Adequate CD4 Research Articles

Tailoring cytomegalovirus prophylaxis based on T cell immunity panel assessment in kidney transplant patients at high risk of cytomegalovirus.

Valganciclovir prophylaxis against cytomegalovirus (CMV) is recommended for solid organ transplant recipients, but is associated with drawbacks, including expense and leukopenia. Our center adopted a strategy of serial assessment with a CMV-specific T cell immunity panel (CMV-TCIP) and cessation of valganciclovir prophylaxis upon demonstration of adequate CD4+ responses in kidney transplant patients at high risk of CMV disease. We retrospectively reviewed adult recipients of a kidney or pancreas transplant between August 2019 and July 2021 undergoing serial CMV-TCIP monitoring. Included patients were considered high risk for CMV, defined by donor positive (D+)/recipient negative (R-) CMV IgG serostatus, or recipient positive (R+) patients who received induction with a lymphocyte-depleting agent. Prophylaxis was discontinued after a patient's first CMV-specific CD4+ T cell value of ≥0.20%. Risk of clinically significant CMV infection (csCMVi) in those who underwent early discontinuation of CMV prophylaxis and predictors of CMV T cell immunity were analyzed. Of 54 included patients, 22 stopped prophylaxis early due to CMV-specific CD4+ T cell immunity at a median of 4.7 (IQR: 3.8-5.4) months after transplant. No instances of csCMVi were observed in the 22 patients who had prophylaxis discontinued early, of whom 19/22 were CMV R+ and 3/22 were CMV D+/R-. Donor/recipient CMV serostatus was predictive of immunity (p <.001). Early discontinuation of valganciclovir prophylaxis in patients with CMV CD4+ T cellular immunity appears safe and potentially beneficial in this preliminary series, especially in R+ patients. Further study is warranted, given that truncated prophylaxis may yield patient-level benefits.

Accuracy, use and acceptability of the VISITECT CD4 semi-quantitative test to advance HIV disease screening in routine programmatic settings in Tanzania

BackgroundThe available few laboratory-based CD4 assay for People Living with HIV (PLHIV) experience supply stock-outs and instrument breakdowns in developing countries, affecting the ability to diagnose Advance HIV disease (AHD). We evaluated the performance of the VISITECT CD4 point of care test among healthcare workers in HIV program in Tanzania. MethodsA retrospective diagnostic accuracy study was conducted among PLHIV who received both the VISITECT CD4 and a standard-of-care. Acceptability of the VISITECT CD4 by healthcare workers was assessed using a structured questionnaire. Both FACS Count and Pima CD4 assay were considered as reference standards. Findings were summarized as proportions with 95 % confidence intervals (CI). Data were analyzed using STATA 17 (StataCorp, College Station, TX). ResultsA total of 1370 PLHIV were tested using VISITECT CD4 across 20 facilities between 3 April and 14 September 2022. The median age was 37 (Interquartile range (IQR):29–46). Overall, 897 (65.5 %) were females and 449 had both VISITECT CD4 test and standard of care. The sensitivity and specificity were; 95.9 % (95 % CI: 91.8 %–98.3 %) and 78.3 % (95 % CI: 73.0 %–83.0 %) respectively. 47 healthcare workers used the VISITECT CD4, of whom 57.5 % were non-laboratory healthcare workers. Majority of the healthcare workers were of the opinion that the training was adequate and VISITECT CD4 was easy and useful in clinical decisions. ConclusionThe VISITECT CD4 test was accurate, useable and acceptable among healthcare workers in Tanzania. The scale up of VISITECT CD4 should consider development of training curriculum and the use of job aids particularly for non-laboratory healthcare workers.

Outcomes of human immunodeficiency virus-associated Burkitt lymphoma and diffuse large B-cell lymphoma treated in Australia: A report from the Australasian Lymphoma Alliance.

