RESUMEN
Background: Confirming the efficacy of dolutegravir/lamivudine in clinical practice solidifies recommendations on its use. Methods: Prospective cohort study (DUALING) in 24 human immunodeficiency virus (HIV) treatment centers in the Netherlands. HIV RNA-suppressed cases were on triple-drug antiretroviral regimens without prior virological failure or resistance and started dolutegravir/lamivudine. Cases were 1:2 matched to controls on triple-drug antiretroviral regimens by the use of dolutegravir-based regimens, age, sex, transmission route, CD4+ T-cell nadir, and HIV RNA zenith. The primary endpoint was the treatment failure rate in cases versus controls at 1 year by intention-to-treat and on-treatment analyses with 5% noninferiority margin. Results: The 2040 participants were 680 cases and 1380 controls. Treatment failure in the 390 dolutegravir-based cases versus controls occurred in 8.72% and 12.50% (difference: -3.78% [95% confidence interval {CI}, -7.49% to .08%]) by intention-to-treat and 1.39% and 0.80% (difference: 0.59% [95% CI, -.80% to 1.98%]) by on-treatment analyses. The treatment failure risk in 290 non-dolutegravir-based cases was also noninferior to controls. Antiretroviral regimen modifications unrelated to virological failure explained the higher treatment failure rate by intention-to-treat. A shorter time on triple-drug antiretroviral therapy and being of non-Western origin was associated with treatment failure. Treatment failure, defined as 2 consecutive HIV RNA >50 copies/mL, occurred in 4 cases and 5 controls but without genotypic resistance detected. Viral blips occured comparable in cases and controls but cases gained more weight, especially when tenofovir-based regimens were discontinued. Conclusions: In routine care, dolutegravir/lamivudine was noninferior to continuing triple-drug antiretroviral regimens after 1 year, supporting the use of dolutegravir/lamivudine in clinical practice. Clinical Trials Registration: NCT04707326.
RESUMEN
BACKGROUND: Access to HIV testing is crucial for detection, linkage to treatment, and prevention. In less urbanised areas, reliance on general practitioners (GPs) for HIV testing is probable, as sexual health centres (SHC) are mostly located within urbanised areas. Limited insight into individuals undergoing HIV testing stems from sparse standard registration of demographics at GPs. This cross-sectional study aims (1) to assess and compare HIV testing at the GP and SHC, and (2) to assess population- and provider-specific HIV incidence. METHODS: Individual HIV testing data of GPs and SHC were linked to population register data (aged ≥ 15 years, Rotterdam area, 2015-2019). We reported the proportion HIV tested, and compared GP and SHC testing rates with negative binomial generalised additive models. Data on new HIV diagnoses (2015-2019) from the Dutch HIV Monitoring Foundation relative to the population were used to assess HIV incidence. RESULTS: The overall proportion HIV tested was 1.14% for all residents, ranging from 0.41% for ≥ 40-year-olds to 4.70% for Antilleans. The GP testing rate was generally higher than the SHC testing rate with an overall rate ratio (RR) of 1.61 (95% CI: 1.56-1.65), but not for 15-24-year-olds (RR: 0.81, 95% CI: 0.74-0.88). Large differences in HIV testing rate (1.36 to 39.47 per 1,000 residents) and GP-SHC ratio (RR: 0.23 to 7.24) by geographical area were observed. The GPs' contribution in HIV testing was greater for GP in areas further away from the SHC. In general, population groups that are relatively often tested are also the groups with most diagnoses and highest incidence (e.g., men who have sex with men, non-western). The overall incidence was 10.55 per 100,000 residents, varying from 3.09 for heterosexual men/women to 24.04 for 25-29-year-olds. CONCLUSIONS: GPs have a pivotal role in HIV testing in less urbanised areas further away from the SHC, and among some population groups. A relatively high incidence often follows relatively high testing rates. Opportunities to improve HIV testing have been found for migrants, lower-educated individuals, in areas less urbanised areas and further away from GP/SHC. Strategies include additional targeted testing, via for example SHC branch locations and outreach activities.
