Increase in 2-long terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with treated HIV Infection: A randomized, placebo-controlled trial

Hiroyu Hatano, Matthew C. Strain, Rebecca Scherzer, Peter Bacchetti, Deborah Wentworth, Rebecca Hoh, Jeffrey N. Martin, Joseph M. Mccune, James D. Neaton, Russell P. Tracy, Priscilla Y. Hsue, Douglas D. Richman, Steven G. Deeks

Research output: Contribution to journalArticlepeer-review

145 Scopus citations


Background. The degree to which human immunodeficiency virus (HIV) continues to replicate during antiretroviral therapy (ART) is controversial. We conducted a randomized, double-blind, placebo-controlled study to assess whether raltegravir intensification reduces low-level viral replication, as defined by an increase in the level of 2-long terminal repeat (2-LTR) circles.Methods. Thirty-one subjects with an ART-suppressed plasma HIV RNA level of <40 copies/mL and a CD4+ T-cell count of ≥350 cells/mm3 for ≥1 year were randomly assigned to receive raltegravir 400 mg twice daily or placebo for 24 weeks. 2-LTR circles were analyzed by droplet digital polymerase chain reaction at weeks 0, 1, 2, and 8.Results. The median duration of ART suppression was 3.8 years. The raltegravir group had a significant increase in the level of 2-LTR circles, compared to the placebo group. The week 1 to 0 ratio was 8.8-fold higher (P =. 0025) and the week 2 to 0 ratio was 5.7-fold higher (P =. 023) in the raltegravir vs. placebo group. Intensification also led to a statistically significant decrease in the D-dimer level, compared to placebo (P =. 045).Conclusions. Raltegravir intensification resulted in a rapid increase in the level of 2-LTR circles in a proportion of subjects, indicating that low-level viral replication persists in some individuals even after long-term ART. Intensification also reduced the D-dimer level, a coagulation biomarker that is predictive of morbidity and mortality among patients receiving treatment for HIV infection.

Original languageEnglish (US)
Pages (from-to)1436-1442
Number of pages7
JournalJournal of Infectious Diseases
Issue number9
StatePublished - Nov 1 2013

Bibliographical note

Funding Information:
Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (grants R01 AI087145, K24 AI069994, AI080193, AI69432, AI047745, and AI74621); the Delaney AIDS Research Enterprise (grant U19 AI0961090); the Collaboratory for AIDS Research on Eradication (grant U19 AI096113); the National Heart Lung and Blood Institute (grant R01 HL095130); the American Foundation for AIDS Research (grant 106710–40-RGRL); the UCSF/Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR; grant P30 AI027763); the University of California, San Diego, CFAR (grant AI306214); the University of California, San Francisco, Clinical and Translational Research Institute Clinical Research Center (grant UL1 RR024131); the Center for AIDS Prevention Studies (grant P30 MH62246); the CFAR Network of Integrated Systems (grant R24 AI067039); and the Department of Veterans Affairs.


  • 2-LTR circles
  • D-dimer
  • HIV
  • ongoing viral replication
  • raltegravir intensification


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