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Summary: SARS-CoV-2 Omicron quickly spread globally, also in regions with high vaccination coverage, emphasizing the importance of exploring the immunological requirements for protection against Omicron breakthrough infection.The test-negative matched case-control study (N = 964) characterized Omicron breakthrough infections in triple-vaccinated individuals from the ENFORCE cohort. Within 60 days before a PCR test spike-specific IgG levels were significantly lower in cases compared to controls (GMR [95% CI] for BA.2: 0.83 [0.73–0.95], p = 0.006). Multivariable logistic regression showed significant associations between high antibody levels and lower odds of infection (aOR [95% CI] for BA.2 spike-specific IgG: 0.65 [0.48–0.88], p = 0.006 and BA.2 ACE2-blocking antibodies: 0.46 [0.30–0.69], p = 0.0002). A sex-stratified analysis showed more pronounced associations for females than males.High levels of vaccine-induced antibodies provide partial protection against Omicron breakthrough infections. This is important knowledge to further characterize a threshold for protection against new variants and to estimate the necessity and timing of booster vaccination.

Abstract Background Indicator condition guided HIV testing is a proven effective strategy for increasing HIV diagnosis in health care facilities. As part of the INTEGRATE Joint Action, we conducted four pilot studies, aiming to increase integrated testing for HIV/HCV/HBV and sexually transmitted infections, by introducing and expanding existing indicator condition guided HIV testing methods. Methods Pilot interventions included combined HIV/HCV testing in a dermatovenerology clinic and a clinic for addictive disorders in Lithuania; Increasing HIV testing rates in a tuberculosis clinic in Romania by introducing a patient information leaflet and offering testing for HIV/HCV/sexually transmitted infections to chemsex-users in Barcelona. Methods for implementing indicator condition guided HIV testing were adapted to include integrated testing. Testing data were collected retrospectively and prospectively. Staff were trained in all settings, Plan-do-study-act cycles frequently performed and barriers to implementation reported. Results In established indicator conditions, HIV absolute testing rates increased from 10.6 to 71% in the dermatovenerology clinic over an 18 months period. HIV testing rates improved from 67.4% at baseline to 94% in the tuberculosis clinic. HCV testing was added to all individuals in the dermatovenerology clinic, eight patients of 1701 tested positive (0.47%). HBV testing was added to individuals with sexually transmitted infections with a 0.44% positivity rate (2/452 tested positive). The Indicator condition guided HIV testing strategy was expanded to offer HIV/HCV testing to people with alcohol dependency and chemsex-users. 52% of chemsex-users tested positive for ≥ 1 sexually transmitted infection and among people with alcohol dependency 0.3 and 3.7% tested positive for HIV and HCV respectively. Conclusions The four pilot studies successfully increased integrated testing in health care settings, by introducing testing for HBV/HCV and sexually transmitted infections along with HIV testing for established indicator conditions and expanding the strategy to include new indicators; alcohol dependency and chemsex. HCV testing of individuals with alcohol abuse showed high positivity rates and calls for further implementation studies. Methods used for implementing indicator condition guided HIV Testing have proven transferable to implementation of integrated testing.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32-97), lowest in Northern Europe (median 44%, IQR 22-68%) and highest in Eastern Europe (median 99%, IQR 86-100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0-4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Many HIV clinics with poor IT-infrastructure are unable to report data on individuals in care with HIV, on antiretroviral treatment (ART) and virologically suppressed (VS), with the aim of monitoring the HIV Continuum of Care to estimate efficacy of HIV treatment programmes. We developed an estimation-tool, ESTIHIV, and determined the minimal data required for a random sample, to produce representative estimates, with a specified level of precision, of people with HIV on ART and VS. For proof of concept, 8852 HIV positive persons from seven clinics in seven different countries, with a follow-up visit during 2017, were included. Of those, 93.8% were on ART (95% CI 93.3-94.2) and 76.7% were VS (95% CI 75.8-77.6). In 2022, we tested the tool in the RESPOND Cohort for all countries with more than 100 participants under follow-up in 2019. We included 26,426 HIV positive persons from clinics in 27 countries, 97.8% (95% CI 97.6-98.0) were on ART and 91.5% were VS (95% CI 91.2-91.8%). There was good agreement between the RESPOND country estimates of ART and VS and the estimations using a random sample calculated in ESTIHIV. With ESTIHIV, clinics can produce a reliable estimate in figures for reporting and for monitoring the effectiveness of care in their clinics., Competing Interests: AM has received personal honoraria, travel support, and lecture fees from Gilead and ViiV, and consultancy fees from Eiland and Bonnin, all outside the submitted work. JG is an employee at Gilead Sciences. HG is an employee at ViiV Healthcare. For the remaining authors none were declared., (Copyright: © 2025 Raben