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OBJECTIVE Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people living with HIV (PLWH). DESIGN Multinational cohort collaboration. METHODS RESPOND participants were followed from latest of 01/01/2012 or cohort enrolment until the first of a CVD event (myocardial infarction [MI], stroke, invasive cardiovascular procedure [ICP]), last follow-up or 31/12/2019. Logistic regression examined odds of starting ABC by 5-year CVD or chronic kidney disease (CKD) D:A:D risk score. We assessed associations between recent ABC use (use within past six months) and risk of CVD with negative binomial regression models, adjusted for potential confounders. RESULTS Of 29,340 individuals, 34% recently used ABC. Compared to those at low estimated CVD and CKD risks, the odds of starting ABC were significantly higher among individuals at high CKD risk (odds ratio 1.12 [95% confidence interval, 1.04-1.21]) and significantly lower for individuals at moderate, high or very high CVD risk (0.80 [0.72-0.88], 0.75 [0.64-0.87], 0.71 [0.56-0.90], respectively). During 6.2 years median follow-up (interquartile range; 3.87-7.52), there were 748 CVD events (incidence rate [IR] 4.7/1000 persons-years of follow up [4.3-5.0]). The adjusted CVD IR ratio was higher for individuals with recent ABC use (1.40 [1.20-1.64]) compared to individuals without, consistent across sensitivity analyses. The association did not differ according to estimated CVD (interaction p = 0.56) or CKD (p = 0.98) risk strata. CONCLUSION Within RESPOND's contemporarily treated population, a significant association between CVD incidence and recent ABC use was confirmed and not explained by preferential ABC use in individuals at increased CVD or CKD risk.

OBJECTIVE: Deaths due to suicide, substance use and violence/accident may reflect similar risk factors and overlap in their classification. This study aimed to investigate incidence and risk factors of mortality among people with HIV (PWH) due to these three related causes.DESIGN: Prospectively collected data from PWH at least 18 years old and under active follow-up in the EuroSIDA study from 2007 to 2019 were analysed.METHODS: Cause-specific Cox regression analysis was used to assess risk factors.RESULTS: A total of 17 881 participants were included, comprising 149 327 person-years of follow-up (PYFU). Forty participants died by suicide {incidence rate [IR] [95% confidence interval (CI)]: 0.3/1000 PYFU (0.2, 0.4)} 93 from substance use [IR (95% CI): 0.6/1000 PYFU (0.5, 0.8)], and 57 by violence/accident [IR (95% CI): 0.4/1000 PYFU (0.3, 0.5)]. An AIDS diagnosis within the last 12 months was associated with nine-fold increased risk of suicide vs. no history of AIDS [adjusted hazard ratio (aHR): 9.06; 95% CI: 2.07, 39.7]. Male gender was associated with double the risk of violent/accidental death (aHR: 2.28; 95% CI: 1.09, 4.78). PWH in Eastern Europe and those who acquired HIV by injection drug use (IDU) demonstrated a greater risk of death due to substance use or violence/accident.CONCLUSIONS: The association between a recent diagnosis of AIDS and suicide highlights a critical period for intervention. HIV infection acquired through IDU demonstrated an expected relationship with death due to substance use and violent/accidental deaths. Increased risk of death due to substance use and violence/accident in Eastern Europe demands investigation into specific differences that may drive that association.

Background & Aims: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection.Methods: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves.Results: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was Conclusions: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. Impact and implications: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of

