Publications by authors named "Eva Wolf"

96 Publications

Virologic outcomes of switching to boosted darunavir plus dolutegravir with respect to history of drug resistance.

AIDS Res Ther 2021 09 8;18(1):58. Epub 2021 Sep 8.

School of Medicine, University Hospital Rechts Der Isar, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Objective: The DUALIS study showed that switching to boosted darunavir (bDRV) plus dolutegravir (DTG; 2DR) was non-inferior to continuous bDRV plus 2 nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs; 3DR) in treatment-experienced virologically suppressed people living with HIV (PLWH). We analyzed virologic outcomes with respect to treatment history and HIV drug resistance.

Design: Post hoc analysis of a randomized trial.

Methods: Main inclusion criteria were an HIV RNA level < 50 copies/mL for ≥ 24 weeks and no resistance to integrase strand transfer inhibitors or bDRV. Resistance-associated mutations (RAMs) were interpreted using the Stanford HIVdb mutation list. Outcomes measures were 48-week virologic response (HIV RNA < 50 copies/mL, FDA snapshot) and HIV RNA ≥ 50 copies/mL (including discontinuation due to a lack of efficacy or reasons other than adverse events and HIV RNA ≥ 50 copies/mL, referred to as snapshot non-response).

Results: The analysis population included 263 patients (2DR: 131, 3DR: 132): 90.1% males; median age, 48 years; CD4 + T-cell nadir < 200/µl, 47.0%; ≥ 2 treatment changes, 27.4%; NRTI, non-NRTI (NNRTI), and major protease inhibitor (PI) RAMs in 9.5%, 14.4%, and 3.4%, respectively. In patients with RAMs in the 2DR and 3DR groups, virologic response rates were 87.8% and 96.0%, respectively; the corresponding rates in those without RAMs were 85.7% and 81.8%. RAMs were unrelated to virologic non-response in either group. No treatment-emergent RAMs were observed.

Conclusions: DTG + bDRV is an effective treatment option without the risk of treatment-emergent resistance for PLWH on suppressive first- or further-line treatment with or without evidence of pre-existing NRTI, NNRTI, or PI RAMs.

Trial Registration: EUDRA-CT Number 2015-000360-34; registered 07 April 2015; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000360-34/DE .
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http://dx.doi.org/10.1186/s12981-021-00384-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425038PMC
September 2021

Health-related quality-of-life in people living with HIV after switching to dual therapy with ritonavir-boosted darunavir + dolutegravir: a DUALIS sub-study.

AIDS Care 2021 Apr 25:1-10. Epub 2021 Apr 25.

Department of Psychosomatic Medicine and Psychotherapy, Klinik Barmelweid AG, Barmelweid, Switzerland.

The DUALIS study demonstrated efficacy and safety of switching to dolutegravir plus ritonavir-boosted darunavir (DRV/r) (2DR) as compared to standard-of-care-therapy with two nucleoside reverse transcriptase inhibitors + DRV/r (3DR) in pretreated people living with HIV (PLWH), 48 weeks after switching. This DUALIS sub-study investigates health-related-quality-of-life (HrQoL) in this study-population. The Hospital Anxiety and Depression Scale (HADS) and the Medical Outcome Survey-HIV (MOS-HIV) were used assessing anxiety and depression symptoms, respectively HrQoL. Data were collected at baseline, 4, 24, and 48 weeks after randomization. Outcome scores were dichotomized and used as criteria in longitudinal models identifying differential developments. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed as main measures of effects. ORs<1 indicate better results for HADS, and worse for MOS-HIV scores in the 2DR compared to 3DR group. In total, 263 subjects were randomized and treated (2DR n=131, 3DR n=132; median age 48 years). Significant different progressions could only be found for HADS-Depression scores (OR=.87, 95% CI: .78, .98, =.02). While HADS-Depression scores decreased in the 2DR group, they increased in 3DR group. This sub-study showed no disadvantages regarding HrQoL in PLWH after switching to DTG+DRV/r. Considering lifelong requirements for antiretroviral medication, close attention to HrQL is required.
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http://dx.doi.org/10.1080/09540121.2021.1916873DOI Listing
April 2021

Dental care - an emotional and physical challenge for the sexually abused.

Eur J Oral Sci 2020 08;128(4):317-324

Department of Psychology, Lund University, Lund, Sweden.

The aim was to explicate persistent psychological and bodily memories of sexual abuse and how they are expressed during dental appointments. The participants comprised 13 sexually abused individuals (11 women), who recalled and expressed these experiences during a dental appointment. They were encouraged to describe, in detail, aspects of the appointment which triggered memories of the sexual abuse. The interviews were recorded, transcribed verbatim, and analyzed using Qualitative Content Analysis. The identified overall theme illustrating the latent content was 'An echo of sexual abuse transformed into (dys) functional reactions'. The first category covering the manifest content was 'The inner invisible struggle', with two subcategories: (i) mental inscriptions of the abuse experience; and (ii) consequences of the dental encounter. The second category was 'The discoverable manifestations', with two subcategories: (i) enigmatic communication; and (ii) expressions of bodily memories. The dental appointment arouses similar psychological stressful reactions as the episodes of abuse; both implicit and explicit expressions are recognizable. Dental staff can contribute to disclosure by improved understanding of the strain a dental appointment can cause in patients who have been subjected to sexual abuse and familiarity with the associated bodily expressions.
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http://dx.doi.org/10.1111/eos.12720DOI Listing
August 2020

Dental care of patients exposed to sexual abuse: Need for alliance between staff and patients.

Eur J Oral Sci 2021 06 24;129(3):e12782. Epub 2021 Mar 24.

Department of Psychology, Lund University, Lund, Sweden.