Antiretroviral therapy (ART) has improved outcomes for human immunodeficiency virus-associated non-Hodgkin lymphoma (HIV-NHL). This is an analysis of 44 patients with HIV with Burkitt lymphoma (HIV-BL) and diffuse large B-cell lymphoma (HIV-DLBCL) treated in Australia over a 10-year period (2009-2019) during the ART and rituximab era. At HIV-NHL diagnosis, the majority of presenting patients had adequate CD4 counts and undetectable HIV viral load <50 copies/mL. More than 80% of patients received chemotherapy with curative intent, rituximab, and concurrent ART with chemotherapy (immunotherapy). R-CODOX-M/IVAC or R-Hyper-CVAD (55%) were most commonly used in HIV-BL. CHOP (58%) was the most commonly used chemotherapy backbone for HIV-DLBCL, although 45% of patients received more intense chemotherapy regimens. Overall, 93% of patients who received curative therapy completed their intended course. The 2-year progression-free survival (PFS) and overall survival (OS) for the HIV-BL cohort was 67% and 67% respectively. The 2-year PFS and OS for the HIV-DLBCL cohort was 77% and 81% respectively. Treatment related mortality was 5%. In all, 83% of patients achieved a CD4 count of >0.2×109 /L 6 months after the end of treatment. Current Australian practice favours the treatment of HIV-BL and HIV-DLBCL similarly to the HIV-negative population with the use of concurrent ART, achieving outcomes comparable to the HIV-negative population.

Influence of HIV infection on clinical course of the new coronavirus infection (COVID-19)

BACKGROUND: Human immunodeficiency virus (HIV)-associated severe immunosuppression, high viral load, non-HIV-related comorbidities and conditions, and lack of antiretroviral therapy may exacerbate the clinical course of coronavirus disease 2019 (COVID-19).&#x0D; AIM: To assess the effect of HIV infection on the clinical course of COVID-19, disease severity, and its outcomes.&#x0D; MATERIALS AND METHODS: Medical records of 35,328 patients who had COVID-19 in 2020 were analyzed, including 46 cases of COVID-19 in individuals with HIV infection. Clinical variants and COVID-19 severity, frequency of COVID-19 detection by polymerase chain reaction, CD4 lymphocyte count, viral load in individuals with HIV infection, and mortality rates were assessed.&#x0D; RESULTS: In 76% of patients with coinfection, signs of HIV infection progression, opportunistic infections, and concomitant diseases were noted. Moreover, 52.2% of the patients analyzed were users of psychoactive substances. Among patients with HIV and COVID-19, men predominated in groups aged 30 years, whereas among the HIV-negative population, women were predominant in groups aged 18 years. The proportion of severe COVID-19 in individuals with HIV infection (47.8%) exceeds that in the group without HIV (12.3%). The mortality rate from COVID-19 in the HIV-infected group was more than seven times higher than that in the HIV-negative group (t=1.81; p=0.01).&#x0D; CONCLUSIONS: In the HIV-infected group, extremely severe COVID-19 was more common. Weakness, cough, shortness of breath, and myalgia were significantly more common in the HIV-infected group. Moreover, the HIV-infected group with an undetectable viral load and adequate CD4 lymphocyte count in the blood was exposed to the same risks of the disease and its progression as the HIV-negative group.

T Cell Metabolism in Infection.

T lymphocytes (T cells) are divided into two functionally different subgroups the CD4+ T helper cells (Th) and the CD8+ cytotoxic T lymphocytes (CTL). Adequate CD4 and CD8 T cell activation to proliferation, clonal expansion and effector function is crucial for efficient clearance of infection by pathogens. Failure to do so may lead to T cell exhaustion. Upon activation by antigen presenting cells, T cells undergo metabolic reprograming that support effector functions. In this review we will discuss how metabolic reprograming dictates functionality during viral infections using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) as examples. Moreover, we will briefly discuss T cell metabolic programs during bacterial infections exemplified by Mycobacterium tuberculosis (MT) infection.

