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: Introduction: There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV‐positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study. Methods: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid‐lowering drugs (LLDs), angiotensin‐converting enzyme inhibitors (ACEIs), anti‐hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders. Results: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti‐hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow‐up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti‐hypertensives (1.17 [1.10, 1.25]). Conclusion: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV‐positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions., Introduction HIV‐positive individuals are known to be at increased risk of cardiovascular disease (CVD) compared to the general population, partly due to an increased prevalence of some CVD risk factors, [...]

Objectives: The Dolutegravir Monotherapy for HIV (DOMONO; NCT02401828) study showed that maintenance monotherapy with dolutegravir (DTG) is associated with virological failure (VF) and leads to DTG resistance and as a result should not be used. However, data on clinical and virological factors associated with VF during DTG monotherapy are lacking. We identified factors associated with VF during DTG monotherapy. Methods: A randomized trial was carried out in which patients on combination antiretroviral therapy (cART) with an HIV‐1 RNA zenith < 100 000 copies/mL and a CD4 T‐cell nadir ≥ 200 cells/μL, who had never experienced VF, switched to DTG monotherapy. Clinical and virological factors were compared between patients with and without VF, using univariate analyses. Results: Eight of the 95 patients developed VF during DTG monotherapy. A total of 78 participants had reached week 48 when the study was discontinued. The median CD4 T‐cell nadir was lower in patients with VF than in patients without VF [260 (interquartile range (IQR) 223–320) versus 380 (IQR 290–520) cells/μL, respectively; P = 0.011]. Patients with VF had a longer time between HIV diagnosis and cART initiation than those without VF [median 49 (IQR 27–64) versus 15 (IQR 1–38) months, respectively; P = 0.015]. The median total peripheral blood mononuclear cell (PBMC) HIV DNA copy number was higher in patients with VF than in those without VF [417 (range 85–4151) versus 147 (range 16–4132) copies/106PBMCs, respectively; P = 0.022]. Conclusions: A lower CD4 nadir, a longer time between HIV diagnosis and cART initiation, and a higher HIV DNA copy number at the time of DTG monotherapy initiation were associated with VF. While there clearly is no future role for DTG monotherapy, ongoing and future studies on the efficacy of maintenance dual therapy (e.g. DTG lamivudine) may have to take these variables into account in their study design and analysis. [ABSTRACT FROM AUTHOR]

Objectives Lamivudine (3 TC) and emtricitabine ( FTC) are considered interchangeable in recommended tenofovir disoproxil-fumarate ( TDF)-containing combination antiretroviral therapies ( cARTs). This statement of equivalence has not been systematically studied. We compared the treatment responses to 3 TC and FTC combined with TDF in boosted protease inhibitor ( PI)-based cART for HIV-1-infected patients. Methods An observational study in the AIDS Therapy Evaluation in the Netherlands ( ATHENA) cohort was carried out between 2002 and 2013. Virological failure rates, time to HIV RNA suppression < 400 copies/mL, and time to treatment failure were analysed using multivariable logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. Results A total of 1582 ART-naïve HIV-1-infected patients initiated 3 TC or FTC with TDF and ritonavir-boosted darunavir (29.6%), atazanavir (41.5%), lopinavir (27.1%) or another PI (1.8%). Week 48 virological failure rates on 3 TC and FTC were comparable (8.9% and 5.6%, respectively; P = 0.208). The multivariable adjusted odds ratio of virological failure when using 3 TC instead of FTC with TDF in PI-based cART was 0.75 [95% confidence interval ( CI) 0.32-1.79; P = 0.51]. Propensity score-adjusted models showed comparable results. The adjusted hazard ratio ( HR) for treatment failure of 3 TC compared with FTC was 1.15 (95% CI 0.58-2.27) within 240 weeks after cART initiation. The time to two consecutive HIV RNA measurements < 400 copies/ mL within 48 weeks ( HR 0.94; 95% CI 0.78-1.16) and the time to treatment failure after suppression < 400 copies/ mL ( HR 0.94; 95% CI 0.36-2.50) were not significantly influenced by the use of 3 TC in TDF/ PI-containing cART. Conclusions The virological responses were not significantly different in treatment-naïve HIV-1-infected patients starting either 3 TC/ TDF or FTC/ TDF and a ritonavir-boosted PI. [ABSTRACT FROM AUTHOR]

Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10-20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillus tracheobronchitis. Azoles are the first-choice antifungal drugs, with liposomal amphotericin B as an alternative in settings where azole resistance is prevalent. Despite antifungal therapy, IAPA and CAPA are associated with poor outcomes, with fatality rates often exceeding 50%. In this Review, we discuss the mechanistic and clinical aspects of IAPA and CAPA. Moreover, we identify crucial knowledge gaps and formulate directions for future research., Competing Interests: Declaration of interests SF received travel grants for conference attendance from Pfizer and Gilead and a speakers' fee from The Healthbook Company. AC received speakers' fees from Gilead. CJC reports research grants from Merck and Cidara; consulting fees or participation on advisory boards for Shionogi, Scynexis, and Venatorx; and lecture honoraria from Gilead. J-PG received consultancy and speaker fees from Gilead, Mundipharma, and Pfizer. MH received grants and research funding from Astellas, Gilead, MSD, Pfizer, Euroimmun, F2G, Pulmocide, AiCuris, Partners, IMMY, Melinta, Mundipharma, Shionogi, and Scynexis. KL received consultancy fees from MRM Health and Mundipharma; speakers' fees from Pfizer and Gilead; a service fee paid to the institution from Thermo Fisher Scientific and TECOmedical; and fees for advisory board participation from MSD and Pfizer. BJAR received research grants from Gilead; consulting fees from F2G; payment for lectures from Gilead; support for attending meetings from Pfizer, Gilead, and F2G; and reports participation on a data safety monitoring and advisory board for Exevir. LV received support for a public doctoral defence from Pfizer; and travel support from Gilead and Pfizer for conference attendance. PEV received research grants from F2G and Gilead; and speakers' fees from Mundipharma, F2G, Gilead, and Pfizer. JW received an institutional research fund from Pfizer; investigator-initiated grants from Pfizer, Gilead, and MSD; speakers' and travel fees from Pfizer, Gilead, and MSD; declares participation in advisory boards of Pfizer and Gilead; and declares receipt of study drugs from MSD. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH)., Design: Prospective observational cohort study., Methods: PWH aged ≥45 years received Wuhan-BA.1 mRNA-1273.214 and those <45 years Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1 : 2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses and cytokine responses up to 180 days post-vaccination., Results: Forty PWH received mRNA-1273.214 ( N  = 35) or BNT162b2 ( N  = 5) following mRNA-based ( N  = 29) or vector-based ( N  = 11) primary vaccination. PWH were predominantly male (87% vs. 26% of non-PWH) and median 57 years [interquartile range (IQR) 53-59]. Their median CD4 + T-cell count was 775 (IQR 511-965) and the plasma HIV-RNA load was <50 copies/ml in 39/40. The GMR of S1-specific antibodies by 28 days post-vaccination was comparable between PWH [4.48, 95% confidence interval (CI) 3.24-6.19] and non-PWH (4.07, 95% CI 3.42-4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180 days, and T-cell responses up to 90 days post-vaccination. Interferon-γ, interleukin (IL)-2, and IL-4 cytokine concentrations increased 28 days post-vaccination in PWH., Conclusion: A bivalent BA.1 booster vaccine was immunogenic in well treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90 days in PWH compared to non-PWH., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Immunocompromised patients (ICPs) have an increased risk for a severe and prolonged COVID-19. SARS-CoV-2 monoclonal antibodies (mAbs) were extensively used in these patients, but data from randomized trials that focus on ICPs are lacking. We evaluated the clinical and virological outcome of COVID-19 in ICPs treated with mAbs across SARS-CoV-2 variants., Methods: In this multicenter prospective cohort study, we enrolled B-cell- and/or T-cell-deficient patients treated with casirivimab/imdevimab, sotrovimab, or tixagevimab/cilgavimab. SARS-CoV-2 RNA was quantified and sequenced weekly, and time to viral clearance, viral genome mutations, hospitalization, and death rates were registered., Results: Two hundred and forty five patients infected with the Delta (50%) or Omicron BA.1, 2, or 5 (50%) variant were enrolled. Sixty-seven percent were vaccinated; 78 treated as outpatients, of whom 2 required hospital admission, but both survived. Of the 159 patients hospitalized at time of treatment, 43 (27%) required mechanical ventilation or died. The median time to viral clearance was 14 days (interquartile range, 7-22); however, it took >30 days in 15%. Resistance-associated spike mutations emerged in 9 patients in whom the median time to viral clearance was 63 days (95% confidence interval, 57-69; P < .001). Spike mutations were observed in 1 of 42 (2.4%) patients after treatment with 2 active mAbs, in 5 of 34 (14.7%) treated with actual monotherapy (sotrovimab), and 3 of 20 (12%) treated with functional monotherapy (ie, tixagevimab/cilgavimab against tixagevimab-resistant variant)., Conclusions: Despite treatment with mAbs, morbidity and mortality of COVID-19 in ICPs remained substantial. Combination antiviral therapy should be further explored and may be preferred in severely ICPs., Competing Interests: Potential conflicts of interest. B. R. reports membership on advisory boards for AstraZeneca, Roche, and Pfizer; and receipt of consulting fees from Roche, AstraZeneca and Pfizer. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The two main objectives were to evaluate the COVID-19 point prevalence and the test performance of the WHO case definition to diagnose COVID-19 clinically in people with HIV in West Ukraine., Methods: Multicenter cross-sectional study in Lviv, Ukraine, from October 2020-November 2021. COVID-19 unvaccinated people with HIV were included regardless of COVID-19 symptoms at routine clinical visits and had standardized medical, quality of life (EQ(5D)) and SARS-CoV-2 serology assessments. Reported symptoms indicating potential COVID-19 events at inclusion or between March 2020 and inclusion were classified by the WHO case definition as suspected, probable or confirmed. A clinical COVID-19 case was defined as being SARS-CoV-2 seropositive with at least a suspected COVID-19 according to the WHO case definition. The primary endpoints were the clinical COVID-19 prevalence and the test characteristics of the WHO case definition with SARS-CoV-2 serology as reference. (Clinicaltrials.gov:NCT04711954)., Results: The 971 included people with HIV were median 40 years, 38.8% women, 44.8% had prior AIDS, and 55.6% had comorbidities. SARS-CoV-2 seroprevalence was 40.1% (95%CI:37.0-43.1) and 20.5% (95%CI:18.0-23.1) had clinical COVID-19 median 4 months (IQR:2-7) before inclusion. Clinical COVID-19 occurred less frequently in people with HIV with tuberculosis history, injecting drug use, CD4+ T-cells <200/mL and unemployment. The quality of life was not impacted after COVID-19. An at least probable COVID-19 classification by the WHO case definition had 44.1% sensitivity (95%CI:38.7-49.7), 85.2% specificity (95%CI:81.5-88.4), 66.6% positive predictive value (95%CI:59.8-73.0) and 69.5% negative predictive value (95%CI:65.5-73.3) to diagnose COVID-19., Conclusions: COVID-19 unvaccinated people with HIV from Ukraine had a significant COVID-19 rate and using the WHO case definition had insufficient diagnostic accuracy to diagnose these cases. The lower burden in vulnerable people with HIV was unexpected but might reflect a shielding effect., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Unrestricted grant from ISS program by ViiV Healthcare (grant nr. 214,684) and the Erasmus MC Foundation aware.hiv Ukraine program (https://www.awarehiv.com/ukraine). The funder had no role in the design of the study, data collection, analysis, writing or the decision to submit for publication. The authors declare no other conflict of interest related to this submission. Results from a planned interim analysis at 500 participants have been presented at EACS conference London, 2021.