The aim was to explore the experiences of sexually abused individuals as dental patients. Purposively selected were 13 informants (11 women) aged 19-56. All had experienced sexual abuse as children or adults and memories of this abuse had been triggered and expressed during a dental appointment. They were encouraged to relate in their own words their experiences of the dental appointment. The interviews were recorded digitally, transcribed verbatim, and analysed according to Qualitative Content Analysis. The overall theme illustrating the latent content was The dental appointment - a volatile base requiring predictability and a secure working alliance. The first category covering the manifest content was The dental care provider "assumes responsibility," with two subcategories: (i) contradictory disclosure, and (ii) alliance formation - a levelling of power. The second category was The patient is "in focus," with two subcategories: (i) alertness to signs of discomfort, and (ii) attention to obvious but subtle expressions of needs. On an understanding that the patient has been sexually abused, an individually tailored, patient-centered approach to treatment is suggested. Dental care providers may also need to be aware of and reflect on their position of power, in relation to the patient and its possible chairside implications.
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http://dx.doi.org/10.1111/eos.12782DOI Listing
June 2021

The lived experience of performing a periodontal treatment in the context of general dentistry.

BDJ Open 2021 Jan 28;7(1). Epub 2021 Jan 28.

Department of Oral Diagnostics, Faculty of Odontology, Malmö University, SE-205 06, Malmö, Sweden.

Aim: To describe what characterises the lived experience of performing a periodontal treatment in the context of general dentistry.

Materials And Methods: Three dental hygienists from general dentistry in Sweden, were purposively selected as participants and interviewed. The participants described a situation in which they had performed a periodontal treatment. The descriptions were analysed using the descriptive phenomenological psychological method.

Results: The general meaning structure of the lived experience of performing a periodontal treatment comprised five constituents, (a) an established treatment routine, (b) importance of oral hygiene, (c) self-awareness and motivation of the patient, (d) support and doubt, and (e) mechanical infection control. The periodontal treatment is perceived as being set prior to its commencement and as following established routines, in which the patients' oral hygiene is experienced as a crucial part. The patients' self-awareness and a supportive clinician are seen as important factors in motivating the patient towards positive behavioural change, although there is a presence of doubt in patients' ability to maintain this positive change. Mechanical infection control is perceived as successful but sometimes difficult to perform.

Conclusions: Important, patient-related, factors are constituting the phenomenon of performing a periodontal treatment but an experience that the pre-existing standardised workflow influences patient management was also present.
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http://dx.doi.org/10.1038/s41405-021-00059-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843605PMC
January 2021

Understanding and avoiding late presentation for HIV diagnosis - study protocol of a trial using mixed methods (FindHIV).

AIDS Care 2021 Jan 23:1-5. Epub 2021 Jan 23.

Institute for Healthcare Management and Research, University of Duisburg-Essen, Essen, Germany.

Many patients infected with HIV are diagnosed at an advanced stage of illness. These late presenters are individuals with a CD4 cell count of less than 350 cells/µL and/or an AIDS defining disease at initial HIV diagnosis. Purpose of FindHIV is to develop and distribute a questionnaire/scoring system aimed at a reduction in late presentation. FindHIV uses a mixed methods approach. In a first step, primary data of patients were collected. Inclusion criteria were: age ≥ 18 years, cognitive ability and language skills to participate in the study, initial HIV diagnosis within the past 6 months, and patient informed consent. Descriptive methods and regression models are used to identify: (1) patient characteristics associated with late presentation and (2) contacts to the healthcare system with indicator diseases that did not lead to HIV testing. Secondly, a questionnaire/scoring system is created by an expert panel. Afterwards the questionnaire/scoring system is to be disseminated. The greatest challenge was in reaching an adequate sample size. Another risk may be a recall bias. Nevertheless, FindHIV is devised as an in-depth study of the phenomenon of late presentation with potential to significantly improve HIV detection.
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http://dx.doi.org/10.1080/09540121.2021.1874276DOI Listing
January 2021

Functional Hypogonadism and Testosterone Deficiency in Aging Males With and Without HIV-infection.

Exp Clin Endocrinol Diabetes 2021 Jan 21. Epub 2021 Jan 21.

MVZ Karlsplatz, Munich, Germany.

Introduction: HIV infection has become a chronic, well-treatable disease and the focus of caretakers has shifted to diagnosis and treatment of comorbidities. Hypogonadism in elderly men with HIV might be of particular relevance, however, little is known about its epidemiology in contrast to non-infected peers and men with other chronic medical conditions, such as type 2 diabetes. This study aimed at comparing the prevalence of testosterone deficiency and functional hypogonadism in men 50 years in these three groups.

Patients And Methods: Multi-center, cross-sectional substudy of the German-wide 50/2010 study, including men aged 50 years or older with HIV-infection, type 2 diabetes, and controls.

Results: Altogether, 322 men were included (mean age: 62 years (SD±7.9)). The prevalence of testosterone deficiency in men living with HIV, type 2 diabetes, and controls was 34.5, 44.9, and 35.0%, respectively; the prevalence of functional hypogonadism was 7.7, 14.3 and 3.5%, respectively. Single-factor ANOVA demonstrated significant differences between the groups for total testosterone (p0.001), SHBG (p0.001), as well as for free testosterone concentrations (p=0.006). Comorbidities were, however, most important single factor in multi-factor analysis.

Discussion: Despite a comparable prevalence of testosterone deficiency, functional hypogonadism was more frequent in men living with HIV when compared to non-infected controls. This was the result of a higher burden of symptoms that might, however, also be secondary to other conditions. Number of comorbidities was a more important factor than belonging to one of the groups.
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http://dx.doi.org/10.1055/a-1210-2482DOI Listing
January 2021

SARS-CoV-2 seroprevalence in Spain.

