Abstract BACKGROUND Until now, immunotherapy has been disappointing in gliomas. Promising results in cancer neoantigen (NeoAg)-directed vaccines have been seen, but final outcomes remain poor. We need a better comprehension of the factors associated with effectively immunogenic NeoAgs along with clinical features that correlate with detectable immune responses. MATERIAL AND METHODS We prospectively enrolled glioma patients from our institution in the IDeATIon project (NCT03706625) exploring tumors occurring in immunosuppressed conditions or in immune-privileged sites such as the CNS. We performed whole exome and RNA sequencing of tumor samples along with patients HLA typing. Using state of the art algorithms and personalized filters, we predicted cancer NeoAg sequences and expression. Peripheral blood mononuclear cells (PBMC) were collected in a subset of patients, and their reactivity to NeoAg-derived peptides was assessed ex vivo using ELISpot assays to validate in silico-predicted immunogenicity. RESULTS We enrolled 36 prospective glioma patients (IDH mutant, n=10; IDH wildtype, n=26). To test the ability of our pipeline to identify the most immunologically relevant NeoAgs among others, we privileged the inclusion of mismatch-repair (MMR)-deficient (MMRd) gliomas (n=21, of which 12 post-temozolomide and 9 de novo), given their expected high NeoAg burden. The median number of predicted immunogenic NeoAgs from 21 patients with both WES and RNASeq data was 274 and was higher for MMRd gliomas (1540 vs. 58, p<0.001). Tumor mutational burden and the number of predicted NeoAgs were correlated (ρ=0.81, p<0.001). Ex vivo PBMC responses were assessed for best ranked peptides (median 48 peptides/patient, range 12-62) in 18 patients (10 MMRd). NeoAg-specific T-cell responses (>50 spot forming units/10e6 PBMC) were detected in 72% (13/18) of patients, including MMRd cases (8/10). All non-responder patients (5/5) were under treatment with cytotoxic chemotherapies (CHT) at the time of blood sampling, compared to 15% (2/13) of responders (p=0.003). Conversely, NeoAg-specific responses were seen in 100% (11/11) of patients not under CHT. CONCLUSION We developed and validated in vitro a robust and reliable pipeline for the identification of effectively immunogenic neoantigens using validated algorithms and personalized filters. Our results suggest that in the absence of CHT, a specific antitumor immune response is present in the majority of gliomas and may represent a therapeutic lever.

OBJECTIVES:HIV/hepatitis C virus (HCV) co-infection leads to major complications, and noninvasive markers developed to stage liver fibrosis could be used as prognostic markers. We aimed to compare the performances of liver stiffness (LS), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI) to predict liver-related events in HIV/HCV co-infected patients.PATIENTS AND METHODS:HIV/HCV co-infected patients from the ANRS CO13 HEPAVIH cohort were included if they had LS, FIB-4, and APRI measurements done in a window of 3 months. Primary outcome was the time between inclusion and occurrence of a liver-related event. Univariable and multivariable Fine and Gray models were performed. Predictive performances were compared by the area under the receiver operating characteristic (AUROC) differences after correction of optimistic by bootstrap samples. Best cutoffs to predict liver-related events were estimated by sensitivity and specificity maximization.RESULTS:A total of 998 patients were included. Overall, 70.7% were men. Their median age was 46.8 years. According to LS value, 204 (20.4%) patients had cirrhosis. Overall, 39 patients experienced at least one liver-related event. In univariable analysis, LS AUROC curve was significantly superior to FIB-4 and APRI AUROC curves, being 87.9, 78.2, and 75.0%, respectively. After adjustment on age, CD4 levels, and insulin resistance, no differences were observed. The best cutoffs to identify patients at low or high risk of liver-related events were below 8.5, 1.00, and 0.35 and above 16.5, 4.00, and 1.75 for LS, FIB-4, and APRI, respectively.CONCLUSION:To predict HCV-related events, APRI had lower performance than LS and FIB-4. FIB-4 is as good as LS to predict HCV-related events, suggesting that it can be used for the management of HIV/HCV co-infected patients and replace LS.