et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction and Objectives: The HepHIV 2023 Conference, held in Madrid in November 2023, highlighted how Europe is not on track to meet the United Nations (UN) sustainable development goals and Joint UN Programme on HIV/AIDS (UNAIDS) targets. This article presents the outcomes of the conference, which focus on ways to improve testing and linkage to care for HIV, viral hepatitis, and other sexually transmitted infections. HIV-related stigma and discrimination, a major barrier to progress, was a key concept of the conference and on the agenda of the Spanish Presidency of the European Union., Methods: The HepHIV 2023 organizing committee, alongside the Spanish Ministry of Health, oversaw the conference organization and prepared the scientific programme based on abstract rankings. Key outcomes are derived from conference presentations and discussions., Results: Conference presentations covered the obstacles that HIV-related stigma and discrimination continue to pose to access to services, models for data collection to better monitor progress in the future, and examples of legislative action that can be taken at national levels. Diversification of testing approaches was also highlighted, to reach key populations, (e.g. migrant populations), to increase testing offered in healthcare settings (e.g. emergency departments), and to account for different stages of epidemics across the region., Conclusion: With a strong call for intensified action to address the impact of HIV-related stigma and discrimination on testing uptake, the conference concluded that strengthened collaboration is required between governments and implementers around testing and linkage to care. There is also an ongoing need to ensure sustainable political commitment and appropriate resource allocation to address gaps and inequalities in access for key populations and to focus on the implementation of integrated responses to HIV, viral hepatitis, and sexually transmitted infections., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Within a year of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, vaccines inducing a robust humoral and cellular immune response were implemented worldwide. However, emergence of novel variants and waning vaccine-induced immunity led to implementation of additional vaccine boosters., Methods: This prospective study evaluated the temporal profile of cellular and serological responses in a cohort of 639 SARS-CoV-2-vaccinated participants, of whom a large proportion experienced a SARS-CoV-2 infection. All participants were infection naïve at the time of their first vaccine dose. Proportions of SARS-CoV-2 spike-specific T cells were determined after each vaccine dose using the activation-induced marker assay, while levels of circulating SARS-CoV-2 antibodies were determined by the Meso Scale serology assay., Results: We found a significant increase in SARS-CoV-2 spike-specific CD4+ and CD8+ T-cell responses following the third dose of a SARS-CoV-2 messenger RNA vaccine as well as enhanced CD8+ T-cell responses after the fourth dose. Furthermore, increased age was associated with a poorer response. Finally, we observed that SARS-CoV-2 infection boosts both the cellular and humoral immune response, relative to vaccine-induced immunity alone., Conclusions: Our findings highlight the boosting effect on T-cell immunity of repeated vaccine administration. The combination of multiple vaccine doses and SARS-CoV-2 infections maintains population T-cell immunity, although with reduced levels in the elderly., Competing Interests: Potential conflicts of interest . T. B. reports the following grants from the past 36 months: unrestricted grant to his institution from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen’s Charitable Fund; unrestricted grant to his institution, principal investigator [PI]/clinical trial, advisory board from Pfizer, MSD, GSK, and Gilead Sciences; and grant for PI/clinical trial from Boehringer Ingelheim, Roche, Novartis, Kancera AB, Janssen, and AstraZeneca. T. B. is board member in Pentabase; serves on advisory boards for Janssen and AstraZeneca; and reports receiving payment or honoraria for lectures at GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie, and AstraZeneca. L. W. M. reports receiving travel support from AbbVie in September 2023. N. B. S. reports receiving funding from Danish Ministry of Health for the manuscript and consulting fees on study regarding respiratory syncytial virus from Pfizer and serving as PI in clinical studies sponsored by Pfizer, Bavarian Nordic, Moderna, and AstraZeneca. O. S. S. reports receiving funding from Danish Ministry of Health for the manuscript and consulting fees from UNION therapeutics and participation on a data and safety monitoring board or advisory board with Immunocore, ViiV Healthcare, and Gilead. M.T. reports funding from Danish Ministry of Health for the manuscript. All other authors report no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Since 2013, the European Testing Week (ETW) awareness campaign has become a key regional event influencing testing efforts for HIV, viral hepatitis, and sexually transmitted infections (STIs) through participation of 720 organizations. Here, we report on a survey from May to June 2022 aimed at assessing the participant-reported impact of the campaign., Methods: All past and current participating organizations were asked to complete an online questionnaire between 12 May and 17 June 2022. Multiple choice and open-text questions