CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

332 Disease Progression in HIV Controllers; Uptake and Outcome of Antiretroviral Therapy Jane R. Deayton 1 ; Katherine C. Groves 2 ; David F. Bibby 2 ; Duncan A. Clark 2 ; Iain Reeves 3 ; Jane Anderson 3 ; Chloe M. Orkin 4 ; Eithne O’Sullivan 1 ; Áine McKnight 1 1 Barts and the London, Que, London, United Kingdom; 2 Barts Health NHS Trust, London, United Kingdom; 3 Homerton University Hospital NHS Foundation Trust, London, United Kingdom; 4 Barts Health NHS Trust, London, United Kingdom Background: We have previously reported a cohort of 86 HIV-1 “controllers” and defined a subset, “discord controllers (DC)” with low or declining CD4 counts (<450) despite control of plasma viral RNA. We showed that DCs are distinct both clinical and immunologically, having depletion of naïve CD4 cells and higher activation in all CD4 subsets compared with typical controllers (TC). Data are scarce on clinical management and outcome of controllers so we undertook a follow-up study of the cohort. Methods: HIV controllers recruited into the prospective cohort were designated DC or TC depending on the geometric mean titre of the last 3 CD4 counts. Controls were HIV non- controllers and uninfected individuals. Baseline HIV-1 DNA load in peripheral blood mononuclear cells was determined by quantitative PCR and expressed as per cell equivalent. Results: 18 DCs were recruited; 2 are lost to follow-up. DCs had higher DNA loads (13-1529, median 601 copies/10 6 CD4 cells) compared to TCs (0-755, median 87) (p=0.002) and were similar to those in non-controllers (27-2188, median 852). Ten DCs had received 12-66 (median 42) months of antiretroviral therapy (ART). RNA loads were 85-19837 (median 796) at ART initiation and all became undetectable on therapy. However, CD4 gain was modest; from baseline 163-308 (median 272), CD4 change was -25 – +318 (median +130) over follow-up. Those with lower nadir CD4 had lowest CD4 gain despite extended ART. Of 6 ART naïve patients, only one remained undetectable. CD4 counts in the naïve patients were unexpectedly low at 217-464 (median 304). Of note, 5 patients had declined to start ART despite low and declining CD4 counts. Conclusions: The significantly higher DNA loads in the DC group suggest productive ongoing HIV-1 replication and are compatible with increased immune activation, poor clinical outcomes and sub-optimal CD4 response to ART as described in this, and other, controller cohorts. Initiation of ART occurred late in DCs (some declined treatment), suggesting that both clinicians and patients may feel falsely reassured by low RNA loads in the face of low CD4 counts. These results suggest that controllers may benefit from earlier ART and that clinicians should remain vigilant to this despite low or undetectable RNA loads. In addition, DNA load may be a better marker of viral replication and disease progression than RNA load and may identify controllers in whom early ART is indicated. Ongoing longitudinal follow-up of this cohort is planned. 333 Immunological and Virological Progression in HIV Controllers Nicolas Noel 1 ; Nathalie Lerolle 1 ; Camille Lecuroux 2 ; Cécile Goujard 1 ; AlainVenet 2 ; Asier Sáez-Cirión 3 ;Véronique Avettand-Fenoel 4 ; Laurence Meyer 5 ; Faroudy Boufassa 5 ; Olivier Lambotte 1 ANRS CO21/CODEX Study Group 1 APHP, Service de Médecine Interne et Immunologie Clinique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France, Le Kremlin Bicêtre, France; 2 Inserm U1012, Régulation de la Réponse Immune, Infection VIH1 et Autoimmunité, Le Kremlin Bicêtre, France; 3 Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France; 4 APHP, Service de Virologie, Hôpital Necker – Enfants Malades, Paris, France; 5 Inserm U1018, Centre de Recherche en Epidémiologie et Santé des Populations, Université Paris Sud, Le Kremlin-Bicêtre, France Background: HIV controllers (HICs) display spontaneous long-term control of HIV replication. Some HICs show a decline in their CD4 T cell count or lose the ability to control the virus. The aim of this study was to investigate the rate and determinants of immunological and/or virological progressions in a large cohort of HICs. Methods: HICs from the French ANRS CO21/CODEX study are ART-naive HIV-1-infected patients diagnosed for > 5 years with 5 last consecutive HIV viral loads (VL) < 400 copies/ mL. Immunological progression during follow-up was suspected if CD4 T cell count fell < 350/mm 3 or declined by more than 200/mm 3 from a last CD4 count < 600/mm 3 . Viral progression was suspected if HIV VL rose > 2000 copies/ml. The events of immunological and virological were confirmed if similar CD4 