Le vieillissement croissant de la population impose de prévenir les infections sévères et fréquentes sur ce terrain par des vaccins. Cependant, l’immunosénescence altère l’intensité et la qualité des réponses vaccinales, limitant ainsi l'efficacité des recommandations vaccinales dirigées après 65 ans contre la grippe, le pneumocoque, la coqueluche mais également le tétanos ou le zona. Ces vaccins élaborés, sauf le zona, pour les jeunes enfants sont peu adaptés au sujet âgé. Mieux comprendre les mécanismes de l’immunosénescence et les raisons de ces limitations devrait permettre d’améliorer dans le futur l’efficacité de ces réponses vaccinales. L’immunosénescence, aggravée par les co-morbidités, varie avec l’âge, devient patente après 60–65 ans et profonde après 85 ans. Toutes les étapes des réponses vaccinales sont touchées par l’immunosénescence, depuis l’immunité innée nécessaire à l’activation de ces réponses jusqu’à l’induction de réponses anticorps protecteurs et de la mémoire immunitaire. Néanmoins, la capacité de développer de nouvelles réponses en primo-vaccination est plus touchée que la capacité de réponse aux rappels, toutefois également altérée. La revue détaille les altérations des réponses vaccinales et l’efficacité des vaccins sur ce terrain et analyse les quelques pistes actuellement poursuivies pour tenter d’améliorer le degré de protection conféré aux sujets âgés par ces vaccins.

BACKGROUND:The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study. METHODS:HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates. RESULTS:1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4-49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2-6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p<0.0001), history of HCV treatment (aHR = 0.53 [0.32; 0.90], p = 0.01) and smoking (past (aHR = 5.69 [1.56; 20.78]) and current (3.22 [0.93; 11.09]) versus never, p = 0.01) were associated with all-cause mortality independently of SVR, age, sex, alcohol use and metabolic disorders. CONCLUSION:Any LSM >12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.

The aging population raises a number of public health issues including a need to address the severity and frequency of infections observed in older people. Vaccines play an important role in prevention. However, immunosenescence alters the intensity and quality of vaccine responses, thus limiting the impact of recommendations directed after 65 years for vaccination against flu, pneumococci, pertussis, tetanus and zoster. Immunosenescence, aggravated by co-morbidities, varies with age, becoming apparent after 60-65 years and more profound after 85 years. All stages of vaccine responses are affected by immunosenescence, from the innate immunity required to activate these responses to the induction of protective antibody responses and immune memory. Nevertheless, the capacity to develop new responses to primary vaccination is more affected than the ability to respond to recalls, although this is also impaired. Responses to vaccines are differentially altered depending on vaccine and age. Influenza vaccines are modestly immunogenic and several meta-analyses agree an estimate for efficacy of about 50% against virologically-proven flu and 40% against flu-related deaths. The anti-pneumococcal 23-valent non-conjugated vaccine does not induce memory while the 13-valent conjugated one does, but their efficacy are likely to be similar between 70 to 52% before 75 years. A sequential vaccination program with the 13-valent primo-vaccination followed by the 23-valent, recommended in immune-suppressed patients, is currently being studied in France. The waning of immunity to pertussis makes recalls necessary in the elderly who develop good antibody responses. Several research avenues are currently being pursued to try improve the degree of protection conferred by these vaccines in elderly. (C) 2019 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Background: Hepatitis C virus (HCV) and HIV infections are associated with higher risk of autoimmune diseases and T-cell dysfunction. Setting: We evaluate prevalence and factors associated with the presence of autoimmune antinuclear (ANA), anti-smooth muscle actin (aSMA), and anti-liver kidney microsome (aLKM1) antibodies (Ab) in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era. Methods: A cross-sectional observational study nested in the ANRS CO13 HEPAVIH cohort (NCT number: NCT03324633). We selected patients with both ANA testing and T-cell immunophenotyping determination during the cohort follow-up and collected aLKM1 and aSMA data when available. Logistic regression models were built to determine factors associated with the presence of autoAb. Results: Two hundred twenty-three HCV/HIV-coinfected patients fulfilled selection criteria. Prevalence of ANA and aSMA was 43.5% and 23.2%, respectively, and both were detected in 13.3% of patients. Isolated aSMA were detected in 9.9% and aLKM1 in 2 patients. In multivariable analysis, only a low nadir CD4 T-cell count was significantly associated with ANA detection. Conclusions: ANA and aSMA detection remain frequent in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era, despite fair immune restoration. These results advocate for a close monitoring of ANA before immune checkpoint inhibitor therapy in these patients with greater caution for those with a low nadir CD4 T-cell count.

