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Background: The prospective identification of patients at high risk for hospital-acquired/ventilator-associated bacterial pneumonia may improve clinical trial feasibility and foster antibacterial development. In a prior study conducted in the United States, clinical criteria were used to prospectively identify these patients; however, these criteria have not been applied in a European population., Methods: Adults considered high risk for pneumonia (treatment with ventilation or high levels of supplemental oxygen) in the intensive care units of 7 European hospitals were prospectively enrolled from June 12 to December 27, 2017. We estimated the proportion of high-risk patients developing pneumonia according to US Food and Drug Administration guidance and a subset potentially eligible for antibacterial trial enrollment. We compared patient characteristics, treatment exposures, and pneumonia incidence in a European cohort and a previously described US cohort., Results: Of 888 high-risk patients, 211/888 (24%) were treated for possible pneumonia, and 150/888 (17%) met the Food and Drug Administration definition for hospital-acquired/ventilator-associated bacterial pneumonia. A higher proportion of European patients treated for possible pneumonia met the pneumonia definition (150/211 [71%] vs 537/1464 [37%]; P  < .001). Among patients developing pneumonia, a higher proportion of European patients met antibacterial trial eligibility criteria (124/150 [83%] vs 371/537 [69%]; P  < .001)., Conclusions: Clinical criteria prospectively identified high-risk patients with high rates of pneumonia in the European cohort. Despite higher rates of established risk factors and incident pneumonia, European patients were significantly less likely to receive antibiotics for possible pneumonia than US patients. Different treatment practices may contribute to lower rates of antibacterial trial enrollment in the United States., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited., Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19., Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020., Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108)., Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%)., Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively., Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1 ) randomization, allowing robust causal inference; 2 ) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3 ) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4 ) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5 ) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Background: Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection., Methods: The Dutch Acute HCV in HIV study number 2 (DAHHS2) study was a single-arm, open-label, multicentre, phase 3b trial. Adult patients (≥18 years) with acute HCV genotype 1 or 4 infection (duration of infection 26 weeks or less, according to presumed day of infection) were recruited at 15 HIV outpatient clinics in the Netherlands and Belgium. All patients were treated with 8 weeks of grazoprevir 100 mg plus elbasvir 50 mg administered as one oral fixed drug combination tablet once daily. The primary efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12; HCV RNA <15 IU/mL) in all patients who started treatment. Reinfection with a different HCV virus was not considered treatment failure in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02600325., Findings: Between Feb 15, 2016, and March 2, 2018, we assessed 146 patients with a recently acquired HCV infection for eligibility, of whom 86 were enrolled and 80 initiated therapy, all within 6 months after infection. All patients who initiated treatment completed treatment and no patients were lost to follow-up. 79 (99%, 95% CI 93-100) of 80 patients achieved SVR12. All 14 patients who were infected with a virus carrying a clinically significant polymorphism in NS5A were cured. If reinfections were considered treatment failures, 75 (94%, 86-98) of 80 patients achieved SVR12. Two serious adverse events not considered related to the treatment were reported (traumatic rectal bleeding and low back surgery). The most common adverse event was a new sexually transmitted infection (19 [24%] of 80 patients). The most common reported possibly drug-related adverse events were fatigue (11 [14%] patients), headache (seven [9%] patients), insomnia (seven [9%] patients), mood changes (five [6%] patients), dyspepsia (five [6%] patients), concentration impairment (four [5%] patients), and dizziness (4 [5%] patients), all of which were regarded as mild by the treating physician. No adverse events led to study drug discontinuation., Interpretation: 8 weeks of grazoprevir plus elbasvir was highly effective for the treatment of acute HCV genotype 1 or 4 infection. The ability to treat acute HCV immediately after diagnosis might help physicians to reach the WHO goal of HCV elimination by 2030., Funding: Merck Sharp and Dohme and Health-Holland., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Treatment of hepatitis C virus infections (HCV) with direct acting antivirals (DAA) can prevent new infections