Lancet 2020 11;396(10261):1484

MUC Research, Munich, Germany.

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http://dx.doi.org/10.1016/S0140-6736(20)32272-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837169PMC
November 2020

The Low Case Fatality Rate of COVID-19 in Hong Kong Could Be Deceptive.

Clin Infect Dis 2020 Oct 29. Epub 2020 Oct 29.

MUC Research GmbH, Munich, Germany.

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http://dx.doi.org/10.1093/cid/ciaa1676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665389PMC
October 2020

Older age groups and country-specific case fatality rates of COVID-19 in Europe, USA and Canada.

Infection 2021 Feb 24;49(1):111-116. Epub 2020 Oct 24.

MUC Research GmbH, 80335, Munich, Germany.

Purpose: To evaluate the association between the percentages of older age groups among confirmed SARS-CoV-2 infections and the country-specific case fatality rate (CFR).

Methods: This ecological study analyzed data from the 20 most severely affected European countries, USA and Canada, in which national health authorities provided data on age distribution and gender among confirmed SARS-CoV-2 cases and deaths.

Results: The proportion of individuals older than 70 years among confirmed SARS-CoV-2 cases differed markedly between the countries, ranging from 4.9 to 40.4%. There was a strong linear association between the proportion of individuals older than 75 years and the country-specific CFRs (R = 0.803 for all countries, R = 0.961 after exclusion of three countries with incongruent data). Each 5% point increase of this older age group among confirmed SARS-CoV-2 cases was associated with an increase in CFR of 2.5% points (95% CI 1.9-3.1).

Conclusion: Data from 20 European countries and the USA and Canada showed that the variance of crude CFR of COVID-19 is predominantly (80-96%) determined by the proportion of older individuals who are diagnosed with SARS-CoV-2. The age distribution of SARS-CoV-2 infections is still far from being homogeneous. Detailed demographic data have to be taken into account in all the analyses on COVID-19-associated mortality. We urgently call for standardized data collection by national health authorities.
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http://dx.doi.org/10.1007/s15010-020-01538-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585357PMC
February 2021

IM30 IDPs form a membrane-protective carpet upon super-complex disassembly.

Commun Biol 2020 10 21;3(1):595. Epub 2020 Oct 21.

Department of Chemistry, Biochemistry, Johannes Gutenberg University Mainz, 55128, Mainz, Germany.

Members of the phage shock protein A (PspA) family, including the inner membrane-associated protein of 30 kDa (IM30), are suggested to stabilize stressed cellular membranes. Furthermore, IM30 is essential in thylakoid membrane-containing chloroplasts and cyanobacteria, where it is involved in membrane biogenesis and/or remodeling. While it is well known that PspA and IM30 bind to membranes, the mechanism of membrane stabilization is still enigmatic. Here we report that ring-shaped IM30 super-complexes disassemble on membranes, resulting in formation of a membrane-protecting protein carpet. Upon ring dissociation, the C-terminal domain of IM30 unfolds, and the protomers self-assemble on membranes. IM30 assemblies at membranes have been observed before in vivo and were associated with stress response in cyanobacteria and chloroplasts. These assemblies likely correspond to the here identified carpet structures. Our study defines the thus far enigmatic structural basis for the physiological function of IM30 and related proteins, including PspA, and highlights a hitherto unrecognized concept of membrane stabilization by intrinsically disordered proteins.
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http://dx.doi.org/10.1038/s42003-020-01314-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577978PMC
October 2020

Cost of Human Immunodeficiency Virus (HIV) and Determinants of Healthcare Costs in HIV-Infected Treatment-Naive Patients Initiated on Antiretroviral Therapy in Germany: Experiences of the PROPHET Study.

Value Health 2020 10 14;23(10):1324-1331. Epub 2020 Aug 14.

Institute for Health Care Management and Research, University of Duisburg-Essen, Essen, Germany.

Objectives: The purpose of the prospective clinical and pharmacoeconomic outcomes study of different first-line antiretroviral treatment strategies (PROPHET) was to examine the healthcare costs of human immunodeficiency virus (HIV)-infected persons in Germany treated with different antiretroviral therapy (ART) strategies and to identify variables associated with high costs.

Methods: The setting was a 24-month prospective multicenter observational cohort study in a German HIV-specialized care setting from 2014 to 2017. A microcosting approach was used for the estimation of healthcare costs. Data were obtained via electronic case report forms. The costs were calculated from both the societal and the statutory health insurance perspective. Regression models were performed that took into consideration the impact of several independent variables.

Results: Four hundred thirty-four patients from 24 centers throughout Germany were included. Average annual healthcare costs were €20 118 (standard deviation [SD] €6451) per patient from the societal perspective (n = 336) and €17 306 (SD €4106) from the statutory health insurance perspective (n = 292). Expenditures for the ART medication had the highest impact. Total costs declined in the second year of therapy. There was a significant association between the amount of total cost and clinical or therapeutic variables from both perspectives; a diagnosis of acquired immune deficiency syndrome (AIDS) led to higher costs as well as the chosen ART strategy. Age also increased cost from the statutory health insurance perspective.

Conclusions: The main cost driver of the healthcare costs for HIV-positive patients was antiretroviral drug expenses. Further variables that influenced the costs were identified. The results provide a detailed overview of the resource use of patients in the PROPHET cohort.
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http://dx.doi.org/10.1016/j.jval.2020.04.1836DOI Listing
October 2020

Efficacy and Safety of Switching to Dolutegravir With Boosted Darunavir in Virologically Suppressed Adults With HIV-1: A Randomized, Open-Label, Multicenter, Phase 3, Noninferiority Trial: The DUALIS Study.