Objectives Although common among patients coinfected with HIV and hepatitis C virus (HCV), sleep disturbances (SD) are still poorly documented in this population in the HCV cure era. This longitudinal study aimed at analysing SD in HIV-HCV coinfected patients and identifying their clinical and sociobehavioural correlates. Methods We used 5-year annual follow-up data from 1047 participants in the French National Agency for Research on Aids and Viral Hepatitis Cohort 13 'Hepatite et VIH' (ANRS C013 HEPAVIH) cohort of HIV-HCV coinfected patients to identify clinical (medical records) and behavioural (self-administered questionnaires) correlates of SD (mixed-effects logistic regression). SD were identified using one item documenting the occurrence of insomnia or difficulty falling asleep (ANRS 'Action Coordonnee 24' self-reported symptoms checklist), and two items documenting perceived sleep quality (Center for Epidemiologic Studies Depression and WHO Quality of Life HIV-specific brief scales). Results Seven hundred and sixteen (68.4%) patients with completed self-administered questionnaires reported SD at their most recent follow-up visit. In the multivariable model, hazardous alcohol consumption (Alcohol Use Disorders Identification Test-Consumption score 4 for men, 3 for women) (adjusted odds ratio =1.61; 95% confidence interval: 1.09-2.36), depressive symptoms (6.78; 4.36-10.55) and the number of other physical and psychological self-reported symptoms (1.10; 1.07-1.13) were associated independently with SD after adjustment for sex, age and employment status. HCV cure was not associated significantly with SD. Conclusion SD remain frequent in HIV-HCV coinfected patients and are associated with a series of modifiable behavioural risk factors. independent of HCV cure, improved screening and comprehensive management of alcohol use, physical and psychological self-reported symptoms and depression are essential in this population. Closer investigation of these risk factors of SDs may both increase sleep quality and indirectly improve patients' clinical outcomes. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.

BackgroundWe describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background.MethodsHIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined.FindingsTwo HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles.InterpretationThis thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection.