since cured individuals cannot transmit HCV. However, as DAAs are expensive, many countries defer treatment to advances stages of fibrosis, which results in ongoing transmission. We assessed the epidemiological impact and cost-effectiveness of treatment initiation in different stages of infection in the Netherlands where the epidemic is mainly concentrated among HIV-infected MSMs., Methods: We calibrated a deterministic mathematical model to the Dutch HCV epidemic among HIV-infected MSM to compare three different DAA treatment scenarios: 1) immediate treatment, 2) treatment delayed to chronic infection allowing spontaneous clearance to occur, 3) treatment delayed until F2 fibrosis stage. All scenarios are simulated from 2015 onwards. Total costs, quality adjusted life years (QALY), incremental cost-effectiveness ratios (ICERs), and epidemiological impact were calculated from a providers perspective over a lifetime horizon. We used a DAA price of €35,000 and 3% discounting rates for cost and QALYs., Results: Immediate DAA treatment lowers the incidence from 1.2/100 person-years to 0.2/100 person-years (interquartile range 0.1-0.2) and the prevalence from 5.0/100 person-years to 0.5/100 person-years (0.4-0.6) after 20 years. Delayed treatment awaiting spontaneous clearance will result in a similar reduction. However, further delayed treatment to F2 will increases the incidence and prevalence. Earlier treatment will cost society €68.3 and €75.1 million over a lifetime for immediate and awaiting until the chronic stage, respectively. The cost will increase if treatment is further delayed until F2 to €98.4 million. Immediate treatment will prevent 7070 new infections and gains 3419 (3019-3854) QALYs compared to F2 treatment resulting in a cost saving ICER. Treatment in the chronic stage is however dominated., Conclusions: Early DAA treatment for HIV-infected MSM is an excellent and sustainable tool to meet the WHO goal of eliminating HCV in 2030., Competing Interests: Stephanie Popping: reports funding in the form of a unrestricted educational grant by Gilead Sciences [NL-2018-000171] and grants from Gilead [215001269], MSD [SDD 343462], ViiV Healthcare [14-0614-ViiV], and Janssen [771290]. Sebastiaan J. Hullegie: reports grants from Merck [MSD IISA 11/jul/2015], during the conduct of the study; non-financial support from Gilead, non-financial support from MSD, outside the submitted work Anne Boerekamps: reports no conflict of interest Bart J.A. Rijnders: reports grants from MSD [MSD IISA 11/jul/2015], Gilead [IN-NL-987- 4558/4652/4653] and honoraria from Jansen-Cilag, BMS, Pfizer and Viiv Robert J. de Knegt: Reports honoraria for consulting or speaking (last 5 years): AbbVie, BMS, Gilead, Janssen-Cilag, Merck/MSD, Roche. Jürgen K. Rockstroh: reports honaria for lectures and/or consultancies from Abbott, AbbVie, Bionor, BMS, Cipla, Gilead, Janssen, Merck, Roche, Viiv A.Verbon: reports no conflict of interest, Charles A.B. Boucher: reports grants from Gilead sciences [NL-2018-000171] and [215001269], MSD [SDD 343462], ViiV Healthcare [14-0614-ViiV], Janssen [771290], and Boehringer [S14064/32844]]. Brooke E. Nichols: no conflict of interest, David A.M.C. van de Vijver: reports grants from Gilead sciences [NL-2018-000171] and [215001269], MSD [SDD 343462], ViiV Healthcare [14-0614-ViiV], and Janssen [771290]. None of these competing interests alter our adherence to PLOS ONE policies on sharing data and materials. We confirm that none of the funders had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: Direct-acting antivirals (DAAa) cure hepatitis C virus (HCV) infections in 95% of infected patients. Modeling studies predict that universal HCV treatment will lead to a decrease in the incidence of new infections but real-life data are lacking. The incidence of HCV among Dutch human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) has been high for >10 years. In 2015 DAAs became available to all Dutch HCV patients and resulted in a rapid treatment uptake in HIV-positive MSM. We assessed whether this uptake was followed by a decrease in the incidence of HCV infections., Methods: Two prospective studies of treatment for acute HCV infection enrolled patients in 17 Dutch HIV centers, having 76% of the total HIV-positive MSM population in care in the Netherlands. Patients were recruited in 2014 and 2016, the years before and after unrestricted DAA availability. We compared the HCV incidence in both years., Results: The incidence of acute HCV infection decreased from 93 infections during 8290 person-years of follow-up (PYFU) in 2014 (11.2/1000 PYFU; 95% confidence interval [CI], 9.1-13.7) to 49 during 8961 PYFU in 2016 (5.5/1000 PYFU; 4.1-7.2). The incidence rate ratio of 2016 compared with 2014 was 0.49 (95% CI, .35-.69). Simultaneously, a significant increase in the percentage positive syphilis (+2.2%) and gonorrhea (+2.8%) tests in HIV-positive MSM was observed at sexual health clinics across the Netherlands and contradicts a decrease in risk behavior as an alternative explanation., Conclusions: Unrestricted DAA availability in the Netherlands was followed by a 51% decrease in acute HCV infections among HIV-positive MSM.

