Coinfections and antimicrobial treatment in a cohort of falciparum malaria in a non-endemic country: a 10-year experience.

INTRODUCTION: Falciparum malaria remains one of the deadliest infectious diseases worldwide. In Germany, it is mainly an imported infection among travellers. Rates of coinfection are often unknown, and a clinical rationale for the beneficial use of calculated antibiotic therapy in patients with malaria and suspected coinfection is lacking. METHODS: We conducted an analysis of all in-patients treated with falciparum malaria at a German infectious diseases centre in vicinity to one of Europe's major airports for 2010-2019. Logistic regression and time-to-event analysis were used to evaluate predictors for bacterial coinfection, the use of antibacterial substances, as well as their influence on clinical course. RESULTS: In total, 264 patients were included. Of those, 64% received an additional antibacterial therapy (n = 169). Twenty-nine patients (11.0%) were found to have suffered from a relevant bacterial coinfection, while only a small fraction had relevant bacteremia (n = 3, 1.4%). However, patients with severe malaria did not suffer from coinfections more frequently (p = 0.283). CRP levels were not a reliable predictor for a bacterial coinfection (OR 0.99, 95% CI 0.94-1.06, p = 0.850), while another clinical focus of infection was positively associated (OR 3.86, 95% CI 1.45-11.55, p = 0.010). CONCLUSION: Although bacterial coinfections were rare in patients with malaria at our centre, the risk does not seem negligible. These data point rather towards individual risk assessment in respective patients than to general empiric antibiotic use.

A novel ultrasound-based algorithm for the detection of pancreatic stents placed for prophylaxis of post-ERCP pancreatitis: a prospective trial.

Before removal of retained pancreatic stents placed during endoscopic retrograde cholangiopancreatography to avoid post-ERCP pancreatitis, imaging is recommended. The aim of the present study was to evaluate a new ultrasound-based algorithm.Patients who received a pancreatic stent for PEP prophylaxis were included. Straight 5Fr (0.035inch) 6cm stents with an external flap that were visualized by ultrasound were removed endoscopically with no further imaging. If the ultrasound result reported the stent to be dislodged or was inconclusive, X-ray imaging was performed. The endpoints were positive and negative predictive value, specificity, sensitivity, and contingency coefficient between ultrasound and X-ray and/or endoscopy.88 patients were enrolled in the present study. X-ray was performed in 23 (26%) patients. Accordingly, the ultrasound algorithm saved an X-ray examination in 65 cases, leading to a reduction of 74%. Stents were retained in 67 patients (76%) and visualized correctly by ultrasound in 54 patients with a sensitivity of 81%. The positive predictive value was 83%. The specificity was 48%, because ultrasound described 10/21 dislodged stents correctly. The negative predictive value was 43%, since 10/23 stents were correctly classified by ultrasound as dislodged. In 11 patients (13%), esophagogastroduodenoscopy was performed even though the pancreatic stent was already dislodged.A novel ultrasound-based algorithm reduced the need for X-ray imaging by three quarters. To avoid unnecessary endoscopic examinations, the algorithm should be implemented with a learning phase and procedures should be performed by experienced examiners. An important limitation might be stent length since shorter stents might be more difficult to visualize by ultrasound.

Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure.

BACKGROUND & AIMS: Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT). METHODS: We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated. RESULTS: A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H. CONCLUSIONS: We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. IMPACT AND IMPLICATIONS: There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

