Addition of Maraviroc Versus Placebo to Standard Antiretroviral Therapy for Initial Treatment of Advanced HIV Infection

Lévy, Yves; Lelièvre, Jean‐Daniel; Assoumou, Lambert; Aznar, E. Ubiña; Pulido, Federico; Tambussi, Giuseppe; Crespo, Manuel; Meybeck, Agnès; Molina, Jean‐Michel; Delaugerre, Constance; Izopet, Jacques; Peytavin, Gilles; Cardon, Fanny; Diallo, Alpha; Lancar, Rémi; Beniguel, Lydie; Costagliola, Dominique

doi:10.7326/m19-2133

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…23 More generally, 2 controlled clinical trials showed that maraviroc added to standard antiretroviral therapy for advanced HIV did not mitigate the risk of developing IRIS. 24,25 We may, however, point that in our study, the overall outcome at last follow-up showed a tendency to a lower degree of disability in the maraviroc group. This clinically meaningful difference may be due in the control group to a longer follow-up and to the late death (>12 months) of 1 patient due to status epilepticus on PML lesions.…”

Section: Discussioncontrasting

confidence: 70%

CCR5 Blockade in Inflammatory PML and PML-IRIS Associated With Chronic Inflammatory Diseases' Treatments

Bernard‐Valnet

Moisset

Maubeuge

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesProgressive multifocal leukoencephalopathy (PML) is a disabling neurologic disorder resulting from the infection of the CNS by JC polyomavirus in immunocompromised individuals. For the last 2 decades, increasing use of immunotherapies leads to iatrogenic PML. Iatrogenic PML is often associated with signs of inflammation at onset (inflammatory PML) and/or after treatment withdrawal immune reconstitution inflammatory syndrome (PML-IRIS). Although immune reconstitution is a key element for viral clearance, it may also be harmful and induce clinical worsening. A C-C chemokine receptor type 5 (CCR5) antagonist (maraviroc) has been proposed to prevent and/or limit the deleterious immune responses underlying PML-IRIS. However, the data to support its use remain scarce and disputed.MethodsWe conducted a multicenter retrospective cohort study at 8 university hospitals in France and Switzerland by collecting clinical, biological, and radiologic data of patients who developed inflammatory PML (iPML) or PML-IRIS related to immunosuppressive therapies used for chronic inflammatory diseases between 2010 and 2020. We added to this cohort, a meta-analysis of individual case reports of patients with iPML/PML-IRIS treated with maraviroc published up to 2021.ResultsOverall, 27 cases were identified in the cohort and 9 from the literature. Among them, 27 met the inclusion criteria: 16 treated with maraviroc and 11 with standard of care (including corticosteroids use). Most cases were related to MS (92.6%) and natalizumab (88%). Inflammatory features (iPML) were present at onset in 12 patients (44.4%), and most patients (92.6%) received corticosteroids within the course of PML. Aggravation due to PML-IRIS was not prevented by maraviroc compared with patients who received only corticosteroids (adjusted odds ratio: 0.408, 95% CI: 0.06–2.63). Similarly, maraviroc did not influence time to clinical worsening due to PML-IRIS (adjusted hazard ratio = 0.529, 95% CI: 0.14–2.0) or disability at the last follow-up (adjusted odds ratio: 2, 95% CI: 0.23–17.3).DiscussionThe use of CCR5 blockade did not help to keep deleterious immune reconstitution in check even when associated with corticosteroids. Despite maraviroc's reassuring safety profile, this study does not support its use in iPML/PML-IRIS.Classification of EvidenceThis study provides Class IV evidence showing that adding maraviroc to the management of iatrogenic iPML/PML-IRIS does not improve the outcome.

