EVALUATION OF RESPONSE TO ADJUVANTED RECOMBINANT ZOSTER VACCINATION IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING UPADACITINIB: RESULTS FROM A RANDOMIZED TRIAL SUB-STUDY

BackgroundUpadacitinib (UPA) is an oral JAK inhibitor (JAKi) approved for the treatment of RA. JAKi have been associated with an elevated risk of herpes zoster (HZ) in patients (pts) with RA. The adjuvanted recombinant zoster vaccine (RZV, Shingrix) was shown to be well-tolerated and effective in preventing HZ in adults aged ≥ 50 years.[1] The efficacy and safety of RZV have not been studied in pts with RA while on UPA in combination with MTX.ObjectivesTo assess the immunogenicity of RZV in pts with RA receiving UPA 15 mg once daily (QD) with background MTX.MethodsEligible adults aged ≥ 50 years with RA enrolled in the ongoing SELECT-COMPARE phase 3 trial (NCT02629159) received two RZV doses, administered at the baseline and week (wk) 12 visits. Pts should have been on stable doses of UPA 15 mg QD and background MTX for ≥ 8 wks before the first vaccination and ≥ 4 wks after the second vaccination. Antibody titers were collected pre-vaccination (baseline), 4 wks post-dose 1 vaccination (wk 4), and 4 wks post-dose 2 vaccination (wk 16). The primary endpoint was the proportion of pts with a humoral response to RZV defined as ≥ 4-fold increase in pre-vaccination concentration of anti-glycoprotein E [gE] titer levels at wk 16. Secondary endpoints included humoral response to RZV at wk 4 and the geometric mean fold rise (GMFR) in anti-gE antibody levels at wks 4 and 16. Cell-mediated immunogenicity to RZV was an exploratory endpoint evaluated by the frequencies of gE-specific CD4+ [2+] T cells (CD4+ T cells expressing ≥ 2 of 4 activation markers: IFN-γ, IL-2, TNF-α, and CD40 ligand) measured by flow cytometry at wks 4 and 16 in a sub-cohort of pts.ResultsOf the 95 pts who received ≥ 1 RZV dose, 93 (98%) received both RZV doses. Pts had a mean (standard deviation) age of 62.4 (7.5) years. The median (range) disease duration was 11.7 (4.9–41.6) years and duration of UPA exposure was 3.9 (2.9–5.8) years. At baseline, all but 2 pts were receiving concomitant MTX and half (50%) were taking an oral corticosteroid (CS) at a median daily dose of 5.0 mg. One pt discontinued UPA by wk 16. Blood samples were available from 90/93 pts. Satisfactory humoral responses to RZV occurred in 64% (95% confidence interval [CI]: 55–74) of pts at wk 4 and 88% (81–95) at wk 16 (Figure 1). Age (50–< 65 years: 85% [95% CI: 75–94];≥ 65 years: 94% [85–100]) and concomitant CS (yes: 87% [77–97];no: 89% [80–98]) use at baseline did not affect humoral responses at wk 16. GMFR in anti-gE antibody levels compared with baseline values were observed at wks 4 (10.2 [95% CI: 7.3–14.3]) and 16 (22.6 [15.9–32.2]). Among the sub-cohort of pts, nearly two-thirds achieved a cell-mediated immune response to RZV (wk 4: n = 21/34, 62% [95% CI: 45–78];wk 16: n = 25/38;66% [51–81]). Within 30 days post-vaccination of either RZV dose, no serious adverse events (AEs) (Table 1) or HZ were reported. AEs that were possibly related to RZV were reported in 17% of pts. One death occurred more than 30 days after wk 16 due to COVID-19 pneumonia.ConclusionMore than three-quarters (88%) of pts with RA receiving UPA 15 mg QD on background MTX achieved a satisfactory humoral response to RZV at wk 16. In a subgroup of pts, two-thirds (66%) achieved a cell-mediated immune response to RZV at wk 16. Age and concomitant CS use did not negatively affect RZV response.Reference[1]Syed YY. Drugs Aging. 2018;35:1031–40.Table 1. Safety Results Through 30-Days Post-RZV Vaccination in UPA-Treated PatientsEvent, n (%)UPA 15 mg QD (N = 95)Any AE38 (40%)AE with reasonable possibility of being related to UPAa13 (14%)AE with reasonable possibility of being related to RZVa16 (17%)Severe AEb1 (1%)Serious AE0AE leading to discontinuation of UPA0Death0AE, adverse event;QD, once daily;RZV, adjuvanted recombinant zoster vaccine;UPA, upadacitinib.aAs assessed by the investigator.bHypersensitivity.AcknowledgementsAbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the . All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie.Disclosure of InterestsKevin Winthrop Consultant of: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Justin Klaff Shareholder of: AbbVie, Employee of: AbbVie, Yanxi Liu Shareholder of: AbbVie, Employee of: AbbVie, CONRADO GARCIA GARCIA: None declared, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Consultant of: AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, GlaxoSmithKline, Pfizer, Roche, and Sandoz, Alvin F. Wells Consultant of: AbbVie, Amgen, BMS, Eli Lilly, Novartis, Pfizer, and Sanofi, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Michael Chen Shareholder of: AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Anthony Cunningham Consultant of: GSK, Merck Sharp & Dohme, and BioCSL/Sequirus.

Characterization of Adaptive Immune Responses to SARS-CoV-2 Updated Bivalent Booster

