Switching to Doravirine in cART-Experienced Patients: An Effective and Highly Tolerated Option With Substantial Cost Savings.

BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor with demonstrated efficacy as a third agent in treatment-naive and treatment-experienced people living with HIV (PLWH) in registration studies. However, limited real-world data are available. METHODS: By searching electronic health care records, PLWH using doravirine-based regimens were selected with at least 1 year of follow-up after their first prescription. All stable PLWH who were switched to a doravirine-based regimen were included in the analysis. The primary outcome was the durability of a doravirine-based regimen 1 year after prescription. Reasons for stopping were also collected. Secondary outcomes for PLWH continuing a doravirine-based regimen after 1 year were routine laboratory assessment, body mass index, and differences in medication costs compared with their previous cART. RESULTS: A total of 687 patients (92% men) were included from September 2019 to August 2022: 97.7% switched to doravirine/tenofovir/lamivudine (DOR/TDF/3TC). After 1 year, 94/687 (13.6%) PLWH stopped this therapy. The main reason for discontinuation was patient-reported adverse events in 70/687 (10.2%). Medical reasons for discontinuation included increased alanine tranaminase levels in 6/687 (0.9%), decreased estimated glomerular filtration rate in 3/687 (0.4%), and precautions after diagnosis of osteoporosis in 2/687 (0.3%) patients. Virologic failure occurred in 4/687 cases (0.6%), and 1 case demonstrated resistance mutations. The secondary outcomes demonstrated a statistically significant increase in alanine tranaminase levels and decrease in LDL-c levels. The switch to a doravirine-based regimen in the Netherlands reduced medication costs by 27%. CONCLUSIONS: This study demonstrated that switching to a doravirine-based regimen, mostly DOR/TDF/3TC, was highly effective and generally well tolerated, with substantial cost savings.

[HIV as a new diagnose in older patients]. / Hiv als nieuwe diagnose bij oudere patiënten.

We describe two patients diagnosed with an HIV-1 infection at an older age. In this article we emphasize the importance of knowledge of HIV indicator diseases and keeping a low threshold for HIV-testing.

Low hepatitis C virus-viremia prevalence yet continued barriers to direct-acting antiviral treatment in people living with HIV in the Netherlands.

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.

Retrospective study on the possible existence of a treatment paradox in sepsis scores in the emergency department.

OBJECTIVE: The quick Sequential Organ Failure Assessment (qSOFA) is developed as a tool to identify patients with infection with increased risk of dying from sepsis in non-intensive care unit settings, like the emergency department (ED). An abnormal score may trigger the initiation of appropriate therapy to reduce that risk. This study assesses the risk of a treatment paradox: the effect of a strong predictor for mortality will be reduced if that predictor also acts as a trigger for initiating treatment to prevent mortality. DESIGN: Retrospective analysis on data from a large observational cohort. SETTING: ED of a tertiary medical centre in the Netherlands. PARTICIPANTS: 3178 consecutive patients with suspected infection. PRIMARY OUTCOME: To evaluate the existence of a treatment paradox by determining the influence of baseline qSOFA on treatment decisions within the first 24 hours after admission. RESULTS: 226 (7.1%) had a qSOFA ≥2, of which 51 (22.6%) died within 30 days. Area under receiver operating characteristics of qSOFA for 30-day mortality was 0.68 (95% CI 0.61 to 0.75). Patients with a qSOFA ≥2 had higher odds of receiving any form of intensive therapy (OR 11.4 (95% CI 7.5 to 17.1)), such as aggressive fluid resuscitation (OR 8.8 95% CI 6.6 to 11.8), fast antibiotic administration (OR 8.5, 95% CI 5.7 to 12.3) or vasopressic therapy (OR 17.3, 95% CI 11.2 to 26.8), compared with patients with qSOFA <2. CONCLUSION: In ED patients with suspected infection, a qSOFA ≥2 was associated with more intensive treatment. This could lead to inadequate prediction of 30-day mortality due to the presence of a treatment paradox. TRIAL REGISTRATION NUMBER: 6916.