Background: An early diagnosis and treatment of invasive fungal disease (IFD) is associated with improved outcome, but the moderate sensitivity of noninvasive diagnostic tests makes this challenging. Invasive diagnostic procedures such as bronchoalveolar lavage (BAL) have a higher yield but are not without risk. The detection and sequencing of microbial cell-free DNA (mcfDNA) may facilitate a noninvasive diagnosis., Materials: In a prospective observational study, we collected plasma in the 120 hours preceding or following a BAL in patients with hematological malignancies suspected for a pulmonary IFD. The EORTC/MSGERC2020 criteria were used for IFD classification. Sequencing was performed by Karius (Redwood City, CA) using their Karius Test (KT) on plasma and a "research use only test" on BAL fluid if available. Cases with a probable/proven IFD were identified based on standard diagnostic tests on serum and BAL (microscopy, polymerase chain reaction, galactomannan, culture) and used to calculate the sensitivity, specificity, and additional diagnostic value of the KT., Results: Of 106 patients enrolled, 39 (37%) had a proven/probable invasive aspergillosis, 7 (7%) a non- Aspergillus IFD, and 4 (4%) a mixed IFD. The KT detected fungal mcfDNA in 29 (28%) patients. Compared with usual diagnostic tests, the sensitivity and specificity were 44.0% (95% confidence interval [CI], 31.2-57.7) and 96.6% (95% CI, 88.5%-99.1%). Sensitivity of the KT was higher in non- Aspergillus IFD ( Mucorales :2/3, Pneumocystis jirovecii : 3/5). On BAL, the sensitivity was 72.2% (95% CI, 62.1-96.3), and specificity 83.3% (95% CI, 49.1-87.5)., Conclusions: Sequencing of mcfDNA may facilitate a noninvasive diagnosis of IFD in particular non- Aspergillus IFD. However, on plasma and similar to currently available diagnostics, it cannot be used as a "rule-out" test., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background and Objective: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing anti-SARS-CoV-2 antibody titers following the administration of ConvP or hyperimmune globulins (COVIg)., Methods: Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination, received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19., Results: Forty-four patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter-individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile range: 17-25 days). Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody titers for > 90% of the time. However, as a result of hybrid immunity and/or repeated vaccination, plasma donors with extremely high antibody titers are now readily available, and a > 90% target attainment should be possible., Conclusion: The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg., Clinical Trial Registration Number: NL9379 (The Netherlands Trial Register)., (© 2024. The Author(s).)