Bivalent COVID-19 vaccines that contain two mRNAs encoding Wuhan-1 and Omicron BA.4/5 spike proteins are successful in preventing infection from the original strain and Omicron variants, but the quality of adaptive immune responses is still not well documented. This study aims at characterizing adaptive immune responses to the bivalent booster vaccination in 46 healthy participants. Plasma and PBMC were collected prior and three weeks after bivalent booster. We measured anti-N, anti-S, and RBD IgM, IgA, IgG plasma titers against original, Omicron BA.1, and BA.5 variants (pending) as well as total anti-S IgG titers and surrogate Virus Neutralization capacity against the Alpha, Delta, and BA.1 variant. With spectral flow-cytometry we identified peripheral blood B-cells specific for the RBD of the S-protein of the original and BA.1 variants. T-cell-specific responses were assessed by cytokine release assay after stimulation with SARS-CoV-2 peptides from the original, BA.1, BA.4, and BA.5 variants (pending). Finally, we performed TRB and IGH repertoire studies on sorted CD4+, CD8+, CD19+ lymphocytes, to study breadth of SARS-CoV-2 specific clonotypes (pending). 27/46 participants were analyzed;9 had SARS-CoV-2 infection (COVID+), while 18 are infection naive (COVID-). In both groups, median time since last dose of SARS-CoV-2 vaccine (3rd or 4th) was 11 months. All subjects were positive for anti-S IgG prior to bivalent booster. The COVID + group displayed anti-S IgG pre-booster levels and neutralization against BA.1 higher than the COVID- group. Significant increase post-boost of total anti-S IgG and BA.1 neutralizing activity was detected in the COVID- but not in the COVID+ group;however, no difference in neutralization activity post-boost was detected between the two groups. Furthermore, the COVIDgroup showed significant increase in the frequency of CD19+ and CD27+ switched memory B-cells specific for BA.1 RBD in post-boost compared to pre-boost samples. However, post-boost frequencies of the same B-cells were higher in the COVID+ compared to the COVID- group. These preliminary findings confirm that among individual immunized with the original COVID-19 mRNAvaccine, prior COVID infection provides increased protection against SARS-CoV-2 variants. They also demonstrate that booster immunization with the bivalent vaccine induces robust adaptive immune responses against Omicron variant.[Formula presented][Formula presented]Copyright © 2023 Elsevier Inc.

Primary immunodeficiency associated with a SAMD9L mutation

Background: SAMD9L is a tumor suppressor involved in regulating the proliferation and maturation of cells, particularly those derived from the bone marrow, and appears to play an important role in cerebellar function. It can be activated in hematopoietic stem cells by type I and type II interferons. It has been hypothesized to act as a critical antiviral gatekeeper regulating interferon dependent demand driven hematopoiesis. Gain of function mutations can present with an immunodeficiency due to transient severe cytopenias during viral infection. Case presentation: We report a 3-year-old boy born full term with a history of severe thrombocytopenia requiring transfusions, developmental delay, ataxia, seizure disorder, and recurrent severe respiratory viral infections. His infectious history was significant for respiratory syncytial virus with shock requiring extracorporeal membrane oxygenation complicated by cerebral infarction and a group A streptococcus empyema, osteomyelitis requiring a left below the knee amputation, and infections with rhinovirus, COVID-19, and parainfluenza requiring hospitalizations for respiratory support. Initial immunologic evaluation was done during his hospitalization for parainfluenza. His full T cell subsets was significant for lymphopenia across all cell lines with CD3 934/microL, CD4 653/microL, CD8 227/microL, CD19 76/microL, and CD1656 61/microL. His mitogen stimulation assay to phytohemagglutinin and pokeweed was normal. Immunoglobulin panel showed a mildly decreased IgM of 25 mg/dL, but normal IgA and IgG. Vaccine titers demonstrated protective titers to 12/22 pneumococcus serotypes, varicella, diphtheria, mumps, rubella, and rubeola. Repeat full T cell subsets 6 weeks later revealed marked improvement in lymphocyte counts with CD3 3083/microL, CD4 2101/microL, CD8 839/microL, CD19 225/microL, and CD1656/microL. A primary immunodeficiency genetic panel was ordered and positive for a heterozygous SAMD9L c.1549T>C (p.Trp517Arg) mutation classified as a variant of unknown significance. Discussion(s): This patient's history of severe viral infections, ataxia, thrombocytopenia, and severe transient lymphopenia during infection is suggestive of a SAM9DL gain of function mutation. Protein modeling done by the laboratory suggests this missense mutation would affect protein structure. The mutation found has been observed in individuals with thrombocytopenia. This case highlights the importance of immunophenotyping both during acute illness and once recovered.Copyright © 2023 Elsevier Inc.

T-cell mediated response to emerging COVID19 strains in patients with cancer studied via deep learning

Cancer patients, particularly those receiving B cell-depleting therapy for lymphoid malignancies, are at risk of prolonged SARS-CoV-2 infection, poorer clinical outcomes, and delayed initiation or disruption of cancer-directed therapy (Lee at al., 2022, Clark et al., 2021). We first studied T-cell mediated response to the Wuhan strain of SARS-CoV-2 in a cohort of 69 patients with hematologic and solid cancers, including 18 patients who received prior B-cell depleting therapy. Patients with prolonged COVID-19 clearance, defined by a positive PCR test for longer than 30 days, had a broad but poorly converged CD8+ dominant response and a lacking CD4+ response. To conduct this analysis, we performed bulk T-cell receptor (TCR) sequencing of 121 blood samples and tracked over time TCR repertoire statistics such as clonality, convergence, breadth, and depth of COVID-19-associated TCRs during the active and convalescent periods of COVID-19 infection. These SARS-CoV-2-associated TCRs were identified leveraging immunoSEQ T-MAP database (Snyder et al., 2020), a set of TCR sequences derived from COVID-19 patients and experimentally identified as responsive to MHC Class I and II epitopes from the Wuhan SARS-CoV-2 strain using the multiplex identification of TCR antigen assay (Klinger et al., 2015). To extend our TCR repertoire analysis to other SARS-CoV-2 variants, including Omicron, we developed a deep learning (DL) method to predict TCR specificities for new SARS-CoV-2 epitopes. This DL approach also permits the identification of SARS-CoV2-responsive TCRs private to an individual. Combining this DL approach with our TCR statistics methodology, we studied the dynamics of T-cell response to COVID-19 vaccinations in a cohort of 50 patients with cancer and analyzed TCR repertoire characteristics associated with different degrees of COVID-19 severity in a cohort of 42 cancer patients who contracted the Omicron. Understanding cellular response to novel infections is critical for patient care in the context of cancer, and our novel DL-based approach can leverage existing datasets to analyze and track response to emerging viral strains.