Asunto(s)
Médicos Generales , Infecciones por VIH , Salud Sexual , Minorías Sexuales y de Género , Masculino , Humanos , Femenino , Países Bajos/epidemiología , Estudios Transversales , Incidencia , Homosexualidad Masculina , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & controlRESUMEN
BACKGROUND: The implications of bariatric surgery (BS) on virologic and metabolic outcomes in people with human immunodeficiency virus (HIV; PWH) on antiretroviral therapy (ART) are unknown. METHODS: Here, we report a retrospective analysis up to 18 months post-BS in PWH from the AIDS Therapy evaluation in The Netherlands (ATHENA) cohort with data from all dutch HIV treating Centers. Primary end points were a confirmed virologic failure (2 consecutive HIV-RNA measurements >200 copies/mL) and the percentage of patients who achieved >20% total body weight loss up to 18 months post-BS. Switches from baseline ART and trough plasma concentrations of antiretrovirals were also reported post-BS. Metabolic parameters and medication usage were compared pre- and post-BS. RESULTS: Fifty-one patients were included. One case of confirmed virologic failure and 3 cases with viral blips were detected in this cohort up to 18 months post-BS. Eighty-five percent of patients achieved >20% total body weight loss at 18 months post-BS, with a mean difference from baseline (95% confidence interval) of -33.5% (-37.7% to -29.3%). Trough plasma concentrations of measured antiretroviral agents were all above minimum effective concentrations, except for 1 sample of darunavir. Lipid profiles, but not serum creatinine and blood pressure, improved significantly (P < .01) post-BS. Total medications and obesity-related comedications declined from 203 to 103 and from 62 to 25, respectively, at 18 months post-BS. CONCLUSIONS: BS was an effective intervention for weight loss and lipid control in PWH using ART in this cohort with no clear link to poor virologic outcomes.
Asunto(s)
Cirugía Bariátrica , Infecciones por VIH , Humanos , VIH , Estudios Retrospectivos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Antirretrovirales/uso terapéutico , Pérdida de Peso , LípidosRESUMEN
[This corrects the article DOI: 10.1371/journal.pmed.1003979.].
RESUMEN
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.
Asunto(s)
COVID-19 , Infecciones por VIH , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vacuna nCoV-2019 mRNA-1273 , Ad26COVS1 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , ChAdOx1 nCoV-19 , Vacunas contra la COVID-19 , Estudios Prospectivos , SARS-CoV-2 , Vacunación , AncianoRESUMEN
BACKGROUND & AIMS: Patients with chronic or resolved hepatitis B are at risk of hepatitis B reactivation (HBVr) when treated with high-risk immunosuppressive therapy such as rituximab. Therefore, international guidelines recommend HBV screening prior to rituximab treatment and subsequent antiviral prophylaxis among patients with a (resolved) infection. In this study, we evaluated the adherence to those recommendations. METHODS: This is a retrospective multicentre study including patients treated with rituximab between 2000-2021. Performance of correct screening was assessed, defined as the measurement of hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc). Next, initiation of antiviral prophylaxis and HBVr rate among patients with a chronic or resolved HBV infection was studied. RESULTS: We enrolled 3,176 patients of whom 1,448 (46%) were screened correctly. Screening rates differed significantly between academic and non-academic hospitals; respectively 65% vs 32% (p<0.001). In addition, screening rates differed across specialties and improved throughout the years; from 32% before 2012 to 75% after 2020 among academic prescribers, versus 1% to 60% among non-academic prescribers (both p<0.001). Antiviral prophylaxis was initiated in 58% vs 36% of the patients with a chronic or resolved HBV infection. Seven patients experienced HBVr, including one fatal liver decompensation. CONCLUSIONS: Many patients treated with rituximab were not correctly screened for HBV infection and antiviral prophylaxis was often not initiated. Although screening rates improved over time, rates remain suboptimal. With the increasing number of indications for rituximab and other immunosuppressive agents these findings could raise awareness among all medical specialties prescribing these agents.
