Residual Viremia Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults Under Efficient Antiretroviral Therapy.

Chronic immune activation persists in persons living with HIV-1 even though they are aviremic under antiretroviral therapy, and fuels comorbidities. In previous studies, we have revealed that virologic responders present distinct profiles of immune activation, and that one of these profiles is related to microbial translocation. In the present work, we tested in 140 HIV-1-infected adults under efficient treatment for a mean duration of eight years whether low-level viremia might be another cause of immune activation. We observed that the frequency of viremia between 1 and 20 HIV-1 RNA copies/mL (39.5 ± 24.7% versus 21.1 ± 22.5%, p = 0.033) and transient viremia above 20 HIV-1 RNA copies/mL (15.1 ± 16.9% versus 3.3 ± 7.2%, p = 0.005) over the 2 last years was higher in patients with one profile of immune activation, Profile E, than in the other patients. Profile E, which is different from the profile related to microbial translocation with frequent CD38+ CD8+ T cells, is characterized by a high level of CD4+ T cell (cell surface expression of CD38), monocyte (plasma concentration of soluble CD14), and endothelium (plasma concentration of soluble Endothelial Protein C Receptor) activation, whereas the other profiles presented low CD4:CD8 ratio, elevated proportions of central memory CD8+ T cells or HLA-DR+ CD4+ T cells, respectively. Our data reinforce the hypothesis that various etiological factors shape the form of the immune activation in virologic responders, resulting in specific profiles. Given the type of immune activation of Profile E, a potential causal link between low-level viremia and atherosclerosis should be investigated.

Microbial Translocation Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults With Suppressed Viremia.

Persistent immune activation in virologically suppressed HIV-1 patients, which may be the consequence of various factors including microbial translocation, is a major cause of comorbidities. We have previously shown that different profiles of immune activation may be distinguished in virological responders. Here, we tested the hypothesis that a particular profile might be the consequence of microbial translocation. To this aim, we measured 64 soluble and cell surface markers of inflammation and CD4+ and CD8+ T-cell, B cell, monocyte, NK cell, and endothelial activation in 140 adults under efficient antiretroviral therapy, and classified patients and markers using a double hierarchical clustering analysis. We also measured the plasma levels of the microbial translocation markers bacterial DNA, lipopolysaccharide binding protein (LBP), intestinal-fatty acid binding protein, and soluble CD14. We identified five different immune activation profiles. Patients with an immune activation profile characterized by a high percentage of CD38+CD8+ T-cells and a high level of the endothelial activation marker soluble Thrombomodulin, presented with higher LBP mean (± SEM) concentrations (33.3 ± 1.7 vs. 28.7 ± 0.9 µg/mL, p = 0.025) than patients with other profiles. Our data are consistent with the hypothesis that the immune activation profiles we described are the result of different etiological factors. We propose a model, where particular causes of immune activation, as microbial translocation, drive particular immune activation profiles responsible for particular comorbidities.

One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study.

Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79-82.86], p=0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.

Reasons for early abacavir discontinuation in HIV-infected patients.

OBJECTIVE: To determine incidence of and reasons for discontinuation of abacavir within the first 6 months of therapy. METHODS: Retrospective study performed in the cohort of HIV-infected adults who started abacavir in a medical unit between 1997 and December 2000. All adverse drug reactions (ADRs) (especially hypersensitivity) observed in this cohort were reported. The association between drugs and complications were evaluated, using the French method to assess unexpected and toxic drug reactions. According to the variables studied, statistical analysis was performed using the chi2 test, Fisher's exact test, Mann-Whitney, Wilcoxon, or Kruskal-Wallis tests. RESULTS: All 331 patients treated with abacavir during this time period were included in this study. Early discontinuation of abacavir was observed in 34.1% of patients, the main reasons being adverse effects (20.8%), virologic failure (3.3%), drug holidays (2.7%), poor adherence (2.7%), and death (1.8%). Adverse effects were mostly represented by hypersensitivity reactions. After retrospective analysis, abacavir was stopped for likely hypersensitivity in 8.5% of patients, for doubtful hypersensitivity in 4.2%, and for other adverse effects in 8.1% of patients. CONCLUSIONS: This study shows that abacavir is mainly stopped during the first 6 months of therapy for ADRs. The rate of likely hypersensitivity reaction observed in this study (8.5%) is higher than that observed in clinical trials (5%). After retrospective evaluation, the causality assessment of abacavir is not always certain.