Open Forum Infect Dis 2020 Sep 13;7(9):ofaa356. Epub 2020 Aug 13.

Bonn University Hospital, Bonn, Germany.

Background: Dolutegravir (DTG) and boosted darunavir (bDRV) are potent antiretrovirals with a high resistance barrier and might be valuable switch options for people with HIV (PWH).

Methods: DUALIS, a randomized, open-label, phase 3b, noninferiority clinical trial, compared the switch to DTG + bDRV (2DR) with continuation of 2 nucleoside reverse transcriptase inhibitors (2NRTI) + bDRV (3DR). PWH with HIV RNA <50 copies/mL taking 2NRTI + bDRV (3DR) for ≥24 weeks (1 accepted blip <200 copies/mL) were randomized to either switch to DTG 50 mg + DRV 800 mg (boosted with 100 mg of ritonavir) or continue taking 3DR. The primary end point (PE) was the proportion of HIV RNA <50 copies/mL at week (W) 48. Change in NRTI backbone was not classified as failure. The estimated sample size for PE analysis was 292; the noninferiority margin was ≤-10.0%.

Results: In total, 263 subjects were randomized and treated (2DR n = 131, 3DR n = 132; 90.1% male; 89.7% Caucasian; median age [interquartile range], 48 [39-54] years). At W48, 86.3% (n = 113/131) of the 2DR subject and 87.9% (n = 116/132) of the 3DR subjects had HIV RNA <50 copies/mL; the difference between arms was -1.6% (95.48% CI, based on the adjusted alpha level accounting for the interim analysis at W24, -9.9% to +6.7%; discontinuations due to adverse events: 2DR, 4.6% [n = 6]; 3DR, 0.8% [n = 1]). Kaplan-Meier estimates of confirmed HIV RNA ≥50 copies/mL at W48 were 1.6% (n = 2) in the 2DR and 3.1% (n = 4) in the 3DR group. Development of treatment-emergent resistance was not observed.

Conclusions: Switching to DTG + bDRV was noninferior to continuing 3DR in subjects already treated with bDRV.
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http://dx.doi.org/10.1093/ofid/ofaa356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491710PMC
September 2020

Nested whole-genome duplications coincide with diversification and high morphological disparity in Brassicaceae.

Nat Commun 2020 07 30;11(1):3795. Epub 2020 Jul 30.

Centre for Organismal Studies, University of Heidelberg, Im Neuenheimer Feld 345, 69120, Heidelberg, Germany.

Angiosperms have become the dominant terrestrial plant group by diversifying for ~145 million years into a broad range of environments. During the course of evolution, numerous morphological innovations arose, often preceded by whole genome duplications (WGD). The mustard family (Brassicaceae), a successful angiosperm clade with ~4000 species, has been diversifying into many evolutionary lineages for more than 30 million years. Here we develop a species inventory, analyze morphological variation, and present a maternal, plastome-based genus-level phylogeny. We show that increased morphological disparity, despite an apparent absence of clade-specific morphological innovations, is found in tribes with WGDs or diversification rate shifts. Both are important processes in Brassicaceae, resulting in an overall high net diversification rate. Character states show frequent and independent gain and loss, and form varying combinations. Therefore, Brassicaceae pave the way to concepts of phylogenetic genome-wide association studies to analyze the evolution of morphological form and function.
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http://dx.doi.org/10.1038/s41467-020-17605-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393125PMC
July 2020

Adequate plasma levels of dolutegravir in combination with ritonavir-boosted darunavir: a pharmacokinetic subgroup analysis of the DUALIS study.

J Antimicrob Chemother 2020 10;75(10):3082-3084

Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Department of Medicine II, Ismaninger Str. 22, 81675 Munich, Germany.

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http://dx.doi.org/10.1093/jac/dkaa234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678892PMC
October 2020

[Future prospects of antiviral HIV therapy: what is in the pipeline?]

MMW Fortschr Med 2020 06;162(Suppl 2):50-54

MVZ Karlsplatz, Karlsplatz 8, D-80335, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-020-0647-9DOI Listing
June 2020

Circadian Regulation: From Molecules to Physiology.

J Mol Biol 2020 05 12;432(12):3423-3425. Epub 2020 May 12.

Chronobiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jmb.2020.05.004DOI Listing
May 2020

High effectiveness of recommended first-line antiretroviral therapies in Germany: a nationwide, prospective cohort study.

Infection 2020 Jun 11;48(3):453-461. Epub 2020 May 11.

ICH Study Center, Hamburg, Germany.

Purpose: Current German/Austrian antiretroviral treatment guidelines recommend more than 20 combination regimens for first-line therapy, without a preference. Regimens include two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an integrase strand transfer inhibitor (INSTI), a non-NRTI (NNRTI) or a boosted protease inhibitor (PI). The objective was to examine the outcomes of recommended first-line ART in Germany.

Methods: This nationwide observational study included treatment-naïve chronically HIV-1 infected patients receiving one of the recommended first-line regimens. Patients were allocated to three arms (INSTI, NNRTI, PI) and were prospectively followed for 24 months. Delayed treatment initiation was defined by a baseline CD4 T-cell count of < 350/µl or CDC clinical stage C.

Results: Among a total of 434 patients enrolled, virologic failure was rare and occurred in 4.3% (6/141) in the PI arm, in 3.3% (4/122) in the NNRTI arm and in 0.6% (1/171) in the INSTI arm (p = 0.10). De novo drug resistance mutations developed in only two patients in the NNRTI arm. Nonetheless, treatment modifications were frequent (51%) and mostly performed for strategic reasons. Retention on all initial compounds at month 24 was 64%, 49%, and 22% in the INSTI, NNRTI and PI arms respectively. Delayed treatment initiation was common (47%) and more frequently observed in patients in the PI arm. It was not associated with virological failure.

