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

J Infect Dis. 2013 Nov 1;208(9):1436-42. doi: 10.1093/infdis/jit453. Epub 2013 Aug 23.


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/mm(3) 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.

Keywords: 2-LTR circles; D-dimer; HIV; ongoing viral replication; raltegravir intensification.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Antiretroviral Therapy, Highly Active
  • Biomarkers / blood
  • Drug Administration Schedule
  • Female
  • Fibrin Fibrinogen Degradation Products / metabolism*
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Integrase Inhibitors / administration & dosage*
  • HIV Long Terminal Repeat / genetics*
  • HIV-1 / drug effects
  • HIV-1 / genetics*
  • Humans
  • Male
  • Middle Aged
  • Pyrrolidinones / administration & dosage*
  • Raltegravir Potassium
  • Treatment Outcome
  • Virus Replication / drug effects


  • Biomarkers
  • Fibrin Fibrinogen Degradation Products
  • HIV Integrase Inhibitors
  • Pyrrolidinones
  • fibrin fragment D
  • Raltegravir Potassium