We assessed the predictive capacity of the HCV-MOSAIC risk score, originally developed for primary early HCV infection, as a screening tool for HCV reinfection in 103 men who have sex with men (MSM) with HIV using data from the MOSAIC cohort, including MSM with HIV/HCV-coinfection who became reinfected (cases, n = 27) or not (controls, n = 76) during follow-up. The overall predictive capacity of the score was assessed using the area under the receiver operating characteristic (AUROC) curve. The effects of covariates on the receiver operating characteristic (ROC) curve were assessed using parametric ROC regression. The score cut-off validated for primary early infection (≥2.0) was used, from which the sensitivity and specificity were calculated. The AUROC was 0.74 (95% confidence interval (CI) = 0.63-0.84). Group sex significantly increased the predictive capacity. Using the validated cut-off, sensitivity was 70.4% (95%CI = 49.8-86.2%) and specificity was 59.2% (95%CI: 47.3-70.4%). External validation from a cohort of 25 cases and 111 controls, all MSM with HIV, resulted in a sensitivity of 44.0% (95%CI = 24.4-65.1) and specificity of 71.2% (95%CI = 61.8-79.4). The HCV-MOSAIC risk score may be useful for identifying individuals at risk of HCV reinfection. In sexual health or HIV-care settings, this score could help guide HCV-RNA testing in MSM with a prior HCV infection.

In two Dutch observational cohorts of people with HIV, the use of TDF, ETR, or INSTIs was not independently associated with either the risk of incident SARS-CoV-2 infection or severe COVID-19 outcomes, as was suggested by previous observational and molecular docking studies. Our findings do not support a strategy of modifying antiretroviral therapy to include these agents to protect against SARS-CoV-2 infection and severe COVID-19 outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy., Methods: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA., Results: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83)., Conclusions: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample)., Competing Interests: Potential conflicts of interest J. M. reports grants from Gilead Sciences, Inc; consulting fees, payment for lectures/presentations, and support for meetings/travel expenses from Gilead Sciences, Inc, MSD, Pfizer, Takeda, and F2G; and participation on a data safety monitoring board or advisory board for Gilead Sciences, Inc, MSD, Pfizer, Takeda, F2G, and Cidara. P. G. reports partial support for travel to Trends In Medical Mycology conference. K. L. reports grants from Thermo Fisher Scientific and TECOmedical paid to their institution; consulting fees from Gilead, MSD, and MRM Health, all paid to their institution; and personal fees for lectures/presentations for Pfizer, Gilead, and FUJIFILM Wako. M. R. reports support for travel to Trends In Medical Mycology conference. J. J. reports grants from Novartis and BMS, both paid to their institution; payment for lectures from AbbVie, Novartis, Pfizer, and Incyte; and serving as president of the Apps for Care and Science, a nonprofit organization, supported by AbbVie, Alexion, Amgen, Astellas, BMS, Daiichi-Sankyo, Janssen-Cilag, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, and Takeda. J. B. reports research grants from Gilead Sciences, Inc, and F2G. P. V. reports research grants from F2G and Gilead, paid to their institution; honoraria for lectures from F2G, Gilead, and Pfizer, all paid to their institution; and participation on a data safety monitoring board for F2G, paid to their institution. S. H. reports support from Gilead for travel to the International Society for Human and Animal Mycology 2022 conference. B. R. reports research grants from Gilead Sciences, Inc; support for meetings/travel expenses from Gilead Sciences, Inc, F2G, and Pfizer; consulting fees from F2G; payment/honoraria for lectures/presentations from Gilead Sciences, Inc; and participation on a data safety monitoring board/advisory board for Exevir. 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.)

Objectives: Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19., Methods: Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values <30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively., Results: Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20-231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations., Conclusions: In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results., Methods: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022., Results: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer., Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher., Competing Interests: Potential conflicts of interest. R. L. has received fees from Pfizer for serving as subinvestigator of a COVID vaccine trial. F. P. has received fees from Pfizer for serving as a principal investigator for a COVID vaccine trial. D. J. S. is a founder and board member of AliquantumRx with stock options; Hemex Health malaria diagnostics consulting; royalties for malaria diagnostic test control standards from Alere (Binax Inc/D/B/A Inverness Medical); consulting fees for legal malaria case from Mabrey Firm (2019); the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, DOD TB210115 (CDMRP Tick-Borne Disease Research Program); the following patents: USP 9642865 (issued 9 May 2017, New angiogenesis inhibitors), USP 7270948 (issued 18 September 2007, Detection of malaria parasites by laser desorption mass spectrometry), Salts and polymorphs of cethromycin for the treatment of disease (pending, application 20210163522), and Macrolide compounds and their use in liver stage malaria and related disease (pending, application PCT/US2015/046665); and participation on 2018 NIAID Safety Monitoring Committee/Independent Safety Monitor Intramural, all outside the submitted work. B. J. A. R. reports advisory board membership for Roche and AstraZeneca on a COVID-19 therapy; membership on a data and safety monitoring board (DSMB) for Exevir; consulting fees from Roche and AstraZeneca; grants or contracts and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Gilead Sciences; and support for attending meetings and/or travel from Pfizer. J. J. Z. reports consulting fees from City of Hope; cell therapy consultant; participation on DSMB for the PACER trial; DSMB for the Tolerant trial; and advisory boards for Sanofi and Sobi. L. J. D. reports the following grants or contracts: 75A50120C00094 (BARDA), Collection, testing, and provision of COVID-19 convalescent plasma for NHLBI/NIH (C3PO) through America's Blood Centers; US Veterans Health Administration, Pittsburgh (contract number 36C24E20D0027, VA CURES-1); and Vanderbilt University (Collection, testing, and provision of COVID-19 convalescent plasma for Association of Convalescent Plasma Treatment with Mortality and Clinical Trajectory in Patients Hospitalized with COVID-19 in the Community Setting). B. P. reports the following grants or contracts: COVID Trials, Incyte, Parexel, Novartis Pharmaceuticals, Partner Therapeutics, Fulcrum Therapeutics (to University Health Science Center), and Pulmonary Hypertension Trials, United Therapeutics, GlaxoSmithKline, Insmed, Merck Sharp & Dohme (to University of Texas Health Center). C. W. C. reports consulting honorarium for participation on NHLBI ACTIV4 CONNECTS Steering Committee. I. E. reports support for attending meetings and/or travel for 50 Congreso Argentino de Medicina Respiratoria 2022, Abstract Scholarship, American Thoracic Society, International Conference in Philadelphia, 2020 Assembly on Pediatrics. G. P. M. reports grants or contracts from Pfizer, Moderna, Medicago, and Merck for clinical research (as principal investigator), and payment for presentations from Moderna. D. O. reports consulting fees paid to author from the Fight Infectious Diseases Foundation and the Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol. B. R. M. reports the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, and DOD TB210115 (CDMRP Tick-Borne Disease Research Program). D. W. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AstraZeneca, and support for attending meetings and/or travel from Laboratorios Raffo. C. R. reports grants or contracts from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, AIDSfonds, and Health∼Holland; participation on a DSMB or advisory board as well as support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare; and gifts for the #awarehivukraine foundation. M. A. H. reports grants or contracts from Gilead, Insmed, and AN2 Therapeutics, as well as participation on the AIDS Clinical Trials Group Tuberculosis Transformative Science Group Study Monitoring Committee. 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.)

