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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. [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) prevalence is high among men who have sex with men (MSM) with HIV in the Netherlands. Large reductions in HCV incidence among MSM with HIV, however, have occurred since treatment with direct-acting antivirals. Over the years, a broader understanding of the HCV epidemic has shown that HCV infections are not solely restricted to MSM with HIV, but they also occur among HIV-negative MSM. Currently, HCV testing among HIV-negative MSM is only provided for PrEP users and is not part of routine sexually transmitted infection (STI) screening among HIV-negative MSM who are not using PrEP. In this study, we screened 1885 HIV-negative MSM who did not participate in a PrEP program, with over 1966 STI screening visits at four different public health clinic sites. Among the 1885 MSM, only one person had a new HCV infection, resulting in a 0.05% (95% confidence interval 0.0–0.3) incidence. Based on our findings, we can conclude that systematic HCV testing at STI clinics may not yield significant benefits for this particular population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34/L98H isolates, which hampers the use of current PCR-based resistance tests. [ABSTRACT FROM AUTHOR]

Background: Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. Methods and findings: PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003–2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999–2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23–2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04–2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67–0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period. Conclusions: Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE. Casper Rokx and colleagues study the risk of recurrent venous thromboembolism in people with HIV infection. Author summary: Why was this study done?: The HIV pandemic affects approximately 40 million people and causes significant morbidity, including a markedly increased risk of a venous thromboembolism (VTE). The recurrence risk of VTE in people living with HIV (PWH) is unknown, although this risk drives the anticoagulant therapy duration after a first VTE. Our study determined the recurrent VTE risk in PWH compared to uninfected controls. What did the researchers do and find?: We performed an observational cohort study using data from the national ATHENA PWH cohort (2003–2015) in the Netherlands and the Dutch Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) cohort (1999–2009) of HIV-uninfected controls with a first VTE. The recurrent VTE incidence rate per 100 person-years of follow-up (PYFU) was higher in PWH (5.2) compared to controls (3.1) yielding a 1.70 hazard ratio (HR; 95% CI 1.23–2.36). Incidence rates were consistently higher for PWH in subgroups stratified by sex or the cause of the first VTE. PWH with lower cluster of differentiation 4 (CD4)+ T-cell counts at their first VTE had fewer recurrent events, which was driven by PWH experiencing a better CD4+ T-cell recovery on HIV treatment prior to anticoagulant discontinuation. What do these findings mean?: The risk of recurrent VTE is apparently increased in PWH but is ameliorated with better immune reconstitution. HIV-associated immunodeficiency reflects a reversible risk factor for VTE specific to PWH and is of relevance for decisions on anticoagulant therapy duration. [ABSTRACT FROM AUTHOR]

Background Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%–100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking. Methods A 5-year retrospective cohort study (2011–2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated. Results Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P =.017) and 25% on day 90 (62% vs 37%; P =.0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P =.045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P =.016), despite switching to appropriate antifungal therapy after a median of 10 days. Conclusions Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality. [ABSTRACT FROM AUTHOR]

Background. The Netherlands has provided unrestricted access to direct-acting antivirals (DAAs) since November 2015. We analyzed the nationwide hepatitis C virus (HCV) treatment uptake among patients coinfected with human immunodeficiency virus (HIV) and HCV. Methods. Data were obtained from the ATHENA HIV observational cohort in which >98% of HIV-infected patients ever registered since 1998 are included. Patients were included if they ever had 1 positive HCV RNA result, did not have spontaneous clearance, and were known to still be in care. Treatment uptake and outcome were assessed. When patients were treated more than once, data were included from only the most recent treatment episode. Data were updated until February 2017. In addition, each treatment center was queried in April 2017 for a data update on DAA treatment and achieved sustained virological response. Results. Of 23 574 HIV-infected patients ever linked to care, 1471 HCV-coinfected patients (69% men who have sex with men, 15% persons who [formerly] injected drugs, and 15% with another HIV transmission route) fulfilled the inclusion criteria. Of these, 87% (1284 of 1471) had ever initiated HCV treatment between 2000 and 2017, 76% (1124 of 1471) had their HCV infection cured; DAA treatment results were pending in 6% (92 of 1471). Among men who have sex with men, 83% (844 of 1022) had their HCV infection cured, and DAA treatment results were pending in 6% (66 of 1022). Overall, 187 patients had never initiated treatment, DAAs had failed in 14 and a pegylated interferon-alfa-based regimen had failed in 54. Conclusions. Fifteen months after unrestricted DAA availability the majority of HIV/HCV-coinfected patients in the Netherlands have their HCV infection cured (76%) or are awaiting DAA treatment results (6%). This rapid treatment scale-up may contribute to future HCV elimination among these patients. [ABSTRACT FROM AUTHOR]

The emergence of voriconazole highly resistant Aspergillus fumigatus is reported in Dutch university hospitals. Patients with azole-resistant invasive aspergillosis failed voriconazole therapy. Resistant isolates with identical resistance mechanisms were recovered from domiciles, indicating an environmental route of resistance selection.Background. Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus.Methods. Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles.Results. Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration ≥16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites.Conclusions. We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases. [ABSTRACT FROM PUBLISHER]

