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Switch to maraviroc/raltegravir dual therapy leads to an unfavorable immune profile with low-level HIV viremia
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AIDS April 24 2015
Campillo-Gimenez, Laurea; Assoumou, Lambertb,c; Valantin, Marc-Antoineb,c,d; Pajanirassa, Priyadharshinia; Villemonteix, Juliettee; Soulie, Cathiab,c,f; Marcelin, Anne-Genevieveb,c,f; Costagliola, Dominiqueb,c; Capeau, Jacquelineg,h,i; Autran, Brigittea,e,j; Katlama, Christineb,c,d,*; Guihot, Ameliea,e,j,*; on behalf of the ROCnRAL ANRS 157 Study Group
Immunovirological consequences of a switch to a maraviroc/raltegravir dual therapy were analyzed in 16 HIV-infected patients with persistent viral load below 50 copies/ml. At 26-week postswitch, the CD4+/CD8+ ratio decreased and the CD8+ T-cell activation increased. A decrease in classical monocytes was associated with a shift toward a proinflammatory monocyte profile and negatively correlated with ultrasensitive viral load. Thus, this therapeutic switch induced a proinflammatory profile probably driven by a slight loss of virus control. Immune activation with an increase in inflammation markers, a decreased CD4+/CD8+ ratio, expression of activation/exhaustion markers on T cells, and monocyte activation are biological hallmarks of HIV infection that may persist despite antiretroviral therapy (ART) induced viral suppression [1,2]. These alterations are associated with the emergence of non-AIDS-related diseases in long-term-treated patients [3,4]. T-cell activation [5] and ART with both nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors [6,7] have been associated with lipodystrophy in up to 40% of patients. Thus, the ROCnRAL Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS) 157 study (ClinicalTrials.gov: NCT1420523) was designed to evaluate whether a NRTI/protease inhibitors-sparing regimen such as maraviroc and raltegravir (MVC/RAL) could maintain viral suppression and be beneficial on both lipodystrophy and immune activation/inflammation parameters as suggested by others [8-13]. However, the trial had to be stopped after a median duration of 19 weeks due to virological failure in five of 44 patients [14].
The present immunological substudy could nevertheless be conducted to explore monocyte and T-cell activation in parallel to plasma soluble markers of activation and inflammation in a subgroup of volunteer patients maintaining a viral load below 50 copies/ml following the MVC/RAL switch. Sixteen patients were included and monitored at baseline (W0) but not all patients reached the end of treatment (eTT; median = 26 weeks, range 12-40) because of the premature termination of the study. Changes in continuous variables were compared using paired Wilcoxon test. At baseline, median age was 55 years [interquartile range (IQR): 53/60], male/female sex 15/1, time since HIV diagnosis 24 years (IQR: 14-25), combination ART duration 17 years (IQR: 12/19), with a median duration of 5.2 years (IQR: 5.0/8.6) of suppressed HIV-viremia (<50 copies/ml), and CD4+ nadir of 162 cells/mm3 (IQR: 129/280). These clinical characteristics were similar to those of the total ROCnRAL cohort [14].
At W0, 13/16 patients had CD4+ cell counts above 500/mm3 (median = 702, IQR: 559/798) and seven of 16 had CD8+ cell counts above 700/mm3 (median = 994, IQR: 799/1012). At eTT compared with W0, CD4 and CD8 counts were similar despite a decrease in CD4+ cell counts in eight of 13 patients, an increase in CD8+ counts in six of 13 patients, and an overall decrease in the CD4+/CD8+ ratios (median = -0.10, IQR: -0.15/+0.02, P = 0.04, Fig. 1a). Moreover, the number of CD38 molecules on CD8+ T cells significantly increased (median = +296 sites/cell, IQR: +4/+791, P = 0.02) reflecting activation of CD8+ T cells, although HLA-DR expression remained unchanged (Fig. 1b).