Weight gain is becoming increasingly prevalent amongst people with HIV (PWH) receiving contemporary antiretroviral treatment. We investigated BMI changes and clinical impact in a large prospective observational study.PWH aged ≥18 years were included who started a new antiretroviral (baseline) during 2010-2019 with baseline and ≥1 follow-up BMI assessment available. Rates of clinical outcomes (cardiovascular disease [CVD], malignancies, diabetes mellitus [DM] and all-cause mortality) were analysed using Poisson regression to assess effect of time-updated BMI changes (gt;1 kg/m 2 decrease, ±1 kg/m 2 stable,gt;1 kg/m 2 increase), lagged by 1-year to reduce reverse causality. Analyses were adjusted for baseline BMI plus key confounders including antiretroviral exposure.6721 PWH were included; 72.3% were male, median age 48 years (interquartile range [IQR] 40-55). At baseline, 8.4% were antiretroviral-naive, and 5.0% were underweight, 59.7% healthy weight, 27.5% overweight, and 7.8% were living with obesity. There was an 8.2% increase in proportion of overweight and 4.8% in obesity over the study period (median follow-up 4.4 years [IQR 2.6-6.7]).100 CVDs, 149 malignancies, 144 DMs, and 257 deaths were observed with incidence rates 4.4, 6.8, 6.6, 10.6 per 1000 person-years of follow-up, respectively. Compared to stable BMI,gt;1 kg/m 2 increase was associated with increased risk of DM (adjusted incidence rate ratio [IRR]: 1.96, 95% confidence interval [CI]: 1.36-2.80) andgt;1 kg/m 2 decrease with increased risk of death (adjusted IRR: 2.33, 95% CI: 1.73-3.13). No significant associations were observed between BMI changes and CVD or malignancies.A BMI increase was associated with DM and a decrease associated with death.

BACKGROUND Although associations between older antiretroviral drug classes and cardiovascular disease in people living with HIV are well described, there is a paucity of data regarding a possible association with integrase strand-transfer inhibitors (INSTIs). We investigated whether exposure to INSTIs was associated with an increased incidence of cardiovascular disease. METHODS RESPOND is a prospective, multicentre, collaboration study between 17 pre-existing European and Australian cohorts and includes more than 32 000 adults living with HIV in clinical care after Jan 1, 2012. Individuals were eligible for inclusion in these analyses if they were older than 18 years, had CD4 cell counts and HIV viral load measurements in the 12 months before or within 3 months after baseline (latest of cohort enrolment or Jan 1, 2012), and had no exposure to INSTIs before baseline. These individuals were subsequently followed up to the earliest of the first cardiovascular disease event (ie, myocardial infarction, stroke, or invasive cardiovascular procedure), last follow-up, or Dec 31, 2019. We used multivariable negative binomial regression to assess associations between cardiovascular disease and INSTI exposure (0 months [no exposure] vs >0 to 6 months, >6 to 12 months, >12 to 24 months, >24 to 36 months, and >36 months), adjusted for cardiovascular risk factors. RESPOND is registered with ClinicalTrials.gov, NCT04090151, and is ongoing. FINDINGS 29 340 people living with HIV were included in these analyses, of whom 7478 (25·5%) were female, 21 818 (74·4%) were male, and 44 (24 to 36 months of exposure). Compared with those with no INSTI exposure, the risk of cardiovascular disease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels similar to those never exposed (>0 to 6 months of exposure: adjusted incidence rate ratio of 1·85 [1·44-2·39]; >6 to 12 months of exposure: 1·19 [0·84-1·68]; >12 to 24 months of exposure: 1·46 [1·13-1·88]; >24 to 36 months of exposure: 0·89 [0·62-1·29]; and >36 months of exposure: 0·96 [0·69-1·33]; p

BACKGROUND There are limited data on end-stage liver disease (ESLD) and mortality in people with HIV (PWH) coinfected with both hepatitis B virus (HBV) and hepatitis C virus (HCV). METHODS All PWH aged greater than 18 under follow-up in EuroSIDA positive for HBsAg (HBV), and/or HCVRNA+, were followed from baseline (latest of 1 January 2001, EuroSIDA recruitment, known HBV/HCV status) to ESLD, death, last visit, or 31 December 2020. Follow-up while HCVRNA- was excluded. In two separate models, Poisson regression compared three groups updated over time; HIV/HBV, HIV/HCV, and HIV/HBV/HCV. RESULTS Among 5733 included individuals, 4476 (78.1%) had HIV/HCV, 953 (16.6%) had HIV/HBV and 304 (5.3%) had HIV/HBV/HCV. In total, 289 (5%) developed ESLD during 34 178 person-years of follow-up (PYFU), incidence 8.5/1000 PYFU [95% confidence interval (CI) 7.5-9.4] and 707 deaths occurred during 34671 PYFU (incidence 20.4/1000 PYFU; 95% CI 18.9-21.9). After adjustment, compared with those with HIV/HCV, persons with HIV/HBV had significantly lower rates of ESLD [adjusted incidence rate ratio (aIRR) 0.53; 95% CI 0.34-0.81]. Those with HIV/HBV/HCV had marginally significantly higher rates of ESLD (aIRR 1.49; 95% CI 0.98-2.26). Those under follow-up in 2014 or later had significantly lower rates of ESLD compared with 2007-2013 (aIRR 0.65; 95% CI 0.47-0.89). Differences in ESLD between the three groups were most pronounced in those aged at least 40. After adjustment, there were no significant differences in all-cause mortality across the three groups. CONCLUSION HIV/HBV-coinfected individuals had lower rates of ESLD and HIV/HBV/HCV had higher rates of ESLD compared with those with HIV/HCV, especially in those aged more than 40. ESLD decreased over time across all groups. CLINICALTRIALSGOV IDENTIFIER NCT02699736.