Background: Pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine prevents HIV infections among men who have sex with men (MSM). PrEP can be given on a daily or intermittent basis. Unfortunately, PrEP is not reimbursed in most European countries. Cost-effectiveness analyses of PrEP among MSM in Europe are absent but are key for decision makers to decide upon PrEP implementation.Methods: We developed a deterministic mathematical model, calibrated to the well defined Dutch HIV epidemic among MSM, to predict the effect and cost-effectiveness of PrEP. PrEP was targeted to 10% of highly sexually active Dutch MSM over the coming 40 years. Cost-effectiveness ratios were calculated to predict the cost-effectiveness of daily and on-demand PrEP. Cost-effectiveness ratios below €20 000 were considered to be cost-effective in this analysis.Findings: Within the context of a stable HIV epidemic, at 80% effectiveness and current PrEP pricing, PrEP can cost as much as €11 000 (IQR 9400-14 100) per quality-adjusted life-year (QALY) gained when used daily, or as little as €2000 (IQR 1300-3000) per QALY gained when used on demand. At 80% effectiveness, daily PrEP can be considered cost-saving if the price of PrEP is reduced by 70%, and on-demand PrEP can be considered cost-saving if the price is reduced by 30-40%.Interpretation: PrEP for HIV prevention among MSM in the Netherlands is cost-effective. The use of PrEP is most cost-effective when the price of PrEP is reduced through on-demand use or through availability of generic PrEP, and can quickly be considered cost-saving.Funding: None. [ABSTRACT FROM AUTHOR]

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.)

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: 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.

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.)

Background: In the Netherlands, access to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has been unrestricted for chronic infection since 2015. We evaluated whether the nationwide incidence of HCV infections in individuals with HIV has changed since 2015., Methods: In this retrospective cohort study, data from the ATHENA cohort of people with HIV aged 18 years or older attending any of the 24 HIV treatment centres in the Netherlands between 2000 and 2019 were assessed. We used parametric proportional hazards models with a piecewise exponential survival function to model HCV primary infection and reinfection incidence per 1000 person-years., Findings: Of the 23 590 individuals without previous HCV infection, 1269 cases of HCV primary infection were documented (incidence 5·2 per 1000 person-years [95% CI 5·0-5·5]). The highest incidence was observed in men who have sex with men (MSM; 7·7 per 1000 person-years [7·3-8·2]) and was lower in people who inject drugs (PWID; 1·7 per 1000 person-years [0·7-4·1]) and other key populations (1·0 per 1000 person-years [0·8-1·2]). In MSM, incidence increased in 2007 to 14·3 per 1000 person-years and fluctuated between 8·7 and 13·0 per 1000 person-years from 2008 to 2015. In 2016, incidence declined to 6·1 cases per 1000 person-years and remained steady between 4·1 and 4·9 per 1000 person-years from 2017 to 2019. Of the 1866 individuals with a previous HCV infection, 274 reinfections were documented (incidence 26·9 per 1000 person-years [95% CI 23·9-30·3]). The highest incidence rate was observed in MSM (38·5 per 1000 person-years [33·9-43·7]) and was lower in PWID (10·9 per 1000 person-years [3·5-33·8]) and other key populations (8·9 per 1000 person-years [6·3-12·5]). In MSM, reinfection incidence fluctuated between 38·0 and 88·9 per 1000 person-years from 2006 to 2015, reaching 55·6 per 1000 person-years in 2015. In 2016, reinfection incidence declined to 41·4 per 1000 person-years, followed by further decreases to 24·4 per 1000 person-years in 2017 and 11·4 per 1000 person-years in 2019., Interpretation: The sharp decline in HCV incidence in MSM with HIV shortly after restrictions on DAAs were lifted suggests a treatment-as-prevention effect. HCV incidence was already low in PWID and other groups before unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but high rate of reinfection, stressing the need for additional preventive measures., Funding: Dutch Ministry of Health, Welfare, and Sport., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

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: Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis., Methods: We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with non-immunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group)., Findings: Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI 2·63-10·26; p<0·0001), along with a higher APACHE II score, male sex, and use of corticosteroids., Interpretation: Influenza was identified as an independent risk factor for invasive pulmonary aspergillosis and is associated with high mortality. Future studies should assess whether a faster diagnosis or antifungal prophylaxis could improve the outcome of influenza-associated aspergillosis., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Patients with haematological malignancies are at risk for invasive fungal diseases (IFD). A survey was conducted in all Dutch academic haematology centres on their current diagnostic, prophylactic and therapeutic approach towards IFD in the context of azole-resistance. In all 8 centres, a haematologist and microbiologist filled in the questionnaire that focused on different subgroups of haematology patients. Fungal prophylaxis during neutropaenia was directed against Candida and consisted of fluconazole and/or amphotericin B suspension. Mould-active prophylaxis was given to acute myeloid leukaemia patients during chemotherapy in 2 of 8 centres. All centres used azole prophylaxis in a subset of patients with graft-versus-host disease. A uniform approach towards the diagnosis and treatment of IFD and in particular azole-resistant Aspergillus fumigatus was lacking. In 2017, all centres agreed to implement a uniform diagnostic and treatment algorithm regarding invasive aspergillosis with a central role for comprehensive diagnostics and PCR-based detection of azole-resistance. This study (DB-MSG 002) will re-evaluate this algorithm when 280 patients have been treated. A heterogeneous approach towards antifungal prophylaxis, diagnosis and treatment was apparent in the Netherlands. Facing triazole-resistance, consensus was reached on the implementation of a uniform diagnostic approach in all 8 centres., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

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.