Altered immune response to vaccination in patients with plasma cell premalignancy

Introduction Patients with hematological malignancies, including multiple myeloma (MM), experience suboptimal responses to SARS-CoV-2 vaccination. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) are precursors to MM and exhibit altered immune cell composition and function. The SARS-CoV-2 pandemic and the subsequent population-wide vaccination represent an opportunity to study the real-life immune response to a common antigen. Here, we present updated results from the IMPACT study, a study we launched in November 2020 to characterize the effect of plasma cell premalignancy on response to SARS-CoV2 vaccination (vx). Methods We performed: (i) ELISA for SARS-CoV-2-specific antibodies on 1,887 peripheral blood (PB) samples (237 healthy donors (HD), and 550 MGUS, 947 SMM, and 153 MM patients) drawn preand post-vx;(ii) single-cell RNA, T cell receptor (TCR), and B cell receptor (BCR) sequencing (10x Genomics) on 224 PB samples (26 HD, and 20 MGUS, 48 SMM, and 24 MM patients) drawn preand post-vx;(iii) plasma cytokine profiling (Olink) on 106 PB samples (32 HD, and 38 MGUS and 36 SMM patients) drawn pre- and post-vx;and (iv) bulk TCR sequencing (Adaptive Biotechnologies) on 8 PB samples from 4 patients (2 MGUS, 2 SMM) drawn pre- and post-vx. Results Patients with MGUS and SMM achieved comparable antibody titers to HD two months post-vx. However, patient titers waned significantly faster, and 4 months post-vx we observed significantly lower titers in both MGUS (Wilcoxon rank-sum, p=0.030) and SMM (p=0.010). These results indicate impaired humoral immune response in patients with MGUS and SMM.At baseline, the TCR repertoire was significantly less diverse in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.039), while no significant difference was observed in the BCR repertoire (p=0.095). Interestingly, a significant increase in TCR repertoire diversity was observed post-vx in patients with SMM (paired t-test, p=0.014), indicating rare T cell clone recruitment in response to vaccination. In both HD and patients, recruited clones showed upregulation of genes associated with CD4+ naive and memory T cells, suggesting preservation of the T cell response in SMM, which was confirmed by bulk TCR-sequencing in 4 patients.Lastly, by cytokine profiling, we observed a defect in IL-1beta and IL-18 induction post-vx in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.047 and p=0.015, respectively), two key monocyte-derived mediators of acute inflammation, suggesting an altered innate immune response as well. Conclusion Taken together, our findings highlight that despite the absence of clinical manifestations, plasma cell premalignancy is associated with defects in both innate and adaptive immune responses. Therefore, patients with plasma cell premalignancy may require adjusted vaccination strategies for optimal immunization.

REVACCINATION OF PATIENTS WITH SLE OR RA WITHOUT AN INITIAL COVID-19 VACCINE RESPONSE ELICITS SEROCONVERSION IN HALF OF THE PATIENTS

BackgroundTreatment with Rituximab (RTX) in patients with rheumatic diseases (RD) has presented a challenge during the COVID-19 pandemic, as RTX leads to markedly reduced and often undetectable antibody responses after COVID-19 vaccination (1).ObjectivesTo investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with RD who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion.MethodsFrom a RD cohort (COPANARD) vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies (abs) and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralizing abs, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. This study was funded by the Danish Rheumatism Association.ResultsPatient demographics are given in Table 1. Forty-seven percent of cases had detectable total SARS-CoV-2 abs and neutralizing abs after revaccination. However, antibody levels were significantly lower than in controls and blood donors (p<0.008), Figure 1A+B. Revaccination induced an antibody class switch in cases with a decrease in detectable IgM abs (Baseline 11/17, Followup 3/17) and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups, Figure 1C. The proportion of cases with detectable CD4+ T cells increased from 69% to 88% (p=0.25), and for CD8+ T cells, the proportion decreased from 88% to 82% (p=1.00). Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors, Figure 1D. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination, Figure 1D.Univariate logistic regression analysis was performed to analyze if active RTX treatment, the presence of B-cells, or a positive T-cell response prior to revaccination predicted seroconversion of total SARS-CoV-2-abs in the patient cohort. We did not find a significant explanatory effect of either variable in the univariate logistic models, data not shown.Table 1.DemographicsCases Revaccination, n=17Controls Boost, n=29Female sex, no(%)1482%2172%Age, median (IQR)6549 - 706762 - 72Disease duration, years1510 - 18229 - 31Rheumatoid Arthritis/SLE13/410/19None DMARD529%828%Prednisone424%13%Methotrexate741%1241%Hydroxychloroquine212%414%None biologic treatment424%931%Rituximab1271%0TNF-inhibitors16%724%JAK-inhibitors0621%IL-6-inhibitors, Abatacept, Benlysta0724%Previous rituximab treatmentAny rituximab treatment1694%13%RTX within the last 15 months, no1488%0Cumulative total dose, mg134-242Time from RTX to revaccination, months95-1249Figure 1.ConclusionIn conclusion, forty-seven percent of initial non-responders were able to seroconvert after two-dose revaccination. However, plasma concentrations of the antibodies against SARS-COV-2 and the levels of neutralizing capacity remained significantly lower than in immunocompetent blood donors. B-cell levels or T-cell responses before revaccination did not predict seroconversion. Our study suggests that patients with RDs who did not mount a detectable serological response to a COVID-19 mRNA vaccine have a T cell response similar to immunocompetent controls. Future studies should establish the antibody levels that identify RD patients without sufficient protection against SARS-CoV-2 infection.References[1]Troldborg A, et al. Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases. J Rheumatol. 2022.AcknowledgementsThe Danish Rheumatism Association [grant number R203-A7217]. We acknowledge all patients and blood donors contributing to the stud for their invaluable participation. The authors would like to thank Sif Kaas Nielsen and Mads Engelhardt Knudsen, the Laboratory of Molecular Medicine at Rigshospitalet, for their excellent technical assistance in analyzing the samples.Disclosure of InterestsNone Declared.

Cellular and humoral immune responses after SARS-CoV-2 vaccination in pediatric kidney recipients

