Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2013 Nov 1;208(9):1436-42.
doi: 10.1093/infdis/jit453. Epub 2013 Aug 23.

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  1 , 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
Affiliations
Randomized Controlled Trial

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 et al. J Infect Dis. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Increase in the level of 2–long terminal repeat (2-LTR) circles in the raltegravir group. The raltegravir group (red) had a significant increase in the level of 2-LTR circles, compared with the placebo group (blue). The week 1 to week 0 ratio was 8.8-fold higher (P = .0025) and the week 2 to week 0 ratio was 5.7-fold higher (P = .023) in the raltegravir group, compared with the placebo group. Nine of the 15 subjects receiving raltegravir had an increase in the level of 2-LTR circles at weeks 1 or 2, compared with 3 of 15 subjects in the placebo group (P = .060; 1 subject in the placebo group was excluded because of no follow-up 2-LTR circle measurements). Black ovals indicate subjects who had an increase in the level of 2-LTR circles at weeks 1 or 2. Asterisks indicate subjects receiving a protease inhibitor as part of their antiretroviral therapy regimen.
Figure 2.
Figure 2.
Raltegravir intensification leads to a decrease in D-dimer levels. Raltegravir intensification led to a significant decrease in D-dimer levels from week 0 to week 24 (change in D-dimer levels, −0.26 log2 μg/mL in the raltegravir group and +0.49 log2 μg/mL in the placebo group; P = .045). Data for 3 subjects (1 in the raltegravir group and 2 placebo group) are missing.
See this image and copyright information in PMC

Comment in

References

    1. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187:1534–43. - PubMed
    1. Hunt PW, Cao HL, Muzoora C, et al. Impact of CD8+ T cell activation on CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS. 2011;25:2123–31. - PMC - PubMed
    1. Hatano H, Jain V, Hunt PW, et al. Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. J Infect Dis. 2013;208:50–6. - PMC - PubMed
    1. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–4. - PubMed
    1. Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12:1198–202. - PubMed

Publication types

MeSH terms