Introduction: COVID-19 convalescent plasma (CCP) is a possible treatment option for COVID-19. A comprehensive number of clinical trials on CCP efficacy have already been conducted. However, many aspects of CCP treatment still require investigations: in particular (1) Optimisation of the CCP product, (2) Identification of the patient population in need and most likely to benefit from this treatment approach, (3) Timing of administration and (4) CCP efficacy across viral variants in vivo. We aimed to test whether high-titre CCP, administered early, is efficacious in preventing hospitalisation or death in high-risk patients., Methods and Analysis: COVIC-19 is a multicentre, randomised, open-label, adaptive superiority phase III trial comparing CCP with very high neutralising antibody titre administered within 7 days of symptom onset plus standard of care versus standard of care alone. We will enrol patients in two cohorts of vulnerable patients [(1) elderly 70+ years, or younger with comorbidities; (2) immunocompromised patients]. Up to 1020 participants will be enrolled in each cohort (at least 340 with a sample size re-estimation after reaching 102 patients). The primary endpoint is the proportion of participants with (1) Hospitalisation due to progressive COVID-19, or (2) Who died by day 28 after randomisation. Principal analysis will follow the intention-to-treat principle., Ethics and Dissemination: Ethical approval has been granted by the University of Ulm ethics committee (#41/22) (lead ethics committee for Germany), Comité de protection des personnes Sud-Est I (CPP Sud-Est I) (#2022-A01307-36) (ethics committee for France), and ErasmusMC ethics committee (#MEC-2022-0365) (ethics committee for the Netherlands). Signed informed consent will be obtained from all included patients. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings., Trial Registration: Clinical Trials.gov (NCT05271929), EudraCT (2021-006621-22)., Competing Interests: Competing interests: PT is an employee of Établissement Français du Sang, the blood establishment responsible for blood collection, qualification and supply in France. HS, SH, SK, TA and ES are employees of the German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen (or its affiliates), the establishment responsible for blood collection, qualification and supply in Baden-Württemberg and Hesse, Germany. CEV, is an employee of Sanquin, the establishment responsible for blood collection, qualification and supply in the Netherlands. The authors declare no other competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