Asunto(s)
Virus de la Hepatitis B , Hepatitis B , Humanos , Rituximab/uso terapéutico , Rituximab/efectos adversos , Incidencia , Antivirales/farmacología , Hepatitis B/diagnóstico , Hepatitis B/tratamiento farmacológico , Hepatitis B/epidemiología , Antígenos de Superficie de la Hepatitis B/farmacología , Antígenos de Superficie de la Hepatitis B/uso terapéutico , Anticuerpos contra la Hepatitis B/farmacología , Anticuerpos contra la Hepatitis B/uso terapéutico , Activación ViralRESUMEN
OBJECTIVES: The potential benefit of convalescent plasma (CP) therapy for coronavirus disease 2019 (COVID-19) is highest when administered early after symptom onset. Our objective was to determine the effectiveness of CP therapy in improving the disease course of COVID-19 among high-risk outpatients. METHODS: A multicentre, double-blind randomized trial was conducted comparing 300 mL of CP with non-CP. Patients were ≥50 years, were symptomatic for <8 days, had confirmed RT-PCR or antigen test result for COVID-19 and had at least one risk factor for severe COVID-19. The primary endpoint was the highest score on a 5-point ordinal scale ranging from fully recovered (score = 1) or not (score = 2) on day 7, over hospital admission (score = 3), intensive care unit admission (score = 4) and death (score = 5) in the 28 days following randomization. Secondary endpoints were hospital admission, symptom duration and viral RNA excretion. RESULTS: After the enrolment of 421 patients and the transfusion in 416 patients, recruitment was discontinued when the countrywide vaccination uptake in those aged >50 years was 80%. Patients had a median age of 60 years, symptoms for 5 days, and 207 of 416 patients received CP therapy. During the 28 day follow-up, 28 patients were hospitalized and two died. The OR for an improved disease severity score with CP was 0.86 (95% credible interval, 0.59-1.22). The OR was 0.58 (95% CI, 0.33-1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95% CI, 0.28-1.34). No difference was found in viral RNA excretion or in the duration of symptoms. CONCLUSIONS: In patients with early COVID-19, CP therapy did not improve the 5-point disease severity score.
Asunto(s)
COVID-19 , Humanos , Persona de Mediana Edad , COVID-19/terapia , COVID-19/etiología , SARS-CoV-2 , Pacientes Ambulatorios , Sueroterapia para COVID-19 , Inmunización Pasiva , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Infecciones por VIH , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ad26COVS1 , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Infecciones por VIH/inmunología , Inmunogenicidad Vacunal , Inmunoglobulina G , Países Bajos/epidemiología , Estudios Prospectivos , ARN Mensajero , SARS-CoV-2 , Vacunas de ARNmRESUMEN
BACKGROUND: Timely identification of deteriorating COVID-19 patients is needed to guide changes in clinical management and admission to intensive care units (ICUs). There is significant concern that widely used Early warning scores (EWSs) underestimate illness severity in COVID-19 patients and therefore, we developed an early warning model specifically for COVID-19 patients. METHODS: We retrospectively collected electronic medical record data to extract predictors and used these to fit a random forest model. To simulate the situation in which the model would have been developed after the first and implemented during the second COVID-19 'wave' in the Netherlands, we performed a temporal validation by splitting all included patients into groups admitted before and after August 1, 2020. Furthermore, we propose a method for dynamic model updating to retain model performance over time. We evaluated model discrimination and calibration, performed a decision curve analysis, and quantified the importance of predictors using SHapley Additive exPlanations values. RESULTS: We included 3514 COVID-19 patient admissions from six Dutch hospitals between February 2020 and May 2021, and included a total of 18 predictors for model fitting. The model showed a higher discriminative performance in terms of partial area under the receiver operating characteristic curve (0.82 [0.80-0.84]) compared to the National early warning score (0.72 [0.69-0.74]) and the Modified early warning score (0.67 [0.65-0.69]), a greater net benefit over a range of clinically relevant model thresholds, and relatively good calibration (intercept = 0.03 [- 0.09 to 0.14], slope = 0.79 [0.73-0.86]). CONCLUSIONS: This study shows the potential benefit of moving from early warning models for the general inpatient population to models for specific patient groups. Further (independent) validation of the model is needed.
RESUMEN
BACKGROUND: Invasive mechanical ventilation is the treatment of choice in COVID-19 patients when hypoxemia persists, despite maximum conventional oxygen administration. Some frail patients with severe hypoxemic respiratory failure are deemed not eligible for invasive mechanical ventilation. OBJECTIVES: To investigate whether High-flow nasal cannula (HFNC) in the wards could serve as a rescue therapy in these frail patients. METHODS: This retrospective cohort study included frail COVID-19 patients admitted to the hospital between March 9th and May 1st 2020. HFNC therapy was started in the wards. The primary endpoint was the survival rate at hospital discharge. RESULTS: Thirty-two patients with a median age of 79.0 years (74.5-83.0) and a Clinical Frailty Score of 4 out of 9 (3-6) were included. Only 6% reported HFNC tolerability issues. The overall survival rate was 25% at hospital discharge. CONCLUSIONS: This study suggests that, when preferred, HFNC in the wards could be a potential rescue therapy for respiratory failure in vulnerable COVID-19 patients.