Heart transplantation for end-stage heart failure combined with Q fever isolated to the heart: a case report.

BACKGROUND: Active infection is generally considered a contraindication for heart transplantation. The rare combination of a patient with an active Coxiella burnetii infection and a congenital corrected transposition of the great arteries requiring heart transplantation impose challenging treatment decisions. We would like to demonstrate that if Q fever is restricted to the heart only, heart transplantation is also beneficial from an infectious point of view, therefore treating two severe conditions simultaneously. CASE SUMMARY: A patient with end-stage heart failure due to congenital corrected transposition of the great arteries and requiring heart transplantation developed chronic Q fever and endocarditis. Different antibiotic regimes were tried due to severe adverse reactions. Antibiotic treatment was precisely monitored by measuring Q fever polymerase chain reaction (PCRs) and phase I IgG antibody titres. A positron emission tomography scan revealed that Q fever was confined to the heart only after which it was decided to perform heart transplantation. Based on the results of PCR and antibody testing, antibiotic treatment was stopped after 1 year. After 5 years of follow-up, patient is still in an optimal condition. DISCUSSION: In case of a patient with end-stage heart failure and chronic Q fever, a combined treatment with PCR-/antibody monitored antibiotics and heart transplantation can cure both conditions.

The prognostic value of red blood cell distribution width in patients with suspected infection in the emergency department.

BACKGROUND: Sepsis is a potential life threatening dysregulated immune response to an infection, which can result in multi-organ failure and death. Unfortunately, good prognostic markers are lacking in patients with suspected infection to identify those at risk. Red blood cell distribution width (RDW) is a common and inexpensive hematologic laboratory measurement associated with adverse prognosis in multiple diseases. The aim of this study was to determine the prognostic value of RDW for mortality and early clinical deterioration in patients with a suspected infection in the emergency department. METHODS: In this single center prospective observational cohort study, consecutive patients with suspected infection presenting for internal medicine in the emergency department between September 2016 and March 2018 were included. For prognostic validation of bedside sepsis scores and RDW receiver operating characteristics were generated. Association between RDW and mortality and ICU admission was analyzed univariate and in a multivariate logistic regression model. RESULTS: 1046 patients were included. In multivariate analyses, RDW was significantly associated with 30-day mortality (OR 1.15, 95% CI: 1.04-1.28) and early clinical deterioration (OR 1.09, 95% CI: 1.00-1.18). For 30-day mortality RDW had an AUROC of 0.66 (95% CI 0.59-0.72). Optimal cut-off value for RDW 2 was 12.95%. For early clinical deterioration RDW had an AUROC of 0.59 (95% CI 0.54-0.63) with an optimal cut-off value of 14.48%. CONCLUSIONS: RDW was found to be a significant independent prognostic factor of 30-day mortality and early clinical deterioration in patients with suspected infection.. Therefore it can be a used as an extra marker besides bedside sepsis scores in identifying patients at risk for worse outcome in patients with suspected infection.

Treatment of Chronic Q Fever: Clinical Efficacy and Toxicity of Antibiotic Regimens.

Background: Evidence on the effectiveness of first-line treatment for chronic Q fever, tetracyclines (TET) plus hydroxychloroquine (HCQ), and potential alternatives is scarce. Methods: We performed a retrospective, observational cohort study to assess efficacy of treatment with TET plus quinolones (QNL), TET plus QNL plus HCQ, QNL monotherapy, or TET monotherapy compared to TET plus HCQ in chronic Q fever patients. We used a time-dependent Cox proportional hazards model to assess our primary (all-cause mortality) and secondary outcomes (first disease-related event and therapy failure). Results: We assessed 322 chronic Q fever patients; 276 (86%) received antibiotics. Compared to TET plus HCQ (n = 254; 92%), treatment with TET plus QNL (n = 49; 17%), TET plus QNL plus HCQ (n = 29, 10%), QNL monotherapy (n = 93; 34%), or TET monotherapy (n = 54; 20%) were not associated with primary or secondary outcomes. QNL and TET monotherapies were frequently discontinued due to insufficient clinical response (n = 27, 29% and n = 32, 59%). TET plus HCQ, TET plus QNL, and TET plus QNL plus HCQ were most frequently discontinued due to side effects (n = 110, 43%; n = 13, 27%; and n = 12, 41%). Conclusions: Treatment of chronic Q fever with TET plus QNL appears to be a safe alternative for TET plus HCQ, for example, if TET plus HCQ cannot be tolerated due to side effects. Treatment with TET plus QNL plus HCQ was not superior to treatment with TET plus HCQ, although this may be caused by confounding by indication. Treatment with TET or QNL monotherapy should be avoided; switches due to subjective, insufficient clinical response were frequently observed.

