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Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy
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PNAS - Proceedings of the Natl Ass of Sciences of the USA. Published online before print May 22, 2009
J. B. Dinosoa,b,1, S. Y. Kima,1, A. M. Wiegandc, S. E. Palmerc,2, S. J. Ganged, L. Cranmera, A. O?Sheae, M. Callendera,
A. Spivaka, T. Brennana, M. F. Kearneyc, M. A. Proschanf, J. M. Micang, C. A. Rehmg, J. M. Coffinc,h,3, J. W. Mellorsi,
R. F. Silicianoa,j, and F. Maldarellic,3
Departments of aMedicine and bPharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; cHIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702; dDepartment of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205; eCritical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892; fBiostatistics Research Branch and gDivision of Clinical Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892; hDepartment of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111; iDepartment of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and jHoward Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
Contributed by J. M. Coffin, March 23, 2009 (sent for review February 13, 2009)
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Abstract
In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.
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