CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Methods: 400 HIV-positive men (98%men who have sex with men (MSM)) were enrolled in this prospective observational study from 2008 to 2011. Participants were seen every 3 to 12 months. All patients received an inspection of the anogenital region, digital rectal examination, high-resolution anoscopy (HRA), anal cytology, anal/penile histology if required, and HPV-typing of anal and penile swabs. The statistical analysis was performed in a descriptive manner; no formal statistical hypotheses were tested. Approximate 95% confidence interval was calculated with an approximate formula [Woodward]. The prevalence analyses were performed by the statistic software SAS version 9.3 TS1M0. Results: At baseline only 25% of the 400 HIV-infected men had normal anal results, 75% of the men presented with abnormal cytological and histological results. 8% presented with ASCUS (atypical squamous cells of undetermined significance), 41%with low-grade (n=164) dysplasia and 24%with high-grade anal dysplasia (n=95), and two men with invasive anal cancer (0.5%). 2.3% had PIN (n=9) and one patient had penile cancer at baseline. Throughout the study period only 16.8% of the patients always had normal anal results. 75% had anal dysplasia (low-grade n=177, high-grade n=125), 3.3% (n=13) had PIN, and two further patients developed anal cancer. Within the study period 52.8% (n=211) had condylomata. At baseline, 88.5% of anal and 39.3% of penile swabs were HPV-DNA positive, and 77.8% of anal and 26.5% of penile swabs carried high-risk HPV-types. HPV16 was the most frequent HPV-type. Conclusions: HIV-positive MSM have a high risk for HPV-induced condylomata, (pre)malignant anogenital lesions and anogenital cancers. Screening for HPV-induced dysplasia is crucial to avoid progression to invasive carcinomas. Additionally, HPV-vaccination recommendations should be extended to high-risk populations. 629 APOBEC3 Boosters Kill Primary Effusion Lymphoma and Other Cancer Cell Lines Chisu Song 1 ; Gary Schiltz 2 ; Meejeon Roh 1 ; Isabelle Clerc 1 ; Neha Malik 2 ; Hannah Hudson 1 ; Kiwon Nam 2 ; Richard T. D’Aquila 1 1 Northwestern Univ, Feinberg Sch of Med, Chicago, IL, USA; 2 Northwestern Univ, Chicago, IL, USA

Background: DNA cytosine deamination of chromosomal DNA by APOBEC3B (A3B) is a major source of mutation associated with worsening of malignant phenotypes in different types of cancer. This includes primary effusion lymphoma (PEL), a continuing treatment challenge in AIDS patients. We have identified small molecules that boost APOBEC3G (A3G) and APOBEC3F (A3F) protein levels by increasing post- translational stability of these proteins (data not shown). Here, we test effects of these compounds on APOBEC3B (A3B) levels in cancer cell lines, and whether they affect proliferation/viability of cancer cell lines . Methods: 3 PEL cell lines (BC-1, BC-3, BCBL1), 5 breast cancer lines (MCF10A, MCF7, T47D, MDA-MB-157 and MDA-MB-231), and a cervical cancer cell line (HeLa) were treated with either one of our A3 boosters or DMSO for 8 days or more. BC-1, BC-3, and BCBL1 are each KSHV-infected, and BC-1 is also co-infected by EBV. MCF-10A and MCF7 breast cancer cells have low baseline A3B mRNA; all other lines studied have higher baseline A3B mRNA levels. Primary CD4+ T lymphocytes and HEK293 were controls lacking A3B expression. Results: No cell line tested had higher cell counts after exposure to any of the A3 boosters than to DMSO. Each of the 3 PEL cell lines had markedly decreased cell numbers after exposure to each A3 booster. The other cell lines previously reported to have elevated baseline A3B levels (T47D, MDA-MB-157, MDA-MB-231, HeLa) also were killed after exposure to each A3 booster studied. Cell counts of HEK293 cells, MCF-10a cells, MCF7 cells, and primary lymphocytes did not differ in A3 boosters versus DMSO. Anti-A3B antibody immunofluorescence of MDA-MB-231 breast cancer cells was increased by A3 booster exposure, relative to DMSO. MDA-MB-231 cells exposed to each of 3 A3 boosters had DNA damage (Fig. 1) and increased staining for activated caspase and PARP. Conclusions: The A3 boosters did not increase proliferation of any cancer cell lines studied, increased A3B protein level in MDA-MB-231 cells, and had marked cytotoxic effects against PEL and several other cancer cell lines with high baseline A3B expression. The data suggest that further increasing high cancer-associated baseline A3B protein levels may enhance DNA damage beyond a ‘mutation catastrophe’ threshold, cause apoptosis-mediated synthetic lethality, and have potential as a novel strategy for PEL in AIDS.

