Although HIV-related deaths have declined dramatically since the introduction of ART, HIV infection is becoming increasingly chronic and people infected with HIV continue to experience raised morbidity and mortality often due to events unrelated to AIDS (19). In fact, due to the inability of antiretroviral drugs to eradicate the virus from infected reservoir cells, treatment of HIV infection requires permanent systemic therapy. However, even when successfully treated, HIV patients still show higher incidence of age-associated co-morbidities than non-infected individuals. Chronic Immune Activation and Senescence (CIADIS), is a process characterized by a progressive decline of immune system function, usually detected by the expression of cellular or soluble markers derived from innate or adaptive immune responses. Immune activation is associated with progression of HIV disease and increased morbidity and mortality in HIV-infected patients despite ART (20). In this regard, the validation of a “CIADIS score” based on activation, senescence, and differentiation markers, could help physicians to identify patients at high risk for non-AIDS-related comorbidities (20). In fact, it is striking evident that cardiovascular diseases are one of the leading non-AIDS causes of death among HIV-positive subjects (21).
Although not fully understood, the probable mechanism involves both chronic inflammation, CD4 cell depletion, endothelial dysfunction and atherosclerosis (22). It is undoubted that the worst lipid profile (e.g. higher total cholesterol, triglycerides, and LDL-cholesterol than recommended values) that accompanies the HIV affected patients may play a significant role in this (23). However, in our study the analysis conducted on total cholesterol and triglycerides did not show statistically significant differences between the three groups. This data contrasts with what has been reported in some papers, according to which INI are more “lipid friendly” (24,25).
Although ART has significantly improved both the quality and lifespan of patients, the life expectancy of treated patients is even shorter than that of uninfected individuals. In particular, while ART may counteract some features of HIV-associated immunosenescence, several anti-HIV drugs may themselves help to amplify other aspects of immune ageing and chronic inflammation (26).
The analysis conducted in the present study reveals that some categories of antiretroviral drugs emphasize the residual inflammation, partly linked to HIV infection itself (12,13).
According to our findings, some inflammatory cytokines of innate immunity (supplementary Figure 1A, C, G) and two pro-inflammatory chemokines (supplementary Figure 1 B, F) are more represented in patients taking PI than those receiving INI.
There are several studies comparing the effects of specific antiretrovirals and antiretroviral combinations in ART-naïve individuals initiating their first ART regimen. In one recent ART initiation trial, INI appear to reduce inflammation to a greater degree than NNRTI; however, in the same study, it is not clear if there are beneficial effects on inflammation resulting from treatment with INI compared to PI or between PI and NNRTI (27).
It is plausible that INI may decrease inflammation and immune activation more than other antiretroviral classes, as INI may concentrate at higher levels in enterocytes (28), which is important because HIV infection results in massive depletion of immune cells within the gastro-intestinal tract and the resultant microbial translocation may be an important driver of immune activation in HIV. In line with this, we found that INI patients had a tendency to show a lower frequency of extreme cytokine levels when compared to the other groups.
However, in contrast with the above statement, our results show that the IFN-γ induced protein 10 (IP-10 or CXCL-10) and eotaxin (also known as C-C chemokine ligand 11, CCL1) are significantly lower in patients treated with NNRTI compared to those belonging to the other groups (Figure 1 E,D). This finding appears relevant especially for IP-10, considering that this mediator is known to be one of the first chemokines to increase following HIV infection (29) and it is involved in immune cell trafficking to inflammatory sites. In particular, the continued production of IFN-γ in the lymphoid organs is responsible for a prolonged increase in IP-10 during chronic HIV infection, even in patients taking ART. In fact, IP-10, by increasing the susceptibility of naive T CD4+ T lymphocytes to HIV infection, improves the production (constitution) of HIV reserves.
The present study is not without limitations, first of all with regard to the small sample size, followed by a cross sectional design and the lack of comparison of the immune mediators tested with other conventional inflammatory or procoagulant markers such as CRP and D-dimer respectively (30). The lack of a complete set of biomarkers hamper an exhaustive evaluation of the cardiovascular risk and the real inflammatory profile among the three groups and represents the main limitation of the present study.
However, although with limitations, our data seem to highlight the importance of how the choice of the third drug in an antiretroviral regimen can promote the imbalance of inflammation-related immune mediators. In particular, our results seem to discourage the administration of PI as a third drug in a virologically effective antiretroviral regimen, as its use is linked to the detection of higher levels of pro-inflammatory mediators than INI and NNRTI.
Further studies in larger cohorts are needed to confirm the results found, to compare it to conventional markers of inflammation, and to provide their usefulness as a significant clinical tool to help clinicians in choosing a “tailored” antiretroviral regimen.