Intensification of Antiretroviral Therapy with a CCR5 Antagonist in Patients with Chronic HIV-1 Infection: Effect on T Cells Latently Infected

Abstract

ObjectiveThe primary objective was to assess the effect of MVC intensification on latently infected CD4+ T cells in chronically HIV-1-infected patients receiving antiretroviral therapy.MethodsWe performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation.ResultsOverall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4+ or CD8+ counts, although a significant decrease was found in the proportion of HLA-DR+/CD38+ CD4+ and CD8+ T-cells. LPS and sCD14 levels increased.ConclusionsIntensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results.Trial RegistrationClinicalTrials.gov NCT00795444

Effect of Maraviroc on HIV Disease Progression-Related Biomarkers

“…The decrease of D dimer levels which have been associated with lower cardiovascular risk in HIV-infected patients (4) could also be clinically relevant. However, these results contradict the increase in sCD14 levels observed after MVC intensification in a recent study (14). In fact, the higher levels found in that study were statistically significant after 24 to 48 weeks, but not at 12 weeks, on cART, and the previous study included a very different set of patients (under an MVC intensification strategy, on suppressive cART, and with much higher CD4 ϩ T-cell levels than patients in the present work).…”

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

“…[36][37][38][39] However, none of these studies was placebo-controlled, and subjects often improve their ART adherence when entering clinical trials, which may have explained the reduction in low-level viremia experienced by placebo-treated subjects in our own trial and in another recently reported intensification study. 40 The apparent reduction in T-cell activation during maraviroc intensification reported in the uncontrolled AIDS clinical trials group study (A5256) was also primarily driven by declines in CD38 expression, whereas HLA-DR expression actually increased significantly (which is largely consistent with our results), and neither of those changes were confirmed when retesting cryopreserved PBMCs from that trial.…”

The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression

“…We combined the data of two pilot open-label phase II clinical trials to evaluate the effect of maraviroc (ERRAD-VIH-01 (MRV): NCT00795444) 30 and raltegravir (ERRADVIH-02 (RAL): NCT00807443) 31 on the HIV latent reservoir. The studies were conducted at the Hospital Universitario Ram on y Cajal in Madrid, Spain, between 2008 and 2010.…”

“…30,31 Briefly, PBMCs were isolated by Ficoll density gradient centrifugation (Lymphocytes Isolation Solution, Rafer, S.L., Zaragoza, Spain) from 300 mL of heparinised whole blood. Resting CD4 þ T-cells (CD3 þ /CD4 þ / HLADR À /CD25 À ) were then isolated and purified using magnetic beads according to the manufacturer's recommendations (Miltenyi Biotec GmbH., Bergisch Gladbach, Germany).…”