Conclusion: High efficacy and low virological failure rates were observed with recommended first-line regimens independent of delayed treatment initiation, chosen regimen and subsequent treatment modifications, demonstrating the validity of the current treatment guidelines.
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http://dx.doi.org/10.1007/s15010-020-01428-1DOI Listing
June 2020

Influence of mental stress and environmental toxins on circadian clocks: Implications for redox regulation of the heart and cardioprotection.

Br J Pharmacol 2020 12 4;177(23):5393-5412. Epub 2020 Feb 4.

Division Heart and Lungs and Regenerative Medicine Centre, University Medical Centre Utrecht and Utrecht University, Utrecht, Netherlands.

Risk factors in the environment such as air pollution and mental stress contribute to the development of chronic non-communicable disease. Air pollution was identified as the leading health risk factor in the physical environment, followed by water pollution, soil pollution/heavy metals/chemicals and occupational exposures, however neglecting the non-chemical environmental health risk factors (e.g. mental stress and noise). Epidemiological data suggest that environmental risk factors are associated with higher risk for cardiovascular, metabolic and mental diseases, including hypertension, heart failure, myocardial infarction, diabetes, arrhythmia, stroke, depression and anxiety disorders. We provide an overview on the impact of the external exposome comprising risk factors/exposures on cardiovascular health with a focus on dysregulation of stress hormones, mitochondrial function, redox balance and inflammation with special emphasis on the circadian clock. Finally, we assess the impact of circadian clock dysregulation on cardiovascular health and the potential of environment-specific preventive strategies or "chrono" therapy for cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.
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http://dx.doi.org/10.1111/bph.14949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680009PMC
December 2020

Comorbidities and costs in HIV patients: A retrospective claims database analysis in Germany.

PLoS One 2019 6;14(11):e0224279. Epub 2019 Nov 6.

Gilead Sciences Europe, Greater London, United Kingdom.

People living with human immunodeficiency virus (PLHIV) are at high risk of developing non-HIV related comorbidities, particularly at older ages. In a retrospective claims database analysis, we compared PLHIV to a matched, non-HIV cohort to assess the prevalence of comorbidities and healthcare costs in PLHIV and the general non-HIV population in Germany. In total, 2,132 adult patients with HIV were identified in the InGef research database with HIV ICD-10 diagnosis within each year from 2011 to 2014. Of these, 1,969 could be matched to a control cohort of 3,938 individuals (1:2 ratio). Matching criteria included age, gender and socio-economic variables. The prevalence of acute renal disease (0.5% vs. 0.2%, p = 0.045), bone fractures due to osteoporosis (6.4% vs. 2.1%, p<0.001), chronic renal disease (4.3% vs. 2.4%, p<0.001), cardiovascular disease (12.8% vs. 10.4%, p = 0.006), Hepatitis B (5.9% vs. 0.3%, p<0.001) and Hepatitis C infection (8.8% vs. 0.3%, p<0.001) was significantly higher in PLHIV compared to the matched non-HIV cohort. Mean costs excluding costs for antiretroviral therapy (ART) were significantly higher in the HIV cohort (8,049€ vs. 3,658€, p<0.05). On average, PLHIV incurred excess costs of 16,441€ for ART, 2,747€ for pharmaceuticals excluding ART (p<0.05), 1,441€ for outpatient care (p<0.05) and 321€ for inpatient care (p<0.05). Devices and remedies' costs were significantly higher in the control cohort with excess costs of 113€ (p<0.05). Considering mean total costs, excluding ART, excess costs for PLHIV amounted to 8,049€ (p<0.05). This analysis demonstrated an increased comorbidity and economic burden of PLHIV compared to matched controls. Our findings suggest that HIV remains an area of high unmet medical need. To improve patient outcomes, adequate HIV management including regular monitoring, screening for comorbidities and optimal ART selection throughout the life course of PLHIV are of key importance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224279PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834270PMC
March 2020

Structural and mechanistic insights into the interaction of the circadian transcription factor BMAL1 with the KIX domain of the CREB-binding protein.

J Biol Chem 2019 11 12;294(45):16604-16619. Epub 2019 Sep 12.

Institute of Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany

The mammalian CLOCK:BMAL1 transcription factor complex and its coactivators CREB-binding protein (CBP)/p300 and mixed-lineage leukemia 1 (MLL1) critically regulate circadian transcription and chromatin modification. Circadian oscillations are regulated by interactions of BMAL1's C-terminal transactivation domain (TAD) with the KIX domain of CBP/p300 (activating) and with the clock protein CRY1 (repressing) as well as by the BMAL1 G-region preceding the TAD. Circadian acetylation of Lys within the G-region enhances repressive BMAL1-TAD-CRY1 interactions. Here, we characterized the interaction of the CBP-KIX domain with BMAL1 proteins, including the BMAL1-TAD, parts of the G-region, and Lys Tethering the small compound 1-10 in the MLL-binding pocket of the CBP-KIX domain weakened BMAL1 binding, and MLL1-bound KIX did not form a ternary complex with BMAL1, indicating that the MLL-binding pocket is important for KIX-BMAL1 interactions. Small-angle X-ray scattering (SAXS) models of BMAL1 and BMAL1:KIX complexes revealed that the N-terminal BMAL1 G-region including Lys forms elongated extensions emerging from the bulkier BMAL1-TAD:KIX core complex. Fitting high-resolution KIX domain structures into the SAXS-derived envelopes suggested that the G-region emerges near the MLL-binding pocket, further supporting a role of this pocket in BMAL1 binding. Additionally, mutations in the second CREB-pKID/c-Myb-binding pocket of the KIX domain moderately impacted BMAL1 binding. The BMAL1(K537Q) mutation mimicking Lys acetylation, however, did not affect the KIX-binding affinity, in contrast to its enhancing effect on CRY1 binding. Our results significantly advance the mechanistic understanding of the protein interaction networks controlling CLOCK:BMAL1- and CBP-dependent gene regulation in the mammalian circadian clock.
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http://dx.doi.org/10.1074/jbc.RA119.009845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851309PMC
November 2019

Tenofovir Disoproxil Fumarate Is Associated with a Set-Point Variation in the Calcium-Parathyroid Hormone-Vitamin D Axis: Results from a German Cohort.