Anti-PD-1 immune checkpoint inhibitors (ICIs) have become the new standard of care for treatment of advanced non-small-cell lung cancer (NSCLC) following platinum-based doublet chemotherapy [1.Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6220) Google Scholar, 2.Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4535) Google Scholar]. In patients living with HIV/AIDS (PLWHA), NSCLC is the most common non-AIDS-related malignancy and the leading cause of cancer-related death. In this population, ICIs are thought to be an attractive therapeutic option, as chemotherapy has proven to produce poor efficacy and higher toxicity in the general population [3.Spano J.P. Poizot-Martin I. Costagliola D. et al.Non-AIDS-related malignancies: expert consensus review and practical applications from the multidisciplinary CANCERVIH Working Group.Ann Oncol. 2016; 27: 397-408Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. The ICI safety profile and efficacy have not yet been evaluated in PLWHAs because they are excluded from clinical trials. Due to the lack of data, the CANCERVIH working group (national French multidisciplinary network dedicated to HIV-infected patients with cancer) has recommended to include all new cases of PLWHAs with cancer in the CANCERVIH database, discuss each case during the bi-monthly National multidisciplinary board and to publish recommendation for immunovirologic monitoring [4.Guihot A. Cadranel J. Lambotte O. et al.Biological follow-up of patients with HIV treated with anti-PD-1 or anti-PD-L1 for non-small cell bronchial carcinoma: a task group proposal.Rev Mal Respir. 2016; 33: 419-421Crossref PubMed Scopus (6) Google Scholar]. From a prospective database of 270 patients followed in the national CANCERVIH network between 2014 and December 2016, 10 consecutive PLWHA suffering from NSCLC and treated with nivolumab after receiving platinum-based doublet chemotherapy were analyzed. Statistical analyses on CD4 cell counts were done using a Wilcoxon nonparametric test on a Graphpad Prism 5.02 software (GraphPad Software Inc., La Jolla, CA). All patients were current or former smokers and received highly active antiretroviral treatment. The median age was 62.5 years (range 46–77). Adenocarcinoma was the most frequent histological subtype (70%) and all were Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase wild type. At nivolumab introduction, the median CD4 lymphocyte count was 357/mm3 (range 190–700) and the plasma HIV load (pVL) was undetectable. Two patients were VHC coinfected. At the cut-off date of analysis (31 August 2017), the median follow-up was 8.2 months (range 1.4–19.6) and patients received a median of 6.5 infusions of nivolumab (range 3–37) (Table 1). The best tumor response was a partial response in two patients, stability in four patients, and a disease progression in the last four patients. The duration of response was 18.1+ and 8.4+ months in patient #5 and #7, respectively. No unexpected toxicity occurred in all patients, except one, patient #7, who developed a hypereosinophilia then an anterior uveitis with confusion after three infusions of nivolumab. Cerebrospinal fluid and plasma examinations confirmed the diagnosis of active neurosyphilis. After nivolumab discontinuation and penicillin G administration, symptoms completely disappeared. Steroids were not administrated and nivolumab not restarted while patient remained in partial response until now.Table 1Clinical and immune-virological follow-up of the 10 HIV-infected patients with NSCLC during treatment by nivolumabPatient (n)CD4/ mm3HIV viral loadDose nivolumab (n)Best tumor responseToxicityIntercurrent infectionStatusNivolumab in progress1202<207SGrade 1 hepatitisNoDeadNo2657<206DPNoNoDeadNo3404<208SNoNoDeadNo4307<2021SNoNoAliveNo5280<2037PRGrade 2 diarrheaNoAliveYes6327<207SNoNoDeadNo7351<203PRHypereosinophiliaYesAliveNo8110<203DPNoNoDeadNo9346<204DPNoNoDeadNo10400<205DPNoNoDeadNo Open table in a new tab Mostly, the HIV-related parameters were not altered with a sustained undetectable pVL and stable CD4 counts with a median of 336/mm3 (range 110–657) after three or four perfusions of nivolumab (P = 0.102, Wilcoxon nonparametric test). To our knowledge, this is the first study evaluating the efficacy and safety of nivolumab administrated in HIV-infected patients with advanced NSCLC. The duration of response in some HIV-infected patients was prolonged and consistent with that observed in phase III trials in which HIV-infected were excluded [1.Brahmer J. Reckamp K.L. Baas P. et al.Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135Crossref PubMed Scopus (6220) Google Scholar, 2.Herbst R.S. Baas P. Kim D.W. et al.Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial.Lancet. 2016; 387: 1540-1550Abstract Full Text Full Text PDF PubMed Scopus (4535) Google Scholar]. Unfortunately, the tumor PDL1 expression was not available in most cases of our study. Low-grade hepatitis (previously reported elsewhere [5.Le Garff G. Samri A. Lambert-Niclot S. et al.Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab.AIDS. 2017; 31: 1048-1051Crossref PubMed Scopus (64) Google Scholar]) and diarrhea were reported in one patient each, while grade 3 or 4 or toxic deaths or non syphilitic opportunistic infection were not observed. One of the most meaningful information concerning HIV replication setting is that the CD4 and viral load remained stable. Further prospective studies are needed to confirm these results and to determine the effect of nivolumab on antiviral immune responses, inflammation, and HIV reservoir. None declared.