Immunovirological discordance among female sex workers who start antiretroviral therapy in Burkina Faso

BackgroundIn people living with HIV/AIDS (PLWHA), initiation of antiretroviral therapy (ART) leads to sustained effective suppression of viral replication and increasing CD4 + T cell count. However, a fraction of ART-treated patients still fail to reach adequate CD4 + T cell number despite a suppressed viral load (VL), and this phenomenon is defined as immunovirological discordance (IVD). In Africa, several studies have reported immunovirological outcomes of antiretroviral therapy, but little is known about IVD occurrence in Female sex workers (FSW). This study aimed to assess the prevalence of IVD and associated factors among a cohort of HIV infected FSW in Burkina Faso.MethodsWe conducted a cohort study from December 2003 to October 2016. Immunovirological discordance was defined as CD4 + T cell gain < 100 cells/µL despite a suppressed VL (VL < 1000 copies/mL) 12 months after ART initiation. The CD4 + T cells were counted using BD FACSCount™ System and point of care Pima™ CD4 + Analyzer. HIV-1 RNA was quantified by real-time polymerase-chain-reaction assay with the use of the ABI 7000 system. We conducted a logistic regression to identify factors associated with discordant responses.ResultsAmong the 123 HIV-1 infected FSW having at least 12 months follow-up on ART, 105 (85.4%) achieved HIV-1 RNA suppression. Among the latter 25 gained less than 100 CD4 + T cells within 12 months follow-up. The IVD rate was 23.8% (95%CI 16.04%–33.11%). After adjustment for age, WHO clinical stage and ART regimen including nucleoside/nucleotide reverse transcriptase inhibitors, only baseline CD4 + T cell count between 200 to 350 cells/µL (adjusted OR: 4.15; 95%CI 1.13–15.22) and 350 to 500 cells/µL (adjusted OR: 17.50; 95%CI 2.68–114.31) remain significantly associated with IVD occurrence.ConclusionsImmunovirological discordance response was common in FSW with proportions close to those observed in the general population. A diagnosis and personalized follow-up of patients who do not achieve full immune reconstitution would make it possible to avoid complications in terms of morbidity and mortality.

High Glucose Concentrations Impair the Processing and Presentation of Mycobacterium tuberculosis Antigens In Vitro.

Type 2 diabetes is an established risk factor for tuberculosis, but the underlying mechanisms are largely unknown. We established an in vitro model to analyze the effect of high glucose concentrations in antigen processing and presentation in antigen-presenting cells. Human monocyte-derived macrophages (MDMs) were exposed to high (11 mM and 30 mM) and low (5.5 mM) glucose concentrations and infected with Mycobacterium tuberculosis (Mtb). Flow cytometry was used to analyze the effect of high glucose concentrations in histocompatibility complex (MHC) class II molecules (HLA-DR) and co-stimulatory molecules (CD80 and CD86), indispensable for an adequate antigenic presentation and CD4+ T cell activation. HLA-DR and CD86 were significantly decreased by high glucose concentrations compared with low glucose concentrations. Confocal microscopy was used to detect Rab 5 and Lamp-1, proteins involved in the kinetics of antigen processing as early markers, and Rab 7 and cathepsin D as late markers. We observed a delay in the dynamics of the acquisition of Rab 7 and cathepsin D in high glucose concentrations. Moreover, the kinetics of the formation M. tuberculosis peptide–MHC II complexes in MDMs was decreased under high glucose concentrations, reducing their capacity for T cell activation. These findings suggest that high glucose concentrations directly affect antigenic processing, and therefore antigenic presentation.