Amongst the derivatives of 4-biphenylcarboxylic acid and amino acid esters, the crystal structure of 4-biphenylcarboxy-(L)-phenylalaninate is unusual owing to its monoclinic symmetry within a pseudo-orthorhombic crystal system. The distortion is described by a disparate rotational property around the chiral centers (φchiral ≃ −129° and 58°) of the two molecules in the asymmetric unit. Each of these molecules comprises planar biphenyl moieties (φbiphenyl = 0°). Using temperature-dependent single-crystal X-ray diffraction experiments we show that the compound undergoes a phase transition below T ∼ 124 K that is characterized by a commensurate modulation wavevector, q = δ(101), δ = ½. The (3+1)-dimensional modulated structure at T = 100 K suggests that the phase transition drives the biphenyl moieties towards noncoplanar conformations with significant variation of internal torsion angle (φmax biphenyl ≤ 20°). These intramolecular rotations lead to dimerization of the molecular stacks that are described predominantly by distortions in intermolecular tilts (θmax ≤ 20°) and small variations in intermolecular distances (Δd max ≃ 0.05 Å) between biphenyl molecules. Atypical of modulated structures and superstructures of biphenyl and other polyphenyls, the rotations of individual molecules are asymmetric (Δφbiphenyl ≈ 5°) while φbiphenyl of one independent molecule is two to four times larger than the other. Crystal-chemical analysis and phase relations in superspace suggest multiple competing factors involving intramolecular steric factors, intermolecular H—C...C—H contacts and weak C—H...O hydrogen bonds that govern the distinctively unequal torsional properties of the molecules.

Using direct acting antivirals (DAA) for recently acquired hepatitis C virus (RAHCV-) infections, particularly in HIV-positive men having sex with men (MSM), dramatically reduced hepatitis C incidence. However, implementation into clinical practice is challenging. The aim of this study was to analyse spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC.The PROBE-C study is an observational European cohort on RAHCV-infections in HIV-positive MSM. Between 2007 and 2017, RAHCV-infections were documented with at least 12 months of follow-up. Fisher's exact, chi-square and Mann-Whitney U test were used for statistical analysis.464 RAHCV-infections were documented. 457/464 (98%) cases were male, median age was 41 years (IQR 38-46). Main risk groups for HCV-transmission were MSM (98.9%). Most participants were infected with HCV-genotype (GT) 1 (78.3%). Median baseline HCV-RNA was 230,000 (135,000-474,432) IU/mL, median CD4+-T cell count was 574 (547-604) cells/µL. 92% of all cases received combination antiretroviral therapy with 91% showing suppressed HIV-RNA (200 copies/mL). Median maximum alanine aminotransferase was 445 (402-522) U/L.SC of RAHCV-infection occurred in 55/464 (11.9%) cases. A2log decline in HCV-RNA four weeks after diagnosis of RAHCV infection was the strongest predictor of SC (p 0.001, sensitivity 96.4%, specificity 97.5%, PPV 84.1%, NPV 99.5%).SC of RAHCV in HIV-positive MSM is only found in 11.9% of cases and a2log drop in HCV-RNA at week four after diagnosis should prompt for early DAA-based treatment. However, immediate DAA treatment for RAHCV-infection may also be favoured in patients with ongoing transmission risk behaviour.

