CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: The NKSC model resulted in infrequent adverse events, low loss to follow-up, and excellent OS. Our results suggest it is safe, effective, and feasible to provide standard-of-care chemotherapy regimens from the developed world, integrated with ART, to treat HIV-KS in rural Malawi. Baseline BMI and hemoglobin may represent important patient characteristics associated with HIV-KS survival in rural sub-Saharan Africa. 722 High Mobility Group Box 1 (HMGB1) and HIV-Associated Kaposi Sarcoma in Africa Helen Byakwaga 1 ; PeterW. Hunt 3 ; Miriam O. Laker-Oketta 2 ; Albert R. Davalos 6 ; Conrad Muzoora 1 ; DavidV. Glidden 3 ; A. Rain Mocello 3 ; David R. Bangsberg 4 ; Edward Mbidde 5 ; Jeffrey N. Martin 3 1 Mbarara University of Science and Technology, Mbarara, Uganda; 2 Infectious Diseases Institute, Kampala, Uganda; 3 University of California San Francisco, San Francisco, CA, US; 4 Massachusetts General Hospital, Center for Global Health, Harvard Medical School, Boston, MA, US; 5 Uganda Virus Research Institute, Entebbe, Uganda; 6 Buck Institute for Research on Aging, Novato, CA, US Background: The high mobility group box 1 (HMGB1) protein, a host transcriptional regulator that promotes cell proliferation and is actively secreted by senescent cells, is also known to interact with Kaposi’s sarcoma-associated herpesvirus (KSHV) in vitro . HMGB1 binds with KSHV latency-associated nuclear antigen (LANA) and stimulates KSHV “replication and transcriptional activator” (RTA) transactivation, thereby facilitating KSHV replication. KSHV may block p53-dependent secretion of HMGB1, thereby increasing intracellular HMGB1 levels even in the setting of senescence. Despite these in vitro associations, the role of HMGB1 in KS pathogenesis in vivo remains unexplored. Methods: In a case-control design, cases were HIV-infected adults, sampled throughout Uganda, with biopsy-confirmed KS and no urgent indications for chemotherapy; they were being seen in preparation for the AntiRetrovirals for Kaposi’s Sarcoma (ARKS) trial. Controls without KS were derived from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, a consecutive sample of HIV-infected adults starting antiretroviral therapy (ART) in Uganda. All biological tests were performed on pre-ART samples. Plasma HMGB1 levels were assayed by an enzyme-linked immunosorbent assay. Results: We studied 674 subjects: 224 KS cases and 450 non-KS controls (Table). KS cases had a wide spectrum of mucocutaneous KS ranging from oral lesions only to widespread cutaneous dissemination. Non-KS controls had a higher median plasma HMGB1 (7.9; IQR: 5.3 to 12.4 ng/ml) than cases (4.6, IQR: 3.2 to 6.6 ng/ml) (p<0.001). Compared to individuals with HMGB1 in the first quartile (i.e., lowest values), there was a 67% (95% CI: 45%-80%), 85% (95% CI: 74%-91%), and 95% (95% CI: 90%-97%) reduction in the odds of KS amongst subjects in the second, third and fourth quartiles of HMGB1, respectively (all p<0.001), which was present even after adjusting for age, sex, CD4+ T cell count, plasma HIV RNA, and interleukin (IL)-6 levels (Table).

Poster Abstracts

Conclusions: Higher plasma HMGB1 levels are strongly associated with lower occurrence of KS, independent of CD4+ count, plasma HIV RNA and IL-6 levels. This is consistent with the hypothesis that KSHV-mediated intracellular sequestration of HMGB1, reflected by lower extracellular levels, increases KSHV replication and subsequent KS. Alternatively, active HMGB1 secretion by senescent KSHV-infected cells may be a mechanism that suppresses KS development in this setting. 723 The CXCL12/CXCR4-CXCR7 Pathway, a Trio Implicated in Kaposi Sarcoma Pathogenesis

Aude Desnoyer 2 ; Francoise Gaudin 2 ; Agnes Carlotti 3 ; Nicolas Dupin 3 ; Francois Boue 2 ; Karl Balabanian 2 ; Valérie Martinez-Pourcher 1 1 Hopital Pitié-Salpêtrière, Paris, France; 2 Inserm, Univ Paris-Sud, LABEX LERMIT, UMR_S996, Clamart, France; 3 Dermatology, Paris, France

Background: Lenakap clinical trial (ANRS 154) is a single-arm, multicenter, open label, phase II trial, evaluating the efficacy and safety of lenalidomide in Kaposi’s sarcoma (KS) associated with HIV infection (AIDS-KS) despite an effective antiretroviral (ARV) therapy (NCT01282047). KS is a human herpesvirus 8 (HHV-8)-associated disease. It is known that cytokines are required for the development of KS, but so far no biomarker has been identified. We investigated if the CXCL12/CXCR4-CXCR7 pathway, a trio of chemokine and G protein-coupled receptors known to be involved in many cancers, could be a candidate. Methods: The expression of CXCL12, CXCR4, CXCR7 and different markers, i.e. LANA (HHV-8 latency-associated nuclear antigen), Ki67 (cell proliferation), TUNEL (apoptosis) and VEGF (angiogenesis), were analyzed in AIDS-KS cutaneous biopsies (CBs) (n=16) by immuno-histochemistry. Twenty angiomas and 21 classic KS CBs were used as negative and positive controls respectively. Protein expression was quantified using the Visilog software. Mann-Withney test and Pearson correlation were estimated using Prism 5 software. P values <0.05 were considered as statistically significant. Results: Overall 379 staining of CXCL12, CXCR4, CXCR7, Ki67, LANA, TUNEL and VEGF were performed. Levels of CXCL12, CXCR4 and CXCR7 expression were increased in AIDS-KS and classic KS versus angioma CBs (p<0.0001), as well as in nodular versus macular and papular lesions (p<0.0005). Similar results were obtained with Ki67 and VEGF expression (p<0.0001). There was no difference in LANA expression in AIDS-KS versus classic KS CBs, but LANA was significantly up-regulated in nodular lesions (p<0.0001). There were

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CROI 2015