Objective: Humoral and cellular immune responses to SARS-CoV-2 vaccination are reduced in adult kidney recipients. After pediatric kidney transplantation there are only few data available - mostly limited to monitoring of SARS-CoV-2 antibodies. Method(s): Cellular and humoral immune responses have been monitored before and after SARS-CoV-2 vaccination in pediatric kidney recipients. After in vitro stimulation with SARS-CoV-2 antigen (spike glycoprotein) virus-specific CD4 and CD8 T cells (SARS-CoV-2-Tvis) have been identified by cytokine flow cytometry. SARS-CoV-2 IgG was measured by CMIA. Result(s): Immune response after SARS-CoV-2 vaccination was analyzed in a total of 30 pediatric kidney recipients (age at 1st vaccine dose 5.2 - 17.8 years, median 14.8 years;43% male;30/30 2 vaccine doses;23/30 3 vaccine doses). At time of vaccination 22 patients (73%) received a tacrolimus (Tac)-based immunosuppression combined with mycophenolate mofetil (MMF;n = 15) or everolimus (n = 6) or neither of them (n = 1);3 patients were exposed to cyclosporine A and 5 patients to a calcineurin inhibitor (CNI)- free immunosuppression. MMF was used in 18/30 patients. After 1st dose of mRNA vaccine SARS-CoV-2 antibodies were detectable in 50% of pediatric kidney recipients, after 2nd dose in 78% and after 3rd dose in 88%. After the 2nd vaccine dose absence of humoral immune response (< 33.8 BAU/ml) was only found in case of MMF use (predominately combined with Tac). Peak IgG values (> 2,080 BAU/ml) were only detected in MMF-free regimens (6/7). Cellmediated response partially differed from humoral response, e. g., in some patients SARS-CoV2-Tvis were found despite lack of virus-specific antibodies. After 1st vaccine dose SARS-CoV-2-Tvis were detectable in 50% of pediatric kidney recipients, after 2nd dose in 92%. After 2nd vaccine dose absence or very low levels of SARS-CoV-2-Tvis (< 0.3 cells/mul) were only found in Tac-based immunosuppressive regimens, whereas higher levels (> 1.3 cells/mul) were exclusively detected in patients with MMFfree medication. Conclusion(s): After pediatric kidney transplantation humoral and cellular immune responses to SARS-CoV-2 vaccination were suboptimal, but more pronounced than in adult kidney recipients. Use of Tac and MMF was associated with impaired immune response to vaccination. SARS-CoV-2-specific humoral response corresponded only partially to cell-mediated response. Additional monitoring of SARS-CoV- 2-Tvis might be recommendable to improve assessment of the individual vaccine response and thereby to personalize the decision on the necessity of further vaccine doses.

Progress towards ending HIV transmission in England by 2030

Background: England is committed to ending HIV transmission by 2030. The HIV Action Plan (2021) set an interim ambition to reduce HIV transmission by 80% to 600 new diagnoses first made in England by 2025. Here we present the progress between 2019 (baseline) and 2021, interpreted in the context of the COVID-19 pandemic. Method(s): People newly diagnosed with HIV were reported to the HIV and AIDS Reporting Section (HARS). The annual number of people having an HIV test in all sexual health services (SHS) including online testing were reported using GUMCAD. HIV diagnoses among people previously diagnosed abroad were excluded (25%). Result(s): New HIV diagnoses first made in England fell by 32% from 2,986 in 2019 to 1,987 in 2020, but plateaued in 2021 (2,023). Among gay/bisexual men, HIV diagnoses plateaued in 2021 (721) after a fall of 45% between 2019 and 2020, from 1,262 to 699. After a fall in HIV testing in 2020 (from 156,631 in 2019 to 144,800 in 2020), the number of people tested in 2021 (178,466) exceeded pre-COVID-19 levels. This suggests a decline in HIV incidence supported by a CD4 back calculation model (80% probability of a decline for the period 2019-2021), but at a slowing rate. Among heterosexual adults, new HIV diagnoses first made in England in 2021 also plateaued (798) following a 31% decrease (from 1,109 in 2019 to 761 in 2020). However, HIV testing coverage has not recovered to pre- COVID-19 levels (628,607 in 2019, 441,017 in 2020 and 489,727 in 2021). This provides no evidence of a fall in incidence in this population. Conclusion(s): A reduction by 360 new diagnoses first made in England year on year from 2022 onwards is required to meet the HIV Action Plan ambition. Despite an estimated 4,500 people with undiagnosed HIV and extremely high levels of antiretroviral therapy and viral suppression, PrEP access remains unequal. HIV testing numbers, which were affected by COVID-19 pandemic, have recovered in gay/bisexual men, but not among heterosexual adults. While the interim ambition is within reach for gay/bisexual men, PrEP and testing levels must be scaled up in heterosexual adults.

Single-centre review of rapid antiretroviral therapy initiation during the COVID-19 pandemic

Background: BHIVA released interim guidance on first line anti-retroviral therapy (ART) initiation during the COVID-19 pandemic, when investigations/follow-up was restricted. Our HIV service didn't restrict follow-up but suspended in-house resistance testing (RT) due to laboratory capacity. Having prescribed 'rapid ART' based on the Northern Algorithm 01/08/2020-01/01/2022 we wanted to evaluate our prescribing during the pandemic. Method(s): All new HIV diagnoses 01/08/2020-31/12/2021 were identified via our HARS dataset. Retrospective casenote review identified ART prescribed, and switches that occurred upon baseline RT availability, to more suitable and/or cost-effective regimes. Result(s): 32 new diagnoses: 11 female, 21 male, median age 41 years (17-81), 10 MSM, 22 Heterosexuals, White British 14, African 9, other 7. Median time to ART initiation 10 days (0-210). Median CD4 count 359 (2-1251), 8 had CD4<200. 7/32 had Primary HIV infection, 5 initiating ART at 1st visit. 30/32 started ART within our service, 1 relocated, 1 initiated abroad. 28/30 started algorithm compliant rapid ART. Of the 2 that delayed, 1 had significant resistance, the other patient choice. 8/30 (27%) 'rapid ART' initiations switched post RT availability. Conclusion(s): All patients initiating ART in our service during the pandemic were algorithm compliant and fulfilled BHIVA recommendations. 7/10 starting Darunavir/ r-based therapy switched to Delstrigo post RT, a more cost-effective STR. Zero patients on Biktarvy switched post RT;implying it's difficult to switch patients from small INSTI-based-STRs. Future work includes comparing our results with other centres and reviewing ART switches post HIV National Prescribing Guide implementation. (Table Presented).