Background: The COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders., Methods: The primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity., Results: Of the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60-66), 86% were male, and median CD4+ T-cell count was 650/μL (IQR, 423-941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24-46) to 4317 BAU/mL (95% CI, 3275-5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed., Conclusions: An additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination. Clinical Trials Registration. EUCTR2021-001054-57-N., Competing Interests: Potential conflicts of interest. S. J. received grants from the Dutch research council (NWO), European Union Horizon 2020, and the Bill and Melinda Gates Foundation. W. F. W. B. declares reimbursement to institution for participation of patient in trial by GSK. R. D. d. V. is listed as inventor of the fusion inhibitory lipopeptide [SARSHRC-PEG4]2-chol on a provisional patent application. K. C. E. S. received honorariums for advisory boards from Gilead and ViiV. C. R. has received research grants from ViiV, Gilead, ZonMw, AIDSfonds, Erasmus MC, and Health∼Holland; and honorariums for advisory boards from Gilead and ViiV. B. J. A. R. declares research grants from Gilead and MSD; and honorary for advisory boards for AstraZeneca, Roche, Gilead, and F2G. K. B. received research and educational grants from ViiV and Gilead; and consulting fees for advisory boards for ViiV, Gilead, MSD, and AstraZeneca. A. R. received grants from the Bill and Melinda Gates foundation and the Leids Universitair Fonds. All other authors report no potential 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) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Illness after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous variants. Data on the disease burden in immunocompromised patients are lacking. We investigated the clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 (COVID-19) caused by Omicron., Methods: Organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients infected with the Omicron variant were included. Characteristics of consenting patients were collected and patients were contacted regularly until symptom resolution. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed., Results: 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received 3 mRNA vaccinations. While only 1 patient died, 23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2 immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL) at diagnosis, being older, being a lung transplant recipient, having more comorbidities, and having a higher frailty score were associated with hospital admission (all P < .01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of these patients, and 1 died., Conclusions: While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. In addition to vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients., Competing Interests: Potential conflicts of interest. B. J. A. R. has served on advisory boards of Roche and AstraZeneca. R. A. S. H. and O. C. M. have served on the advisory board of AstraZeneca. V. A. S. H. D. received grants from ZonMw (paid to their institution), Horizon 2020–Marie Curie Sklodowska (paid to their institution), and Takeda (paid to their institution) and has received payment from Takeda, Pharming, GSK, and CSL Behring paid to their institution for lectures. M. M. L. K. has served on the advisory board of Takeda. 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) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis., Methods: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation., Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001)., Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence., Clinical Trial Registration: ClinicalTrials.gov registration no. NCT00893555., Competing Interests: Competing interests R.J. Bruggeman has received fees for consulting from Gilead, F2G and Amplyx and has received research grants and given lectures for Gilead, Pfizer, Merck and Astellas. All contracts were with Radboudumc and all payments were with Radboudumc. B.J. Biemond has received research support of Sanquin, Global Blood Therapeutics and Novartis. B.J.A. Rijnders reports grants from Gilead Sciences and personal fees from F2G, outside the submitted work. J.J. Swen reports personal fees from Roche, outside the submitted work. P.E. Verweij reports grants from MSD, Gilead Sciences, F2G and Pfizer and non-financial support from IMMY, outside the submitted work. J.W.C. Alffenaar reports other financial support from Pfizer, MSD and Gilead and grants from MSD, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Vaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH., Methods and Findings: We conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44-60] years, 85.5% male) and 440 controls (median age 43 [IQR 33-53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/μL (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508-0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ T-cell count 250-500 cells/μL (2.845, 95% CI 1.876-4.314, p < 0.001) or >500 cells/μL (2.936, 95% CI 1.961-4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients., Conclusions: After vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required., Trial Registration: The trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors have completed the ICMJE disclosure form and declare no competing interests exist directly related to the submitted work Conflicts of interest outside the submitted work CR has received research grants from ViiV, Gilead, ZonMW, AIDSfonds, Erasmus MC, and Health~Holland and honorariums for advisory boards from Gilead and ViiV; WFWB declares reimbursement for participation of patient in trial by GSK to institution. DG and RDdV are supported by the Health~Holland grant EMCLHS20017 co-funded by the PPP Allowance made available by the Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. RDdV is listed as inventor of the fusion inhibitory lipopeptide [SARSHRC-PEG4]2-chol on a provisional patent application. VASHD has received research grants from ZonMw, Horizon 2020 – Marie Curie-Sklodowska, Takeda and payments for lectures and advisory boards from Takeda, CSL Behring, Pharming and GSK. KCES received honorariums for advisory boards from Gilead and ViiV. BJAR declares research grants from Gilead and MSD and honorary for advisory boards for Astra Zeneca, Roche, Gilead, F2G all outside the context of this work. RvM received consultancies fees paid to their institution from ViiV; Gilead; MSD, received research grants paid to their institution from ViiV; Gilead All other authors declare hat no competing interests exist.

Objectives: The COVID-19 pandemic increases healthcare worker (HCW) absenteeism. The bacillus Calmette-Guérin (BCG) vaccine may provide non-specific protection against respiratory infections through enhancement of trained immunity. We investigated the impact of BCG vaccination on HCW absenteeism during the COVID-19 pandemic., Methods: HCWs exposed to COVID-19 patients in nine Dutch hospitals were randomized to BCG vaccine or placebo in a 1:1 ratio, and followed for one year using a mobile phone application. The primary endpoint was the self-reported number of days of unplanned absenteeism for any reason. Secondary endpoints included documented COVID-19, acute respiratory symptoms or fever. This was an investigator-funded study, registered at ClinicalTrials.gov (NCT03987919)., Results: In March/April 2020, 1511 HCWs were enrolled. The median duration of follow-up was 357 person-days (interquartile range [IQR], 351 to 361). Unplanned absenteeism for any reason was observed in 2.8% of planned working days in the BCG group and 2.7% in the placebo group (adjusted relative risk 0.94; 95% credible interval, 0.78-1.15). Cumulative incidences of documented COVID-19 were 14.2% in the BCG and 15.2% in the placebo group (adjusted hazard ratio (aHR) 0.94; 95% confidence interval (CI), 0.72-1.24). First episodes of self-reported acute respiratory symptoms or fever occurred in 490 (66.2%) and 443 (60.2%) participants, respectively (aHR: 1.13; 95% CI, 0.99-1.28). Thirty-one serious adverse events were reported (13 after BCG, 18 after placebo), none considered related to study medication., Conclusions: During the COVID-19 pandemic, BCG-vaccination of HCW exposed to COVID-19 patients did not reduce unplanned absenteeism nor documented COVID-19., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution., Trial Registration: Clinicaltrials.gov NCT04621123 and NCT04589949., Registration: NCT04621123 and NCT04589949 on https://www., Clinicaltrials: gov., (© 2022. The Author(s).)