Using the new polarized neutron diffraction (PND) setup at MLZ the spin reorientation transition in the magnetocaloric orthoferrite HoFeO3 was studied at different wavelength. The various experiments provided reproducible results demonstrating high reliability of the used setup. We show that during the phase transition at TSR=53 K in an external magnetic field applied along crystal c-axis, the ordered magnetic moment of the Fe sublattice rotates from the crystallographic direction b to a not just in the ab plane, but through z axis. This means that the applied field breaks the orthorhombic symmetry allowing some magnetization parallel to z within a short temperature region. Interestingly, this is the same temperature region where large magnetocaloric effect for HoFeO3 was previously reported. A general model of the magnetic structure of HoFeO3, unconstrained by the orthorhombic symmetry, would allow the magnitudes and directions of the moments on each of the 8 magnetic sublattices in the unit cell to be independent of one-another, leading to 24 independent magnetic parameters. PND measurements were used to determine the absolute sign of the Dzyaloshinskii-Moriya interaction (DMI) in the ab plane for the Fe magnetic sublattice at 65 K. DMI plays an important role in the energy balance of the system.

New actively shielded asymmetric vertical field split-coil superconducting magnet with maximal field of 8 T has been recently procured and implemented on the beam line POLI at Maier-Leibnitz Zentrum (MLZ). The magnet is designed in order to facilitate the single crystal diffraction with polarised neutrons. In order to provide high neutron polarisation in the vicinity of the new strong magnet a dedicated compact-size solid-state supermirror bender polariser optimised for the short neutron wavelength on POLI has been built. A Mezei flipper, which had been previously developed for lower field, could be upgraded with additional guide fields in order to be used in combination with new polarizer and magnet. All components are discussed and the performance test for the entire setup is presented. High efficiency of the new polarised neutron diffraction setup on POLI is demonstrated. Polarized neutron diffraction experiments in the fields up to 8 T are now available at MLZ.

Background Limited data exist examining the association between incident cancer and cumulative integrase inhibitor (INSTI) exposure. Methods Participants were followed from baseline (latest of local cohort enrollment or January 1, 2012) until the earliest of first cancer, final follow-up, or December 31, 2019. Negative binomial regression was used to assess associations between cancer incidence and time-updated cumulative INSTI exposure, lagged by 6 months. Results Of 29 340 individuals, 74% were male, 24% were antiretroviral treatment (ART)-naive, and median baseline age was 44 years (interquartile range [IQR], 36–51). Overall, 13 950 (48%) individuals started an INSTI during follow-up. During 160 657 person-years of follow-up ([PYFU] median 6.2; IQR, 3.9–7.5), there were 1078 cancers (incidence rate [IR] 6.7/1000 PYFU; 95% confidence interval [CI], 6.3–7.1). The commonest cancers were non-Hodgkin lymphoma (n = 113), lung cancer (112), Kaposi’s sarcoma (106), and anal cancer (103). After adjusting for potential confounders, there was no association between cancer risk and INSTI exposure (≤6 months vs no exposure IR ratio: 1.15 [95% CI, 0.89–1.49], >6–12 months; 0.97 [95% CI, 0.71–1.32], >12–24 months; 0.84 [95% CI, 0.64–1.11], >24–36 months; 1.10 [95% CI, 0.82–1.47], >36 months; 0.90 [95% CI, 0.65–1.26] [P = .60]). In ART-naive participants, cancer incidence decreased with increasing INSTI exposure, mainly driven by a decreasing incidence of acquired immune deficiency syndrome cancers; however, there was no association between INSTI exposure and cancer for those ART-experienced (interaction P Conclusions Cancer incidence in each INSTI exposure group was similar, despite relatively wide CIs, providing reassuring early findings that increasing INSTI exposure is unlikely to be associated with an increased cancer risk, although longer follow-up is needed to confirm this finding.