Clinical epidemiology of COVID-19 in Black people with HIV in south London, UK

Background: The COVID-19 pandemic disproportionally affected Black communities who were at greater risk of SARS-CoV-2 acquisition, morbidity, and mortality than those of White ethnicity. We describe the clinical epidemiology of COVID-19 in the GEN-AFRICA cohort of Black people with HIV in two South London clinics. Method(s): First reported episodes of COVID-19 up to 12/2021 were ascertained by direct questioning and/or medical records review. The cumulative incidence of COVID-19 and vaccination was determined by Nelson- Aalen methods. Pre-pandemic immunovirological and comorbidity status obtained prior to 01/2020 was used to identify risk factors for COVID-19 using Cox regression. We compared characteristics of participants with mild/ moderate (not requiring hospitalization) and severe (requiring hospitalization or resulting in death) COVID-19. Result(s): COVID-19 status was available for 1184 (95%) of 1289 GEN-AFRICA participants (mean age 49.1 years;55% female;median CD4 565;93% HIV RNA <200), and SARS-CoV-2 vaccination status for 1160;998 (86%) had received at least one vaccine dose (administered to 50% by 16/02/2021). A total of 310 participants (26.2%) reported a first episode of COVID-19 (any severity), with a cumulative incidence of 6%, 14%, 15% and 22% following the initial, alpha, delta, and omicron waves. Women, people of East African ancestry, and those with detectable HIV RNA were more likely to report COVID-19 (Table). CD4 (current/nadir), class of antiretroviral therapy (ART), and comorbidity status were not associated with COVID-19. Findings were similar when restricted to episodes in 2020 (prior to vaccine availability) or testconfirmed COVID-19. Severe COVID-19 cases (N=34) were more often male (p=0.002), of West-African ancestry (p=0.01), with lower CD4 cell counts (p=0.002), and they more often had a history of AIDS, diabetes mellitus, cardiovascular disease, and chronic kidney disease (all p=0.001) compared to mild/moderate cases;they were also more likely to be on protease inhibitor (PI)- containing ART (p=0.01). Conclusion(s): By the end of the second year of the pandemic, 22% of black people with HIV in South London had experienced COVID-19. Immune and comorbidity status were not associated with COVID-19 when all cases were considered but strongly associated with severe COVID-19 disease, as were West-African ancestry and being on a PI. (Table Presented).

An audit of uptake of flu, COVID-19 and pneumococcal vaccines in a cohort of people living with HIV

Background: People living with HIV are at greater risk of complications associated with influenza, SARS-CoV-2 and pneumococcus than the general population and BHIVA guidelines recommend vaccinating all patients against these infections. The purpose of this audit was to determine the uptake of these vaccines, and factors associated with uptake, to inform vaccine delivery models. Method(s): All patients who received HIV care in our service at the end of November 2022 were included. Demographic data were collected from the service database, clinical data and pneumococcal vaccine (Prevenar-13) status were obtained from clinical records and COVID-19 and flu vaccine (2021) uptake was obtained from the Vaccine Management Tool (VMT). At the time of audit all patients were recommended to have received at least 3 doses of a SARS-CoV-2 vaccine. Caldicott approval was received for this work. Result(s): There were 364 patients known to the service of which one was excluded as clinical information was not available. Sixty-seven percent had received flu vaccine, 88% >= one dose of COVID-19 vaccination, 76% at least 3 doses of COVID-19 vaccination and 88% had received Prevenar-13. Three percent had received no vaccines and 60% had completed all vaccines. Uptake of both flu and COVID-19 vaccines were lower in the following groups: <50 years old (51% and 62% respectively), urban residence (65%, 71%), higher deprivation scores (51-65%, 64-75%) less time in HIV care (57%, 70%), those not on ART (13%, 25%), CD4 <200 cells/mm3 (40%, 50%), detectable viral load (33%, 42%), those out of care (23%, 23%) and those known to the harm reduction service (33%, 33%). There was higher uptake of Prevenar-13 in all groups. Uptake of all vaccines was high in those with comorbidities. Conclusion(s): The high uptake of Prevenar-13 in higher risk groups suggests that the model of vaccine delivery, opportunistic and pro-active recall for inhouse vaccination, is more effective for protecting those at highest risk for poor outcomes and for those for whom access is challenging compared to the centralised national recall system at designated Vaccine hubs. Vaccination resourcing, planning and delivery should consider the needs of specific risk groups to ensure best outcomes.

Week 48 results of a phase 3 randomized controlled trial of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) vs dolutegravir 1 emtricitabine/tenofovir disoproxil fumarate (DTG 1 F/TDF) as initial treatment in HIV-1/HBV-coinfected adults (ALLIANCE)

Background/Aims: The clinical course of hepatitis B virus (HBV) infection in individuals with HIV-1 coinfection is marked by accelerated disease progression. A tenofovir-containing antiretroviral regimen is recommended in most people with HIV-1/HBV-coinfection, but there have not been randomized studies of tenofovir disoproxil fumarate (TDF) vs tenofovir alafenamide (TAF) in treatment- naive HIV-1/HBV-coinfected individuals. We report primary endpoint results from a Phase 3 study comparing bictegravir/emtricitabine/ TAF (B/F/TAF) vs dolutegravir + emtricitabine/TDF (DTG + F/TDF) at Week (W)48 in participants initiating treatment for both viruses. Method(s): Adults with HIV-1/HBV coinfection were randomized 1:1 to initiate blinded treatment with B/F/TAF or DTG + F/TDF (with placebo). Primary endpoints were the proportion of participants with HIV-1 RNA<50 copies/mL (FDA Snapshot) and plasma HBV DNA<29 IU/mL (missing = failure) at W48. Noninferiority was assessed with 95% CI (12% margin). Secondary and other endpoints included change from baseline cluster of differentiation 4 (CD4) count, proportion with hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) loss/seroconversion, and alanine transaminase (ALT) normalization (AASLD criteria). Result(s): Participants (N = 243) were randomized and treated (B/F/ TAF [n = 121], DTG + F/TDF [n = 122]) from 11 countries in Asia, Europe, North, and Latin America. Baseline characteristics were median age of 32 years, 4.5% female, 88% Asian, 30% HIV-1 RNA>100,000 c/mL, 40% CD4<200 cells/lL, median HBV DNA 8.1 log10 IU/mL, 78% HBeAg+. At W48, B/F/TAF was noninferior to DTG + F/TDF at achieving HIV-1 RNA<50 copies/mL (95% vs 91%, difference 4.1%;95% CI -2.5%-10.8%;P = 0.21), with mean CD4 gains of + 200 and + 175 cells/lL, respectively. B/F/TAF was superior to DTG + F/TDF at achieving HBV DNA<29 IU/mL (63% vs 43%, difference 16.6%;95% CI 5.9%-27.3%;P = 0.0023). Participants treated with B/F/TAF vs DTG + F/TDF had numerically higher HBsAg loss (13% vs 6%;P = 0.059), HBeAg loss (26% vs 14%;P = 0.055), HBeAg seroconversion (23% vs 11%;P = 0.031), and ALT normalization (73% vs 55%;P = 0.066). The most frequent adverse events among participants treated with B/F/TAF vs DTG + F/TDF were upper respiratory tract infection (17% vs 11%), COVID- 19 (13% vs 11%), pyrexia (9% vs 12%), ALT increase (7% vs 11%), and nasopharyngitis (11% vs 4%). ALT flares (elevations at >= 2 consecutive postbaseline visits) occurred in 11 participants (7 B/F/ TAF, 4 DTG + F/TDF), and all resolved. Conclusion(s): Among adults with HIV-1/HBV-coinfection starting antiviral therapy, both B/F/TAF and DTG + F/TDF had high HIV-1 suppression at year 1, with B/F/TAF resulting in superior HBV DNA suppression and significantly more HBeAg seroconversion. Safety findings were similar between groups.