Stages of pregnancy and HIV affect diagnosis of tuberculosis infection and Mycobacterium tuberculosis (MTB)-induced immune response: Findings from PRACHITi, a cohort study in Pune, India

BackgroundAccurate tuberculosis infection (TBI) tests are critical for pregnant women, especially those with HIV, who have a high risk of TB disease. MethodsWe enrolled interferon gamma release assay (IGRA)+ pregnant women with and without HIV in a longitudinal study, followed up at delivery and 6 months postpartum. Tuberculin skin test (TST) and IGRA were compared by HIV status at each timepoint. ResultsOf 165 enrolled IGRA+ pregnant women: 35 (21%) had HIV and were on antiretroviral therapy with median CD4 of 476 (IQR 399–586). Compared to antepartum, significantly fewer women remained IGRA+ at delivery [HIV+ n=21/35 (62%, p=0.009); HIV- n=100/130 (77%, p=0.002)] and postpartum [HIV+ n=30/35 (87%, p=0.03); HIV– n=116/130 (89%, p=0.01)]. IGRA/TST discordance was high in pregnant women (HIV+: 51%; HIV-: 25%). Median IFN-γ was lowest for all women at delivery; significantly lower in women with HIV at all timepoints compared to women without HIV. TB incidence was 50/ 1000 person-years and 18/1000 person-years among women with and without HIV respectively. ConclusionsPregnancy affects TBI test results and reduces IFN-γ response to M. tuberculosis stimulation. Despite adequate CD4 counts, women with HIV express less IFN-γ than women without HIV, which may explain the high TB incidence in postpartum women with HIV.

Lymphoid and myeloid immune cell reconstitution after nicotinamide-expanded cord blood transplantation

Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR: > 50 × 106/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13–63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.

Metabolic Alterations Of Patients With Acquired Immunodeficiency Syndrome

Objective: To evaluate the metabolic changes in patients with acquired immunodeficiency syndrome. Methods: This is an observational analytical cross-sectional study that was carried out with 120 patients on regular use of antiretroviral therapy, from May to July 2018. The metabolic changes were determined through the collection of biochemical parameters: CD4, CD4 absolute, CD8, absolute CD8, hemoglobin, High-Density Lipoprotein, Low-Density Lipoprotein, triglycerides, and fasting blood glucose. Results: The lipid profile, in most individuals, showed serum values ​​of total cholesterol, triglycerides, and Low-Density Lipoprotein, within the normal range, while the serum levels of High-Density Lipoprotein were decreased by 53.6%, being related to the mean time disease of 8.7 years (± 6.1). As for hematological indices, 62 and 60 (80.5% and 77.9%) of the patients had adequate serum hemoglobin and hematocrit values, however, it was observed that those who had anemia lived with the virus for a longer time (9.27 years ± 6.89). When observing the parameters related to the immune system, it was seen that CD4 levels were low in 38% of patients, adequate absolute CD4 in 56.5%, increased CD8 in 90.7%, and absolute CD8 in 63%. Conclusion: It is known that metabolic changes, such as the decrease in serum levels of High-Density Lipoprotein are common in patients with the virus, as well as, it is known that the survival of these individuals is being prolonged by antiretroviral therapy, which can result in exposure important risk factors for cardiovascular disease. Emphasizing the importance of nutritional monitoring in this population.

A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930)