Asunto(s)
COVID-19 , Ventilación no Invasiva , Insuficiencia Respiratoria , Anciano , Cánula , Hospitales , Humanos , Terapia por Inhalación de Oxígeno , Insuficiencia Respiratoria/terapia , Estudios Retrospectivos , SARS-CoV-2RESUMEN
In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/terapia , Citocinas/sangre , SARS-CoV-2/inmunología , Anciano , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Donantes de Sangre , COVID-19/sangre , COVID-19/virología , Progresión de la Enfermedad , Femenino , Hospitalización , Humanos , Inmunización Pasiva , Inmunoglobulina G/sangre , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Glicoproteína de la Espiga del Coronavirus/inmunología , Resultado del Tratamiento , Sueroterapia para COVID-19RESUMEN
OBJECTIVE: To evaluate the implementation of home telemonitoring and oxygen therapy in COVID-19 patients. Primary outcomes were safety, patient satisfaction, reduction of hospital stay, and cost-effectiveness. DESIGN: Retrospective cohort study. METHOD: All COVID-19 patients who were discharged with home telemonitoring and oxygen therapy between June 1st and November 1st 2020 were included. Eligible patients had a maximum oxygen requirement of 2 liters per minute during the 24 hours prior to discharge with a minimal peripheral oxygen saturation of 94%. A mobile application for telemonitoring was used, which patients or relatives had to be able to use independently. Patient demographics, clinical parameters, data on telemonitoring and readmissions were extracted from the electronic patient records. A survey for patient satisfaction and a cost-effectiveness analysis were performed. RESULTS: Out of 619 admissions, 49 patients were discharged with home telemonitoring and oxygen therapy. Median duration of home oxygen therapy was 11 days with a potential reduction in hospitalization of 616 days. Six patients were readmitted and were significantly more febrile on discharge (67% versus 14%, p=0.01) and had lower oxygenation (95%, (IQR 93-96) versus 96%, (IQR 95-97), p=0.02) with similar levels of oxygen administration. Patient satisfaction was high with a mean score of 5 to 6 on a scale measuring satisfaction from 1 to 7. Estimated total cost reduction was 146.736. CONCLUSION: This study shows that home telemonitoring and oxygen administration can be safely applied in COVID-19 patients resulting in a high patient satisfaction and reduction in hospital stay and costs.
Asunto(s)
COVID-19 , Servicios de Atención a Domicilio Provisto por Hospital/organización & administración , Tiempo de Internación , Monitoreo Fisiológico/métodos , Terapia por Inhalación de Oxígeno/métodos , Telemedicina , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/rehabilitación , COVID-19/terapia , Análisis Costo-Beneficio , Determinación de la Elegibilidad , Femenino , Humanos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Alta del Paciente , Seguridad del Paciente , Satisfacción del Paciente , Estudios Retrospectivos , SARS-CoV-2/aislamiento & purificación , Telemedicina/economía , Telemedicina/métodosRESUMEN
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 23â590 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.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/epidemiología , Abuso de Sustancias por Vía Intravenosa/epidemiología , Adulto , Coinfección , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/prevención & control , Hepatitis C Crónica/virología , Homosexualidad Masculina , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Estudios Retrospectivos , Abuso de Sustancias por Vía Intravenosa/virologíaRESUMEN
Hypercoagulation is one of the most distinct prognostic factors of patients with COVID-19 and has been associated with arterial thrombosis and other venous thrombotic events (VTE). Bleeding complications are far less encountered. The International Society on Thrombosis and Haemostasis (ISTH) guidance advises giving prophylactic low-molecular-weight heparin (LMWH) to prevent these events, although there is evidence that the incidence remains high despite using prophylactic LMWH. We describe three cases of COVID-19 pneumonia that were admitted to our intensive care unit (ICU) and developed acute pulmonary embolisms (APE) despite high dosage prophylactic LMWH. These cases raise concerns about using prophylactic LMWH instead of therapeutic anticoagulation in severe and critically COVID-19 patients.
RESUMEN
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.
Asunto(s)
Antivirales/uso terapéutico , Benzofuranos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Imidazoles/uso terapéutico , Quinoxalinas/uso terapéutico , Enfermedad Aguda , Administración Oral , Adulto , Amidas , Antivirales/administración & dosificación , Antivirales/efectos adversos , Bélgica/epidemiología , Benzofuranos/administración & dosificación , Benzofuranos/efectos adversos , Carbamatos , Ciclopropanos , Quimioterapia Combinada/métodos , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/epidemiología , Hepatitis C/etnología , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , Enfermedades de Transmisión Sexual/epidemiología , Sulfonamidas , Respuesta Virológica Sostenida , Factores de Tiempo , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.