Therapy with immune check point inhibitors (ICPIs) may have dual benefits in HIV infection by acting not only on the cancers frequently associated but also by helping to purge the HIV reservoirs that indefinitely persist despite antiretroviral therapy. Indeed, it is hypothesized that ICPIs could de-repress the blockade of HIV transcription in the reservoirs concentrated in memory CD4 T cells co-expressing ICPs and simultaneously restore functions in exhausted HIV-specific T cells displaying high Programmed Cell Death-1 (PD-1) levels [1.Deeks S.G. Lewin S.R. Ross A.L. et al.International AIDS Society Towards a Cure Working Group. International AIDS Society global scientific strategy: towards an HIV cure 2016.Nat Med. 2016; 22: 839-850Crossref PubMed Scopus (326) Google Scholar]. This hypothesis has not been confirmed yet. Two case reports of HIV-infected patients treated for cancer with an anti-Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) [2.Wightman F. Solomon A. Kumar S.S. et al.Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma.AIDS. 2015; 29: 504-506Crossref PubMed Scopus (110) Google Scholar], or an anti-PD1 [3] monoclonal antibody showed a good safety profile that was recently confirmed by two series of patients treated for melanoma (N = 9) [4.Heppt M.V. Schlaak M. Eigenlter T.K. et al.Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients.Ann Oncol. 2017; 28: 3104-3106Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] or lung cancer (N = 10) [5.Samri A, Lavolé A, Even S, et al. 2017. Immunovirological evolution in HIV-infected patients treated with anti-PD-1 therapy International Aids Society Conference Abstract #MOPEB0362Google Scholar]. However, no clear effect on HIV reservoirs was reported despite some transient increase in HIV transcription after anti-CTLA-4, and in HIV-specific T cells after anti-PD1 therapy [2.Wightman F. Solomon A. Kumar S.S. et al.Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma.AIDS. 2015; 29: 504-506Crossref PubMed Scopus (110) Google Scholar, 3.Le Garff G. Samri A. Lambert-Niclot S. et al.Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab.AIDS. 2017; 31: 1048-1051Crossref PubMed Scopus (64) Google Scholar]. Here, we report for the first time a new case with a drastic and sustained decrease of the HIV reservoir paralleling the increase in HIV-specific CD8 T cells under anti-PD1 therapy. A 51-year-old man, smoker, HIV-infected since 1995, diagnosed with stage IIIa epidermal growth factor receptor-/BRAF-/Kras-/Programmed Cell Death Ligand-1- non-small-cell lung cancer in May 2015 was treated with lobectomy and adjuvant chemotherapy (cisplatin and pemetrexed). Relapse occurred <6 months after the end of chemotherapy and nivolumab was introduced as a second line in December 2016, upon the CANCERVIH working group recommandations. CANCERVIH is a national French multidisciplinary network dedicated to HIV-infected patients with cancer. Pre-treatment plasma HIV load was undetectable (<20 copies/ml) under emtricitabin, tenofovir and dolutegravir started in August 2016. Fifteen injections were administered every 14 days until July 2017, with a stable disease, and a good tolerance with stable CD4 and CD8 counts despite a slight CD4 drop at D30 (Figure 1A). The plasma HIV load progressively and modestly increased up to 101 copies/ml at D45, decreasing afterwards to 31 copies/ml at D120. In parallel, T-cell activation slightly increased between D14 and D45 while PD-1+ CD4 and CD8 T cells declined at D30 (Figure 1B and C). Then frequencies of HIV RT- and Nef-specific CD8 T cells markedly increased from D30 to D120 (Figure 1D). Finally, the cell-associated HIV–DNA showed a drastic and persistent decrease from 369 at D0 to 30 copies/106 cells at D120 (Figure 1A). Taken together, those results suggest that nivolumab in this patient had induced synergistic ‘shock and kill’ mechanisms: (i) a transient reactivation of HIV replication within infected CD4 T cells together with a T-cell activation and (ii) a decrease in exhausted CD4 and CD8 T cells followed by a durable and major restoration of HIV-specific CD8 T cells function that might have killed the HIV-producing cells, altogether resulting in a drastic and durable diminution of the reservoir. This first report of a successful depletion of the HIV reservoirs opens new therapeutic perspectives towards an HIV cure. Whether this encouraging result is reproducible is also currently being analyzed in the French cohort of HIV-infected people treated with ICPIs (ANRS-CO24, OncoVIHAC cohort). The authors want to thank the members of the CANCERVIH working group, S Even, K Dorgham, S Sayon, M Veyri. INCA (no grant numbers apply); Agence Nationale de Recherche sur le SIDA et les Hépatites virales (D17256).

Objectives: The objective of this study is to investigate immunogenicity and safety of the yellow fever vaccine (YFV) in HIV-infected (HIV+) patients with high CD4(+) T-cell counts. Design: In this prospective, comparative study of YFV-naive adults: 40 HIV+ under antiretroviral therapy (ART) with CD4(+) T-cell count above 350 cells/mu l and plasma HIV-RNA less than 50 copies/ml for at least 6 months and 31 HIV-negative (HIV-) received one injection of the YF-17D strain vaccine. Methods: Serologic response was assessed by using a plaque reduction neutralizing test and YFV-specific T cells by using an INF gamma-Elispot assay. Results: YFV was well tolerated in both groups. Most participants had asymptomatic YFV viremia at day (D) 7 after vaccination (77% of HIV- and 82% of HIV+, P = 0.58), with higher plasma level of YFV RNA in HIV+ than in HIV (median 2.46 log(10) copies/ml (range: 1.15-4.16) and 1.91 log(10) copies/ml (1.15-3.19), respectively, P = 0.011). A significant but transient decrease in CD4(+) cell counts was seen at D7 in both groups, more pronounced in HIV- than in HIV+ patients (-261.5 versus -111.5 cells/mu l, respectively, P = 0.0003), but no HIV breakthrough was observed in plasma. All participants developed protective neutralizing antibody levels from D28 and up to 1 year after injection. At D91, fewer HIV+ than HIV- participants exhibited YFV T-cell response (20 versus 54%, respectively, P = 0.037). Conclusion: At 1 year, YFV was immunogenic and well tolerated in HIV-infected adults under ART with CD4(+) T-cell counts above 350 cells/mu l. However, a lower immunity of YFV T cells in HIV-infected patients was observed as compared with HIV-participants.Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.