Background:T-follicular helper (TFH) cells are a novel CD4+ T-cell subset that participates in germinal center maintenance/proliferation. Proliferation of TFH is a postulated mechanism of pathogenesis for T-cell lymphomas (AITL, PTCL and others). The inducible T-cell costimulator (ICOS) is highly expressed in TFHand hence in AITL, PTCL FH type, and some cutaneous T cell lymphomas (CTCL) and follicular lymphomas (FL). MEDI-570 is a human afucosylatedIgG1 kappa monoclonal antagonistic antibody directed against ICOS, which binds to and eliminates ICOS expressing cells in preclinical in vivo models. We investigate the safety, pharmacokinetics (PK) and clinical activity of ICOS blockade by MEDI-570 in T-cell lymphomas. Methods: NCI-9930 is a Phase I study of MEDI-570 in R/R malignant lymphomas. It is a 3+3 study design that evaluated 5 dose levels . MEDI-570 was administered intravenously (IV) every 3 weeks for 12 cycles. Eligibility criteria included: age &amp;gt;18 years, ECOG &amp;lt;2, diagnosis of R/R PTCL, AITL, CTCL, mycosis fungoides, or FL, that have received and are refractory to at least 1 line of therapy (at least 2 lines of therapy and post autologous cell transplantation for FL), adequate organ functions and CD4+ T-cells &amp;gt;200 cells/uL (&amp;gt;100 for AITL). Primary endpoints are safety of MEDI-570, dose limiting toxicities (DLT)s and its recommended phase 2 dose (RP2D). Secondary endpoints include: pharmacokinetics (PK), overall response rate (ORR) based on Lugano classification and progression-free survival (PFS). Exploratory endpoints include various correlative studies. This study is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP) (NCT02520791). Results: As of June 2020, the dose escalation phase has been completed. Patients were enrolled and evaluable for safety and efficacy. Median age is 63 (range: 29-80), female/male ratio=5/13, histologic types consisted in AITL (n= 12, 71%), PTCL NOS (n=3, 18%) and CTCL (n=2, 12%). The median number of prior therapies were 7.5 (1 - 16), stage III/IV in 83%, prior autologous HCT in 18%. There were 4 partial remissions (PR) and 7 with stable disease (SD), all patients with AITL. Two patients (1 PR and 1 SD) remain on treatment. One patient completed treatment and remains in a stable PR for over a year without further treatment. One patient in PR underwent allogeneic hematopoietic transplantation (HCT) and remains in remission. The most common grade 3/4 AEs were decreased CD4+ T-cells as expected anemia (12%), hypophosphatemia (12%), thrombocytopenia (6%), infusion related reactions (6%). No DLTs were reported, and the maximum tolerated dose was not established. Initial PK analyses demonstrated that MEDI-570 systemic exposure increased in a dose-dependent manner, and a RP2D was determined. Peripheral blood flow cytometry analysis of T-cell subsets showed that MEDI-570 caused a rapid and sustained decrease in CD4+ T-cells. It also resulted in reductions in circulating of certain ICOS+ T-cells, especially on days 7-21 post treatment. Conclusion: MEDI-570 was safe, well tolerated and showed promising clinical activity in poor-risk refractory and heavily pretreated AITL. A RP2D was established. MEDI-570 results in sustained reduction of the targeted ICOS+T lymphocytes. The study continues enrolling in the expansion phase. Disclosures Chavez: Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Epizyme: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy. William:Dova: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Smith:Pharmacyclics: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; Acerta: Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Zain:Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding; Seattle Genetics: Research Funding. Glenn:Genentech: Research Funding. Mehta-Shah:Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Genetech: Research Funding; C4 Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding. Boutrin:Astrazeneca: Current Employment, Current equity holder in private company. Zhao:Astrazeneca: Current Employment, Current equity holder in private company. Cheng:Astrazeneca: Current Employment, Current equity holder in private company. Standifer:Astrazeneca: Current Employment, Current equity holder in private company. Carlesso:Astrazeneca: Current Employment, Current equity holder in private company. Siu:Shatthucks: Research Funding; Symphogen: Consultancy, Research Funding; Tessa: Consultancy; Treadwell Therapeutics: Consultancy, Current Employment; Pfizer: Research Funding; Voronol: Consultancy; Rubius Therapeutics: Consultancy; Abbvie: Research Funding; Agios: Current equity holder in publicly-traded company; Arvinas: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy, Research Funding; Bayer: Research Funding; Boerhinger-Ingelheim: Research Funding; Bristol-Myers Squibb: Research Funding; Glaxo Smith Kline: Research Funding; Intensity Therapeutics: Research Funding; Navire: Consultancy; Novartis: Research Funding; Oncorus: Consultancy; Mirati: Consultancy, Research Funding; Roche/Genentech: Consultancy; Relay Therapeutics: Consultancy; Roche: Consultancy; Merck: Consultancy.

Lues Maligna in an Immune-Reconstituted Patient with Retroviral Infection: A Case Report

Lues Maligna in an Immune-Reconstituted Patient with Retroviral Infection: A Case Report

TB prevention strategies and unanswered questions for pregnant and postpartum women living with HIV: the need for improved evidence.