Adv Pharmacol Sci 2018 31;2018:6069131. Epub 2018 Dec 31.

MUC Research, 80335 München, Germany.

Background: Higher levels of parathyroid hormone have been associated with the use of tenofovir disoproxil fumarate (TDF) in people with and without HIV infection. Yet, alterations in calcium levels have never been elucidated in detail.

Objective: To compare the association of parathyroid hormone with serum calcium levels and other markers of calcium and bone metabolism in people living with HIV on TDF- and non-TDF-containing antiretroviral therapy.

Patients And Methods: A retrospective single center cohort study in Munich, Germany. Median and interquartile ranges and absolute and relative frequencies were used to describe continuous and categorical variables, respectively. The Mann-Whitney test and chi-test were used for comparisons. Multivariate median regression was performed in a stepwise backward approach.

Results: 1,002 patients were included (786 (78.4%) male; median age 48 (40-55) years). 564 patients (56.3%) had a TDF-containing ART regimen. PTH concentrations were 46.9 (33.0-64.7) pg/mL and 35.2 (26.4-55.4) pg/mL (=0.001), 43.3 (30.8-59.8) pg/mL and 31.8 (22.3-49.6) pg/mL ( < 0.001), 46.1 (29.5-65.4) pg/mL and 33.4 (22.6-50.1) pg/mL ( < 0.001), and 37.8 (25.3-57.9) pg/mL and 33.8 (20.1-45.3) pg/mL (=0.012) within the first, second, third, and fourth quartile of corrected calcium levels for patients with and without TDF-containing ART, respectively. In multivariate median regression, PTH concentration was significantly associated with Ca (-32.2 (-49.8 to -14.8); < 0.001), female sex (5.2 (1.2-9.2); =0.010), 25(OH)D (-0.4 (-0.5 to -0.3); < 0.001), and TDF-use (9.2 (6.0-12.5); < 0.001).

Discussion: Higher levels of PTH seem to be needed to maintain normal calcium levels in PLWH on TDF-containing ART compared to non-TDF-containing ART. Optimal concentrations for 25-hydroxy vitamin D and calcium might therefore be different in people using TDF than expected from general populations but also people living with HIV with non-TDF-containing antiretroviral therapy. This might require different supplementation strategies but warrants further investigation.
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http://dx.doi.org/10.1155/2018/6069131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330833PMC
December 2018

Development of criteria for investigation of periapical tissue from root-filled teeth.

Acta Odontol Scand 2019 May 9;77(4):269-274. Epub 2019 Jan 9.

a Department of Endodontics, Faculty of Odontology , Malmö University , Malmö , Sweden.

Objective: To develop and assess a set of criteria to grade inflammation including relative area of inflammation in periapical lesions in endodontically treated teeth.

Material And Methods: A set of criteria was developed, encompassing data on: Lymphocytes, denoting chronic inflammation, were graded 0 (occasional) to 4 (heavy/dense inflammation). Polymorphonuclear cells, denoting acute inflammation, were graded 0 (none) to 2 (many). The third parameter, area of inflammation, that is, the relative area of the specimen that was inflamed, was graded 0 (none) to 4 (76-100%). The criteria were tested on 199 consecutive biopsies from 180 patients (aged 31-75 years). Information about symptoms was retrieved from the referrals. Mann-Whitney's U-test was used to calculate possible differences in average values for the histopathological variables in the two groups of patients: symptomatic or asymptomatic.

Results: Using the criteria, varying grades of inflammation were seen in the biopsies. The majority showed few or no PMN cells. There was a correlation between symptoms and the extent of infiltration of lymphocytes and plasma cells (p = .001), PMN cells (p < .001) and the area of inflammation (p = .002): biopsies from the asymptomatic patients exhibited less pronounced and relatively smaller areas of inflammation.

Conclusions: Using the criteria on a specific selection of root-filled teeth with persisting apical periodontitis, periapical inflammation was common, but varied in extent and severity. The inflammation was less pronounced and affected a relatively smaller area in asymptomatic teeth, although outliers in both directions were identified.
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http://dx.doi.org/10.1080/00016357.2018.1538534DOI Listing
May 2019

Alleviation of acute dental pain from localised apical periodontitis: A prospective randomised study comparing two emergency treatment procedures.

J Oral Rehabil 2019 Feb 1;46(2):120-126. Epub 2018 Nov 1.

Department of Endodontics, Faculty of Odontology, Malmö University, Malmö, Sweden.

Objective: To compare the outcomes of two emergency treatment procedures to alleviate pain from localised symptomatic apical periodontitis: complete chemo-mechanical disinfection (CMD) of the root canal system, or removal of necrotic tissue from the pulp chamber (RNT), that is without instrumentation of the root canals.