Introduction: Affordable and sensitive screening methods for acute hepatitis C (HCV) are necessary to successfully intervene in the current HCV epidemic among HIV-positive men having sex with men. HCV core antigen (Ag) testing has been proven effective in diagnosing chronic HCV-infected patients at low costs. We studied the characteristics of HCV Ag testing in acute HCV-infected HIV-positive patients. Methods Plasma samples were selected from acutely HCV genotype 1-infected patients treated with peginterferon, ribavirin and boceprevir in the Dutch Acute HCV in HIV Study. The control group consisted of HIV-positive patients with a newly raised alanine aminotransferase (ALT) (>41 U/L) in whom HCV RNA was undetectable and who were tested for HCV Ag. Spearman correlation coefficient between HCV RNA and HCV Ag was calculated together with the sensitivity and specificity of HCV Ag testing at acute HCV diagnosis., Results and Discussion: Upon acute HCV diagnosis, HCV Ag was identified in 39 out of 44 patients with detectable HCV RNA levels. In all 23 control patients without detectable HCV RNA in plasma, HCV Ag was undetectable as well. This resulted in a sensitivity and specificity of HCV Ag of respectively 89% (95% CI 75-96) and 100% (95% CI 82-100). The correlation between HCV Ag and HCV RNA was 0.97 ( p  < 0.001) upon diagnosis., Conclusion: The data presented in this study suggest that HCV Ag testing is a sensitive and specific method that can be used in diagnosing AHCV in HIV-infected patients., Competing Interests: SH: travel grants from Gilead and MSD, CG: none, CR: personal fees from Roche Diagnostics, outside the submitted work, AE: TKI LSH aka Match, Health Holland, BR: grants from MSD, during the conduct of the study; grants from Gilead, other from MSD, Jansen-Cilag, BMS, Gilead, Pfizer, ViiV, outside the submitted work.

Patients in high-risk groups continue to transmit the hepatitis C virus (HCV) and frequently experience reinfections. Since little is known regarding the immune response to HCV during reinfection, we compared primary and consecutive acute HCV infections in patients with an HIV infection, and focused on the cytokine bridging innate to adaptive immunity. We observed that the serum levels of IL-12p40, MIP-1β, MIG and IP-10 increased during primary acute HCV infection, but not during subsequent secondary acute reinfections. The weaker pro-inflammatory cytokine responses observed during HCV reinfections suggest more limited secondary acute immune responses, which may prevent damage to the infected liver.

Objective: Within HIV-positive men having sex with men, the epidemic of hepatitis C virus (HCV) is ongoing. Transmission of resistant variants of HCV after failure of treatment with directly acting antivirals (DAA) could be a major threat to the effectivity of therapy. We determined whether HCV-resistant variants to DAAs were prevalent amongst patients with an acute HCV infection diagnosed in 2013 and 2014 in the Netherlands., Methods: Target enrichment for viral nucleic acid separation and deep sequencing were used to recover whole HCV genomes of 50 patients with an acute HCV infection. The genomes were assembled by de novo assembly and analysed for known DAA resistance mutations., Results: In acute HCV infected treatment-naive patients, the relevant resistance-associated substitutions were Q80K (40%) in NS3/4a, M28V (24%) and Q30H combined with Y93H (2%) in NS5A and M414T (2%) or S556G (2%) in NS5b. Patients whose HCV infection failed to respond to boceprevir, peginterferon and ribavirin therapy developed mutations in NS3 at position T54A and R155K., Conclusions: Target enrichment and whole genome sequencing were successfully applied directly on clinical samples from patients with an acute HCV infection., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Objective: Mucosal-associated invariant T (MAIT) cells comprise a subpopulation of T cells that can be activated by bacterial products and cytokines to produce IFN-γ. Since little is known on MAIT cells during HCV infection, we compared their phenotype and function in comparison to HIV and HCV/HIV co-infected patients, and determined the effect of IFN-α-based and direct-acting antiviral therapy on MAIT cells of HCV patients., Methods: Blood samples from patients with chronic HCV (CHCV), virologically suppressed HIV, acute HCV/HIV co-infection (AHCV/HIV) and healthy individuals were examined by flowcytometry for phenotype and