TB prevention strategies and unanswered questions for pregnant and postpartum women living with HIV: the need for improved evidence.

Early CD4+ T-Cell Reconstitution Is an Excellent Predictor for Survival and Non-Relapse Mortality in Pediatric and Young Adult Patients Who Develop Moderate to Severe Acute Graft-Versus-Host-Disease; A Dual Center Validation

Background Acute Graft-versus-Host-Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic (stem) cell transplantation (HCT). Studies evaluating the relation between immune reconstitution (IR) and aGvHD are largely lacking. We previously showed that successful CD4+ IR strongly predicts non-relapse mortality (NRM) and survival after HCT. We hypothesized that adequate CD4+ IR may influence outcomes in patients who develop aGvHD, because (CD4+) T regulatory (Tregs) play a crucial role in tolerance. Therefore, we studied the relation between CD4+ IR after HCT and outcomes (survival, NRM) in patients who developed moderate to severe aGvHD, in 2 separate pediatric / young adult cohorts. Methods Patients receiving their first allogeneic HCT at the UMC Utrecht / Princess Maxima Center (UMC/PMC; 2004 and 2018) and at Memorial Sloan Kettering Cancer Center (MSK; 2008 – 2018), New York were included. No restrictions applied in terms of donor source, indication, conditioning, age. CD4+ IR was measured every 2-4 weeks. The main outcomes of interest were 5-year overall survival (OS) and 5-year NRM, stratified for aGvHD 2-4 and adequate CD4+ IR (twice >50*106 CD4+/uL) prior to aGvHD onset. Fine and Gray competing risk models and cox-proportional hazard models were used. Results 591 patients (276 UMC/PMC; 315 MSK) were included (table 1); median age at UMC/PMC was 7.06 years (range 0.16-22.74) and at MSK 10.4 years (range 0.1-35.6). At UMC/PMC 73 (26.4%) and at MSK 70 (22.2%) patients developed aGvHD 2-4, while 29 (10.5%) and 32 (10.2%) developed aGvHD 3-4. At UMC/PMC 35% (26/73) developed aGvHD in the presence of CD4+ IR and at MSK 64% (45/70). The 5-yr OS for patients without aGvHD at UMC/PMC and MSK was 75% and 72%, resp. The only multivariate predictor for OS and NRM in patients with aGvHD 2-4 was CD4+ IR. In both cohorts, CD4+ IR before onset of aGvHD 2-4 was associated with higher 5-yrs OS compared to those who developed aGvHD 2-4 without CD4+ IR; 77% vs 48%, p Interpretation In 2 separate cohorts adequate ‘CD4+ IR prior to onset aGvHD' was found to be a simple and robust predictor for survival and NRM. These findings provide insight in the importance of adequate IR for HCT patients to survive moderate to severe aGvHD. Finding strategies to better predict CD4+ T cell recovery after HCT may influence survival chances.

A Novel Vaccine Strategy to Overcome Poor Immunogenicity of Avian Influenza Vaccines through Mobilization of Memory CD4 T Cells Established by Seasonal Influenza.

Avian influenza vaccines exhibit poor immunogenicity in humans. We hypothesized that one factor underlying weak B cell responses was sequence divergence between avian and seasonal influenza hemagglutinin proteins, thus limiting the availability of adequate CD4 T cell help. To test this, a novel chimeric hemagglutinin protein (cH7/3) was derived, comprised of the stem domain from seasonal H3 hemagglutinin and the head domain from avian H7. Immunological memory to seasonal influenza was established in mice, through strategies that included seasonal inactivated vaccines, Flumist, and synthetic peptides derived from the H3 stalk domain. After establishment of memory, mice were vaccinated with H7 or cH7/3 protein. The cH7/3 Ag was able to recall H3-specific CD4 T cells, and this potentiated CD4 T cell response was associated with enhanced early germinal center response and rapid elicitation of Abs to H7, including Abs specific for the H7 head domain. These results suggest that in pandemic situations, inclusion of CD4 T cell epitopes from seasonal viruses have the potential to overcome the poor immunogenicity of avian vaccines by helping B cells and conferring greater subtype-specific Ab response to viral HA.