Pulmonary impairment independently determines mortality in critically ill patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: In ACLF patients, an adequate risk stratification is essential, especially for liver transplant allocation, since ACLF is associated with high short-term mortality. The CLIF-C ACLF score is the best prognostic model to predict outcome in ACLF patients. While lung failure is generally regarded as signum malum in ICU care, this study aims to evaluate and quantify the role of pulmonary impairment on outcome in ACLF patients. METHODS: In this retrospective study, 498 patients with liver cirrhosis and admission to IMC/ICU were included. ACLF was defined according to EASL-CLIF criteria. Pulmonary impairment was classified into three groups: unimpaired ventilation, need for mechanical ventilation and defined pulmonary failure. These factors were analysed in different cohorts, including a propensity score-matched ACLF cohort. RESULTS: Mechanical ventilation and pulmonary failure were identified as independent risk factors for increased short-term mortality. In matched ACLF patients, the presence of pulmonary failure showed the highest 28-day mortality (83.7%), whereas mortality rates in ACLF with mechanical ventilation (67.3%) and ACLF without pulmonary impairment (38.8%) were considerably lower (p < .001). Especially in patients with pulmonary impairment, the CLIF-C ACLF score showed poor predictive accuracy. Adjusting the CLIF-C ACLF score for the grade of pulmonary impairment improved the prediction significantly. CONCLUSIONS: This study highlights that not only pulmonary failure but also mechanical ventilation is associated with worse prognosis in ACLF patients. The grade of pulmonary impairment should be considered in the risk assessment in ACLF patients. The new score may be useful in the selection of patients for liver transplantation.

Occurrence of extrapulmonary tuberculosis is associated with geographical origin: spatial characteristics of the Frankfurt TB cohort 2013-2018.

INTRODUCTION: Tuberculosis (TB) is caused by M. tuberculosis complex (MTB) and pulmonary tuberculosis (PTB) is its classical manifestation. However, in some regions of the world, extrapulmonary TB (EPTB) seems to be more frequent. METHODS: We performed a retrospective cohort study of all TB patients treated at University Hospital Frankfurt, Germany, for the time period 2013-2018. Patient charts were reviewed and demographic, clinical, and microbiological data recorded. Patients were subdivided according to their geographic origins. RESULTS: Of the 378 included patients, 309 were born outside Germany (81.7%). Three WHO regions were significantly associated with the occurrence of isolated EPTB: the South-East Asian Region (OR 3.37, CI 1.74-6.66, p < 0.001), the African Region (2.20, CI 1.25-3.90, p = 0.006), and the Eastern Mediterranean Region (OR 3.18, CI 1.78-5.76, p < 0.001). On a country level, seven countries of origin could be demonstrated to be significantly associated with the occurrence of isolated EPTB: India (OR 5.58, CI 2.30-14.20, p < 0.001), Nepal (OR 12.75, CI 1.73-259.28, p = 0.027), Afghanistan (OR 3.64, CI 1.14-11.98, p = 0.029), Pakistan (OR 3.64, CI 1.14-11.98, p = 0.029), Eritrea (OR 3.32, CI 1.52-7.47, p = 0.003), Somalia (OR 7.08, CI 2.77-19.43, p < 0.001), and Turkey (OR 9.56, CI 2.52-47.19, p = 0.002). CONCLUSION: Geographical origin is a predictor for the occurrence of extrapulmonary TB. This might be linked to a delay in diagnosis in these patients, as well as specific responsible impairments of the host's immune system, possible virulence factors of MTB, and relevant comorbidities.

Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy.

BACKGROUND & AIMS: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. METHODS: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. RESULTS: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. CONCLUSIONS: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. LAY SUMMARY: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Efficacy of Direct-acting Antivirals for Chronic Hepatitis C Virus Infection in People Who Inject Drugs or Receive Opioid Substitution Therapy: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment uptake for hepatitis C virus (HCV) infection in people who inject drugs (PWID) and patients on opioid substitution therapy (OST) is still low despite treatment guidelines that advocate the use of direct-acting antivirals (DAAs) in all patients. Our aim in this review was to investigate treatment outcomes among PWID and patients on OST in comparison to control cohorts. METHODS: A search of Embase, Medline, PubMed, and Web of Science (from October 2010 to March 2018) was conducted to assess sustained virologic response (SVR), discontinuation rates, adherence, and HCV reinfection in PWID and patients on OST. RESULTS: We identified 11 primary articles and 12 conference abstracts comprising 1702 patients on OST, 538 PWID, and 19 723 patients who served as controls. Among patients on OST, the pooled SVR was 90% (95% confidence interval [CI], 87% to 93%) and pooled treatment discontinuation rate was 7% (95% CI, 4% to 11%). Similarly, the pooled SVR was 88% (95% CI, 80% to 93%) in PWID and the pooled treatment discontinuation rate was 9% (95% CI, 5% to 15%). There was no significant difference regarding pooled rates of SVR, adherence, and discontinuation between patients on OST and controls as well as between PWID and controls. HCV reinfection rates among patients on OST ranged from 0.0 to 12.5 per 100 person-years. CONCLUSIONS: HCV treatment outcomes in PWID and patients on OST are similar to those in patients without a history of injecting drugs, supporting current guideline recommendations to treat HCV in these patient populations.

Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen.

OBJECTIVES: To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. METHODS: Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. RESULTS: We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. CONCLUSIONS: One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

Sex specificity of kidney markers to assess prognosis in cirrhotic patients with TIPS.

BACKGROUND & AIMS: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta-trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex. PATIENTS AND METHODS: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)-patients from the NEPTUN-STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used. RESULTS: Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow-up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33-2.06)) with an AUC of 0.75 and identified a cut-off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25-1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34-7.52)). CONCLUSION: This study demonstrates for the first time that in TIPS-patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS-patients.

Treatment outcomes in hepatitis C virus genotype 1a infected patients with and without baseline NS5A resistance-associated substitutions.

BACKGROUND&AIMS: The presence of baseline resistance-associated substitutions (RASs) reduced sustained virologic response (SVR) rates in chronic hepatitis C virus (HCV) genotype 1a infected patients treated with Elbasvir/Grazoprevir (EBR/GZR). This study aimed to evaluate the frequency of NS5A RASs and treatment outcomes in patients for whom EBR/GZR was intended. METHODS: We sequenced NS5A in 832 samples from German genotype1a-infected DAA-naïve patients population-based, which were collected in the European Resistance Database. Treatment outcomes and clinical parameters were evaluated in 519 of these patients retrospectively. RESULTS: Overall, 6.5% of patients harbored EBR-specific NS5A RASs at baseline, including Q30H/R (3.3%), L31M (1.8%), Y93H (1.6%) and other individual variants. Antiviral treatment, including EBR/GZR, was initiated in 88% of patients. In the absence of RASs, the majority of patients received EBR/GZR for 12 weeks (57%) and the SVR rate was 97% compared to 99% SVR achieved using other DAA regimens (LDV/SOF±RBV, G/P, PrOD+RBV, VEL/SOF). Various regimens were used in the presence of RASs and SVR rates were high following treatment with LDV/SOF (100%), G/P (83%), PrOD/RBV (100%), VEL/SOF (100%), SMV/SOF (100%) and EBR/GZR+RBV for 16 weeks (100%). However, two patients received EBR/GZR for 16 weeks without RBV and one relapsed. CONCLUSIONS: EBR/GZR treatment with or without RBV for 12 or 16 weeks according to a baseline RAS analysis was highly effective with ≥97% SVR in patients with genotype 1a. EBR/GZR without RBV should be avoided in patients with RASs. High SVR rates were also achieved using other 8 or 12 weeks DAA regimens.

Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: A systematic review and meta-analysis.

BACKGROUND&AIMS: Since the introduction of direct-acting antivirals (DAAs) several studies have reported high efficacy and safety in Hepatitis C infected patients, even in those earlier considered difficult-to-treat. We aimed to assess the efficacy and safety of DAA therapy in elderly patients. METHODS: The PubMed MEDLINE, Embase and Cochrane databases were searched through July 2018. Two independent researchers extracted data and assessed the quality and risk of bias. Risk ratios (RRs) were pooled using random effects models. The primary outcome was efficacy of DAA therapy assessed by the RR for non-sustained virologic response (SVR) among patients aged <65 vs ≥65 years. RESULTS: Overall, we identified 63 studies including 34 082 patients treated with different DAAs. Risk for non-SVR was comparable in patients <65 and ≥65 years of age (RR 1.00, 95% CI 0.86-1.15; P = 0.979) and even lower in a subgroup analysis of cirrhotic patients ≥65 years of age (RR 0.59, 95% CI 0.35-0.99, P = 0.044). Risk for non-SVR was similar between age groups in all other subgroup analyses. Elderly patients had a significantly increased risk of adverse events (AEs) (RR 1.30, 95% CI 1.11-1.52, P = 0.001), but not for serious adverse events (P = 0.43) or treatment discontinuation (P = 0.15). Risk for anaemia if treated with additional ribavirin was 2.84 (95% CI 1.73-4.66, P < 0.001) in elderly patients compared to patients <65 years. CONCLUSION: Our results show that DAAs are highly effective and safe in elderly patients. Ribavirin should be avoided in the elderly as more AEs and particularly anaemia is observed. Further cost-effectiveness analyses are needed to evaluate the socio-economic benefit of treating elderly people without advanced liver disease.