Progressive multifocal leukoencephalopathy and black fungus in a patient with rheumatoid arthritis without severe lymphocytopenia.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating brain infection caused by JC polyomavirus (JCV), primarily seen in patients with severely compromised cellular immunity. Clinical presentation varies depending on the affected white matter. PML prognosis is variable and effective treatments are lacking. CASE PRESENTATION: A 75-year-old Chinese woman with type 2 diabetes mellitus, chronic kidney disease and rheumatoid arthritis, treated with low-dose methotrexate and prednisolone for 2.5 years, developed a Pleurostomophora richardsiae infection of her left arm. After 6 months of treating this rare black fungus infection with voriconazole, surgery and immunosuppression discontinuation, she presented with progressive afebrile encephalopathy with right-sided hemiparesis. There were no signs of inflammation or metabolic abnormalities. Brain magnetic resonance imaging revealed diffuse frontal white matter lesions and a cerebrospinal fluid PCR confirmed PML due to JC virus. Severe lymphopenia was never present, and at PML diagnosis, CD4 and CD8 T-cell counts were 454 mm-3 and 277 mm-3. CD8 T-cells were able to respond to JCV VP1 peptide stimulation with TNFα secretion. Peripheral B-cell count was only 8 mm-3. Mirtazapine and Maraviroc were started, but unfortunately, she rapidly deteriorated and died 5 weeks after PML diagnosis. CONCLUSION: Although peripheral lymphocyte counts were never low and CD4 T-cell count was close to normal, the persistent black fungus infection was a hallmark of severely compromised cellular immunity. The unexpected extremely low absolute B-cell count might suggest a protective role for B-cells. The paradoxical, clinical PML onset months after immunosuppressive discontinuation suggests that it was only discovered in the context of an immune reconstitution inflammatory syndrome.

Hospital and community ampicillin-resistant Enterococcus faecium are evolutionarily closely linked but have diversified through niche adaptation.

BACKGROUND: Ampicillin-resistant Enterococcus faecium (ARE) has emerged as a nosocomial pathogen. Here, we quantified ARE carriage in different community sources and determined genetic relatedness with hospital ARE. METHODS AND RESULTS: ARE was recovered from rectal swabs of 24 of 79 (30%) dogs, 11 of 85 (13%) cats and 0 of 42 horses and from 3 of 40 (8%) faecal samples of non-hospitalized humans receiving amoxicillin. Multi-locus Sequence Typing revealed 21 sequence types (STs), including 5 STs frequently associated with hospital-acquired infections. Genes previously found to be enriched in hospital ARE, such as IS16, orf903, orf905, orf907, were highly prevalent in community ARE (≥79%), while genes with a proposed role in pathogenesis, such as esp, hyl and ecbA, were found rarely (≤5%) in community isolates. Comparative genome analysis of 2 representative dog isolates revealed that the dog strain of ST192 was evolutionarily closely linked to two previously sequenced hospital ARE, but had, based on gene content, more genes in common with the other, evolutionarily more distantly related, dog strain (ST266). CONCLUSION: ARE were detected in dogs, cats and sporadically in healthy humans, with evolutionary linkage to hospital ARE. Yet, their accessory genome has diversified, probably as a result of niche adaptation.

