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.
Bibliographical noteFunding 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
- ongoing viral replication
- raltegravir intensification