A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B., (© 2015 Blackwell Verlag GmbH.)

Chemotherapy-induced neutropenia can be complicated by invasive pulmonary aspergillosis (IPA). In 2008, liposomal amphotericin B (L-AmB) inhalation was shown to prevent IPA in a placebo-controlled trial. Patients with acute myeloid leukaemia (AML) are the subset of haematology patients at high risk for IPA. In 2008, L-AmB inhalation prophylaxis became the standard of care for all AML patients in Erasmus MC. In this study, the efficacy and cost effectiveness of L-AmB inhalation were evaluated in a prospective cohort of AML patients. In total, 127 consecutive AML patients received chemotherapy and prophylactically inhaled L-AmB during their first and second chemotherapy cycles; 108 patients treated for AML at the same sites from 2005-2008 served as controls. A standardised diagnostic protocol was used and probable/proven IPA served as the primary endpoint. Diagnostic and therapeutic costs were also comprehensively analysed and compared. A significant decrease in probable/proven IPA in the L-AmB inhalation group was observed (L-AmB 9.5% vs. controls 23.4%; P=0.0064). Systemic antifungal therapy given at any time during the entire AML therapy decreased from 52.8% to 29.9%. Per-patient equipment and drug costs for L-AmB inhalation (1292 €/patient) were more than compensated for by a decrease in costs for diagnostics and therapeutic voriconazole use (-1816 €/patient). No serious adverse events related to L-AmB inhalation were observed. In an unselected AML patient group, L-AmB inhalation resulted in a significant and substantial decrease in IPA and was cost saving. Now that azole resistance is more frequent, non-azole-based prophylaxis may become an attractive strategy., (Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Background: Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART., Methods: This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models., Results: Therapy-naive HIV-1-infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11-2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25-3.52) in on-treatment analysis. Propensity score-adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61-3.42) with efavirenz and 2.01 (95% CI, 1.36-2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression., Conclusions: The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the percentage of patients in whom the diagnosis 'HIV infection' was made late, which factors are associated with an increased risk of a late HIV diagnosis, and if there are opportunities for an earlier diagnosis., Design: Retrospective analysis., Method: We included all HIV positive patients who were treated at the Erasmus Medical Center Rotterdam in the period January 1996-March 2012. We divided these patients into two groups: patients with a timely diagnosis and patients with a late diagnosis (CD4+ T cell count < 350/mm3). We performed a structured interview in patients who were diagnosed in the period January 2009-March 2012. To determine possible risk factors for a late diagnosis we used univariate and multivariate analyses., Results: A late diagnosis 'HIV infection' was made in 59% of the 2256 patients. Independent patient characteristics associated with a late diagnosis were heterosexual transmission (odds ratio (OR): 1.87; 95% CI: 1.44-2.43; p < 0.001), age > 50 years (OR: 1.73; 95% CI: 1.28-2.34; p < 0.001), and a Sub-Saharan African (OR: 1.66; 95% CI: 1.02-2.71; p = 0.043) or Asian origin (OR: 2.31; 95% CI: 1.20-4.43; p = 0.012). The interviews showed that more than 75% of patients with a late HIV diagnosis were already known with a risk factor for HIV, according to the STD practice guideline from the Dutch College of General Practitioners., Conclusion: In the past 15 years, 59% of HIV positive patients in Rotterdam presented late. This mainly concerned patients older than 50 years and immigrants originating from HIV endemic areas. It is important to prevent a late diagnosis, as this can lead to poorer response to combination antiretroviral therapy and higher mortality.

The prevalence and spread of azole resistance in clinical Aspergillus fumigatus isolates in the Netherlands are currently unknown. Therefore, we performed a prospective nationwide multicenter surveillance study to determine the effects of resistance on patient management strategies and public health. From June 2007 through January 2009, all clinical Aspergillus spp. isolates were screened for itraconazole resistance. In total, 2,062 isolates from 1,385 patients were screened; the prevalence of itraconazole resistance in A. fumigatus in our patient cohort was 5.3% (range 0.8%-9.5%). Patients with a hematologic or oncologic disease were more likely to harbor an azole-resistant isolate than were other patient groups (p<0.05). Most patients (64.0%) from whom a resistant isolate was identified were azole naive, and the case-fatality rate of patients with azole-resistant invasive aspergillosis was 88.0%. Our study found that multiazole resistance in A. fumigatus is widespread in the Netherlands and is associated with a high death rate for patients with invasive aspergillosis.