Maraviroc as intensification strategy in HIV-1 positive patients with deficient immunological response: an Italian randomized clinical trial

Stefano Rusconi, Paola Vitiello, Fulvio Adorni, Elisa Colella, Emanuele Focà, Amedeo Capetti, Paola Meraviglia, Clara Abeli, Stefano Bonora, Marco D'Annunzio, Antonio Di Biagio, Massimo Di Pietro, Luca Butini, Giancarlo Orofino, Manuela Colafigli, Gabriella d'Ettorre, Daniela Francisci, Giustino Parruti, Alessandro Soria, Anna Rita Buonomini, Chiara Tommasi, Silvia Mosti, Francesca Bai, Silvia Di Nardo Stuppino, Manuela Morosi, Marco Montano, Pamela Tau, Esther Merlini, Giulia Marchetti, Stefano Rusconi, Paola Vitiello, Fulvio Adorni, Elisa Colella, Emanuele Focà, Amedeo Capetti, Paola Meraviglia, Clara Abeli, Stefano Bonora, Marco D'Annunzio, Antonio Di Biagio, Massimo Di Pietro, Luca Butini, Giancarlo Orofino, Manuela Colafigli, Gabriella d'Ettorre, Daniela Francisci, Giustino Parruti, Alessandro Soria, Anna Rita Buonomini, Chiara Tommasi, Silvia Mosti, Francesca Bai, Silvia Di Nardo Stuppino, Manuela Morosi, Marco Montano, Pamela Tau, Esther Merlini, Giulia Marchetti

Abstract

Background: Immunological 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.

Methods: We 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.

Results: By 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.

Conclusions: Maraviroc 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 https://ichgcp.net/clinical-trials-registry/NCT00884858.

Conflict of interest statement

Competing Interests: Stefano Rusconi has been involved with CME activities and speakers bureau fees by GlaxoSmithKline, now ViiV Healthcare and received funding from a commercial source (Pfizer, Inc.). This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. All other authors have nothing to declare.

Figures

Figure 1. Flow chart illustrating the entire…
Figure 1. Flow chart illustrating the entire study population.
Figure 2. Plasma CD4+/CD8+ count and overtime…
Figure 2. Plasma CD4+/CD8+ count and overtime change at baseline, week 12, and week 48 in the two study arms in the intention to treat analysis.
A CD4+ count at baseline at week 12 and week 48 in arm A and B on the ITT analysis. CD4+ ITT analysis evidenced: in arm A a median count of 192 cell/µL at baseline, 212 cells/µL at week 12 and 223 cells/ µL at week 48; in arm B a median count of 169 cell/µL at baseline, 175 cells/µL at week 12 and 169 cells/µL at week 48. Box-plots (25% and 75% values) are presented. B CD4+ count change from baseline at week 12 and week 48 in the two study arms in the intention to treat analysis. The vertical lines represent the standard deviation. C CD8+ count at baseline at week 12 and week 48 in arm A and B on the ITT analysis. CD8+ ITT analysis evidenced: in arm A a median count of 580 cells/µL at baseline, 634 cells/µL at week 12 and 585 cells/µL at week 48; in arm B a median count of 725 cells/µL at baseline, 681 cells/µL at week 12 and 687 cells/µL at week 48. Box-plots (25% and 75% values) are presented. D CD8+ count change from baseline at week 12 and week 48 in the two study arms in the intention to treat analysis. The vertical lines represent the standard deviation.
Figure 3. Naive and memory T-cell phenotypes…
Figure 3. Naive and memory T-cell phenotypes in Immunological Non Responders with and without HAART intensification with MVC.
A. Percentage of naive CD45RA+CD62L+CD4+ T-cells. B. Percentage of naïve CD45RA+CD62L+CD8+ T-cells. C. Percentage of memory CD45RA-CD4+ T-cells. D. Percentage of memory CD45RA-CD8+ T-cells. The vertical lines represent median and interquartile ranges (25th and 75th percentiles).
Figure 4. T-cells activation and proliferation in…
Figure 4. T-cells activation and proliferation in Immunological Non Responders with and without HAART intensification with MVC.
A-B. T-cell activation defined as the co-expression of HLA-DR and CD38 on CD4+ and CD8+. C-D. T-cell proliferation defined as the expression of Ki67 on CD4+ and CD8+. The vertical lines represent median and interquartile ranges (25th and 75th percentiles).
Figure 5. IL-7/IL-7R system in Immunological Non…
Figure 5. IL-7/IL-7R system in Immunological Non Responders with and without HAART intensification with MVC.
A. Percentage of CD127+CD4+ T-cells. B. Percentage of CD127+CD8+ T-cells. C. Plasma levels of IL-7. The vertical lines represent median and interquartile ranges (25th and 75th percentiles).

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