Background: Following the introduction of direct-acting antiviral therapy in 2013, WHOlaunched the first Global Health Sector Strategy on Viral Hepatitis. We describe a hepatitis C virus (HCV) cascade of care in people with HIV (PWH) across Europe in terms of reaching the WHO elimination targets of diagnosing 90% and treating 80% of HCV-infected individuals. Methods: HIV/HCV-coinfected participants in the EuroSIDA cohort under prospective follow-up at October 1, 2019, were described using a nine-stage cascade of care. Care cascades were constructed across Europe, on a regional (n 5) and country (n 21) level. Results: Of 4773 anti-HCV positive PWH, 4446 [93.1%, 95% confidence interval (CI) 92.4-93.9)] were ever tested for HCV RNA, and 19.0% (95% CI 16.4-21.6) were currently HCV RNA positive, with the highest prevalence in Eastern and Central-Eastern Europe (33.7 and 29.6%, respectively). In Eastern Europe, 78.1% of the estimated number of chronic infections have been diagnosed, whereas this proportion was above 95% in the other four regions. Overall, 3116 persons have ever started treatment (72.5% of the ever chronically infected, 95% CI 70.9-74.0) and 2404 individuals (55.9% of the ever chronically infected, 95% CI 53.9-57.9) were cured. Cure proportion ranged from 11.2% in Belarus to 87.2% in Austria. Conclusion: In all regions except Eastern Europe, more than 90% of the study participants have been tested for HCV-RNA. In Southern and Central-Western regions, more than 80% ever chronically HCV-infected PWH received treatment. The proportion with cured HCV infection did not exceed 80% in any region, with significant heterogeneity between countries. Summary: In a pan-European cohort of PWH, all regions except Eastern Europe achieved the WHO target of diagnosing 90% of chronic HCV infections, while the target of treating 80% of eligible persons was achieved in none of the five regions.

Objectives: In some eastern European countries, serious challenges exist to meet the HIV-, tuberculosis (TB)- and hepatitis-related target of the United Nations Sustainable Development Goals. Some of the highest incidence rates for HIV and the highest proportion of multi-drug-resistant (MDR) tuberculosis worldwide are found in the region. The purpose of this article is to review the challenges and important next steps to improve healthcare for people living with TB, HIV and hepatitis C (HCV) in eastern Europe. Methods: References for this narrative review were identified through systematic searches of PubMed using pre-idientified key word for articles published in English from January 2000 to August 2020. After screening of titles and abstracts 37 articles were identified as relevant for this review. Thirty-eight further articles and sources were identified through searches in the authors’ personal files and in Google Scholar. Results: Up to 50% of HIV/MDR-TB-coinfected individuals in the region die within 2 years of treatment initiation. Antiretroviral therapy (ART) coverage for people living with HIV (PLHIV) and the proportion virological suppressed are far below the UNAIDS 90% targets. In theory, access to various diagnostic tests and treatment of drug-resistant TB exists, but real-life data point towards inadequate testing and treatment. New treatments could provide elimination of viral HCV in high-risk populations but few countries have national programmes. Conclusion: Some eastern European countries face serious challenges to achieve the sustainable development goal-related target of 3.3 by 2030, among others, to end the epidemics of AIDS and tuberculosis. Better integration of healthcare systems, standardization of health care, unrestricted substitution therapy for all people who inject drugs, widespread access to drug susceptibility testing, affordable medicines and a sufficiently sized, well-trained health workforce could address some of those challenges.

Metastable Ln-orthophosphates (Ln = Tb, Dy) with monoclinic monazite-type structure were obtained via a precipitation route in aqueous solutions and subsequent thermal treatment. The lattice parameters and fractional coordinates of the atoms in the crystal structures were determined by Rietveld refinement of X-ray diffraction data. The lattice parameters of the metastable monazites obtained here fit well into the linear trends observed for stable LnPO4 monazites (Ln = La–Gd). Infrared spectroscopic investigations on TbPO4 and DyPO4 with monazite structure confirmed the expected shift of the modes to higher wavenumbers with increasing atomic number and decreasing cation radius. Raman spectra of the metastable Tb- and Dy-monazites were obtained for the first time, revealing a typical monazite spectrum for monoclinic TbPO4, continuing the general linear correlation between the Raman shifts and Ln3+ radii observed for the lighter LnPO4 monazites. In contrast, the Raman spectrum of DyPO4 was severely biased by fluorescence effects.

Background The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients. Methods A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson’s co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease. Results HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2–556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9–116.8], p Conclusions Among infected critically ill patients, subtle liver impairment, (elevated HA and bilirubin), was associated with a progressive and highly increased risk of death for the patient; this was robust to adjustment for other predictors of mortality. HA can identify patients at high risk.