counts or VL were found on a consecutive measurement. Clinical characteristics were analysed at inclusion in the cohort and prior to the event. Immune activation and inflammatory parameters (% of HLADR+CD38+ T cells, IP10 levels), ultrasensitive HIV VL and total HIV DNA were compared using non parametric tests with the non-progressor HICs. Results: Out of 217 patients followed in the cohort between 2009 and 2013, 37 patients experienced at least one suspicion of progression. Progression was confirmed in 15 patients (immunological progression, n=10; viral progression, n=5). Compared with non-progressor HICs, viral progressors (VP) were enrolled younger ( p <0.01). No differences in terms of HLA B57 status or HCV coinfection were observed. Unprotected sexual intercourse and sexually transmitted infections were reported in the recent history of some HICs, but not more frequently in progressors. Relative to non-progressors, immunological progressors HICs had lower CD4 T cell nadir (median (IQR): 292 (236-373) vs. 516 (412-681)/mm 3 , p <0.001), as well as the CD4 count at inclusion, and viral progressors had higher ultrasensitive HIV RNA levels at inclusion (i.e., 1-2 years before progression) ( p <0.01 for all). Interestingly, CD8 T cell activation and IP10 levels at inclusion in immunological progressors were significantly higher than in non-progressors ( p <0.001), almost as elevated as observed in viremic non HICs patients. Conclusions: CD4 T cell nadir, level of residual HIV replication and levels of basal immune activation seemmajor determinants to progression in HICs, and should be considered in order to adjust their follow-up and optimize the timing of cART initiation. 334 HIV Replication History Is AssociatedWith Plasma IL-7 Levels in Aviremic Youths Daniel Scott-Algara 1 ; Jerome Lechenadec 2 ; JosianeWarszawski 2 ;Thomas Montange 1 ; Jean-PaulViard 3 ; Catherine Dollfus 3 ;Véronique Avettand-Fenoel 4 ; Christine Rouzioux 4 ; Stéphane Blanche 3 ; Florence Buseyne 1 1 Institut Pasteur, Paris, France; 2 Inserm, Le Kremlin-Bicêtre, France; 3 AP-HP, Paris, France; 4 Université Paris Descartes, Paris, France Background: IInterleukin-7 (IL-7) is a key molecule regulating thymopoiesis and peripheral T-lymphocyte proliferation. We previously reported that thymopoiesis was maintained and that naive T cells had high levels of IL-7 high-affinity receptor in both viremic and aviremic youths infected with HIV-1 during the perinatal period. Plasma IL-7 levels were associated with CD4 T-cell count only in viremic patients. Here, we focused on aviremic patients, investigating the factors of HIV disease history associated with plasma IL-7. Methods: The ANRS-EP38-IMMIP study comprised youths between the ages of 15 and 24 years that had been perinatally infected with HIV and were living in France. Fifty-eight treated patients with < 80 copies of HIV RNA/ml at the time of the study were included in the analysis. T-cell subsets were quantified by flow cytometry. Plasma IL-7 was quantified by ELISA. Univariate and multivariate linear regression analyses were performed. Results: : Median (interquartile range) plasma IL-7 concentration at the time of the study was 3.9 (2.7-4.6) pg/ml. Higher IL-7 levels were associated with higher cumulative viremia over the last 10 years and higher levels of cell-associated HIV DNA (coefficient [95% CI]: 1.43 [0.20; 2.65] per 10000 days x log 10 HIV RNA copies/ml, P =0.02, and 0.77 [-0.03; 1.59] per log 10 HIV DNA copies/10 6 PBMCs, P =0.06, respectively). The weak negative correlation between IL-7 levels and CD4 T-cell count was not significant (-0.13 [-0.30; 0.04] per 100 cells/ m l, P =0.13). Neither nadir CD4 T-cell percentage nor duration of severe immunosuppression were correlated with IL-7 levels (-0.11 [0.71; 0.49] per 100 cells/ m l, P =0.72 and -0.05 [-0.10; 0.20] per year, P =0.53). IL-7 levels were not associated with sex, ethnicity, previous CDC stage C events, HIV-1 subtype or tropism. In multivariate analysis, IL-7 levels were significantly associated with cumulative viremia only (1.26 [0.02; 1.46] per 10000 days x log 10 HIV RNA copies/ml, P =0.05). In addition, higher IL-7 levels were associated with lower central-memory CD4 percentage and weaker CD127 expression on this CD4 T-cell subset. Conclusions: In youths with suppressed HIV viremia, plasma IL-7 levels were associated with exposure to viral replication over the previous 10 years. A similar association was reported with the naive CD4 T cells, consistent with a major impact of past HIV replication on current naive CD4 T-cell homeostasis in patients with perinatally acquired HIV infection.

Poster Abstracts

262

CROI 2015