Switching From a Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen: A Randomized Clinical Trial to Determine the Effect on Peripheral Blood and Ileum Biopsies From Antiretroviral Therapy-suppressed Human Immunodeficiency Virus-infected Individuals

Abstract

Background: Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy.

Methods: Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers.

Results: There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4+ T cells in both groups (P < .01). Residual viremia in plasma decreased in the switch group (P = .03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells.

Conclusions: The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4+ T cells.

Clinical trials registration: EudraCT 2014-004331-39.

Keywords: HIV reservoir; dolutegravir; ileum biopsies; immunological and inflammation markers; switching.

Figure 1.

Trial design. A, Consolidated Standards of Reporting Trials (CONSORT) flow diagram for the trial showing the enrollment of 44 subjects who were randomized to the switch or control groups. According to our experience, in order to assess the impact on cryptic human immunodeficiency virus (HIV) replication, it is important to evaluate changes affecting 2-LTR, which, owing to their ephemeral nature, can only be detected in recently infected cells, and changes affecting HIV RNA expression during the first 4 weeks following switching from boosted protease inhibitor to dolutegravir (DTG). Consequently, sample size was estimated on the assumption that switching to DTG is associated with an increase of >30% in the proportion of patients with detectable episomal HIV DNA (2-LTR) in peripheral blood mononuclear cells at study week 4 [13]. Mathematical modeling of data obtained from this study suggests that the transient increase in measured 2-LTR concentration is consistent with the blocking effect of the integrase inhibitor on de novo infection [27]. Taking into account all of the above, a total of 40 individuals was needed, 20 in each group. We recruited 44 subjects to accommodate for dropouts and a 10% loss to follow-up. B, Study design. Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI/r, boosted protease inhibitor.

Figure 2.

Analysis of human immunodeficiency virus (HIV) reservoir dynamics in peripheral CD4⁺ T cells. A, 2-LTR circles. B, Ultrasensitive viral load in plasma. C, Total HIV DNA. D, Integrated HIV DNA. E, Cell-associated unspliced HIV RNA. The switch group is shown in blue and the control group in gray. Solid black dots represent determinations below the limit of quantification. Abbreviations: caHIV, cell-associated HIV; LOQ, limit of quantification.

Figure 3.

Human immunodeficiency virus (HIV) reservoir dynamics and T-cell activation in ileum biopsies. A, Total HIV DNA in ileal vs peripheral CD4⁺ T cells. B and C, Comparison of CD4⁺ and CD8⁺ CD38⁺HLA-DR⁺ T cells in ileum biopsies and in peripheral blood mononuclear cells quantified by FACSAria II and longitudinal follow-up of CD4⁺ and CD8⁺ CD38⁺HLA-DR⁺ T cells in the switch and the control groups. The switch group is shown in blue and the control group in gray. Abbreviation: PBMC, peripheral blood mononuclear cell.

Figure 4.

Analysis of CD4⁺ and CD8⁺ T-cell subsets and activation markers. A, Median CD4⁺ T-cell values for the frequency of the maturation subsets (naive, central memory, effector memory, transitional memory, and effector memory RA⁺) in the control and switch groups at 3 different time points (weeks 0, 12, and 24). Maturation stages were defined based on the combination of CD45RA, CD197 (CCR7), and CD27, as described in “Materials and Methods.” B–G, Dynamics of CD4⁺ T-cell activation (percentage CD4⁺HLA-DR⁺CD38⁺ cells), exhaustion (percentage CD4⁺PD-1⁺), and potential HIV reservoir markers (percentage of CD4⁺LAG-3⁺, CD4⁺TIM-3⁺, CD4⁺CD2^bright, and CD4⁺CD32^bright) in both groups. H, Median CD8⁺ T-cell values for the frequency of the maturation subsets (naive, central memory, effector memory, transitional memory, and effector memory RA⁺) in the control and switch groups at 3 different time points (weeks 0, 12, and 24). I, Dynamics of CD8⁺ T-cell activation (percentage CD8⁺HLA-DR⁺CD38⁺ cells) in both groups. The switch group is shown in blue and the control group in gray.