Maraviroc as Intensification Strategy in HIV-1 Positive Patients with Deficient Immunological Response: an Italian Randomized Clinical Trial

Abstract

BackgroundImmunological non-responders (INRs) lacked CD4 increase despite HIV-viremia suppression on HAART and had an increased risk of disease progression. We assessed immune reconstitution profile upon intensification with maraviroc in INRs.MethodsWe designed a multi-centric, randomized, parallel, open label, phase 4 superiority trial. We enrolled 97 patients on HAART with CD4+<200/µL and/or CD4+ recovery ≤25% and HIV-RNA<50 cp/mL. Patients were randomized 1:1 to HAART+maraviroc or continued HAART. CD4+ and CD8+ CD45+RA/RO, Ki67 expression and plasma IL-7 were quantified at W0, W12 and W48.ResultsBy W48 both groups displayed a CD4 increase without a significant inter-group difference. A statistically significant change in CD8 favored patients in arm HAART+maraviroc versus HAART at W12 (p=.009) and W48 (p=.025). The CD4>200/µL and CD4>200/µL + CD4 gain ≥25% end-points were not satisfied at W12 (p=.24 and p=.619) nor at W48 (p=.076 and p=.236). Patients continuing HAART displayed no major changes in parameters of T-cell homeostasis and activation. Maraviroc-receiving patients experienced a significant rise in circulating IL-7 by W48 (p=.01), and a trend in temporary reduction in activated HLA-DR+CD38+CD4+ by W12 (p=.06) that was not maintained at W48.ConclusionsMaraviroc intensification in INRs did not have a significant advantage in reconstituting CD4 T-cell pool, but did substantially expand CD8. It resulted in a low rate of treatment discontinuations.Trial Registration ClinicalTrials.gov NCT00884858 http://clinicaltrials.gov/show/NCT00884858

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…The compound has been associated with some immunological benefits such as a higher CD4 increase and, although less than expected, reduced immune activation in patients with poor immunological recovery. [186] The drug, used in combination with other ARVs, has been proven to be effective in blocking HIV entry both in naïve and in experienced patients. The CNS target cells are usually expressing the CCR5 and most of the viruses are R5 tropic in the CSF (even if patients harbour X4-tropic viruses); discordant tropism (X4 in CSF samples and R5 in plasma)…”

Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy

“…Further, up to 30% of treated patients fail to recover peripheral CD4 þ [immunological nonresponders (INR)] [35], particularly those starting cART late in the course of disease, with severe CD4 þ depletion. This particular outcome has been associated with a high risk of clinical events and death [36][37][38] as well as poor response to experimental treatments [39][40][41][42][43][44].…”

A Four-Drug Induction Therapy Including Raltegravir for the Treatment of Naïve HIV-Infected Patients

“…This increase might be due to the effect of intensification therapy, especially on the ongoing viral replication. Several clinical trials have argued on ART intensification, and the results were conflicting; no effects on the residual viremia measured by the single copy assay [20][21][22] or on immunological recovery [23] were reported. Some observational studies showed that at least 76% of HIV infected patients starting ART achieved an undetectable viral load within the first 6 months of therapy [24], while a percentage of 9%-45% did not obtain an appropriate recovery of CD4+ T cells count [25,26].…”