Malignancies represent a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. The introduction of combined antiretroviral therapy has modified the spectrum of malignancies in HIV infection with a decreased incidence of acquired immunodeficiency syndrome (AIDS) malignancies such as Kaposi's sarcoma and non-Hodgkin's lymphoma due to partial immune recovery and an increase in non-AIDS-defining malignancies due to prolonged survival. Management of HIV-infected patients with cancer requires a multidisciplinary approach, involving both oncologists and HIV physicians to optimally manage both diseases and drug interactions between anticancer and anti-HIV drugs. The French CANCERVIH group presents here a review and an experience of managing non-AIDS malignancies in HIV-infected individuals.

ObjectivesThe aim of the study was to assess the impact of rapid and sustained viral control produced by combination antiretroviral therapy (cART) on HIV‐associated immune activation and inflammation.MethodsIn this longitudinal observational study, we examined changes in interleukin‐6 (IL‐6), interferon‐γ‐inducible protein‐10 (IP‐10), monokine induced by interferon‐γ (MIG) and soluble CD14 (sCD14) levels during 2 years of effective first‐line cART. Biomarker levels before and after cART were compared with those observed in healthy subjects, using the Wilcoxon signed rank test. Elevated biomarker levels were defined with respect to values for healthy subject (mean + 2 standard deviations). Factors associated with persistently elevated biomarker levels after 2 years of cART were identified by logistic regression.ResultsWe included in the study 139 patients with a median HIV‐1 RNA level of 4.8 log10 HIV‐1 RNA copies/mL and a median CD4 cell count of 294 cells/μL at cART initiation [day 0 (D0)]. At D0, all biomarker levels were higher than in healthy subjects (P < 0.05). After 2 years of cART, IL‐6, IP‐10 and MIG levels fell significantly, by a median of 0.54, 420 and 1107 pg/mL, respectively (all P < 0.001), and were no longer elevated in > 75% of patients. In contrast, sCD14 levels did not change significantly (0.18 × 106 pg/mL; P = 0.102) and remained elevated. Older age was associated with elevated levels of IP‐10 [odds ratio (OR) 1.60 per 10 years older; P = 0.047] and MIG (OR 1.92 per 10 years older; P = 0.007) after 2 years of cART.ConclusionsThe rapid and sustained viral suppression produced by first‐line cART reduced IL‐6, IP‐10 and MIG to normal levels, while sCD14, a marker of monocyte activation, remained elevated. High levels of IP‐10 and MIG tended to persist in older patients.

Exploration du réservoir dans les sous-populations CD4 circulantes (SP) après 2 ans d’un traitement antirétroviral initié en primoinfection VIH (PHI2). 12 patients randomisés de l’essai OPTIPRIM. J0 et M24 : quantification de l’ADN-VIH total et analyse phylogénétique de la quasiespèce virale dans les cellules triées quiescentes, naïves (TN), mémoires centrales (TCM), transitionnelles (TTM), effectrices (TEM). M24 : capacité des SP à produire des virus par activation in vitro et comparaison des niveaux d’ADN-VIH dans les SP des PHI2 versus 9 patients traités en PHI 6 ans en médiane (PHI6) et 11 contrôleurs post-traitement traités en PHI (PTC). De J0 à M24 : augmentation du nombre des SP (p < 0,004), diminution du niveau d’ADN-VIH médian dans les PBMC de – 1,43 (p = 0,001), – 0,74 (TN), – 1,45 (TCM), – 1,48 (TTM), – 1,34 (TEM) (p < 0,004). Pas d’évolution de la diversité virale et production virale induite dans toutes les SP. Les TN et TCM étaient moins infectées que TTM et TEM (p < 0,009) et contribuaient moins au réservoir que les TTM (p = 0,019). Les niveaux d’ADN-VIH dans les SP des PHI2 étaient plus élevés que les faibles et similaires niveaux chez les PHI6 et PTC (p < 0,019). Un PHI2 maintien un statut de PTC 18 mois après arrêt du traitement avec des niveaux de réservoir, similaires à ceux des PTC. Un traitement précoce de deux ans en PHI protège les TCM et TN de l’infection. Un traitement de plus longue durée est nécessaire pour atteindre une réduction profonde du réservoir VIH et augmenter les cas de PTC.