Mortality among people with HIV in the UK in 2021: findings from the National HIV Mortality Review

Background: The National HIV Mortality Review (NHMR) was launched by UK Health Security Agency (UKHSA) and British HIV Association to better recognise causes of death and preventable death, and to describe end-of-life care, among people with HIV. Method(s): UK HIV services submitted data on all known deaths among people with HIV under their care in 2021 through a secure online form. Cause of death was categorised by an epidemiologist and four clinicians using the Coding Causes of Death in HIV protocol. Result(s): In 2021, 101 services reported 606 deaths among people with HIV to NHMR. In 2019, 74 services reported to the NHMR while 121 reported in 2020. Median age at death was 58 [interquartile range (IQR): 56-59] and most (76%) were male. Death cause was ascertainable for 78% (n=475), with the most common being non-AIDS-related cancers (26%), followed by non-AIDS-defining infections (19%), cardiovascular disease (16%), AIDS (9%), substance misuse (8%), respiratory disease (4%), accident/suicide (3%), liver disease (2%) and other causes (11%). COVID- 19 caused or contributed to 11% of all deaths. Thirtythree people (5%) died within a year of HIV diagnosis, 90% of these were diagnosed late (CD4<350 cells/mm3), 80% very late (CD4<200 cells/mm3), 54% diagnosed with AIDS and 33% had documented missed opportunities for earlier diagnosis. Viral suppression (<200 copies/mL) (87%) and treatment coverage (98%) was high with the median time on treatment 13 years [IQR: 8-20]. Common lifestyle risk factors in the preceding year included smoking (33%;n=179), excessive alcohol use (20%;n=103). Other factors included drug use (non-injecting and injecting) and opioid substitution therapy. Death had been expected for 298 (49%) individuals, of whom 230 had discussed end-of-life care and 108 had a documented advanced end-of-life care plan in place. Conclusion(s): Over half of people living with diagnosed HIV are aged over 50. Most deaths were not AIDS related however, one in eleven people with diagnosed HIV in the UK died from AIDS. Of people that died within a year of diagnosis, one in three had documented missed opportunities for earlier HIV diagnosis.

Immune Responses to Mrna Vaccines against Sars-Cov2 in Patients with Immune-Mediated Inflammatory Rheumatic Diseases

Background/Aims Patients with immune-mediated rheumatic diseases (IMRD) are commonly treated with immunosuppressors and are prone to infections. Recently introduced mRNA SARS-Cov2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-We aim to fully characterize B and T cell immune responses elicited by mRNA SARS-Cov2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine's immunogenicity. Methods Humoral, CD4 and CD8 immune responses were investigated in 147 SARS-Cov2-naive patients with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-Cov2 mRNA vaccine. Responses were compared with age, gender, and diseasematched IMRD patients not receiving immunosuppressors and with healthy controls Results IMRD patients showed decreased seroconversion rates (63% vs 100%, p=0.04) and cellular immune responses (59% vs 100%, p=0.007). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept deeply affected humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed severely impaired humoral responses but cellular responses were often preserved. Antibody titers were reduced with mycophenolate and azathioprine but preserved with leflunomide. Conclusion IMRD patients exhibit impaired SARS-CoV-2 vaccine-immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show the most deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine's immunogenicity.

Neutralising antibodies (NAbs) against SARS-CoV-2 in BNT162b2 vaccine recipients with a history of advanced HIV infection: cPass as a simpler alternative to gold-standard tests

Background: Established SARS-CoV-2 NAb tests are labor-intensive. We prospectively measured NAbs vs Wuhan-1 and Omicron BA.2 using the novel GenScript cPass assay and examined correlations with responses measured by gold-standard plaque reduction neutralisation test (PRNT) (Cotugno, Ruggiero et al. Cell Rep 2021) and with anti-Spike IgG quantified by Roche Elecsys. Given the paucity of data, we selected BNT162b2 vaccine recipients with a history of advanced HIV infection (prior AIDS-defining conditions and/or nadir CD4 <200 cells). Method(s): In Mar 2021-Apr 2022, 55 PWH received 2 vaccine doses median 3 weeks apart [IQR 3-3] and a 3rd dose 27 weeks later [23-31]. Plasma samples (n=147) were stored immediately before dose-1 (T0), median 4 weeks [3-5] after dose-2 (T1) and median 13 weeks [9-19] after dose-3 (T2) for batch testing. Result(s): Participants' characteristics: 74% male, 85% white, all on ART, 82% HIV-RNA <50 cps/ml;median age 55 years, ART duration 7 years, nadir CD4 83 cells [36-211], current CD4 440 cells [270-710], CD4:CD8 ratio 0.6 [0.4-1.0];73% had a history of advanced HIV infection;15% received a COVID-19 diagnosis during the study. At T0, T1 and T2, proportions with quantifiable anti-S IgG (>0.8 U/ml) were 11/49 (22%), 50/54 (93%) and 43/43 (100%), respectively;their median anti-S IgG titres were 30 [15-124], 15949 [596-3389] and 8527 [3146-17190] U/ml. Proportions showing Wuhan-1 neutralisation by cPass were 6/50 (12%), 45/53 (85%) and 40/43 (93%), with median neutralisations of 67% [47-70], 97% [91-98] and 98% [98-98] and corresponding NAb titres of 1332 [792-1436], 5354 [3529-6187] and 6242 [5765-6766] U/ml. At T2, 25/28 (89%) showed BA.2 neutralisation by cPass (median 83% [68-93];NAb titre 7836 [3172-12173] U/ml) (Fig 1A). Two participants lacking NAbs at T2 had a history of advanced HIV infection. cPass data were highly correlated with anti-S IgG titres (rho 0.82;p<0.0001) and with PRNT data for both Wuhan-1 (n=27, Fig 1B) and Omicron BA.2 (n=28, Fig 1C). Conclusion(s): cPAss offers a simple methodology for measuring SARS-CoV-2 NAbs. Despite prior advanced HIV infection, neutralising activity improved with successive vaccinations and most participants showed NAbs against both Wuhan-1 and Omicron BA.2 after 3 vaccine doses. (Figure Presented).

