Long term follow-up of the STOPAGO study.

An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974.

Safety and tolerability of immune checkpoint inhibitors in people with HIV infection and cancer: insights from the national prospective real-world OncoVIHAC ANRS CO24 cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been a major advance in cancer management. However, we still lack prospective real-world data regarding their usage in people with HIV infection (PWH). METHODS: The ANRS CO24 OncoVIHAC study (NCT03354936) is an ongoing prospective observational cohort study in France of PWH with cancer treated with ICI. We assessed the incidence of grade ≥3 immune-related adverse events (irAEs). All grade ≥3 irAEs were reviewed by an event review. RESULTS: Between January 17, 2018, and December 05, 2023, 150 participants were recruited from 33 sites and 140 were included in this analysis. At the data cut-off date of December 05, 2023, the median follow-up was 9.2 months (IQR: 3.9-18.3), with a total of 126.2 person-years.Median age was 59 years (IQR: 54-64) and 111 (79.3%) were men. Median time since HIV diagnosis was 25 years (12-31), the median duration on antiretroviral (ARV) was 19.5 years (7.7-25.4), and the CD4 nadir was 117/µL (51-240). ICI regimens comprised anti-programmed cell death protein-1 (PD-1) for 111 (79.3%) participants, anti-programmed death-ligand 1 for 25 (17.9%), a combination of anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 for 3 (2.1%), and anti-PD-1 along with anti-vascular endothelial growth factor receptor for 1 (0.7%). The most frequent cancers were lung (n=65), head/neck (n=15), melanoma (n=12), liver (n=11) and Hodgkin's lymphoma (n=9).During follow-up, a total of 34 grade ≥3 irAEs occurred in 20 participants, leading to an incidence rate of 26.9 per 100 person-years. The Kaplan-Meier estimates of the proportion of participants with at least one episode of grade ≥3 irAEs were 13.8% at 6 months, 15.0% at 12 months and 18.7% at 18 months. One treatment-related death due to myocarditis was reported (0.7%). Multivariable analysis of cumulative incidence showed that participants with time since HIV diagnosis >17 years (incidence rate ratio (IRR)=4.66, p=0.002), with CD4<200 cells/µL (IRR=4.39, p<0.0001), with positive cytomegalovirus (CMV) serology (IRR=2.76, p=0.034), with history of cancer surgery (IRR=3.44, p=0.001) had a higher risk of incidence of grade ≥3 irAEs. CONCLUSION: This study showed that the incidence of a first episode of grade ≥3 irAE was 15.0% (95% CI: 9.6% to 22.9%) at 1 year and the cumulative incidence of all severe irAE episodes was 26.9 per 100 person-years. Low CD4 count, positive CMV serology, history of cancer surgery and a longer time since HIV diagnosis were associated with the occurrence of severe irAEs.

Whole-body distribution of tenofovir, emtricitabine and dolutegravir in non-human primates.

BACKGROUND: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues. OBJECTIVES: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs). METHODS: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection. RESULTS: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%. CONCLUSIONS: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure.

Major depletion of insulin sensitivity-associated taxa in the gut microbiome of persons living with HIV controlled by antiretroviral drugs.

BACKGROUND: Persons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated. METHODS: In this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc. RESULTS: Three major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80-82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc. CONCLUSION: High resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.

Budd-Chiari syndrome after BNT162b2 mRNA vaccination: two case reports.

Budd-Chiari syndrome (BCS) is a rare disease characterised by an obstruction in the hepatic venous outflow. We describe two cases of patients hospitalised a few days after tozinameran vaccination. Liver tests and medical imaging were carried out, and BCS was diagnosed. After treatment including anticoagulant therapy, the first patient improved clinically, unlike the second patient with persistent hepatic thrombosis. According to the WHO-UMC causality assessment system, the vaccine's share was assessed as 'probable' for the first patient as BCS occurred during anticoagulant therapy, and 'possible' for the second patient as no other aetiology was found. Further epidemiological studies are needed to confirm or refute the causal relationship between BCS and tozinameran vaccination.