included organization information, usage of ETW to engage in local testing-related activities, and the effect of a regional campaign to reach a wider audience and generate impact., Results: Of the 52 respondents, 34 (65%) stated first participating in ETW 5-10 years ago. ETW was used for awareness raising by 40 respondents (83%), new testing activities by 37 (77%), advocacy initiatives by 15 (31%), and training/capacity building by 18 (38%). For awareness raising, 95% used ETW to highlight the importance of and to encourage testing; for new testing activities, 74% used ETW to reach new groups. In total, 44 (85%) reported added benefits of a Europe-wide campaign compared with national/local campaigns, particularly the increased visibility and collaboration opportunities. Impact at the local level was observed by 24 (51%), and impact at a national level was observed by 20 (43%). A total of 28 (79%) reported increases in the number of tests performed and 25 (75%) reported increases in clients accessing services., Conclusions: Regional awareness campaigns reach wider audiences, boost local and national efforts to increase testing, and sensitize key populations about the critical value of testing compared with local/national campaigns., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outpaces monovalent vaccine cross-protection to new viral variants. Consequently, bivalent coronavirus disease 2019 (COVID-19) vaccines including Omicron antigens were developed. The contrasting immunogenicity of the bivalent vaccines and the impact of prior antigenic exposure on new immune imprinting remains to be clarified., Methods: In the large prospective ENFORCE cohort, we quantified spike-specific antibodies to 5 Omicron variants (BA.1 to BA.5) before and after BA.1 or BA.4/5 bivalent booster vaccination to compare Omicron variant-specific antibody inductions. We evaluated the impact of previous infection and characterized the dominant antibody responses., Results: Prior to the bivalent fourth vaccine, all participants (N = 1697) had high levels of Omicron-specific antibodies. Antibody levels were significantly higher in individuals with a previous polymerase chain reaction positive (PCR+) infection, particularly for BA.2-specific antibodies (geometric mean ratio [GMR] 6.79, 95% confidence interval [CI] 6.05-7.62). Antibody levels were further significantly boosted in all individuals by receiving either of the bivalent vaccines, but greater fold inductions to all Omicron variants were observed in individuals with no prior infection. The BA.1 bivalent vaccine generated a dominant response toward BA.1 (adjusted GMR 1.31, 95% CI 1.09-1.57) and BA.3 (1.32, 1.09-1.59) antigens in individuals with no prior infection, whereas the BA.4/5 bivalent vaccine generated a dominant response toward BA.2 (0.87, 0.76-0.98), BA.4 (0.85, 0.75-0.97), and BA.5 (0.87, 0.76-0.99) antigens in individuals with a prior infection., Conclusions: Vaccination and previous infection leave a clear serological imprint that is focused on the variant-specific antigen. Importantly, both bivalent vaccines induce high levels of Omicron variant-specific antibodies, suggesting broad cross-protection of Omicron variants., Competing Interests: Potential conflicts of interest. N. B. S. declares to have served as an investigator in clinical trials sponsored by Pfizer, Gilead, and Bavarian Nordic, and AstraZeneca. H. N. declares to have been on advisory boards for GSK and MSD and reports grants or contracts from Novo Nordisk Foundation (payment to institution, RCT of brain abscess treatment strategy). T. B. declares receipt of unrestricted grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, Pfizer, Gilead Sciences, and MSD; and being advisory board member for GSK, Pfizer, Gilead Sciences, MSD, Janssen, and Astra Zeneca; and being principal investigator on clinical trials conducted by Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis, Kancera AB, Bavarian Nordic, and Janssen; and being board member on Pentabase; and receiving consulting fees from GSK and Pfizer; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, Astra Zeneca, and Bavarian Nordic; and receiving donation of trial medication (baricitinib) from Eli Lilly. M. T. declares to be on a Data Safety Monitoring Board for ImmunoCore. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Side effects to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are a key concern contributing to vaccine hesitancy, but more individuals may be encouraged if SARS-CoV-2 vaccines were known to lead to a stronger immune response., Methods: Included were adult participants from the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE) who completed a questionnaire to assess systemic reactions following SARS-CoV-2 vaccination (BTN162b2, mRNA-1273, ChAdOx1) and had SARS-CoV-2 spike immunoglobulin G (IgG) levels measured at baseline and post-vaccine. A symptom score was developed to measure severity of systemic adverse reactions (+1 for each moderate, +2 for each severe). Post-vaccination SARS-CoV-2 spike IgG levels were compared between participants with different scores using multivariable linear regression., Results: A total of 6528 participants were included (56.3% females; median age [interquartile range], 64 [54-75] years). After the first vaccination, no association was found between symptom score and post-vaccine dose spike IgG level ( P = .575). Following the second vaccination, significantly higher spike IgG levels were observed according to higher symptom