts and higher HIV RNA levels for drug conservation participants compared with viral suppression participants during the post–study modification period.

First Page Preview

View Large
/>
First page PDF preview

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

* Discontinues or defers antiretroviral therapy (ART) until CD4+ cell count decreases to <0.250 × 109 cells/L, treats to increase CD4+ cell counts >0.350 × 109 cells/L, then uses episodic ART based on CD4+ cell count.

† Uses ART to maintain viral load as low as possible, regardless of CD4+ cell count, by changing ART when viral load is not suppressed.‡ Recommended restarting ART in participants in the drug conservation group unless they are still ART-naive.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Percentages of participants with HIV RNA levels of 400 copies/mL or less and mean CD4+ cell counts through follow-up.

ART = antiretroviral therapy; DC = drug conservation; VS = viral suppression. A. Percentage of participants with HIV RNA levels ≤400 copies/mL, by treatment group from randomization through the first 4 months and from study modification in January 2006 through study closure. Follow-up time before study modification ranged from 0 to 48 months, depending on the date of enrollment. B. Mean CD4+ cell counts, by treatment group. The gray bars in panels A and B show the percentage of participants in the DC group who received ART. The percentage increased from 35.6% at study modification to 67.0%, 74.2%, 80.5%, and 83.4% at 3, 6, 12, and 18 months after study modification, respectively. The vertical bars show ±2 SEs. C. Percentage with HIV RNA levels ≤ 400 copies/mL among DC participants who received ART at study entry, did not receive ART on 11 January 2006, and restarted ART after study modification. D. Mean CD4+ counts for DC group participants who received ART at study entry, did not receive ART on 11 January 2006, and restarted ART after 11 January 2006.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Kaplan–Meier curves for the cumulative probability of opportunistic disease or death from any cause before (top) and after (bottom) study modification.

Estimated cumulative probabilities of the primary end point for the first 18 months after randomization, censored at study modification (top). Cumulative probabilities from study modification to study closure 18 months later; participants who experienced a primary event before study modification were excluded (bottom). DC = drug conservation; HR = hazard ratio; VS = viral suppression.* Censored at the date of study modification.† After study modification.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Percentages of follow-up time spent in categories by latest CD4+ cell counts and latest HIV RNA levels and rates of opportunistic disease or death during this time.

Stacked vertical bars on the left show the percentage of follow-up time spent in each of the 6 categories, by latest CD4+ counts <0.350, 0.350 to 0.499, and ≥0.500 × 109 cells/L and latest HIV RNA levels >400 and ≤400 copies/mL for participants in the drug conservation (DC) group (solid line) and viral suppression (VS) group (dotted line). Percentage of follow-up time appears to the right of the stacked vertical bars. Horizontal bars show the rates of opportunistic disease (OD) or death during follow-up spent at the latest CD4+ and HIV RNA levels in the DC and VS groups. Numbers to the right of the bars are the rates per 100 person-years (PY) (number of events, number of PY).

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Renal Outcomes in SMART
Posted on September 25, 2008
Samir K. Gupta
Indiana University School of Medicine
Conflict of Interest: None Declared

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.

References

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.

Conflict of Interest:

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.

Re: Renal Outcomes in SMART
Posted on October 22, 2008
James D. Neaton
University of Minnesota
Conflict of Interest: None Declared

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

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

Outcomes of HIV Infection in Persons Who Resume Treatment after Interruptions

The summary below is from the full report titled “Risk for Opportunistic Disease and Death after Reinitiating Continuous Antiretroviral Therapy in Patients with HIV Previously Receiving Episodic Therapy. A Randomized Trial.” It is in the 2 September 2008 issue of Annals of Internal Medicine (volume 149, pages 289-299). The author is the SMART Study Group.

Read More...

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Topic Collections
PubMed Articles

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)