Dr Samantha Westrop. Imperial College London. DrSJ Westrop 1 G Moyle 2, A Jackson 2, M Nelson 2, S Mandalia 2 and N Imami 1

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1 8 th Annual Conference of the British HIV Association (BHIVA) Dr Samantha Westrop Imperial College London 8-2 April 22, The International Convention Centre, Birmingham DrSJ Westrop G Moyle 2, A Jackson 2, M Nelson 2, S Mandalia 2 and N Imami Department of Medicine, Imperial College London and 2 Department of HIV/GU Medicine, Chelsea and Westminster Hospital

2 Objectives HIV- entry blockade by CCR5-antagonists potentiates immunomodulation. We hypothesised that maraviroc-intensification favourably impacts - Response to immunisation - T-cell phenotype and function -Delayed-type hypersensitivity (DTH) in HIV- + subjects. Study Design Screen Screen +48h Baseline Week 4 Week 2 Week 6 Week 24 Week h Concomitant medication and Adverse Events monitoring Clin care Clin care Clin care Clin care Clin care Clin care DTH DTH read DTH DTH read Immuno Immuno Immuno Immuno Immuno Immuno : random Maraviroc 5mg BD or matching placebo Ab titres Ab titres Ab titres Oral Chol Oral Chol IM Tet IM MenC 2

3 Referral, Screening and Randomisation 57 referred 67 screened 47randomised :, placebo:mvc 9declined consent 2 excluded 24assigned to placebo + background therapy 23assigned to MVC + background therapy Week 24: 7 attended, 6 LTFU, DO Week 6: 8 attended, DNA, 5 LTFU, DO Week 2: 8 attended, 5 LTFU, DO Week 4: 2 attended, 3 LTFU, DO Week 24: 2 attended, LTFU, 2 DO Week 6: 9 attended, DNA, LTFU, 2 DO Week 2: 2 attended, LTFU, 2DO Week 4: 2 attended, LTFU, DO 24 were included in ITT analysis 23 were included in ITT analysis Methods Clinical Care Delayed Type Hypersensitivity; Mantoux skin test Detailed Immunology T-cell Phenotype; surface markers of differentiation, activation, senescence, exhaustion, co-stimulation and co-inhibition T-cell Function; IFN-γ, IL-2, perforinand proliferation in response to HIV- Gag peptides, CMV and TTox Humoral Immunity; anti-tetanus, -MenC and -cholera antibody titres 3

4 Methods Statistical Methods Linear mixed model (SAS v9..3) compared between group data collected over time to derive time-weighted differences from baseline to each time-point. Point estimates and 95% CI of changes from baseline are presented. Adverse Events and Clinical Parameters Oral MVC System Placebo System Grade & 2 Grade 3 Possibly Probably Definitely Possibly Probably Definitely 49 8 GI, CNS, MS, Psych, ENT GI, CNS, Skin GI No clinically relevant changes in: Lymphocyte subsets Viral load Haematology Biochemistry 4

5 Delayed Type Hypersensitivity Pre baseline reaction results (%) Negative (< 5mm induration) Positive (= 5mm induration) Week 24 reaction results (%) Negative (< 5mm induration) Positive (= 5mm induration) Not known Not applicable as not administered Agreement baseline to week 24 κ (95%CI) Oral MVC n=23 22 (95.7) (4.4) 5 (75.) (.) 5 (25.) 3 % (78-) Placebo n=24 2 (87.5) 3 (2.5) (64.7) (5.9) 5 (29.4) 7 % (74-) p-value T-cell Phenotype Late (CD28-CD27-) CD4 T cells Costimulation (CD28+) Early (CD28+CD27+) CD8 T cells Costimulation (CD28) Coinhibition (CTLA-4) Interm(CD28-CD27+) Late (CD28-CD27-) Activated (CD38+HLA-DR+) MHC II (CD38-HLA-DR+) CD27+ Coinhibition (CTLA-4) 5

6 T-cell Function Immune function details HIV--specific anti-viral function TTox immunisation-specific function Humoral Responses to Immunisation Response to TToxsignificantly increased in Response to MenC enhanced by MVC both groups Response to Cholera dampened by MVC 6

7 Summary No excess of AE or clinically relevant changes (VL, LSS, Chem, Haem) No change in DTH Reduced CD4 T-cell activation Increased number of MHC-II expressing and late-stage CD4 T cells Normalisation of CD8 T-cell skewing towards early and intermediate Less expression of co-stimulatory and more co-inhibitory molecules Improved anti-gag and anti-ttoxt-cell functionandexpedited proliferation to Tetanus boost Enhanced humoralneo-response to MenCimmunisation, however reduced humoral neo-response to Cholera immunisation No effect on recall humoral response to Tetanus boost Conclusion Maraviroc-intensification favourably influences immune profiles of HIV- + patients, supporting immunomodulatoryuse in HIV- infection and potentially other immunologically relevant settings. 7

8 Acknowledgements Patients and Staff of the St Stephen s Centre EudraCT Number: Funded and sponsored by St Stephen s AIDS Trust, with an unrestricted grant from Pfizer Inc. (New York, USA). 8