Methods: Fifty-seven consecutive patients from the emergency clinic at Malmö University met the inclusion criteria: spontaneous pain and/or pain on percussion and palpation, non-bleeding pulp in the canal orifice, pain ≥4 on a Numeric Rating Scale and ≥18 years of age. The diagnosis was symptomatic apical periodontitis, in the absence of swelling and/or fever. Pre-operative pain levels and intake of analgesics were registered. The patients were randomised to one of the two treatment groups. Three to five days post-operatively, the patients were contacted by telephone and asked to grade their current pain level and report any post-operative intake of analgesics and antibiotics.

Results: Of the patients treated with CMD of the root canal system, 26/30 (87%) reported satisfactory pain relief, compared with 22/27 (81%) of those treated by RNT. There was no mean difference in pain relief between the two groups (P = 0.879). Post-operatively, 37% in each group reported using analgesics and one in each group reported using antibiotics.

Conclusion: Three to five days after treatment, a majority (>80%) in both groups reported adequate pain relief, in some cases in combination with analgesics. Removal of necrotic and infected tissue from the pulp chamber might therefore be a cost-effective emergency treatment alternative to complete chemo-mechanical disinfection.
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http://dx.doi.org/10.1111/joor.12730DOI Listing
February 2019

Effects of antiretroviral combination therapies F/TAF, E/C/F/TAF and R/F/TAF on insulin resistance in healthy volunteers: the TAF-IR Study.

Antivir Ther 2018 3;23(7):629-632. Epub 2018 Oct 3.

Department of Medicine II, University Hospital Klinikum rechts der Isar, Munich, Germany.

Background: Increased insulin resistance (IR), associated with specific antiretroviral drugs or drug classes, is an established risk factor for type 2 diabetes in HIV patients, ultimately increasing morbidity and mortality. To date, data on the risk of IR in tenofovir alafenamide (TAF)-based protocols are unavailable.

Methods: This prospective randomized, open-label study evaluated the effects of IR on 30 healthy volunteers receiving fixed-dose combinations (FDCs) of emtricitabine/tenofovir alafenamide (F/TAF), elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF). IR was measured before and after 14-day treatments using the hyperinsulinemic-euglycaemic clamp technique (HEGC). Changes in IR in each group were evaluated using the mean glucose disposal rate, normalized with body weight (M [mg glucose/(min×kg)]).

Results: A total of 30 subjects underwent randomization: one subject in the F/TAF arm withdrew consent after randomization and one in the R/F/TAF arm had to be excluded because of technical failure during HEGC, resulting in 28 subjects in the per-protocol population (F/TAF, n=9 subjects; E/C/F/TAF, n=10 subjects; R/F/TAF n=9 subjects). No significant differences were detected on the baseline characteristics. IR did not differ among the groups before treatment. None of the studied antiretroviral combinations resulted in a significant change in IR after 14 days compared with baseline values, as measured by M (F/TAF, 11.42 ±3.04 mean [±sd] versus 11.43 ±3.23, P=0.49; E/C/F/TAF, 10.04 ±2.49 versus 10.95 ±4.26, P=0.30; R/F/TAF, 11.03 ±1.96 versus 13.01 ±4.11, P=0.13).

Conclusions: Short-term treatment for F/TAF, E/C/F/TAF or R/F/TAF did not increase IR in healthy male volunteers.
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http://dx.doi.org/10.3851/IMP3271DOI Listing
September 2019

Monthly or Weekly Supplementation with Cholecalciferol 20,000 IU in People Living with HIV: Results from a Nested Cohort Study.

Interdiscip Perspect Infect Dis 2018 2;2018:7502127. Epub 2018 Sep 2.

University Hospital Klinikum rechts der Isar, Department of Medicine II, Technische Universität München, 80675 Munich, Germany.

Background: There is still considerable uncertainty in handling vitamin D deficiency in people living with HIV (PLWH), due to a lack of comparative data and the wide range of recommended daily intake. Nondaily supplementation might be preferred in many PLWH, but recommendation on dosing has not been established. We aimed to compare the efficacy of weekly versus monthly supplementation with cholecalciferol 20,000 IU in a group of PLWH with vitamin D deficiency in Western Europe.

Study Design: Longitudinal, retrospective nested cohort study of PLWH from two large clinical care centers in Munich, Germany.

Results: Of 307 patients with vitamin D deficiency, 124 patients received vitamin D supplementation (weekly supplementation in 84 (67.7%)). 46.4% and 22.5% of patients achieved 25(OH)D levels ≥30 ng/mL after 12 months of weekly and monthly supplementation with cholecalciferol 20,000 IU, respectively (p=0.011). Dosing interval as well as 25(OH)D baseline levels >15 ng/mL were associated with the normalization of 25(OH)D.

Conclusion: A higher rate of 25(OH)D level normalization can be achieved via weekly supplementation. For several PLWH, even a weekly dose of cholecalciferol 20,000 IU might not be adequate to maintain 25(OH)D levels >30 ng/mL without an initial "loading" dose. The response to supplementation is poorly predictable at an individual level.
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http://dx.doi.org/10.1155/2018/7502127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139192PMC
September 2018

Multicenter Evaluation of Two Next-Generation HIV-1 Quantitation Assays, Aptima Quant Dx and Cobas 6800, in Comparison to the RealTie HIV-1 Reference Assay.

J Clin Microbiol 2018 10 25;56(10). Epub 2018 Sep 25.

PZB Aachen, Medical Center for Infectious Diseases, Aachen, Germany.