Combined Flow-Fluorescence in situ hybridization to HHV-8 and EBV reveals the viral heterogeneity of primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma associated with Kaposi Sarcoma-associated herpesvirus (KSHV/HHV8) infection. Lymphoma cells are coinfected with Epstein-Barr virus (EBV) in 60-80% of cases. Tools allowing a reliable PEL diagnosis are lacking. This study reports PEL diagnosis in 4 patients using a Flow-Fluorescence in situ hybridization (FlowFISH) technique that allowed detection of differentially expressed EBV and HHV8 transcripts within the same sample, revealing viral heterogeneity of the disease. Moreover, infected cells exhibited variable expressions of CD19, CD38, CD40, and CD138. Therefore, FlowFISH is a promising tool to diagnose and characterize complex viral lymphoproliferations.

Reactions and adverse events induced by T-cell engagers as anti-cancer immunotherapies, a comprehensive review.

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE.

Toxicity of immunotherapy combinations with chemotherapy across tumor indications: Current knowledge and practical recommendations.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma. We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes. Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Impact of immunosuppressive agents on the management of immune-related adverse events of immune checkpoint blockers.

BACKGROUND: Immune checkpoint blockers (ICBs) can induce immune-related adverse events (irAEs) whose management is based on expert opinion and may require the prescription of steroids and/or immunosuppressants (ISs). Recent data suggest that these treatments can reduce the effectiveness of ICBs. OBJECTIVE: To investigate the relationship between the use of steroids and/or ISs and overall survival (OS) and progression-free survival (PFS) among ICB-treated patients with an irAE. METHODS: We prospectively collected data from the medical records of patients with solid tumors or lymphoma in the French REISAMIC cohort and who had been treated with ICBs between June 2014 and June 2020. RESULTS: 184 ICB-treated patients experienced at least one Common Terminology Criteria for Adverse Events grade ≥ 2 irAE. 107 (58.2%) were treated with steroids alone, 20 (10.9%) with steroids plus IS, 57 (31.0%) not received steroids or IS. The median OS was significantly shorter for patients treated with steroids alone (25.2 months [95% confidence interval (CI): 22.3-32.4] than for patients treated without steroids or IS (63 months [95%CI: 40.4-NA]) and those receiving an IS with steroids (53.4 months [95%CI: 47.3-NA]) (p < 0.001). The median PFS was significantly shorter for patients treated with steroids alone (17.0 months [95%CI: 11.7-22.9]) than for patients treated without steroids or IS (33.9 months [95%CI: 18.0-NA]) and those receiving an IS with steroids (41.1 months [95%CI: 26.2-NA]) (p = 0.006). There were no significant intergroup differences in the hospital admission and infection rates. CONCLUSION: In a prospective cohort of ICB-treated patients, the use of IS was not associated with worse OS or PFS, contrasting with the use of steroids for the management of irAEs.

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

Identification of macaque dendritic cell precursors in blood and tissue reveals their dysregulation in early SIV infection.

Distinct dendritic cell (DC) subsets play important roles in shaping immune responses. Circulating DC precursors (pre-DCs) are more susceptible to HIV infection in vitro, which may explain the inefficiency of immune responses against HIV. However, the interplay between HIV and pre-DC is not defined in vivo. We identify human pre-DC equivalents in the cynomolgus macaque and then analyze their dynamics during simian immunodeficiency virus (SIV) infection to illustrate a sharp decrease of blood pre-DCs in early SIV infection and accumulation in lymph nodes (LNs), where they neglect to upregulate CD83/CD86 or MHC-II. Additionally, SIV infection attenuates the capacity of stimulated LN pre-DCs to produce IL-12p40. Analysis of HIV cohorts provides correlation between costimulatory molecule expression on pre-DCs and T cell activation in spontaneous HIV controllers. These findings pinpoint certain dynamics and functional changes of pre-DCs during SIV infection, providing a deeper understanding of immune dysregulation mechanisms elicited in people living with HIV.

Use of Vonicog Alpha and Acquired von Willebrand Syndrome, a New Approach: A Case Report.