The impact of the COVID-19 pandemic on cervical screening and outcomes for women living with HIV

Background: Current published Faculty of Sexual and Reproductive Health (FSRH) guidelines recommend annual cervical screening for women living with HIV(WLHIV) but do not reflect current evidence. Aim(s): 1. To assess the impact of the Covid-19 pandemic on frequency and interval of cervical screening in WLHIV 2. To report any changes in outcomes of cervical screening in WLHIV during Covid-19 Method: Data were collected retrospectively over 3 years defined as Pre-Covid (23/3/2019-22/3/2020), during Covid lockdowns (23/3/2020-22/3/2021) and Post-Covid lockdowns (23/3/2021-22/3/2022). Data was collated on demographics, HIV-related data, previous abnormal cervical screens/colposcopy, smoking and high-risk Human Papilloma Virus(hrHPV) vaccination. Result(s): Data was available for 70 women. Mean age was 48 years, 44.3%(n=31) were of African ethnicity. Mean duration of HIV diagnosis was 19 years. 22.9% (n=16) had a previous ADI, median CD4 was 768(range 35-1891), median nadir-CD4 439(range 3-1472), 94.3% (n=66) were taking ARVs and 87.1%(n=61) had HIV-VL <40 copies/ml. 42.9%(n=30) had a previous abnormal cervical screen and 78.6%(n=55) had undergone colposcopy. 4.3%(n=3) were vaccinated against hrHPV. 18.6% (n=13) currently smoked. 60%(n=42) women underwent cervical screening Pre- Covid, 41.4%(n=29) during and 78.6%(n=55) Post-Covid. 19.6-37.2% fewer women were screened during Covid compared to Pre and Post-Covid. 9.5%(n=4) women screened Pre-Covid tested positive for hrHPV compared with 6.9%(n=2) during Covid and 12.7%(n=7) Post-Covid. No cytology changes were seen for the majority however cervical intraepithelial neoplasia(CIN) grade 1 was detected in 2.4%(n=1) Pre- Covid, compared with 3.4%(n=1) during covid and 5.4% (n=3) Post-covid. Post-Covid 1.82%(n=1) had CIN grade 2 detected, no women pre or during covid had CIN grade 2 detected. No women Pre, during or Post-covid had CIN grade 3 or cervical neoplasm detected on cytology. Conclusion(s): Covid increased cervical screening intervals for WLHIV but did not result in delayed cervical cancer diagnosis. FSRH guidelines are currently under review regarding screening intervals. This data, although small in number, may support European AIDS Clinical Society and Department of Health and Human Services guidelines which have extended screening intervals for PWLH especially for those who tested negative for hrHPV.

HIV care during the SARS-COV-2 pandemic for Black people with HIV in the UK

Background: The COVID-19 pandemic disproportionally affected black communities but the impact on HIV care in this group remains poorly understood. We evaluated measures of HIV care during the COVID-19 pandemic in the GEN-AFRICA cohort of black people with HIV living in the U.K. Method(s): We evaluated interruptions to HIV care during the COVID-19 pandemic (01/2020-09/2022) in the GENAFRICA cohort at nine UK clinics who provided HIV outcomes for >80% of their participants. We ascertained death, transfers of care, loss to follow up for >12 months, the highest HIV viral load and interruptions to antiretroviral therapy (ART). We evaluated factors associated with the composite outcome of HIV viraemia (viral load >200 c/mL) and/or an ART interruption using logistic regression analysis;factors associated (P<0.1) in univariable analysis were included in the multivariable model. We also summarized reasons for ART interruptions where recorded. Result(s): 2321 participants (mean age 51.3 years;55.8% women;pre-pandemic current/nadir CD4 of 500/204 cells/mm3 and HIV RNA <200 c/mL in 92.3%) were in care on 01/01/2020. Thirty (1.3%) subsequently died, 24 (1.0%) transferred care and 48 (2.1%) became lost to follow up. 523 (22.7%) reported an episode of COVID-19 and 1771 (87.1%) having been vaccinated against SARSCoV- 2. The composite outcome could be evaluated in 2130 (91.8%);259 (11.2%) had a documented HIV VL >200 c/mL, 228 (9.8%) an ART interruption and 325 (14%) had HIV viraemia/ART interruption. In multivariable analysis, older age, a pre-pandemic HIV RNA <200 c/mL and being vaccinated against SARS-CoV-2 were associated with reduced odds of HIV viraemia/ART interruption (Table) while sex, CD4 (current/nadir), comorbid status and having had COVID-19 were not associated. Reasons for ART interruption were available for 52 participants;38% cited domestic logistic reasons, 27% issues related to foreign travel, 19% psychological reasons, 12% lockdown or changes to the daily routine and 4% personal choice. Conclusion(s): During the COVID-19 pandemic, one in seven black people with HIV experienced an ART interruption and/or HIV viraemia. Pre-pandemic measures of suboptimal engagement in care, pandemic restrictions, and wider health beliefs as reflected by COVID-vaccination, contributed to these undesirable HIV outcomes. (Table Presented).

