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Lack of regression of anal squamous intraepithelial lesions and anal HPV infection despite immune restoration under cART.

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  1. Lack of regression of anal squamous intraepithelial lesions and anal HPV infection despite immune restoration under cART C. Piketty1*, A. Si-Mohamed1, E. Lanoy2, B. Cochand-Priollet3, S. Trabelsi2, P-M. Girard4, R. Tubiana5, L. Abramowitz6, E. Tartour1,7, L. Weiss1,7, D. Costagliola2,5, and the Valparaiso Study group. 1HôpitalEuropéen Georges Pompidou, Paris , 2INSERM U943 - UPMC UMR S943, Paris , 3Hôpital Lariboisière, Paris , 4Hôpital Saint Antoine, Paris , 5Hôpital Pitié Salpêtrière, Paris , 6Hôpital Bichat-Claude Bernard, Paris , 7Université Paris 5, René Descartes, Paris, France.

  2. Background • High prevalence of anal squamous intraepithelial lesions (SIL) and anal HPV infection in HIV-infected MSM in the pre-cART era. • The impact of cART on the natural history of HPV infection and anal SIL is poorly documented. • High prevalence of anal SIL and anal HPV infection in HIV-infected MSM despite immune restoration under cART • The incidence of invasive anal cancer had increased despite the use of cART • The aim of the Valparaiso study was to better assess the impact of cART associated immune restoration on HPV anal disease in HIV-infected MSM

  3. Patients and Methods • 94 HIV-infected MSM naïve of cART starting a first line regimen of cART • 7 academic hospitals located in Paris, France • Each patient provided anal samples for cytology, histology in case of visible lesion under anoscopy or high resolution anoscopy • Anal cytology was processed by the Thin Prep™ method (Hologic®) • HPV DNA was detected by real time PCR and Roche Linear Array assay at baseline, month 12 and month 24 of cART • CD4+ and CD8+ T cells responses to HPV-16 E6 and E7 proteins were measured in a subgroup of individuals exhibiting HPV-16 anal infection at inclusion • T cell proliferation Assay • Proliferation tests were performed with pools of 25-35 peptides covering the whole sequences of E6 and E7 proteins from HPV16. Tetanus toxin, PPD and PHA were included as positive controls. Proliferation was considered as positive if stimulation index was superior to 2.5 • CD8 Elispot • PBMC were cultured with HLA-A2 restricted E7 derived peptides (E711-20 and E786-93). IL2 was added after two days; after 6 days of culture, cells were collected and assessed for IFN gamma-secreting cells by ELISpot

  4. Characteristics of the study population

  5. Change in CD4 cell count and HIV VL Plasma HIV VL < 50: 0% 47% 77% 89% 96%

  6. Anal HPV infection

  7. High Risk-HPV genotype distribution 50 40 30 Baseline Proportion, % M12 20 10 0 18 26 31 33 35 39 45 51 52 53 56 58 59 66 68 73 16 IS39_82 Overall HR-HPV: Baseline = 95% M12 = 91%

  8. Histology and/or cytology at baseline

  9. Histology and/or cytology at M12

  10. Anal disease status at M12 stratified by baseline diagnosis • Progression or persistence in 32/70 patients (46%) • Incident ASIL in 13/29 (44%) • Regression in 20/41 patients (49%) • Regression of prevalent ASIL to normality in 13/41 (32%)

  11. Anti-HPV T cell proliferative responses at M12 n=40 Positivethreshold (2.5)

  12. Change in anti-HPV T cell responses at M12 in HPV-16-infected patients n =12 Positivethreshold (2.5)

  13. 250 E711-20 200 E786-93 150 100 50 Positivethreshold (10 spots) 0 Patients #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 Presence of anti-E7 CD8+T cells after 12 months of cART Number of spots/105 PBMC Anti-E7-CD8+T cells directed against the two immunodominant HLA-A2 restricted E7 peptides (E711-20 and E786-93) were detected by indirect IFN-γ Elispot in 4/12 patients tested.

  14. Discussion • Taken together, the data suggest that cART exhibits: • No effect on the incidence of anal HPV infection, • No effect on the incidence of anal SIL, • No restoration of anti-HPV T cell responses • M24 results are pending. • Few data are available regarding correlation of anti-HPV T cell responses with HPV anogenital lesions. • Given the natural history of HPV infection, in situ anti HPV T cell responses should probably be more relevant. • These findings are in accordance with data indicating an increase in the incidence of anal invasive cancer despite cART. • These lines of evidence support the need for developing anal screening programs for HIV-infected individuals, whether untreated or on cART.

  15. Acknowledgements • VALPARAISO study group • HôpitalEuropéen Georges Pompidou, Paris (L. Weiss, C. Piketty, D. Tisne-Dessus); • Hôpital Saint Antoine, Paris (P-M. Girard, B. Levebvre, J-F Contou ); • HôpitalPitiéSalpétrière, Paris (C. Katlama, R. Tubiana, A. Simon); • Hôpital Henri Mondor, Creteil (Y. Levy); • Hôpital Necker, Paris (J-P. Viard); • Hôpital Bichat, Paris (P. Yeni, R. Landman, L. Abramowitz); • HôpitalLariboisière, Paris, France (A . Rami). • VALPARAISO Study Scientific committee • C. Piketty, D. Costagliola, A. Si Mohamed, E. Tartour, E. Lanoy, B. Cochand-Priolet, C. Rouzioux, J-P. Viard, S. Trabelsi, M. Leruez, L. Weiss. • THE PATIENTS ENROLLED IN THE VALPARAISO STUDY

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