Therapeutic management of acquired von Willebrand syndrome (AVWS) can be challenging, particularly in cases of AVWS associated with monoclonal IgM such as Waldenström macroglobulinemia (WM) where several therapeutic options may be ineffective. Here, we describe the case of an 88-year-old patient who developed AVWS during follow-up for WM. The presence of a severe bleeding symptomatology not controlled by several therapies (plasma-derived von Willebrand factor, plasmapheresis) led us to introduce a supplementation with recombinant von Willebrand factor, vonicog α (Veyvondi, Takeda, Japan), starting at a dose of 50 IU/kg/d. This supplementation allowed clinical (no further bleeding) and biological (hemoglobin level, von Willebrand factor parameters) improvements. Because of the persistence of bleeding risk factors, the treatment was maintained at a prophylactic dose (20 UI/kg three times a week), without recurrence of bleeding events for a period of 9 months.

Assessing respiratory epidemic potential in French hospitals through collection of close contact data (April-June 2020).

The transmission risk of SARS-CoV-2 within hospitals can exceed that in the general community because of more frequent close proximity interactions (CPIs). However, epidemic risk across wards is still poorly described. We measured CPIs directly using wearable sensors given to all present in a clinical ward over a 36-h period, across 15 wards in three hospitals in April-June 2020. Data were collected from 2114 participants and combined with a simple transmission model describing the arrival of a single index case to the ward to estimate the risk of an outbreak. Estimated epidemic risk ranged four-fold, from 0.12 secondary infections per day in an adult emergency to 0.49 per day in general paediatrics. The risk presented by an index case in a patient varied 20-fold across wards. Using simulation, we assessed the potential impact on outbreak risk of targeting the most connected individuals for prevention. We found that targeting those with the highest cumulative contact hours was most impactful (20% reduction for 5% of the population targeted), and on average resources were better spent targeting patients. This study reveals patterns of interactions between individuals in hospital during a pandemic and opens new routes for research into airborne nosocomial risk.

Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells.

HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac251-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8+ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.

BACKGROUND: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. OBJECTIVE: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. METHODS: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. RESULTS: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003). CONCLUSIONS: HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Ocular surface toxicities associated with modern anticancer therapies.

Cancer treatments have recently shifted from broad-spectrum cytotoxic therapies to more focused treatments, maximizing anticancerous activity while reducing toxicity to healthy cells. These modern anticancer therapies (MATs) encompass a wide range of innovative molecules that include immune checkpoint inhibitors and other targeted anticancer therapies, comprising antibody drug conjugates and inhibitors of signal transduction. Some MATs are associated with ocular surface adverse events that can cause severe discomfort and even lead to loss of vision. While these complications remain rare, they are probably underreported. It is likely that both oncologists and ophthalmologists will come across MATs-associated ocular surface-adverse events in their practices, owing to the increasing number of patients being treated with MATs. Rapid identification of ocular surface-adverse events is crucial, as early intervention can manage these conditions to avoid vision loss and reduce negative impacts on quality of life. We discuss characteristics of ocular surface pathologies attributed to MATs, describe the suspected underlying pathophysiological mechanisms, and outline the main lines of treatment.

CD8 + T-cell priming is quantitatively but not qualitatively impaired in people with HIV-1 on antiretroviral therapy.

BACKGROUND: The induction of de novo CD8 + T-cell responses is essential for protective antiviral immunity, but this process is often impaired in people with HIV-1 (PWH). We investigated the extent to which the immune competence of naive CD8 + T cells, a key determinant of priming efficacy, could be preserved or restored in PWH via long-term antiretroviral therapy (ART). METHODS: We used flow cytometry, molecular analyses of gene transcription and telomere length, and a fully validated priming assay to characterize naive CD8 + T cells ex vivo and evaluate the induction of antigen-specific effector/memory CD8 + T cells in vitro , comparing age-matched healthy uninfected donors (HUDs), PWH on ART, and natural HIV-1 controllers (HICs). RESULTS: We found that naive CD8 + T cells were numerically reduced and exhibited a trend toward shorter telomere lengths in PWH on ART compared with HUDs and HICs. These features associated with impaired priming efficacy. However, we also found that naive CD8 + T cells were fully equipped proliferatively and transcriptionally in PWH on ART, enabling the generation of antigen-specific effector/memory CD8 + T cells with functional and phenotypic attributes comparable to those primed from HUDs. CONCLUSION: Our data suggest that naive CD8 + T cells in PWH on ART are intrinsically capable of generating functionally and phenotypically intact effector/memory CD8 + T cells in response to antigen, despite evidence of senescence and an overall numerical reduction that compromises priming efficacy relative to HUDs and HICs.