Background: Two years into the pandemic, convincing evidence in favour of convalescent plasma (ConvP) as a treatment for coronavirus disease 2019 (COVID-19) is still lacking. This contrasts sharply with the efficacy of potent virus-neutralizing monoclonal antibodies. However, resistance of the Omicron variant against almost all licensed monoclonals turns back the clock, and we can expect that ConvP will regain interest. Indeed, the efficacy of virus-neutralizing monoclonal antibodies supports the premise that ConvP will work when used at the right time, at the right dose, and containing antibodies with the right affinity., Objectives: This study aimed to review available evidence on dosing of ConvP for COVID-19 and provide guidance for future trials or patient care., Sources: Because no dose-finding human trials were ever performed, we reviewed COVID-19 animal model studies and human trials that provide (in)direct data on the pharmacokinetics and pharmacodynamics of ConvP. We also discuss the identification of appropriate ConvP donors in the context of emerging severe acute respiratory syndrome coronavirus 2 variants., Content: Compared with dosing in animal studies, almost all human trials used substantially lower doses. Identifying donors with sufficiently high virus-neutralizing antibody titres is challenging, in particular when new variants escape immunity induced by ancestral variants. Ways to avoid underdosing are (a) use of ConvP from two different donors, (b) use only ConvP known to neutralize the variant with which the patient is infected, (c) use two ConvP units with a neutralizing antibody titre ≥1/1250 (when only one plasma unit is available, neutralizing antibody titre of ≥1/2500 is recommended), (d) use an antibody test that correlates well with virus neutralization (use of international units per ml (IU/ml) for virus neutralization is strongly encouraged), and (e) use of donors shortly after a third mRNA vaccination may simplify the donor selection process., Implications: In future trials on ConvP for COVID-19, more stringent donor selection criteria and/or higher volume transfusions should be used., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To describe hepatitis C virus (HCV)-viremia prevalence and barriers to direct-acting antiviral (DAA) treatment during unrestricted access to DAA in a nationwide cohort of people with HIV (PWH)., Design: Retrospective analysis of prospectively collected data., Methods: We calculated yearly HCV-viremia prevalence as proportion of HCV RNA-positive individuals ever HCV-tested. We then included HCV-viremic individuals with ≥1 visit during the era of universal DAA-access (database lock = December 31, 2018). Based on their last visit, individuals were grouped as DAA-treated or -untreated. Variables associated with lack of DAA-treatment were assessed using targeted maximum likelihood estimation. In November 2020, physicians of DAA-untreated individuals completed a questionnaire on barriers to DAA-uptake and onward HCV-transmission risk., Results: Among 25 196 PWH, HCV-viremia decreased from 4% to 5% between 2000 and 2014 to 0.6% in 2019. Being DAA-untreated was associated with HIV-transmission route other than men who have sex with men, older age, infrequent follow-up, severe alcohol use, detectable HIV-RNA, HCV-genotype 3, and larger hospital size. With universal DAA-access, 72 of 979 HCV-viremic individuals remained DAA-untreated at their last visit. Of these, 39 were no longer in care, 27 remained DAA-untreated in care, and six initiated DAA since database lock. Most common physician-reported barriers to DAA-uptake were patient refusal (20/72, 28%) and infrequent visit attendance (19/72, 26%). Only one DAA-untreated individual in care was engaging in activities associated with onward HCV-transmission., Conclusions: Prevalence of HCV-viremic PWH is low in the Netherlands, coinciding with widespread DAA-uptake. Barriers to DAA-uptake appear mostly patient-related, while HCV-transmission seems unlikely from the few DAA-untreated in care., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Twenty-five B-cell-depleted patients (24 following anti-CD19/20 therapy) diagnosed with coronavirus disease 2019 had been symptomatic for a median of 26 days but remained antibody negative. All were treated with convalescent plasma with high neutralizing antibody titers. Twenty-one (84%) recovered, indicating the potential therapeutic effects of this therapy in this particular population., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T cell responses targeting SARS-CoV-2 D614G [wild type (WT)] and the Beta, Delta, and Omicron variants of concern in a cohort of 60 health care workers after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273, or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which substantially decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays showed consistent cross-neutralization of the Beta and Delta variants, but neutralization of Omicron was significantly lower or absent. BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV2 priming partially restored neutralization of the Omicron variant, but responses were still up to 17-fold decreased compared with WT. SARS-CoV-2-specific T cells were detected up to 6 months after all vaccination regimens, with more consistent detection of specific CD4 + than CD8 + T cells. No significant differences were detected between WT- and variant-specific CD4 + or CD8 + T cell responses, including Omicron, indicating minimal escape at the T cell level. This study shows that vaccinated individuals retain T cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations are needed to further restore Omicron cross-neutralization by antibodies.