Asunto(s)
Anemia/tratamiento farmacológico , Antivirales/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Adulto , Anciano , Anemia/complicaciones , Anemia/virología , Antivirales/efectos adversos , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/virología , Determinación de la Elegibilidad/métodos , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/crecimiento & desarrollo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/virología , Países Bajos , Neutropenia/complicaciones , Neutropenia/virología , Selección de Paciente , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Análisis de Regresión , Estudios Retrospectivos , Ribavirina/administración & dosificación , Ribavirina/efectos adversos , Factores de RiesgoRESUMEN
During a large hospital outbreak of OXA-48 producing bacteria, most K. pneumoniaeOXA-48 isolates were phenotypically resistant to meropenem or imipenem, whereas most E. coliOXA-48 isolates were phenotypically susceptible to these antibiotics. In the absence of molecular gene-detection E. coliOXA-48 could remain undetected, facilitating cross-transmission and horizontal gene transfer of blaOXA-48. Based on 868 longitudinal molecular microbiological screening results from patients carrying K. pneumoniaeOXA-48 (n = 24), E. coliOXA-48 (n = 17), or both (n = 40) and mathematical modelling we determined mean durations of colonisation (278 and 225 days for K. pneumoniaeOXA-48 and E. coliOXA-48, respectively), and horizontal gene transfer rates (0.0091/day from K. pneumoniae to E. coli and 0.0015/day vice versa). Based on these findings the maximum effect of horizontal gene transfer of blaOXA-48 originating from E. coliOXA-48 on the basic reproduction number (R0) is 1.9%, and it is, therefore, unlikely that phenotypically susceptible E. coliOXA-48 will contribute significantly to the spread of blaOXA-48.
Asunto(s)
Farmacorresistencia Bacteriana/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Transferencia de Gen Horizontal , Klebsiella pneumoniae/genética , beta-Lactamasas/genética , Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/transmisión , Proteínas de Escherichia coli/metabolismo , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/transmisión , Klebsiella pneumoniae/metabolismo , beta-Lactamasas/metabolismoRESUMEN
OBJECTIVES: The incidence of anal cancer is increasing especially in HIV-positive men having sex with men. Screening for the cancer precursor, high-grade squamous intraepithelial lesions (HSIL), is challenging, as current treatment is suboptimal. The aim of this prospective study was to establish the efficacy of five consecutive days a week self-administered treatment with imiquimod 5% cream for both perianal and intra-anal HSIL and to assess the adverse effects and burden of this regimen. METHODS: 44 patients with histologically proved perianal or intra-anal HSIL were treated with a five consecutive days a week imiquimod 5% cream regimen. When no response could be confirmed after the first 16 weeks of therapy, patients were encouraged to continue the use of the cream for a further 16 weeks. Side effects were routinely assessed. RESULTS: Complete or partial response was observed in 20 (45%) of 44 patients with HSIL after 16 weeks of treatment; another nine patients showed complete or partial response after an additional 16 weeks of treatment, resulting in a response rate of 29 (66%) out of 44 patients. CONCLUSIONS: Topical imiquimod 5% cream is useful in HSIL. A five consecutive days treatment regimen with imiquimod 5% cream for HSIL does not seem to be more effective compared with the customary prescription for 3 days a week. A prolonged course of imiquimod 5% cream is warranted for intra-anal HSIL. Adverse effects are comparable between 3 and 5 days treatment regimen.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Aminoquinolinas/administración & dosificación , Canal Anal/efectos de los fármacos , Antineoplásicos/administración & dosificación , Neoplasias del Ano/prevención & control , Seropositividad para VIH/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Lesiones Intraepiteliales Escamosas de Cuello Uterino/tratamiento farmacológico , Administración Tópica , Canal Anal/patología , Canal Anal/virología , Neoplasias del Ano/patología , Neoplasias del Ano/virología , Progresión de la Enfermedad , Electrocoagulación , Femenino , Seropositividad para VIH/complicaciones , Humanos , Imiquimod , Masculino , Pomadas , Papillomaviridae/patogenicidad , Estudios Prospectivos , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/virologíaRESUMEN
The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic (k w) = 0.73 (95 % confidence interval (CI), 0.41-0.94)), with a higher agreement between the reference evaluation and the PFPE samples (k w = 0.86 (95 % CI, 0.67-1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory (k w = 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.