Effects of probiotics on acquisition and spread of multiresistant enterococci.

Ampicillin-resistant Enterococcus faecium (ARE) and vancomycin-resistant E. faecium (VRE) are important nosocomial pathogens. We quantified effects of probiotics and antibiotics on intestinal acquisition of ARE colonization in patients hospitalized in two non-intensive care unit (non-ICU) wards with high ARE prevalence. In a prospective cohort study with crossover design, all patients with a length of stay of >48 h were offered a multispecies probiotic product twice daily until discharge (4.5 months, intervention period) or not (4.5 months, control period). Perianal ARE carriage was determined <48 h after admission, twice weekly, and <48 h before discharge. The first isolates were genotyped by multiple-locus variable-number tandem repeat analysis (MLVA). Risk factors for acquisition were determined by Cox proportional hazards modeling, with special emphasis on ecological postantibiotic effects and delays between actual acquisition and culture positivity. Of 530 patients included, 94 (18%) were ARE colonized on admission. Of the remaining 436 noncolonized patients, 92 acquired ARE colonization: 28 (25%) of 110 probiotic users and 64 (20%) of 326 control patients (chi(2) test, P = 0.325). In all, 661 ARE strains were isolated from 186 patients, of which 186 were genotyped. In both wards, two MLVA types (MTs; MT1 and MT159) were responsible for >80% of acquisitions. Both MTs were genetically different from the probiotic E. faecium strain. Antibiotics to which ARE is resistant (hazard ratio [HR], 7.73 [95% confidence interval (CI), 4.52 to 13.22]), an ecological postantibiotic effect (HR, 7.11 [95% CI, 3.10 to 16.30]), and age (HR, 1.01 [95% CI, 0.99 to 1.02]) were associated with ARE acquisition. The HR of probiotics was 1.43 (95% CI, 0.88 to 2.34). In a setting with high selective antibiotic pressure, probiotics failed to prevent acquisition of multiresistant enterococci.

High acquisition and environmental contamination rates of CC17 ampicillin-resistant Enterococcus faecium in a Dutch hospital.

BACKGROUND: Enterococcus faecium has rapidly emerged as a nosocomial pathogen worldwide, and the majority of these isolates belong to clonal complex-17 (CC17). In Europe, CC17 isolates are usually ampicillin-resistant, but most are still vancomycin-sensitive. We aimed to study ampicillin-resistant E. faecium (ARE) epidemiology in our hospital. METHODS: In a 3 month study, 210 of 358 admissions (59%) to haematology and gastroenterology/nephrology were screened for rectal ARE colonization on admission (<48 h) and 148 of 210 (70%) also at discharge (<72 h). In a second (3 month) study, environmental swabs from eight predetermined sites were obtained from ARE-colonized haematology patients once weekly. All ARE isolates were genotyped by multiple-locus variable-number tandem repeat analysis (MLVA). RESULTS: ARE admission prevalence was 10% and 16% and acquisition rates were 39% and 15% in haematology and gastroenterology/nephrology, respectively. Carriage on admission was associated with previous admission <1 year (OR 5.0, 95% CI 1.8-14.0) and acquisition with beta-lactam (OR 2.7, 95% CI 1.1-6.7) and quinolone use (OR 3.1, 95% CI 1.1-8.2). Five of the 57 (9%) colonized patients developed invasive ARE infections. Genotyping revealed 12 genotypes (all CC17) with two MLVA types responsible for 94% of acquisitions. In 18 of the 19 colonized patients, the environment was contaminated with ARE. Sites most often contaminated were the toilet seat (43%), over-bed table (34%) and television remote control (28%). CONCLUSIONS: CC17 ARE epidemiology is characterized by high admission (10% to 16%), acquisition (15% to 39%) and environmental contamination (22%) rates, resulting from cross-transmission, readmission and antibiotic pressure. A multifaceted infection control approach will be needed to curtail further spread.