Quantitative or qualitative differences in immunity may drive clinical severity in COVID-19. Although longitudinal studies to record the course of immunological changes are ample, they do not necessarily predict clinical progression at the time of hospital admission. Here we show, by a machine learning approach using serum pro-inflammatory, anti-inflammatory and anti-viral cytokine and anti-SARS-CoV-2 antibody measurements as input data, that COVID-19 patients cluster into three distinct immune phenotype groups. These immune-types, determined by unsupervised hierarchical clustering that is agnostic to severity, predict clinical course. The identified immune-types do not associate with disease duration at hospital admittance, but rather reflect variations in the nature and kinetics of individual patient's immune response. Thus, our work provides an immune-type based scheme to stratify COVID-19 patients at hospital admittance into high and low risk clinical categories with distinct cytokine and antibody profiles that may guide personalized therapy., (© 2022. The Author(s).)

During COVID-19 lockdown, the in-hospital number of HIV indicator conditions decreased disproportionally compared with other non-COVID-19 diseases, which was accompanied by reduced HIV testing rates, number and proportion of positive HIV tests, and new HIV referrals, with more late presentation after lockdown cessation, indicating a significantly impacted HIV care continuum., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: To study the effect of interferon-α2 auto-antibodies (IFN-α2 Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α2 Abs transfer during convalescent plasma treatment., Methods: Sera from healthy controls, cases of COVID-19, and other respiratory illness were tested for IFN-α2 Abs by ELISA and a pseudo virus-based neutralization assay. The effects of disease severity, sex, and age on the risk of having neutralizing IFN-α2 Abs were determined. Longitudinal analyses were performed to determine association between IFN-α2 Abs and survival and viral load and whether serum IFN-α2 Abs appeared after convalescent plasma transfusion., Results: IFN-α2 neutralizing sera were found only in COVID-19 patients, with proportions increasing with disease severity and age. In the acute stage of COVID-19, all sera from patients with ELISA-detected IFN-α2 Abs (13/164, 7.9%) neutralized levels of IFN-α2 exceeding physiological concentrations found in human plasma and this was associated with delayed viral clearance. Convalescent plasma donors that were anti-IFN-α2 ELISA positive (3/118, 2.5%) did not neutralize the same levels of IFN-α2. Neutralizing serum IFN-α2 Abs were associated with delayed viral clearance from the respiratory tract., Conclusions: IFN-α2 Abs were detected by ELISA and neutralization assay in COVID-19 patients, but not in ICU patients with other respiratory illnesses. The presence of neutralizing IFN-α2 Abs in critically ill COVID-19 is associated with delayed viral clearance. IFN-α2 Abs in COVID-19 convalescent plasma donors were not neutralizing in the conditions tested., (© 2021. The Author(s).)

Importance: Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact., Objective: To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics., Design, Setting, and Participants: This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants)., Exposure: Receipt of CCP., Main Outcomes and Measures: World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI., Results: A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs., Conclusions and Relevance: The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

Importance: COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing., Objective: To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP., Data Sources: From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly., Study Selection: Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally., Data Extraction and Synthesis: A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board., Main Outcomes and Measures: Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization., Results: Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics., Conclusions and Relevance: This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.

Background: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at high risk of hepatitis C virus (HCV) reinfection following clearance of HCV, but risk factors specifically for reinfection have never been comprehensively assessed., Methods: Using data from a prospective observational cohort study among HIV-positive MSM with an acute HCV infection (MOSAIC), the incidence of HCV reinfection following spontaneous clearance or successful treatment was assessed. A univariable Bayesian exponential survival model was used to identify risk factors associated with HCV reinfection., Results: In total, 122 HIV-positive MSM who had a spontaneously cleared or successfully treated HCV infection between 2003 and 2017 were included. During a median follow-up of 1.4 years (interquartile range [IQR] 0.5-3.8), 34 HCV reinfections were observed in 28 patients. The incidence of HCV reinfection was 11.5/100 person-years and among those with reinfection, median time to reinfection was 1.3 years (IQR 0.6-2.7). HCV reinfection was associated with receptive condomless anal intercourse, sharing of sex toys, group sex, anal rinsing before sex, ≥10 casual sex partners in the last 6 months, nadir CD4 cell count <200 cells/mm3, and recent CD4 cell count <500 cells/mm3., Conclusions: Incidence of HCV reinfection was high and strongly associated with sexual risk behavior, highlighting the need for interventions to reduce risk behavior and prevent HCV reinfections among HIV-positive MSM., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)