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

• Published in: The Journal of infectious diseases Vol. 208; no. 9; pp. 1436 - 1442
• Main Authors: Hatano, Hiroyu, Strain, Matthew C., Scherzer, Rebecca, Bacchetti, Peter, Wentworth, Deborah, Hoh, Rebecca, Martin, Jeffrey N., McCune, Joseph M., Neaton, James D., Tracy, Russell P., Hsue, Priscilla Y., Richman, Douglas D., Deeks, Steven G.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-11-2013
• Series: Editor's choice
• Subjects: AIDS; Antiretroviral Therapy, Highly Active; Antiretrovirals; Biological and medical sciences; Biological markers; Biomarkers - blood; DNA; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products - metabolism; Fundamental and applied biological sciences. Psychology; HIV; HIV 1; HIV infections; 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; HIV/AIDS; Human immunodeficiency virus; Human viral diseases; Humans; Infectious diseases; Major and Brief Reports; Male; Medical sciences; Microbiology; Middle Aged; Placebos; Pyrrolidinones - administration & dosage; Raltegravir Potassium; RNA; T lymphocytes; Treatment Outcome; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virus Replication - drug effects; Infection; Immunopathology; Antiretroviral agent; Integrase inhibitor; Viral disease; Antiviral; AIDS; LTR sequence; Immune deficiency; Raltegravir; D-dimer; 2-LTR circles; HIV; ongoing viral replication; raltegravir intensification
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit453

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.