Track B report by Juergen Rockstroh
TUSY04 Immune Activation, Inflammation and HIV Disease
Untreated and to a lesser degree treated HIV infection is associated with increased frequency of “activated” T cells which are a sign of ongoing inflammation. More recently these forms of HIV-associated immune activation and inflammation have been discussed as the potential background cause for the increased burden of non/AIDS defining disease events and the acceleration of co morbidities in particular cardiovascular, renal and hepatic disease.
In this symposium Steve Deeks examined the pathogenesis of immune activation in the setting of successful ART treatment. Among the multiple mechanisms which may contribute to T cell activation several controversial factors such as residual HIV replication and microbial translocation were discussed, but also recent findings about other potential contributing factors such as co infection with CMV. Additional mechanisms may be loss of regulatory T/cells, lymphoid fibrosis, treatment toxicities or the increasing development of metabolic syndromes.
Subsequently Jens Lundgren summarized the evidence for the link between markers of inflammation, coagulation and immune activation and end organ disease particularly with new data from the SMART and ESPRIT trial. Clearly, the higher rates of cardiovascular and renal disease events in the treatment interruption arm SMART have strongly impacted corresponding inflammation and coagulation marker research in this area. However, it still appears that these markers of inflammation and coagulation are not yet ready for routine use in HIV medicine but for now remain a research tool.
Georg Behrens reviewed the data on metabolic disease and inflammation and showed how these two are interlinked and contribute to each other. Peter Hunt then addressed possible interventions for targeting the increased activation. Interventions that were reviewed included chloroquine, valganciclovir, atorvastatin and COX-2 inhibition.
Although many questions remain, clearly more exploratory studies are needed to address the increasing comorbidities and links between inflammation HIV infected patients in the HAART era.
Track A report by Giulia Marchetti
TUSY04 symposium - Immune Activation/Inflammation and HIV Disease focused on the role of chronic immune activation and inflammation in the pathogenesis of long-term co-morbidities in HAART-treated HIV infection.
The symposium started with: “update on the pathogenesis of inflammation/immune activation and HIV in the setting of treated HIV disease” by S. Deeks, United States.
Virologically-suppressed patients on HAART maintain elevated T-cell activation mainly within the CD8+ pool. Possible mechanisms behind elevated activation are:
1. residual viremia. Despite contrasting data, there is at least one study showing that intensification with raltegravir results in reduction of HIV viral replication and T-cell activation. Interesting data on the correlation between T-cell activation and viral replication in the gut will be presented in the Late Breaker session.
2. Persistent microbial translocation on HAART. Circulating sCD14 predicts death and morbidity/mortality in the INSIGHT study.
3. CMV-specific T-cell in HAART-treated patients, which associate to atherosclerosis.
4. Inefficient thymic output. NRTI have been shown to inhibit telomerase resulting in shorter telomeres in treated HIV.
5. Lack of immunoregulatory responses and lymphoid fibrosis.
All of these factors likely concur to chronic inflammation and immuno-senescence, in turn contributing to non-infectious complications.
J. Lundgren, Denmark discussed “Evidence for the link between markers of inflammation, coagulation and immune activation and end organ disease” byreviewing data on inflammation markers. The higher plasma D-dimer, the higher the risk of death in the SMART study, with similar data in both arms (interruption vs continuous therapy). Interestingly, the HR of death was increased in patients with higher D-dimer even after >4 years. Both D-dimer and IL-6 were predictive of non-AIDS events (with lower HRs).
G. Behrens, Germany discussed “Inflammation and metabolic complications in HIV disease” in the attempt to resolve the issue of what come first between inflammation and metabolic complications, mainly lypodistrophy. He provided evidence of a likely bidirectional linkage between the two phenomena.
P. Hunt, United States (“Interventions to reduce inflammation and immune activation in treated HIV infection”) reviewed all the immunomodulant approaches that failed thus far, such as IL-2 and Maraviroc intensification and underlined the strong need for: i)carefully designed placebo-controlled trials, ii) validation of surrogate activation markers in the clinic, iii) identification of the specific pathway of immune activation to be turned off (IDO pathway, innate/monocyte activation?). Recent data on bovine colostrum (anti-LPS) had no effect on LPS, CD4, sCD14, T-cell activation, refreshing the need to understand the causal relationship between microbial translocation and immune activation. Ongoing ACTG are now investigating LPS-binding molecules; interesting data have been shown on the blockade of TLR by Cloroquine and its derivatives.
Further possible approaches include valganciclovir (reduced T cell activation), atorvostatin (cox-2 inhibition) , CCR5/CCR2 blockade, IDO inhibitors.