Impact of intensification with raltegravir on HIV-1-infected individuals receiving monotherapy with boosted PIs

Maria C Puertas, Elisabet Gómez-Mora, José R Santos, José Moltó, Víctor Urrea, Sara Morón-López, Agueda Hernández-Rodríguez, Silvia Marfil, Marta Martínez-Bonet, Lurdes Matas, Mª Angeles Muñoz-Fernández, Bonaventura Clotet, Julià Blanco, Javier Martinez-Picado, Maria C Puertas, Elisabet Gómez-Mora, José R Santos, José Moltó, Víctor Urrea, Sara Morón-López, Agueda Hernández-Rodríguez, Silvia Marfil, Marta Martínez-Bonet, Lurdes Matas, Mª Angeles Muñoz-Fernández, Bonaventura Clotet, Julià Blanco, Javier Martinez-Picado

Abstract

Background: Monotherapy with ritonavir-boosted PIs (PI/r) has been used to simplify treatment of HIV-1-infected patients. In previous studies raltegravir intensification evidenced ongoing viral replication and reduced T cell activation, preferentially in subjects receiving PI-based triple ART. However, data about low-level viral replication and its consequences in patients receiving PI/r monotherapy are scarce.

Methods: We evaluated the impact of 24 weeks of intensification with raltegravir on markers of viral persistence, cellular immune activation and inflammation biomarkers in 33 patients receiving maintenance PI/r monotherapy with darunavir or lopinavir boosted with ritonavir. ClinicalTrials.gov identifier: NCT01480713.

Results: The addition of raltegravir to PI/r monotherapy resulted in a transient increase in 2-LTR (long-terminal repeat) circles in a significant proportion of participants, along with decreases in CD8+ T cell activation levels and a temporary increase in the expression of the exhaustion marker CTLA-4 in peripheral T lymphocytes. Intensification with raltegravir also reduced the number of samples with intermediate levels of residual viraemia (10-60 HIV-1 RNA copies/mL) compared with samples taken during PI/r monotherapy. However, there were no changes in cell-associated HIV-1 DNA in peripheral CD4+ T cells or soluble inflammatory biomarkers (CD14, IP-10, IL-6, C-reactive protein and D-dimer).

Conclusions: Intensification of PI/r monotherapy with raltegravir revealed persistent low-level viral replication and reduced residual viraemia in some patients during long-term PI/r monotherapy. The concomitant change in T cell phenotype suggests an association between active viral production and T cell activation. These results contribute to understanding the lower efficacy rates of PI/r monotherapies compared with triple therapies in clinical trials.

Figures

Figure 1.
Figure 1.
Effect of raltegravir intensification on residual viraemia. (a) Blood samples were obtained before intensification (week −8, week −4 and baseline), during intensification (from baseline to 24 weeks) and for up to 24 weeks after withdrawal of raltegravir (week 48). (b) Raw data from ultrasensitive viral load determination (left y-axis) and the percentages of samples with >10 HIV-1 RNA copies/mL of plasma (right y-axis) are shown for each timepoint. The grey zone represents the intensification period (week 0 to 24). (c) Difference in the probability of detecting intermediate residual viraemia levels (10–60 HIV-1 RNA copies/mL) during raltegravir intensification and after drug withdrawal, compared with the pre-intensification period. A mixed-effects logistic model was fitted for the binary outcome indicative of intermediate residual viraemia, assuming constant probabilities of exceeding 10 copies of residual viraemia for each patient in each period. BL, baseline; RAL, raltegravir; vRNA, HIV-1 RNA.
Figure 2.
Figure 2.
Viral reservoir dynamics upon intensification of PI monotherapy with raltegravir. (a) Increases in 2-LTR circles compared with individual baseline levels are shown as the median and IQR. The frequency diagram in (b) summarizes the timepoint at which each individual reached the maximum level of 2-LTR. (c) The dynamics of the proviral reservoir is shown as a fold change in total HIV-1 DNA in CD4+ T cells compared with individual baseline levels. The median and IQR are shown. The grey zone represents the intensification period (week 0 to 24). BL, baseline; vDNA, HIV-1 DNA.
Figure 3.
Figure 3.
Effect of intensification with raltegravir on T cell activation. The graph shows the immune activation levels (determined as a percentage of CD38+ cells) of all HIV-infected individuals analysed both in CD4+ (open symbols) (a) and CD8+ (filled symbols) (b) T cell populations. The median and IQR are represented. Asterisks denote significant differences between timepoints detected using the Wilcoxon signed rank test (*P < 0.05, **P < 0.01, ***P < 0.001). T cell activation was compared between 2-LTR+ (black continuous line) and 2-LTR− (grey broken line) subgroups within CD4+ (c) and CD8+ (d) T cell subsets. The median and IQR are shown. Asterisks denote significant differences between 2-LTR subgroups detected using a linear mixed-effects model (*P < 0.05, **P < 0.01, ***P < 0.001). The grey zone represents the intensification period (week 0 to 24).
Figure 4.
Figure 4.
Effect of intensification with raltegravir on T cell exhaustion. The graph shows immune exhaustion levels (determined as a percentage of CTLA-4+ cells) of all HIV-infected individuals analysed both in CD4+ (open symbols) (a) and CD8+ (filled symbols) (b) T cell populations. The median and IQR are represented. Asterisks denote significant differences between the timepoints assessed using the Wilcoxon signed rank test (*P < 0.05, **P < 0.01, ***P < 0.001). T cell exhaustion was compared between 2-LTR+ (black continuous line) and 2-LTR− (grey broken line) subgroups within CD4+ (c) and CD8+ (d) T cell subsets. The median and IQR are shown. Asterisks denote significant differences between 2-LTR subgroups assessed using a linear mixed-effects model (*P < 0.05, **P < 0.01, ***P < 0.001). The grey zone represents the intensification period (week 0 to 24).

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Source: PubMed

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