[The status of national and global hepatitis C elimination]. / Stand der nationalen und globalen Hepatitis-C-Elimination.

BACKGROUND: In 2016, the World Health Organization propagated the elimination of hepatitis C virus (HCV) by 2030 in order to address the public health threat posed by viral hepatitis. This article looks at the progress that has been made globally and in Germany since 2016. METHODS: A selective literature search was conducted, with particular focus on studies and reviews relating to the elimination of hepatitis C infection both globally and in Germany. RESULTS: In 2020, 56.8 million HCV infections were counted worldwide, which corresponds to a decline of 6.8 million since 2015. Countries that made a significant contribution to the elimination figures during this period included Egypt, Georgia, and Iceland, which were able to drastically reduce the number of HCV infections by means of national commitment in politics and healthcare. With regard to the status of elimination in Germany, the inclusion of screening for viral hepatitis in the general health check-up ("Check-up 35") in 2022/2023 has led to a significant increase in HCV case numbers. Globally and in Germany, men who have sex with men, intravenous drug users, migrants, and prison inmates are particularly vulnerable groups with regard to HCV infection. CONCLUSION: In order to sustainably eliminate HCV, it is necessary to optimize education and prevention strategies in risk groups. With regard to the subgroup of prison inmates, political measures must be used to create a standardized approach in prison medicine. At a global level, elimination in low- and middle-income countries needs to be promoted in the future.

Is a higher frequency of esophageal dilations more effective in treating benign esophageal strictures? Retrospective, multicenter study.

Background and study aims There is still a lack of evidence-based recommendations concerning endoscopic bougienage in benign esophageal strictures. Our study aimed to assess the relevance of the time interval between endoscopic dilation (ED) sessions with regard to endoscopic and clinical response. Patients and methods We performed a retrospective study including patients treated with endoscopic bougienage for a benign esophageal stricture in two German centers. Primary endpoint was the number of ED until freedom from dysphagia was achieved. Secondary endpoints were analyses on reaching a diameter of 15 mm and on achieving clinical freedom from symptoms. Results Between April 2014 and March 2020, bougienage was used as the primary treatment for benign esophageal strictures in 238 patients (194 patients in Center 1; 44 patients in Center 2). Both centers differed in their endoscopic bougienage regime: Center 1 was characterized by a higher frequency of interventions compared to Center 2 (median: 2 days [range 1-28] vs. 10 days [range 1-41]; P <0.001). Clinical response was achieved significantly earlier using the high-frequency regimen in all patients except for those with post-radiogen strictures, who clinically benefited from a low-frequency ED program. Accordingly, patients receiving higher-frequency ED reached a significantly larger post-dilation diameter and considerably larger diameter differences. Conclusions The results of our study demonstrate that a treatment concept consisting of higher-frequency bougienages seems to be more effective in treating most types of esophageal stricture. Radiogenic strictures were the only types of stenoses that benefited from a lower frequency ED program.

Stealthy Invader: Clinically Inapparent But Rapidly Progressive Multifocal Metastatic Melanoma Unveiled as Root Cause of Liver Failure.

BACKGROUND: Acute liver failure (ALF) secondary to metastatic melanoma presents a rare and diagnostically challenging clinical scenario. CASE REPORT: We report the case of a 57-year-old male who succumbed to fulminant liver failure attributed to hepatic infiltration by malignant melanoma. Despite extensive diagnostic evaluation, the underlying cause of ALF remained elusive until postmortem examination revealed multifocal metastatic melanoma. Notably, the autopsy disclosed a remarkable finding: a 10 cm lymph node in the right axilla, conspicuously harboring metastatic melanoma cells. Surprisingly, this progressive lymph node was not detected on admission or during comprehensive imaging studies conducted 24 h prior to death. Rigorous cross-referencing of radiological and autopsy findings highlighted the accuracy of prior interventions visible on imaging, further accentuating the dynamic nature of metastatic melanoma progression. CONCLUSION: This case underscores the importance of vigilance in detecting metastatic melanoma, even in atypical sites, and emphasizes the need for multidisciplinary collaboration in complex clinical scenarios.