Monocytes were subdivided on the basis of CD14 and CD16 expression into classical (CD14+ CD16-), intermediate (CD14+ CD16+/low) and nonclassical (CD14low CD16hi) monocytes. At eTT, the percentage of classical monocytes decreased (median = -6.7%, IQR: -2.0/-12.4, P = 0.03) to the benefit of both intermediate and nonclassical monocytes, and CD14 expression significantly decreased on classical monocytes (median = -48.8%, IQR: -41.7-62.1, P = 0.01) (Fig. 1c). These characteristics suggested a progressive phenotypic shift from classical (CD14+) to proinflammatory monocytes (CD14lowCD16hi and CD14+CD16+/low). In contrast, there was no modification of HLA-DR or CD38 molecule expression on the monocyte subpopulations (data not shown). Several soluble plasma molecules related to monocyte activation (sCD14, sCD163), monocyte recruitment (CCL4/MIP-1ß, CXCL9/MIG, CXCL10/IP-10, CCL2/MCP-1), or cytokines monocyte production (interleukin-18, interleukin-6) were quantified. A decrease in sCD14 was observed (median = -277 ng/ml, IQR: -386/-9, P = 0.02), together with a trend toward a sCD163 increase (median = +59 ng/ml, IQR: -3/+101, P = 0.06), whereas there was no differences in cytokines/chemokines levels between W0 and eTT (Fig. 1d).
Finally, the levels of ultrasensitive-HIV-1 viral load (threshold 1 copy/ml) [15] were measured at W0 and eTT despite the fact that all patients remained with viral load below 50 copies/ml. Among the 10/14 patients who had a viral load below 1 copy/ml at W0, four patients showed an increase ultrasensitive-HIV-1 viral load above 1 copy/ml at eTT. Among the four patients with detectable baseline ultrasensitive-HIV-1 viral load, two patients showed a higher eTT viral load (Fig. 1e). Moreover, the eTT viral load levels were inversely correlated with the percentage of classical monocytes (Spearman's test, P = 0.04, rho = -0.77, Fig. 1f), but not with CD38 expression on CD8 T cells (data not shown).
In summary, despite a limited number of patients, this immunological ROCnRAL substudy revealed that the switch to the dual MVC/RAL therapy, even in the absence of apparent viral failure, did not improve but even exaggerated the activation/inflammation status, as shown by, first, decreased CD4+/CD8+ ratios with an increased CD38 expression on CD8 T cells and, second, a monocyte switch toward a proinflammatory phenotype with an increase of sCD163 plasma levels, contrasting with third, a decrease in sCD14 plasma levels.
There might be two potential explanations for this unfavorable biological outcome: first, a paradoxical effect of MVC on CD4+ and CD8+ T-cell activation and CD8+ numbers in blood as previously reported, and presumably linked with an increase in circulating levels of CCR5 ligands [16-19], and, second, a loss of full control of HIV replication as shown by ultrasensitive real time-PCR and as attested by the number of patients with detectable replication even if below 50 copies/ml. The increase in CD8+CD38+ cells and sCD163, two markers of HIV replication [20,21], are in favor of this second HIV replication scenario. In addition, the increase in proinflammatory monocytes, known as the main responders to viral Toll-like receptor (TLR) 7/8 ligands [22], and the negative correlation between the classical monocyte percentages and ultrasensitive-HIV-1 viral load at eTT suggests this shift toward a proinflammatory monocyte profile could be driven by a TLR activation of viral origin. Altogether, these findings proposed that the MVC/RAL switch induces a loss of viral control conducting either to full relapses of virus replication in a few patients, or to low-level virus production in others, and participating to monocytes and T-cell activation and inflammation.
sCD14, derived from membrane CD14 shedding, is a marker of monocyte activation mainly in response to TLR4/lipopolysaccharide signaling [23] and was suggested to reflect microbial translocation [24]. Decreased sCD14 plasma level has been reported after a switch to RAL therapy [17,25,26]. This decline, independently to TLR7/8 derived-monocyte activation might be related to the preservation of the intestinal barrier integrity and limitation of bacterial translocation as a consequence of an optimal penetration of RAL into the gut [27].
In conclusion, this substudy highlighted a dual immunological profile induced by a switch to MVC/RAL therapy in lipohypertrophic ART-suppressed HIV-infected patients, with a favorable decline of CD14 shedding but an unfavorable monocyte and CD8+ activation status that goes along with the previously reported poor viral outcome [14]. These data further stress the necessity that clinical trials evaluating new strategies should include immunological substudies in order to accurately evaluate their consequences on activation and inflammation markers.
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