function of MAIT and NK cells., Results and Conclusions: Compared to healthy individuals, the frequency of CD161+Vα7.2+ MAIT cells was significantly decreased in patients with CHCV, HIV and AHCV/HIV co-infection. CD38 expression on MAIT cells was increased in AHCV/HIV patients. MAIT cells were responsive to IFN-α in vitro as evidenced by enhanced frequencies of IFN-γ producing cells. IFN-α-based therapy for CHCV decreased the frequency of IFN-γ+ MAIT cells, which was still observed 24 weeks after successful therapy. Importantly, even after successful IFN-α-based as well as IFN-α-free therapy for CHCV, decreased frequencies of MAIT cells persisted. We show that the frequencies of MAIT cells are reduced in blood of patients with CHCV, HIV and in AHCV/HIV co-infection compared to healthy individuals. Successful therapy for CHCV did not normalize MAIT cell frequencies at 24 weeks follow up. The impact of HIV and HCV infection on the numbers and function of MAIT cells warrant further studies on the impact of viral infections and the antimicrobial function of MAIT cells.

Background & Aims: Acute hepatitis C virus infections (AHCV) are prevalent among HIV positive men having sex with men and generally treated with pegylated interferon-alpha (PegIFN) and ribavirin (RBV) during 24weeks. The addition of a protease inhibitor could shorten therapy without loss of efficacy., Methods: We performed an open-label, single arm study to investigate the efficacy and safety of a 12-week course of boceprevir, PegIFN and RBV for AHCV genotype 1 infections in 10 Dutch HIV treatment centers. The primary endpoint of the study was achievement of sustained virological response rate at week 12 (SVR12) in patients reaching a rapid viral response at week 4 (RVR4) and SVR12 in the intent to treat (ITT) entire study population was the most relevant secondary endpoint., Results: One hundred twenty-seven AHCV patients were screened in 16 months, of which 65 AHCV genotype 1 patients were included. After spontaneous clearance in six patients and withdrawal before treatment initiation in two, 57 started therapy within 26 weeks after infection. RVR4 rate was 72%. SVR12 rate was 100% in the RVR4 group. SVR12 rate in the ITT group was 86% and comparable to the SVR12 rate of 84% in 73 historical controls treated for 24 weeks with PegIFN and RBV in the same study centers., Conclusion: With the addition of boceprevir to PegIFN and RBV, treatment duration of AHCV genotype 1 can be reduced to 12 weeks without loss of efficacy. Given the high drug costs and limited availability of interferon-free regimens, boceprevir PegIFN and RBV can be a considered a valid treatment option for AHCV. ClinicalTrials.gov, number NCT01912495., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Within the Dutch Acute HCV in HIV Study, a surveillance system was initiated to estimate the incidence of hepatitis C virus (HCV) infections in 2014. Following the Dutch HIV treatment guidelines, HIV-positive men having sex with men (MSM) in 19 participating centers were screened. Ninety-nine acute HCV infections were reported, which resulted in a mean incidence of 11 per 1000 patient-years of follow-up. Unfortunately, the HCV epidemic among Dutch HIV-positive MSM is not coming to a halt., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Acute hepatitis C virus (HCV) infections are frequently seen worldwide in certain risk groups, with an annual incidence rate varying between 0.08% and 66%. Although this incidence is substantial, a delayed diagnosis during chronic infection is most often made in the absence of clinical symptoms in the acute phase of the infection. Currently used methods to diagnose acute HCV infection are IgG antibody seroconversion and repeated HCV RNA measurements, although no definitive diagnostic test is currently available. Progress in the field of adaptive and innate immune responses has aided both advances in the field of HCV vaccine development and a more basic understanding of viral persistence. The rapid changes in the treatment of chronic HCV infection will affect therapeutic regimens for acute HCV infection in the coming years, leading to shorter treatment courses and pegylated interferon-free modalities. This review gives an overview of the current knowledge and uncertainties, together with some future perspectives on acute hepatitis C epidemiology, virology, immunology, and treatment., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)