Correction: Is a higher frequency of esophageal dilations more effective in treating benign esophageal strictures? Retrospective, multicenter study.

[This corrects the article DOI: 10.1055/a-2117-8197.].

Real-world effectiveness of voxilaprevir/velpatasvir/sofosbuvir in patients following DAA failure.

Background & Aims: Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is highly effective for re-treatment of direct-acting antiviral (DAA)-experienced patients with chronic HCV infection. In the present study, predictors of virologic treatment response were analyzed in an integrative analysis of three large real-world cohorts. Methods: Consecutive patients re-treated with VOX/VEL/SOF after DAA failure were enrolled between 2016 and 2021 in Austria, Belgium, Germany, Italy, Spain and Switzerland. Results: A total of 746 patients were included: median age was 56 (16-88) years and 77% were male. Most patients were infected with HCV genotype 1 (56%) and 3 (32%). 86% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Overall, 95.4% (683/716) of patients achieved a sustained virologic response. Treatment effectiveness was significantly affected by advanced liver disease (p <0.001), hepatocellular carcinoma (p <0.001), higher baseline ALT levels (p = 0.02), HCV genotype 3 (p <0.001), and prior VEL/SOF treatment (p = 0.01). In a multivariate analysis, only HCV genotype 3, hepatocellular carcinoma and cirrhosis turned out to be independent predictors of treatment failure. Resistance-associated substitutions, as well as the presence of rare genotypes, did not impact treatment outcome. The effectiveness of rescue therapy with glecaprevir/pibrentasvir and SOF, with or without ribavirin, for 12 to 24 weeks was found to be high (100%). Conclusions: Infection with HCV genotype 3, the presence of liver cancer and cirrhosis are independently associated with failure of VOX/VEL/SOF re-treatment. It is unclear whether the addition of ribavirin and/or extension of treatment duration may be effective to avoid virologic relapse on VOX/VEL/SOF. However, rescue treatment with glecaprevir/pibrentasvir+SOF seems to be effective. Impact and implications: Representative data on the effectiveness of voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given. Thus, we aimed to analyze treatment effectiveness and predictors of virologic response to VOX/VEL/SOF in an integrative analysis of three large real-word cohorts. The study results, derived from a multicenter cohort consisting of 746 patients, demonstrated that re-treatment with VOX/VEL/SOF is an effective salvage therapy associated with an overall per protocol sustained virologic response rate of 95%. Hepatocellular carcinoma onset, cirrhosis and HCV genotype 3 were identified as independent negative predictors of treatment response, whereas resistance-associated substitutions, as well as rare genotypes and chimera, did not impact sustained virologic response rates following re-treatment with VOX/VEL/SOF.

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients.

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Clinical characteristics and outcome of Mycobacterium chimaera infections after cardiac surgery: systematic review and meta-analysis of 180 heater-cooler unit-associated cases.

OBJECTIVES: Since 2013, heater-cooler unit (HCU) associated Mycobacterium chimaera infections linked to a global outbreak have been described. These infections were characterised by high morbidity and mortality due to delayed diagnosis, as well as challenges in antimycobacterial and surgical therapy. This study aimed to investigate the clinical characteristics and outcome of published cases of HCU-associated M. chimaera infections. METHODS: We searched PubMed and the Web of Science until 15 June 2022 for case reports, case series, and cohort studies, without language restriction, on patients with M. chimaera infection and a prior history of cardiac surgery. In this systematic review of case reports, no risk of bias assessment could be performed. Clinical, microbiological, and radiological features were recorded. Logistic regression and time-to-event analyses were performed to identify the potential factors associated with better survival. RESULTS: One hundred eighty patients from 54 publications were included. Most patients underwent surgical aortic valve (67.0%; 118/176 of patients with available data) or combined aortic valve and root replacement (15.3%; 27/176). The median period between the time point of surgery and the first symptoms was 17 months (interquartile range 13-26 months). The overall case fatality rate was 45.5% (80/176), with a median survival of 24 months after the initiation of antimycobacterial therapy or diagnosis. A reoperation (including the removal or exchange of foreign material) was associated with better survival in multivariate logistic regression (OR 0.32 for lethal events; 95% CI 0.12-0.79; p 0.015) and in time-to-event analysis (p 0.0094). DISCUSSION: This systematic review and meta-analysis confirm the high overall mortality of HCU -associated disseminated M. chimaera infections after cardiac surgery. A reoperation seems to be associated with better survival. Physicians have to stay aware of this infection, as patients might still be present today due to the long latency period.