Background Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. Methods The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. Findings 14 703 people were included in this study, of whom 7863 (53middot5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1middot27, 95% CI 1middot17-1middot38), raltegravir (1middot37, 1middot20-1middot56), and tenofovir alafenamide (1middot38, 1middot22-1middot35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2middot10, 1middot91-2middot31 for underweight vs healthy weight) and Black ethnicity (1middot61, 1middot47-1middot76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0middot97, 0middot96-0middot98 per 100 cells per mu L increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1middot21, 95% CI 1middot19-1middot32) and tenofovir alafenamide without dolutegravir (1middot33, 1middot15-1middot53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1middot79, 1middot52-2middot11, and 1middot70, 1middot44-2middot01, respectively). Interpretation Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. Funding The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

Background The role of hepatitis C virus (HCV) coinfection and HCV-RNA in the development of diabetes mellitus (DM) in HIV-positive persons remains unclear. Methods Poisson regression was used to compare incidence rates of DM (blood glucose >11.1 mmol/L, HbA1C >6.5% or >48 mmol/mol, starting antidiabetic medicine or physician reported date of DM onset) between current HIV/HCV groups (anti-HCV-negative, spontaneously cleared HCV, chronic untreated HCV, successfully treated HCV, HCV-RNA-positive after HCV treatment). Results A total of 16 099 persons were included; at baseline 10 091 (62.7%) were HCV-Ab-negative, 722 (4.5%) were spontaneous clearers, 3614 (22.4%) were chronically infected, 912 (5.7%) had been successfully treated, and 760 (4.7%) were HCV-RNA-positive after treatment. During 136 084 person-years of follow-up (PYFU; median [interquartile range], 6.9 [3.6–13.2]), 1108 (6.9%) developed DM (crude incidence rate, 8.1/1000 PYFU; 95% CI, 7.7–8.6). After adjustment, there was no difference between the 5 HCV strata in incidence of DM (global P = .33). Hypertension (22.2%; 95% CI, 17.5%–26.2%) and body mass index >25 (22.0%; 95% CI, 10.4%–29.7%) had the largest population-attributable fractions for DM. Conclusions HCV coinfection and HCV cure were not associated with DM in this large study. The biggest modifiable risk factors were hypertension and obesity, and continued efforts to manage such comorbidities should be prioritized., Cirrhosis, but not HCV coinfection per se was associated with increased incidence of diabetes in a European cohort of >16000 PLWH. The biggest modifiable risk factors for diabetes were hypertension and obesity. Management of comorbidities in PLWH should be prioritised.

Objectives: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. Methods: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12±3months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL'200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4count '750cells/μL or a 33% increase where the baseline CD4 count was ≥500 cells/μL. Poisson regression compared clinical failures (AIDS/death≥14days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. Results: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged ' 50years, 2539 (49.4%) had CD4 counts '350 cells/μL and 1891 (36.8%) had VL'100000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40–50 and '50 years), CD4 count categories (≤ 350 vs. '350 cells/μL) and VL categories at ART initiation (≤ 100000 vs. '100000copies/mL), with all investigated interactions being nonsignificant (P'0.05). Conclusions: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.

BACKGROUND Hepatitis C virus (HCV) infection has been associated with increased risk of chronic kidney disease (CKD). We investigated the impact of HCV cure on CKD in HIV-positive persons in the EuroSIDA study. METHODS HIV-positive persons with known HCV status and at least three serum creatinine measurements after 1/1/2004 were compared based on time-updated HCV-RNA and HCV treatment: anti-HCV-negative, spontaneously cleared HCV, chronic untreated HCV, successfully treated HCV, and HCV-RNA positive after HCV treatment. Poisson regression compared incidence rates of CKD [confirmed (>3 months apart) eGFR

Synthetic La $$_{1-{x}}$$ Pr $$_{{x}}$$ PO $$_4$$ monazite-type powders and ceramics with 0 $$\le$$ x $$\le$$ 1 were analysed by scanning electron microscopy, high-temperature powder X-ray diffraction, dilatometry, and plane wave ultrasound spectroscopy. Ceramics were synthesised in a two-step sintering process at 1273 and 1573 K. Final densities were up to 99.3% of the theoretical densities. Each sample shows a homogeneous distribution of grain sizes, which increase with increasing sintering temperature. Grain sizes also depend on composition, with intermediate compositions yielding the largest grains. In-situ high-temperature powder X-ray diffraction shows that the volumetric thermal expansion coefficients of the monazite powders decrease with increasing Pr content. This behavior is not observed in dilatometry measurements of the bulk samples (ceramics) because their thermal expansion mainly depends on their density. Elastic properties show the same dependence on the density.

