Immunological Changes after Highly Active Antiretroviral Therapy with Lopinavir–Ritonavir in Heavily Pretreated HIV-Infected Children

Abstract

We evaluated the effect of salvage antiretroviral therapy with lopinavir/ritonavir (LPV/r) on the immune system of heavily antiretroviral pretreated HIV-infected children. We carried out a longitudinal study in 20 antiretroviral experienced HIV-infected children to determine the changes in several immunological parameters (T cell subsets, thymic function) every 3 months during 18 months of follow-up on salvage therapy with LPV/r. Statistical analyses were performed with the Wilcoxon test, taking as a reference the basal value at the entry in the study. HIV-infected children showed an increase of CD4+ T cells, a decrease in CD8+ T cells, and an increase in T cell rearrangement excision circle (TRECs) levels. The percentage of HIV children with undetectable viral load (VL < or = 400 copies/ml) increased significantly (p = 0.007) and the percentage with SI viral phenotype decreased significantly (p = 0.002) at the end of the study. Thus, the viral phenotype changed to NSI/R5 after salvage therapy with LPV/r. Interestingly, we observed a significant decrease of memory (CD4+ CD45RO+) and a moderate decrease of activated (CD4+ HLA-DR+, CD4+ HLA-DR+CD38, CD4+, CD45RO+HLA-DR+) CD4+ T cells during the follow-up. On the other hand, memory (CD8+ CD45RO+ and CD8+ CD45RO+CD38+), activated (CD8+ HLA-DR+CD38+, CD8+ HLA-DR+, CD8+ CD38+), and effector (CD8+ CD57+, CD8+ CD28(-)CD57+) CD8+ T cells had a very significant decrease during follow-up. Our data indicate an immune system reconstitution in heavily pretreated HIV-infected children in response to salvage therapy with LPV/r as a consequence of a decrease in immune system activation and an increase in thymic function.

Factors associated with clinical, immunological and virological responses in protease-inhibitor-experienced brazilian children receiving highly active antiretroviral therapy containing Lopinavir-Ritonavir

“…Nine children receiving three ARV drugs plus LPV/r showed immunological response (100%), in contrast to 10 of 20 (50%) children receiving two drugs plus LPV/r (p=0.01). A recent study has correlated immune system recovery in heavily pretreated, HIV-infected children, in response to salvage therapy with LPV/r, to a decrease in immune system activation and an increase in thymus function [16]. Further, restoration of thymus function and a higher thymus output may play a critical role in sustaining peripheral CD4 + cell increases despite the persistence of viral replication.…”

CD57+ T lymphocytes and functional immune deficiency

“…In both groups, these cells showed specificity for multiple antigens and produced large amounts of IFN-␥ and TNF-␣ [29]. On the contrary of CD4 ϩ CD57 ϩ T lymphocytes, CD8 ϩ CD57 ϩ T lymphocytes have a significant decrease during follow-up of salvage antiretroviral therapy with lopinavir/ritonavir [63], and pediatric patients responsive to HAART produce similar percentages of CD8 ϩ CD57 ϩ T lymphocytes compared with controls [64]. The functional meaning of CD8 ϩ CD57 ϩ T lymphocytes in HIV infection is still under debate: In contrast to maturation of EBVand CMV-specific memory CD8 ϩ T lymphocytes, HIV-1-specific CD8 ϩ T lymphocytes do not display coordinated down-regulation of CD27 and up-regulation of CD57 and accumulate in an atypical CD27 high CD57 low subset.…”

Boosted protease inhibitors as a therapeutic option in the treatment of HIV‐infected children

“…A continuous progressive increase in CD4 cell counts was observed throughout the study period. LPV/r has been shown to be effective in ARV-experienced children with severe immune suppression [50][51][52]. Moreover, there is evidence of an ongoing immune recovery after 4 years in heavily pretreated children after salvage therapy with LPV/r [51].…”

“…LPV/r has been shown to be effective in ARV‐experienced children with severe immune suppression [50–52]. Moreover, there is evidence of an ongoing immune recovery after 4 years in heavily pretreated children after salvage therapy with LPV/r [51]. Nevertheless, a lower CD4 percentage at baseline and a longer duration of PI therapy appear to be independent predictors of not achieving a CD4 cell count above 25% after 4 years of suppressive therapy with LPV/r‐containing regimens [52].…”