Is Olfactory Testing a Useful Diagnostic Tool to Identify SARS-CoV-2 Infections Early? A Cross-Sectional and Longitudinal Analysis.

BACKGROUND: Genesis and the prognostic value of olfactory dysfunction (OD) in COVID-19 remain partially described. The objective of our study was to characterize OD during SARS-CoV-2 infection and to examine whether testing of OD may be a useful tool in clinical practice in order to early identify patients with SARS-CoV-2 infection. METHODS: Olfactory function assessment was objectively carried out using the u-Smell-it® test. In a cross-sectional study part, we evaluated this test in a control cohort of SARS-CoV-2 negative tested patients, who attended the University Hospital Frankfurt between May 2021 and March 2022. In a second longitudinal study part, sensitivity and specificity of OD was evaluated as a diagnostic marker of a SARS-CoV-2 infection in Frankfurt am Main, Germany in SARS-CoV-2 infected patients and their close contacts. RESULTS: Among 494 SARS-CoV-2 negative tested patients, OD was detected in 45.7% and was found to be significantly associated with the male gender (p < 0.001), higher age (p < 0.001), cardiovascular and pulmonary comorbidities (p < 0.001; p = 0.03). Among 90 COVID-19 positive patients, OD was found in 65.6% and was significantly associated with male gender and positive smoking status (p = 0.04 each). Prevalence and severity of OD were significantly increased in infections with the Delta variant (B.1.617.2) compared to those with the Omicron variant (BA.1.1.529). Diagnostic sensitivity and specificity of OD for diagnosis of SARS-CoV-2 infection were 69% and 64%, respectively. CONCLUSION: OD is common in COVID-19 negative and positive tested patients with significantly different prevalence rates observed between different variants. Diagnostic accuracy of OD is not high enough to implement olfactory testing as a tool in diagnostic routine to early identify patients with a SARS-CoV-2 infection.

Risk Factors and Role of Antibiotic Prophylaxis for Wound Infections after Percutaneous Endoscopic Gastrostomy.

BACKGROUND AND STUDY AIM: The incidence of wound infections after percutaneous endoscopic gastrostomy (PEG) varies widely in recent studies. The present study systematically investigates the underlying risk factors for the development of wound infections in a large cohort of patients over a long-term follow-up period. PATIENTS AND METHODS: A retrospective cohort study of patients undergoing PEG insertion using either the pull or push technique was conducted and patients followed up for 3 years. Tube-related wound infections were identified, and pathogens regularly cultured from wound swabs. Adjusted analysis was performed via univariate and multivariate logistic regression analysis. RESULTS: 616 patients were included in this study. A total of 25% percent of patients developed wound infections upon PEG tube insertion and 6.5% showed recurrent infections. Nicotine abuse (p = 0.01), previous ischemic stroke (p = 0.01) and head and neck cancer (p < 0.001) showed an increased risk for wound infection after PEG placement. Moreover, radio-chemotherapy was associated with the occurrence of wound infections (p < 0.001). Infection rates were similar between pull and push cohorts. The most common bacterial pathogen detected was Enterobacterales (19.2%). Staphylococcus aureus, Pseudomonas aeruginosa and enterococci were frequently detected in recurrent infection (14.2%, 11.4% and 9.6%, respectively). Antibiotic prophylaxis showed no effect on infection rates. CONCLUSIONS: Wound infections after PEG placement are common and occasionally occur as recurrent infections. There is potential for improvement in everyday clinical practice, particularly regarding antibiotic prophylaxis in accordance with guidelines.