L’apparato gastro- intestinale

AIDS: infezioni opportunistiche Protozoarie Toxoplasmosi cerebrale Criptosporidiosi con diarrea Isosporiasi con diarrea Fungine Esofagite da Candida Criptococcosi Histoplasmosi Coccioidomicosi Virali CMV HSV PML EBV: leucoplakia orale capelluta Batteriche MAC setticemia da salmonella Infezioni piogeniche

Eventi avversi Eventi avversi > 10% nei 2 gruppiQuota d’interruzioni La percentuale d’interruzione è stata identica nei 2 bracci (0.3%) Quad (n=353) ATV/r + FTC/TDF (n=355) Diarrea22%27% Nausea20%19% Infezioni delle alte vie respiratorie 15%16% Cefalea15%12% Affaticamento14%13% Ittero sclerale1%14% Quad (n=353) ATV/r + FTC/TDF (n=355) Totale4%5% Diarrea1%<1% Nausea<1%1% Vomito<1%1% Ittero sclerale0%1% Ittero0%1% Esantema0%1% DeJesus E, et al. 19th CROI; Seattle, WA; March 5-8, Abst. 627.

The GI tract as a site of HIV pathogenesis Sandler & Douek, Nat Reviews 2012 Brenchley et al. Nat Med 2006

Persistent Depletion of CD4+ T cells in the GI Tract despite Normalization in the Peripheral Blood Mehandru S, Plos Med HIV+ patients (acute)

Persistent damage to the gut tight epithelial barrier despite cART HIV negative HIV+ cART- treated Tincati C et al. CROI 2014 Chung; Plos. Path. 2014; (see also Somsouk AIDS 2015)

Persistent microbial translocation during cART Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009 Chung et al. Plos. Path. 2014; (see also Somsouk AIDS 2015)

Altered gut microbioma in SIV/HIV Brenchley Nat Med 2006; in humans: Gori et al. JCM 2008

Microbial translocation causes immune activation: colocalization of E.coli and IFN-  in colon Estes J et al. PLoS Pathogens 2010

Microbial translocation is associated to immune activation Brenchley J et al. Nat Med 2006 Marchetti G et al. AIDS 2008; Jiang et al. J Infect Dis 2009

Exogenous LPS administration enhances immune activation and HIV replication Pandrea et al J Immunol 2008; Pandrea et al. Blood 2012

A role in immune-reconstitution

Only partial recovery of gut-homing T- cells upon cART 20 HIV+ before and at 12 months cART 20 HIV+ cART- treated Mavigner et al. JCI 2012 Basilissi M ICAR 2015

Only partial recovery of gut microbioma upon successful cART 50 HIV+ patients before (T0) and after 12 months cART (T12)

Microbial translocation hampers CD4+ T-cell recovery upon cART Marchetti G et al. AIDS 2008; Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009

AIDS 2015 I miofibroblasti intestinali sono associati alla deposizione di collagene e all’immunoricostituzione che segue la terapia antiretrovirale

Klatt et al. Immunol Rev 2013

Possibili strategie terapeutiche

IDO= Indolamina deossigenasi

IL7

PlosOne ottobre 2015

Int J STD AIDS Jun 30. pii: [Epub ahead of print] The potential risks of probiotics among HIV-infected persons: Bacteraemia due to Lactobacillus acidophilus and review of the literature. Haghighat L1, Crum-Cianflone NF2. Author information Abstract SummaryLactobacillus sp. are commensal organisms that are increasingly reported to cause invasive infections among immunosuppressed persons. However, little data exist regarding the occurrence and risk factors of these infections among HIV-infected persons. Further, the safety of products that contain lactobacilli (e.g. probiotics) in certain populations, including those with HIV/AIDS, is unclear. We report a case of Lactobacillus acidophilus bacteraemia in a patient with AIDS temporally related to excessive consumption of probiotic-enriched yogurt, and provide a comprehensive review of the literature of Lactobacillus sp. infections among HIV-infected persons. Ci sono possibili rischi?

CONCLUSIONI L’apparato gastroenterico è certamente centrale nella patogenesi e nella storia naturale come localizzazione di alcune infezioni opportunistiche. E’ fondamentale nella tollerabilità alla terapia antiretrovirale e nell’immunoricostituzione Il ruolo nella patogenesi e nel mantenimento dell’infiammazione rende questo apparato il target ideale per vaccini e possibili terapie alternative