Neutralizing Activity and T Cell Response after Bivalent Third Booster Dose in Plwh

Background: Aim of the study was to analyze neutralizing activity against BA.5,BQ.1.1 and T cell response after 3rd booster dose [3BD (5th shot)] with BA.4/5 bivalent vaccine by hybrid immunity (HI) and CD4 count in advanced PLWH. Method(s): In PLWH with previous AIDS and/or CD4< 200/mm3 receiving 3BD (original strain/BA.4/5),immunogenicity was assessed at time of 3BD (T0) and at day 15 (T1) by microneutralization assay [MNA90] against Omicron BA.5, BQ.1.1 and by IFNgamma-ELISA. PLWH were stratified by HI vs. nHI and by CD4 count at T0 ( >or< 500/3). For crude mean comparisons, neutralizing antibodies (nAbs) were expressed in natural scale and fold changes, IFNgamma and all values for regression analyses in log2 scale, paired t-test used to test changes over T0-T1. Two 2-arms parallel trials were emulated: HI and CD4 count as exposure, log2 nAbs and IFNgamma as outcome. Average treatment effect (ATE) of the two exposures were estimated by marginal models weighted for potential confounders (age, CD4 nadir, years from AIDS;when HI was the exposure also CD4 count). Result(s): N=48 PLWH on ART, 15% female, median age 56 yrs, 45% >1 comorbidity, 87% with previous AIDS, median CD4 nadir 44 cell/mm3 (16-102), 98% with HIV-RNA < 50 cps/mL. A significant increase of nAbs against BA.5 (fold-increase 8.8,p< 0.0001) and BQ.1.1 (6.4, p< 0.0001) was observed from T0 to T1. At T1, in nHI (n=29), mean nAb was 176 and 53 against BA.5 and BQ.1.1, respectively, with a fold change reduction (FCR) vs BA.5 of 3.3;in HI (n=19), 496 and 128, respectively, with a FCR of 3.8 (Fig.1A). After controlling for confounders, HI was associated with a higher level of neutralizing response against BA.5 [ATE=1.17 log2 (95%CI 0.34;2.00), P=0.006] but not against BQ.1.1 [0.65 log2 (-0.18;1.48), p=0.124]. At T1, among PLWH with CD4 count< 500 (n=29), mean nAb was 290.8 and 83.9 against BA.5 and BQ.1.1, respectively, with a FCR of 3.4;in those with CD4 count >500 (n=19), 230.4 and 64.3, respectively, with a FCR of 3.6 (Fig. 1C).There was no impact of CD4 count on neutralization after controlling for potential confounding factors. No evidence for a difference between T0 and T1 was detected for IFNg (Fig.1B,D). Conclusion(s): In PLWH with advanced diseases, bivalent BA.5 3BD elicited strong neutralization against BA.5, and retained cross-neutralization against BQ.1.1, even if 3 times lower. HI but not CD4 count >500 appeared to enhance neutralization against BA.5. Importantly, bivalent vaccine appeared to have no effect on T-cell mediated response. (Figure Presented).

Unique Differentiation and Homing Features of T Cells in Individuals with Long Covid

Background: A significant portion of individuals experience persistent symptoms months after SARS-CoV-2 infection, broadly referred to as Long COVID (LC). Although the frequencies of subsets of SARS-CoV-2-specific T cells have been shown to differ in individuals with LC relative to those with complete recovery, a deep dive into phenotypic and functional features of total and SARSCoV- 2-specific T cells from individuals with LC has yet to be performed. Method(s): Here, we used CyTOF to characterize the phenotypes and effector functions of T cells from LIINC cohort. The median age was 46, the cohort was 55.8% female, and 9/43 had been hospitalized. Participants were reported a median of 7 LC symptoms at 8 months. SARS-CoV-2-specific total antibody levels were also measured in concurrent sera. Manual gating was used to define T cell subsets, SPICE analyses for polyfunctionality, T cell clustering for phenotypic features, and linear regression for correlation. Permutation tests, Student's t tests, and Welch's t test were used for statistical analysis. Result(s): SARS-CoV-2 total antibody responses were elevated in the LC group (p=0.043), and correlated with frequencies of SARS-CoV-2-specific T cells in those without LC (r=0.776, p< 0.001) but not those with LC. While the frequencies of total SARS-CoV-2-specific CD4+ and CD8+ T cells were similar between individuals with and without LC, those from individuals without LC tended to be more polyfunctional (co-expressing IFNgamma, TNFalpha, IL2, and/or MIP1beta). CD4+ T cells from individuals with LC harbored higher frequencies of Tcm (p=0.003), Tfh (p=0.037), and Treg subsets (p=0.0412), and preferentially expressed a variety of tissue homing receptors including CXCR4 and CXCR5 (p=0.037). SARS-CoV-2-specific CD4+ T cells producing IL6, albeit rare, were observed exclusively among those with LC (p=0.016). In addition, participants with LC harbored significantly higher frequencies of SARS-CoV-2-specific CD8+ T cells co-expressing exhaustion markers PD1 and CTLA4 (p=0.018). Conclusion(s): Long COVID is characterized by global phenotypic differences in the CD4+ T cell compartment in ways suggesting preferential migration of these cells to inflamed mucosal tissues. Individuals with LC also harbor higher numbers of exhausted SARS-CoV-2-specific CD8+ T cells, potentially implicating viral persistence. Finally, our data additionally suggest that individuals with LC may uniquely exhibit an uncoordinated T cell and antibody response during COVID-19 convalescence.

Isolating the Effect of Covid-19 Related Disruption on Hiv Diagnoses in the Us, 2020

Background: Diagnoses of HIV in the US decreased by 17% in 2020 due to COVID-related disruptions. The extent to which this decrease is attributable to changes in HIV testing versus HIV transmission is unclear. We seek to better understand this issue by analyzing the discrepancy in expected versus observed HIV diagnoses in 2020 among persons who acquired HIV between 2010-2019, as changes in diagnosis patterns in this cohort cannot be attributed to changes in transmission. Method(s): We developed three methods based on the CD4-depletion model to estimate excess missed diagnoses in 2020 among PWH infected from 2010-2019. We stratified the results by transmission group, sex assigned at birth, race/ ethnicity, and region to examine differences by group and confirm the reliability of our estimates. We performed similar analyses projecting new diagnoses in 2019 among PWH infected from 2010-2018 to evaluate the accuracy of our methods against surveillance data. Result(s): There were approximately 3100-3300 fewer diagnoses than expected in 2020 among persons who acquired HIV from 2010-2019. Females (at birth), heterosexuals, persons who inject drugs, and Hispanic/Latino PWH missed diagnoses at higher levels than the overall population. By transmission category, MSM accounted for the highest percentage (61%) of missed diagnoses. Validation and stratification analyses confirmed the accuracy and reliability of our estimates. Conclusion(s): PWH infected from 2010-2019 showed a significant drop in diagnosis rate during 2020, suggesting that changes in testing played a substantial role in the observed decrease in new HIV diagnoses. Levels of missed diagnoses differed substantially across population subgroups. These analyses may be used to inform future estimates of HIV transmission during the COVID-19 pandemic and prioritize populations with increased testing needs.