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No Effect of Raltegravir Intensification on Viral Replication Markers in the Blood of HIV-1–Infected Patients Receiving Antiretroviral Therapy

Gandhi, Rajesh T. MD*; Coombs, Robert W. MD, PhD†,‡; Chan, Ellen S. MSc§; Bosch, Ronald J. PhD§; Zheng, Lu PhD§; Margolis, David M. MD; Read, Sarah MD; Kallungal, Beatrice BS#; Chang, Ming PhD; Goecker, Erin A. MSc; Wiegand, Ann MS**; Kearney, Mary PhD**; Jacobson, Jeffrey M. MD††; D'Aquila, Richard MD‡‡; Lederman, Michael M. MD§§; Mellors, John W. MD‖‖; Eron, Joseph J. MD§For the AIDS Clinical Trials Group (ACTG) A5244 Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2012 - Volume 59 - Issue 3 - p 229–235
doi: 10.1097/QAI.0b013e31823fd1f2
Basic and Translational Science

Background: Controversy continues regarding the extent of ongoing viral replication in HIV-1–infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication.

Methods: We previously reported the outcome of a randomized placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies per milliliter that showed no effect on residual viremia measured by single copy assay. We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication as follows: 2-LTR HIV-1 circles, total cellular HIV-1 DNA, and T-cell activation.

Results: Of 50 patients tested, 12 (24%) had 2-LTR circles detected at baseline. Patients who were 2-LTR–positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR–negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T-cell activation.

Conclusions: In HIV-1–infected individuals on effective ART, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.

*Division of Infectious Diseases and Ragon Institute, Massachusetts General Hospital, Boston, MA

Department of Laboratory Medicine, Virology Division and

Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA

§Department of Biostatistics, Harvard School of Public Health, Boston, MA

Center for Infectious Diseases, University of North Carolina, Chapel Hill, NC

HIV Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD

#ACTG Operations Center, Social & Scientific Systems, Inc., Silver Spring, MD

**HIV Drug Resistance Program, National Cancer Institute, Frederick, MD

††Division of Infectious Diseases and HIV Medicine, Drexel University, Philadelphia, PA

‡‡Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN

§§Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH

‖‖Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA.

Correspondence to: Rajesh T. Gandhi, MD, Massachusetts General Hospital, GRJ 504, 55 Fruit Street, Boston, MA 02114 (e-mail rgandhi@partners.org).

Supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases. The project was also supported by a grant from the National Institute of Allergy and Infectious Diseases to the Statistical and Data Analysis Center (AI 068634). In addition, J.W.M. was supported by Virology Support Laboratory subcontract (204VC009) of the AIDS Clinical Trials Group Central Group Grant (1U01AI068636) and by National Cancer Institute/Science Applications International Corporation Contract 25XS119. R.T.G. is supported by National Institute of Health R01 AI066992-04A1 and National Institute of Health G08LM008830-01 and by grants to the AIDS Clinical Trials Group (National Institute of Health U01 AI 694722) and the Harvard University Center for AIDS Research (National Institute of Health 2P30 AI060354-06). The Case Western Reserve Immunology Specialty Laboratory is supported by grant AI-68636. R.W.C. received support from the University of Washington Center for AIDS Research (P30-AI-27757) and the AIDS Clinical Trials Group Virology Specialty Laboratory (AI-38858). R.W.C. has received grant support from Roche Molecular Systems and served as a consultant to Abbott Laboratories. The study was also supported in by a research grant from the Investigator-Initiated Studies Program of Merck Sharp and Dohme, Corp.

Portions of this study were previously presented at the 18th Conference on Retroviruses and Opportunistic Infections, February 27 to March 2, 2011, Boston, MA.

R.T.G. has received grant support from Tibotec and Gilead. D.M.M. has served as a consultant and received grant support from Merck, Bristol-Myers Squibb, and Tibotec. J.W.M. is a consultant for Gilead Sciences, Merck, and RFS Pharma and owns share options in RFS Pharma. M.M.L. has served as a consultant to Merck. J.J.E. has served as a consultant and received grant support from Merck and GlaxoSmithKline/Viiv and has served as a consultant for Bristol-Myers Squibb, Tibotec, Gilead, and Tobira. R.D. has received grant support from Merck and Virco and served as a consultant to Tibotec.

The opinions expressed in this article are those of the authors and do not necessarily represent those of Merck Sharp and Dohme Corp.

The content is solely the responsibility of the authors and does not represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Received September 8, 2011

Accepted November 1, 2011

© 2012 Lippincott Williams & Wilkins, Inc.