Background According to guidelines all HIV–HBV-coinfected patients should receive tenofovir-based combination antiretroviral therapy (cART). We aimed to investigate uptake and outcomes of tenofovir-based cART among HIV–HBV patients in the EuroSIDA study. Methods All hepatitis B surface antigen (HBsAg)+ patients followed up after 1 March 2002 were included. Changes in the proportion taking tenofovir-based cART over time were described. Poisson regression was used to investigate the relationship between tenofovir use and clinical events. Results 953 HIV–HBV patients were included. Median age was 41 years and patients were predominantly male (85%), White (82%) and ART-experienced (88%). 697 and 256 were from Western and Eastern Europe, respectively. 55 started cART during follow-up, the proportion starting with CD4+ T-cell count 3 decreased from 85% to 52% in the periods 2002–2006 to 2007–2015. Tenofovir use, among those taking cART, increased from 4% in 2002 to 73% in 2015. Compared to West, tenofovir use was lower in East in 2005 (7% versus 42%), and remained lower in 2015 (63% versus 76%). Among 602 patients taking tenofovir-based cART during follow-up, 155 (26%) discontinued tenofovir. 27 of all discontinuations were due to adverse effects. Only 14 started entecavir and/or adefovir after tenofovir discontinuation, whereas 10 started pegylated interferon. Tenofovir use was not significantly associated with lower risk of liver-related clinical events ( n=51), adjusted incidence rate ratio (IRR) 0.64 (95% CI 0.35, 1.18) for comparing patients on tenofovir with those off tenofovir. Conclusions Although use of tenofovir-based cART among HIV–HBV patients has increased across Europe, a substantial proportion are still starting cART late and are receiving suboptimal HBV therapy.

The spread of bird flu outside of Asia, particularly in Africa and Europe, topped headlines in 2006. The migration of wild birds brought the virus to Europe, where for the first time it spread to productive livestock, bringing it closer to the Western world. Due to today's globalized and highly interconnected world, the consequences of a potential bird flu pandemic are expected to be much more severe than those of the Spanish flu, which killed 50-100 million people between 1918 and 1921. A vaccine for the bird virus is currently not available. As of July 2006, 232 cases of human infection had been documented, mostly through direct contact with poultry. Of those, 134 people died. The best medication available to treat bird flu was Roche's antiviral drug Tamiflu. However, Tamiflu was not widely available; current orders of government bodies would not be fulfilled until the end of 2008. Well aware that today's avian flu might become a global pandemic comparable to the Spanish flu, Roche CEO Franz Humer had to decide how Roche should respond. While the pharmaceutical industry continued its research efforts on vaccines and medications, Tamiflu could play an important role by protecting healthcare workers and helping to contain the virus---or at least slow down its spread. Due to patent protection and a complicated production process with scarce raw ingredients, Roche had been the only producer of the drug. Partly in response to U.S. political pressure, in November 2005 Roche allowed Gilead to produce Tamiflu as well. Even so, it would take at least until late 2007 for Roche and Gilead to meet the orders of governments worldwide. The issue was a difficult one for Roche: What were the risks; what were the opportunities? If a pandemic occurred before sufficient stockpiles of Tamiflu had been built up, would Roche be held responsible? What steps, if any, should Roche take with respect to patent protection and production licensing in the shadow of a potential pandemic?Students will weigh the benefits of short-term profit maximization against the risks that a highly uncertain event could pose to a business and consider nonstandard approaches to mitigate these risks. Students will discuss the challenges of addressing low-probability, high-impact events; potential conflicts with the short-term view of the stock market and analyst community; and challenges of the patent protection model for drugs for life-threatening diseases.

The monazite-type solid solution La 1 − x Pr x PO 4 was synthesized by solid-state reaction and extensively investigated using electron microprobe and thermogravimetric analyses, differential scanning and high-temperature oxide melt solution calorimetry, powder X-ray diffraction, infrared and Raman spectroscopy. Lattice parameters and Ln-O bond lengths show a decrease with increasing Pr content. A small excess volume is observed for the solid solution. IR spectra of the solid solution members present no detectable differences, while a blue shift of the PO4-related modes is seen in the Raman data. This shift can be attributed to the lanthanide contraction. Within errors, calorimetry data show no systematic deviation from an ideal behavior, though one might interpret the data as an indication of a slightly asymmetric mixture. All data indicate that deviations from ideality of the solid solution – if present – are very small.