Poster Abstracts

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Risk Factors for Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL) in Europe Leah Shepherd 1 ; Alvaro H. Borges 2 ; Johannes Bogner 3 ; Andrzej Horban 4 ; Elena Kuzovatova 5 ; Manuel Battegay 6 ; Marcelo Losso 7 ; Jens D. Lundgren 8 ; Amanda Mocroft 1 ; for the EuroSIDA in EuroCOORD 1 Univ Coll London, London, UK; 2 CHIP, Rigshospitalet, Univ of Copenhagen, Copenhagen, Denmark; 3 Medizinische Poliklinik, Munich, Germany; 4 Hosp for Infectious Diseases in Warsaw, Med Univ of Warsaw, Warsaw, Poland; 5 Academician Blokhina Nizhny Novgorod Rsr Inst of Epi and Microbiology, Novgorod, Russian Federation; 6 Univ Hosp Basel, Basel, Switzerland; 7 Hosp J.M. Ramos Mejia, Buenos Aires, Argentina; 8 Rigshospitalet, Univ of Copenhagen, Copenhagen, Denmark Background: NHL and HL are common in HIV+ people. Previous research has described significant declines in NHL and, to a lesser extent, HL after cART, but data on individual risk factors is limited. We sought to determine the role of demographic factors, and cumulative time spent with immunodeficiency (CD4 <200) and viral suppression (HIV RNA<400) on NHL and HL across Europe. Methods: EuroSIDA participants with follow-up after 1/1/2001 and without NHL or HL at baseline were included and followed to first NHL or HL diagnosis, last visit or death. Risk factors for NHL and HL were assessed separately using Poisson regression including current and cumulative measures of HIV RNA (% of time with HIV RNA<400 copies/ml) and immunosuppression (% of time with CD4<200 cells/mm 3 ). Results: 14820 people contributed 101281 person years of follow-up (PYFU), 117 developed NHL (incidence rate 1.2/1000 PYFU, 95%CI 1.0-1.5) and 45 developed HL (0.5/1000 PYFU, 95%CI 0.3–0.6). Crude incidence of NHL and HL declined by 12% (95%CI: 7–16%) and 9% (95% CI: 1–15%) per year, however, no trend remained after adjustment ( figure ). In adjusted analyses, NHL incidence was lower in North and West and HL incidence in North and East compared to south Europe ( figure ). Lower current CD4 cell count ( Figure ), but not cumulative exposure to immunodeficiency (P>0.05), was associated with higher incidence of both NHL and HL. NHL incidence was strongly associated with current HIV RNA in univariate analyses (incidence rate ratio [IRR]: 3.35 95%CI: 2.33,4.83), but after adjustment, a history of poor control of HIV infection were more strongly associated with NHL, such as a prior diagnosis of AIDS-defining malignancies and lower % of time with controlled HIV RNA ( figure ). Other risk factors included older age (NHL only) and region of follow-up (both), whereas nadir CD4 was not associated with either HL or NHL (P>0.05). Conclusions: Incidence of NHL and HL vary significantly by region, possibly reflecting differences in long term virological suppression through access to and availability of cART. NHL incidence was associated with lower CD4 and cumulative exposure to viral replication over time, suggesting that exposure to uncontrolled viral replication may play a part in NHL development in addition to current immunodeficiency. Conversely, HL incidence was elevated in those with current severe immunodeficiency (CD4<200), but cumulative exposure to uncontrolled HIV replication or immunodeficiency were not found to be significant risk factors.

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CROI 2016