scores ( P < .001); adjusted geometric mean ratios were 1.16 (95% CI, 1.04-1.30), 1.24 (95% CI, 1.09-1.41), 1.25 (95% CI, 1.06-1.46), and 1.21 (95% CI, 1.08-1.35), for scores of 2, 3, 4, and ≥5, respectively, compared with a score of 0. After adjustment for pre-vaccine dose spike IgG, this association was attenuated., Conclusions: An association was found between more severe adverse reactions and stronger antibody response after the second vaccination but not the first, likely attributed to higher levels of preexisting immunity gained from response to first vaccination. Regardless of side effects, most people experienced an effective immune response following vaccination., Competing Interests: Potential conflicts of interest. N.B.S. declares having served as primary investigator on clinical studies sponsored by Pfizer and Bavarian Nordic. T.B. declares receipt of unrestricted research or travel grants from GSK, Pfizer, Gilead Sciences, and MSD; being principal investigator on trials conducted by Boehringer Ingelheim, Roche, Novartis, Kancera, Pfizer, MSD, and Gilead; being a board member for Pentabase; and being an advisory board member for MSD, Gilead, Pfizer, GSK, Janssen, and AstraZeneca; receipt of consulting fees from GSK and Pfizer; receipt of a donation of study drug from Eli Lilly; and receipt of honoraria for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie, and AstraZeneca. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood., Methods: In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51-72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections., Results: We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified., Conclusions: SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization., (© 2023. The Author(s).)

Background: For people with HIV and CD4 + counts >500 cells/mm 3 , early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4 + counts are <350 cells/mm 3 . Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain., Methods: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4 + counts .500 cells/mm 3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021., Results: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4 + count was 648 and 460 cells/mm 3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4 + difference was 199 cells/mm 3 . After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4 + count difference was 155 cells/mm 3 . After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference)., Conclusions: Among adults with CD4 + counts >500 cells/mm 3 , excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Introduction: In recent years, HIV testing frequency has increased, resulting in more people being diagnosed during seroconversion with a temporarily low CD4 count. Using the current consensus definition of late HIV presentation ('presenting for care with a CD4 count < 350 cells/μL or an AIDS-defining event, regardless of CD4 count') these individuals would be incorrectly assigned as being diagnosed late., Methods: In spring 2022, a European expert group convened to revise the current late HIV presentation consensus definition. A survey on data availability to apply this revised definition was sent to nominated European focal points responsible for HIV surveillance (n = 53)., Results: Experts agreed that the updated definition should refer to late HIV diagnosis rather than presentation and include the following addition: People with evidence of recent infection should be reclassified as 'not late', with evidence of recent infection considered hierarchically. The individual must have: (i) laboratory evidence of recent infection; (ii) a last negative HIV test within 12 months of diagnosis; or (iii) clinical evidence of acute infection. People with evidence of being previously diagnosed abroad should be excluded. A total of 18 countries responded to the survey; 83% reported capturing CD4 count and/or AIDS at diagnosis through national surveillance, 67% captured last negative test and/or previous HIV diagnosis, 61% captured seroconversion illness at diagnosis and 28% captured incident antibody results., Conclusions: Accurate data on late diagnosis are important to describe the effects of testing programmes. Reclassification of individuals with recent infection will help to better identify populations most at risk of poor HIV outcomes and areas for intervention., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Five-year survival for human papilloma virus-unrelated head and neck squamous cell carcinomas remain below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy with single-dose durvalumab (anti-PD-L1) neoadjuvantly (n = 21) ( NCT03635164 ). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic and objective response; locoregional control; progression-free survival; and overall survival. Among evaluable patients at an early median follow-up of 16 months (448 d or 64 weeks), overall survival was 80.1% with 95% confidence interval (95% CI) (62.0%, 100.0%), locoregional control and progression-free survival were 75.8% with 95% CI (57.5%, 99.8%), and major pathological response or complete response was 75% with 95% exact CI (51.6%, 100.0%). For patients treated with 24 Gy, 89% with 95% CI (57.1%, 100.0%) had MPR or CR. Using high-dimensional multi-omics and spatial data as well as biological correlatives, we show that responders had: (1) an increase in effector T cells; (2) a decrease in immunosuppressive cells; and (3) an increase in antigen presentation post-treatment., (© 2022. The Author(s).)