A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear.People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody-negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA-negative); or HCV treatment failures (HCV RNA-positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non-acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD).There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1-13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0-6.9) for CVD, 6.5 (95% CI 6.1-6.9) for NADM, and 3.1 (95% CI 2.8-3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14-0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36-1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02-2.13) or treatment failure (aIRR 1.80, 95% CI 1.22-2.66) had significantly raised rates of ESLD, compared to those who were cured.Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD.

Frontiers in Chemistry 7, 94 (2019). doi:10.3389/fchem.2019.00094, Published by Frontiers Media, Lausanne

Background & Aims: Robust data on hepatocellular carcinoma (HCC) incidence among HIV/hepatitis B virus (HBV)-coinfected individuals on antiretroviral therapy (ART) are needed to inform HCC screening strategies. We aimed to evaluate the incidence and risk factors of HCC among HIV/HBV-coinfected individuals on tenofovir disoproxil fumarate (TDF)-containing ART in a large multi-cohort study. Methods: We included all HIV-infected adults with a positive hepatitis B surface antigen test followed in 4 prospective European cohorts. The primary outcome was the occurrence of HCC. Demographic and clinical information was retrieved from routinely collected data, and liver cirrhosis was defined according to results from liver biopsy or non-invasive measurements. Multivariable Poisson regression was used to assess HCC risk factors. Results: A total of 3,625 HIV/HBV-coinfected patients were included, of whom 72% had started TDF-containing ART. Over 32,673 patient-years (py), 60 individuals (1.7%) developed an HCC. The incidence of HCC remained stable over time among individuals on TDF, whereas it increased steadily among those not on TDF. Among individuals on TDF, the incidence of HCC was 5.9 per 1,000 py (95% CI 3.60–9.10) in cirrhotics and 1.17 per 1,000 py (0.56–2.14) among non-cirrhotics. Age at initiation of TDF (adjusted incidence rate ratio per 10-year increase: 2.2, 95% CI 1.6–3.0) and the presence of liver cirrhosis (4.5, 2.3–8.9) were predictors of HCC. Among non-cirrhotic individuals, the incidence of HCC was only above the commonly used screening threshold of 2 cases per 1,000 py in patients aged >45 years old at TDF initiation. Conclusions: Whereas the incidence of HCC was high in cirrhotic HIV/HBV-coinfected individuals, it remained below the HCC screening threshold in patients without cirrhosis who started TDF aged

The impact of early allograft dysfunction on the outcome after liver transplantation is yet to be established. We explored the independent predictive value of the Model for End-Stage Liver Disease (MELD) score measured in the post-transplant period on the risk of mortality or re-transplantation.Retrospective cohort study on adults undergoing orthotopic deceased donor liver transplantation from 2004 to 2014. The MELD score was determined prior to transplantation and daily until 21 days after. The risk of mortality or re-transplantation within the first year was assessed according to quartiles of MELD using unadjusted and adjusted stepwise Cox regression analysis.We included 374 consecutive liver transplant recipients of whom 60 patients died or were re-transplanted. The pre-transplant MELD score was comparable between patients with good and poor outcome, but from day 1 the MELD score significantly diversified and was higher in the poor outcome group (MELD score quartile 4 versus quartile 1-3 at day 10: HR 5.1, 95% CI: 2.8-9.0). This association remained after adjustment for non-identical blood type, autoimmune liver disease and hepatocellular carcinoma (adjusted HR 5.3, 95% CI: 2.9-9.5 for MELD scores at day 10). The post-transplant MELD score was not associated with pre-transplant MELD score or the Eurotransplant donor risk index.Early determination of the MELD score as an indicator of early allograft dysfunction after liver transplantation was a strong independent predictor of mortality or re-transplantation and was not influenced by the quality of the donor, or preoperative recipient risk factors.

We show that the combination of fluorescence spectroscopy and low temperature heat capacity measurements of Pr-containing samples in the (La, Pr)PO 4 solid solution series can be employed to strongly constrain the Stark energy levels of Pr 3+ in monazite type structures. The resulting set of Stark energy levels for the 3 H 4 ground state of Pr 3+ reproduces the low temperature Schottky anomaly of the heat capacity much more accurately than theoretical models published earlier. We also show that there is no excess heat capacity along the binary solid solution with respect to an interpolation between the two end members LaPO 4 and PrPO 4 .

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naive persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naive HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.