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Section: Discussioncontrasting

confidence: 70%

CCR5 Blockade in Inflammatory PML and PML-IRIS Associated With Chronic Inflammatory Diseases' Treatments

Bernard‐Valnet

Moisset

Maubeuge

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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“…In our research, tumor buddings can recruit broblasts through CCR5 receptor in the process of invasion and it is a vital step for further angiogenesis and collagen synthesis. CCR5 inhibitor Maraviroc, as a therapeutic drug for HIV, has been relatively mature in clinical treatment [44][45][46]. There is also study demonstrated that tumoral immune cells can be targeted effectively in CRC metastasis by anti-CCR5 therapy in cancer patients [47].…”

Section: Discussionmentioning

confidence: 99%

Tumor Budding-Derived CCL5 Recruits Fibroblasts to Promote Colorectal Cancer Progression Through CCR5-SLC25A24 Signaling

Gao¹,

Zhong²,

Long³

et al. 2021

Preprint

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Background: Tumor buddings have been included in the routine diagnosis of colorectal cancer (CRC) and considered to be a tumor prognostic factor independent of TNM staging. This study aimed at identifying the contribution of tumor budding-derived C-C chemokine ligand 5 (CCL5) to tumor microenvironment (TME) through fibroblasts. Methods: Co-cultivation recruitment assays and human cytokine array were used to detect the main cytokine derived from CRC tumor buddings to recruit fibroblasts. siRNA transfection and inhibitor treatment were applied to investigate the effective receptor of CCL5 on fibroblasts. Transcriptome sequencing was performed to explore the mechanism inside fibroblasts when stimulated by CCL5. Stimulation with CCL5 in vitro, orthotopic xenograft mouse model and clinical specimens were designed to clarify the contribution of CCL5 to angiogenesis and collagen synthesis.Results: H&E and immunochemistry staining confirmed that CRC with tumor buddings in the invasive front was accompanied by more fibroblasts compared with CRC without tumor buddings. Further vitro study indicated that CCL5 derived from tumor buddings could recruit fibroblasts through CCR5 receptor on fibroblasts and positively regulate solute carrier family 25 member 24 (SLC25A24) expression in fibroblasts, which could activate pAkt-pmTOR signaling. Moreover, CCL5 can increase the number of α-SMA+CD90+FAP- fibroblasts to promote tumor angiogenesis through enhancing the expression of VEGFA and making fibroblasts transdifferentiate into vascular endothelial cells. Meanwhile, CCL5 also can promote collagen synthesis through fibroblasts, thus contributing to tumor progression.Conclusions: In the invasive front of CRC, tumor-budding-derived CCL5 can recruit fibroblasts through CCR5-SLC25A24 signaling, further promoting angiogenesis and collagen synthesis through fibroblasts, eventually creating a tumor-promoting microenvironment.

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“… 85 Furthermore, in 2 randomized studies, maraviroc failed to prevent IRIS observed in the context of ART introduction. 86 , 87 Further studies are needed to determine the role of maraviroc in PML‐IRIS.…”

Section: Prevention and Treatment Of Irismentioning

confidence: 99%

“…In HIV‐infected patients, ART including maraviroc was not efficient at preventing PML‐IRIS 85 . Furthermore, in 2 randomized studies, maraviroc failed to prevent IRIS observed in the context of ART introduction 86,87 . Further studies are needed to determine the role of maraviroc in PML‐IRIS.…”

Section: Prevention and Treatment Of Irismentioning

confidence: 99%

Advances in Treatment of Progressive Multifocal Leukoencephalopathy

Bernard‐Valnet

Koralnik

Pasquier

2021

Annals of Neurology

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Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti‐JCV immune responses, and include T‐cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865–873

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Addition of Maraviroc Versus Placebo to Standard Antiretroviral Therapy for Initial Treatment of Advanced HIV Infection

Cited by 7 publications

References 26 publications

CCR5 Blockade in Inflammatory PML and PML-IRIS Associated With Chronic Inflammatory Diseases' Treatments

CCR5 Blockade in Inflammatory PML and PML-IRIS Associated With Chronic Inflammatory Diseases' Treatments

Tumor Budding-Derived CCL5 Recruits Fibroblasts to Promote Colorectal Cancer Progression Through CCR5-SLC25A24 Signaling

Advances in Treatment of Progressive Multifocal Leukoencephalopathy

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