Adequate CD4+ T-cell reconstitution enhances survival probability after acute graft-versus-host-disease

Background & Aim Background Acute Graft-versus-Host-Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic (stem) cell transplantation (HCT). Studies evaluating the relation between immune reconstitution (IR) and aGvHD are largely lacking. We previously showed that successful CD4+ IR strongly predicts event-free survival chances. Therefore, we studied how CD4+ IR post-HCT influences survival chances in patients suffering from aGvHD. Methods, Results & Conclusion Methods Pediatric patients receiving their first allogeneic HCT between 2004 and 2018 were included. Blood samples and outcome data were collected and registered prospectively. The main outcomes of interest were 5-year overall survival (OS) and non-relapse mortality (NRM) probabilities, stratified for aGvHD (grade II-IV) and for the presence or absence of adequate CD4+ IR (twice >50*10 6 CD4+CD3+ cells/L) prior to aGvHD onset. For this, we applied a time-to-event multivariate Log-rank test with HCT-source; cord blood transplantation, and bone marrow or peripheral blood transplantation, as covariates. Results 276 pediatric patients with a median age of 7.06 years (range 0.16-22.74), were included; 73 (26.4%) had moderate-severe aGvHD (grade II-IV) and 29 (10.5%) had severe aGvHD (grade III-IV). Adequate early CD4+ IR before diagnosis of aGvHD grade II-IV was associated with higher 5-year OS probability (77% versus 48%, p Interpretation Adequate CD4+ IR prior to aGvHD onset protects against increased mortality risk after aGvHD in HCT. These findings provide insight in the importance of adequate IR in HCT patients in surviving severe aGvHD. Patients with inadequate CD4+ T-cells prior to aGvHD onset might may have insufficient development of regulatory processes and are more at risk for viral infections. As such, these patients may benefit from personalized (anti-viral / immune suppressive) treatment to improve survival chances.

Adequate CD4+ T Cell Reconstitution Prior to Onset of Agvhd Grade II-IV Protects Against Transplantation Related Mortality

Background Graft-versus-Host-Disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic (stem) cell transplantation (HCT). Studies evaluating the relation between immune reconstitution (IR) and GvHD are largely lacking. We previously showed that successful CD4+ IR strongly predicts event-free survival chances (JACI 2018, Blood 2018). Therefore, we were interested in relating IR to acute and chronic GvHD after HCT. Methods Pediatric patients receiving their first allogeneic HCT between 2004 and 2018 were included. Blood samples and outcome data were collected and registered prospectively. Our main outcomes of interest were 5-year overall survival (OS) and non-relapse mortality (NRM) probabilities, stratified for aGvHD (grade II-IV) and for the presence or absence of adequate CD4+ IR (twice >50*106 CD4+CD3+ cells/L) prior to aGvHD onset. Other outcomes of interest were IR of T-cells, B-cells, NK-cells, monocytes, neutrophils, reticulocytes, and basophils, in patients with or without grade II-IV aGvHD or cGvHD. We applied a time-to-event multivariate Log-rank test to evaluate aGvHD-related survival. IR data were analyzed as continuous variables using multivariate linear-mixed-effects-regression modelling. HCT-source; cord blood transplantation, and bone marrow or peripheral blood transplantation, was analyzed as covariate. Results 391 pediatric patients were included; 97 (24.8%) had moderate-severe aGvHD (grade II-IV) and 42 (10.7%) had cGvHD (limited-extensive). Adequate early CD4+ IR before diagnosis of aGvHD grade II-IV was associated with reduced mortality compared to no CD4 +IR; OS was 77% versus 48% (p Interpretation Adequate CD4+ IR prior to aGvHD onset protects against aGvHD-related mortality after HCT. Either regulatory T-cell development or a lower risk of infection may be possible explanations. A specific delay in B-cell recovery after HCT provides an interesting clinical indicator for cGvHD, which demands further research. Our findings provide insight in the importance of monitoring the immune system after HCT to better understand the biology and determine strategies to prevent and treat GvHD.

