Effect of maraviroc on HIV disease progression-related biomarkers

Abstract

The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8(+) T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8(+) T-cell counts and preserved CD4(+) T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8(+) T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients.

Fig 1

Study design. The MVC-specific effect was assessed in patients with the MCT. Afterward (8 days), the patients were divided into two groups, MCT⁻ and MCT⁺, according to the virological response experienced after the MCT. According to this response, the patients were followed for 12 weeks on MVC-containing (MCT⁺ patients) or MVC-sparing (MCT⁻ patients) cART. The same study variables were analyzed at day 8 and week 12 in a control group of patients on MVC-sparing cART.

Fig 2

MVC-specific effects after eight-day therapy. The results are expressed as absolute T-cell numbers (cells/mm³) at day 0 (D0) and day 8 (D8) for every study group. (A and B) CD4⁺ T-cell activation (A) and senescence (B) levels. (C and D) CD8⁺ T-cell activation (C) and senescence (D) levels. (E and F) sCD14 and D dimer levels (E and F, respectively). Horizontal gray bars represent the median values for each data point. Differences along the follow-up were studied using the Wilcoxon test; significant values are depicted with an asterisk. Data from the MCT-negative group (MCT⁻) are represented as triangles, data from the MCT-positive group (MCT⁺) are shown as circles, and data from the control group are shown as squares. The numbers of analyzed patients in the MCT⁻, MCT⁺, and control groups were 12, 28, and 24 (A), 12, 29, and 24 (B), 15, 29, and 23 (C), 14, 27, and 20 (D), 11, 27, and 25 (E), and 9, 19, and 23 (F), respectively.

Fig 3

Absolute TemRA senescent CD4⁺ T-cell levels after 8-day MVC monotherapy and after 12 weeks on cART. The figures show senescent TemRA CD4⁺ T-cell numbers (cells/mm³) at day 0 and day 8 for every study group in panel A and senescent TemRA CD4⁺ T-cell numbers (cells/mm³) at day 0 and week 12 (W12) for every study group in panel B. Horizontal gray bars represent the median values for each data point. Differences during the follow-up were studied using the Wilcoxon test; significant values are depicted with an asterisk. Data from the MCT-negative group (MCT⁻) are represented as triangles, data from the MCT-positive group (MCT⁺) are shown as circles, and data from the control group are shown as squares. The numbers of analyzed patients in the MCT⁻, MCT⁺, and control groups were 6, 22, and 19 (A) and 5, 19, and 9 (B), respectively.

Fig 4

Effect of MVC-containing or MVC-sparing cART after 12 weeks. The results are expressed as absolute T-cell numbers (cells/mm³) at day 0 and week 12 for every study group. (A and B) CD4⁺ T-cell activation (A) and senescence (B) levels. (C and D) CD8⁺ T-cell activation (C) and senescence (D) levels. (E and F) sCD14 and D dimer levels (E and F, respectively). Horizontal gray bars represent the median values for each data point. Differences along the follow-up were studied using the Wilcoxon test; significant values are depicted with an asterisk. Data from the MCT-negative group (MCT⁻) are represented as triangles, data from the MCT-positive group (MCT⁺) are shown as circles, and data from the control group are shown as squares. The numbers of analyzed patients in the MCT⁻, MCT⁺, and control groups were 8, 22, and 13 (A), 10, 23, and 13 (B), 10, 22, and 13 (C), 9, 22, and 9 (D), 9, 22, and 13 (E), and 8, 15, and 13 (F), respectively.