High accuracy and precision at the lower end of quantification are crucial requirements of a modern HIV viral load (VL) assay, since some clinically relevant thresholds are located at 50 and 200 copies/ml. In this study, we compared the performance of two new fully automated HIV-1 VL assays, Aptima HIV-1 Quant Dx and Cobas HIV-1 (Cobas 6800), with the established RealTie 2000 assay. Assay precision and accuracy were evaluated in a retrospective evaluation out of excess plasma material from four HIV-1+ individuals (subtypes B, C, CRF01_AE, and CRF02_AG). Native plasma samples were diluted to nominal concentrations at 50 and 200 copies/ml (according to the RealTie 2000 assay). All dilutions were tested in triplicate in five independent runs over 5 days and in three labs per system. Assay concordance was determined using 1,011 surplus clinical routine samples, as well as selected retrospective longitudinal samples from 7 patients on treatment. The three assays yielded highly concordant results for individual clinical samples ( > 0.98; average difference, ≤0.2 log copies/ml) and retrospective longitudinal samples from patients on treatment. The Aptima and RealTie assays showed similar high precision, meeting the 5σ criterion for the majority of samples across all labs and subtypes. The Cobas assay was less precise, missing the 5σ criterion for the majority of samples at low concentrations. In this analysis, results from the Cobas assay appeared less reliable near the clinically relevant cutoff and should be interpreted with more caution in this context. Due to high precision, full automation, and high concordance with the RealTie assay, the Aptima assay represents a good alternative in routine VL monitoring.
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http://dx.doi.org/10.1128/JCM.00292-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156314PMC
October 2018

Treatment Intensification in HIV-Infected Patients Is Associated With Reduced Frequencies of Regulatory T Cells.

Front Immunol 2018 30;9:811. Epub 2018 Apr 30.

Division of Infectious Diseases, Medizinische Klinik und Poliklinik IV, Ludwig Maximilian University of Munich, Munich, Germany.

In untreated HIV infection, the efficacy of T cell responses decreases over the disease course, resulting in disease progression. The reasons for this development are not completely understood. However, immunosuppressive cells are supposedly crucially involved. Treatment strategies to avoid the induction of these cells preserve immune functions and are therefore the object of intense research efforts. In this study, we assessed the effect of treatment intensification [=5-drug antiretroviral therapy (ART)] on the development of suppressive cell subsets. The New Era (NE) study recruited patients with primary HIV infection (PHI) or chronically HIV-infected patients with conventional ART (CHI) and applied an intensified 5-drug regimen containing maraviroc and raltegravir for several years. We compared the frequencies of the immune suppressive cells, namely, the myeloid-derived suppressor cells (MDSCs), regulatory B cells (Bregs), and regulatory T cells (Tregs), of the treatment intensification patients to the control groups, especially to the patients with conventional 3-drug ART, and analyzed the Gag/Nef-specific CD8 T cell responses. There were no differences between PHI and CHI in the NE population ( > 0.11) for any of the studied cell types. Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic myeloid-derived suppressor cell (M-MDSC), and the Breg frequencies were comparable to those of patients with a 3-drug ART. However, the Treg levels were significantly lower in the NE patients than those in 3ART-treated individuals and other control groups ( ≤ 0.0033). The Gag/Nef-specific CD8 T cell response was broader ( = 0.0134) with a higher magnitude ( = 0.026) in the NE population than that in the patients with conventional ART. However, we did not find a correlation between the frequency of the immune suppressive cells and the interferon-gamma CD8 T cell response. In the treatment intensification subjects, the frequencies of the immune suppressive cells were comparable or lower than those of the conventional ART-treated subjects, with surprisingly broad HIV-specific CD8 T cell responses, suggesting a preservation of immune function with the applied treatment regimen. Interestingly, these effects were seen in both treatment intensification subpopulations and were not attributed to the start of treatment in primary infection.
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http://dx.doi.org/10.3389/fimmu.2018.00811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936794PMC
June 2019

Ginkgo biloba's footprint of dynamic Pleistocene history dates back only 390,000 years ago.

BMC Genomics 2018 Apr 27;19(1):299. Epub 2018 Apr 27.

Center for Organismal Studies (COS) Heidelberg/Botanic Garden and Herbarium Heidelberg (HEID), University of Heidelberg, Im Neuenheimer Feld 345, D-69120, Heidelberg, Germany.

Background: At the end of the Pliocene and the beginning of Pleistocene glaciation and deglaciation cycles Ginkgo biloba went extinct all over the world, and only few populations remained in China in relict areas serving as sanctuary for Tertiary relict trees. Yet the status of these regions as refuge areas with naturally existing populations has been proven not earlier than one decade ago. Herein we elaborated the hypothesis that during the Pleistocene cooling periods G. biloba expanded its distribution range in China repeatedly. Whole plastid genomes were sequenced, assembled and annotated, and sequence data was analyzed in a phylogenetic framework of the entire gymnosperms to establish a robust spatio-temporal framework for gymnosperms and in particular for G. biloba Pleistocene evolutionary history.

Results: Using a phylogenetic approach, we identified that Ginkgoatae stem group age is about 325 million years, whereas crown group radiation of extant Ginkgo started not earlier than 390,000 years ago. During repeated warming phases, Gingko populations were separated and isolated by contraction of distribution range and retreated into mountainous regions serving as refuge for warm-temperate deciduous forests. Diversification and phylogenetic splits correlate with the onset of cooling phases when Ginkgo expanded its distribution range and gene pools merged.

Conclusions: Analysis of whole plastid genome sequence data representing the entire spatio-temporal genetic variation of wild extant Ginkgo populations revealed the deepest temporal footprint dating back to approximately 390,000 years ago. Present-day directional West-East admixture of genetic diversity is shown to be the result of pronounced effects of the last cooling period. Our evolutionary framework will serve as a conceptual roadmap for forthcoming genomic sequence data, which can then provide deep insights into the demographic history of Ginkgo.
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http://dx.doi.org/10.1186/s12864-018-4673-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5921299PMC
April 2018
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