Antiretroviral therapy immunologic non-response in a Brazilian population: association study using pharmaco- and immunogenetic markers

BackgroundAntiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. ObjectiveTo identify predictive genetic markers of immune response to ART. MethodsCase–control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. ResultsMale patients were overrepresented in non-responder group (p=0.01). Non-responders also started with lower absolute CD4+ T cell counts (p<0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p=0.04), rs1128503 (ABCB1) A allele (p=0.03) and rs707265 (CYP2B6) A allele (p=0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p=0.004) and rs4646437 (CYP3A4) A allele (p=0.04). ConclusionSome significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.

The effect of unstable housing on HIV treatment biomarkers: An instrumental variables approach

Unstable housing, including homelessness, is a public policy concern for all populations, and more critically for people with a serious health condition such as HIV. We measure the effect of unstable housing on HIV treatment biomarkers: viral suppression (viral load < 200 HIV RNA copies per ml) and adequate CD4+ T-cell count (CD4>350 cells per μl). We use panel data (1995–2015) from 3082 participants of the Women's Interagency HIV Study (WIHS) sites in Bronx and Brooklyn (NY), Chicago (IL), Los Angeles and San Francisco (CA), and Washington (DC). The instrumental variable (IV) measures allocations for the Housing Opportunities for People with AIDS (HOPWA) per person newly infected with HIV, and it represents actual availability of housing assistance for HIV-positive persons at the metropolitan area level. Using an extended probit model with the IV, we find that unstable housing reduces the likelihood of viral suppression by 51 percentage points, and decreases the probability of having adequate CD4 cell count by 53 percentage points. The endogeneity-corrected results are larger than naïve probits, which show decreases of 8.1 and 7.8 percentage points, respectively. The hypothesized pathways for the effect are: decreased use of mental healthcare/counseling, any healthcare, and less continuity of care. Increasing efforts to improve housing assistance, including HOPWA, and other interventions to make housing more affordable for low-income populations, and HIV-positive populations in particular, may be warranted not only for the benefits of stable housing, but also to improve HIV-related biomarkers.

The occurrence of human papilloma virus (HPV)-related cancers in human immunodeficiency virus (HIV)-infected women compliant with highly active antiretroviral therapy (HAART).

185 Background: HAART has been demonstrated effective at maintaining immunocompetence (as measured in part by CD4 levels) and reducing the occurrence and severity of cervical cancer in HIV-infected women. Conversely, rapid disease progression, poor treatment response and the development of multiple cancers has been associate with suboptimal HIV therapy and low CD4 counts. Methods: 17 HIV-infected women presenting to an inner-city, academic medical center from 1996-2016 were diagnosed with cervical cancer and at least one other HPV-associated cancer. Data recorded include: year of diagnosis and treatment for cervical cancer; the type, year of diagnosis and treatment of subsequent HPV-associated cancers; compliance with HAART and CD4 counts at diagnosis and death (if applicable). Results: 15/17 (88.2%) used HAART and had CD4 counts &gt; 200 at cervical cancer diagnosis. The time from diagnosis of cervical cancer to a second HPV-associated cancer was 0-19 years, with 52.9% developing a second cancer within 3 years. Second cancer diagnoses included vulvar(9), vaginal(2), anal(3), oropharyngeal(1), urethral(1), and bladder/urethral(1). Seven patients developed third cancers: anal(3), oropharyngeal(3), vaginal(1). Conclusions: Despite the effective use of HAART, HIV-infected women appear to be at risk for the development of multiple cancers following a diagnosis of cervical cancer, even years to decades later. Screening for HPV-associated cancers (including oropharyngeal) should therefore be maintained and emphasized, even in highly compliant subjects with adequate CD4 levels.