Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study.

Background: The life expectancy of people with human immunodeficiency virus (PWH) has significantly increased, thanks to combined antiretrovirals with improved potency and tolerability. One further step has been achieved with the development of long-acting (LA) injectable antiretrovirals, which allow for infrequent dosing. However, the pharmacokinetics of LA antiretrovirals has been poorly characterized in older PWH, as they are generally excluded from trials. We performed virtual studies using physiologically based pharmacokinetic (PBPK) modeling to determine the anticipated exposure of LA cabotegravir/rilpivirine in older individuals. Methods: Our PBPK model was verified against available observed data for LA cabotegravir and rilpivirine. Cohorts of virtual individuals aged 20-50, 50-65, or 65-85 years were generated to simulate the exposure of LA cabotegravir/rilpivirine for each age group. The fold changes in trough concentration (Cmin) and in drug exposure (area under the time-concentration curve [AUC]) were determined for older relative to young individuals. Results: The verified PBPK models predicted an increase in exposure within the 0.8-1.25 fold range for monthly LA cabotegravir/rilpivirine. The Cmin and AUC were predicted to be 29% and 26% higher in older compared with young adults for LA cabotegravir administered bimonthly (every 2 months) and 46% and 41% higher for LA rilpivirine bimonthly. The Cmin and AUC of LA cabotegravir and rilpivirine were predicted to be modestly increased in female compared with male individuals for all age groups. Conclusions: LA cabotegravir/rilpivirine exposure and trough concentrations are predicted to be higher in older than in young PWH; thus, older adults could have a lower risk to present suboptimal concentrations during the dosing interval.

Impact of shift work and other work-related factors on anti-SARS-CoV-2 spike-protein serum concentrations in healthcare workers after primary mRNA vaccination - a retrospective cohort study.

BACKGROUND: Knowing whether shift work negatively affects the immune system's response to COVID-19 vaccinations could be valuable for planning future vaccination campaigns for healthcare workers. We aimed to determine the impact of working late or night shifts on serum anti-SARS-CoV-2 spike protein immunoglobulin G (anti-S) antibody levels after primary SARS-CoV-2-mRNA vaccination. METHODS: To obtain detailed information on shift work, we sent a separate online questionnaire to 1475 eligible healthcare workers who participated in a prospective longitudinal study conducted in 15 healthcare institutions in Switzerland. We asked all vaccinated healthcare workers with available anti-S antibody levels after vaccination to complete a brief online survey on their working schedules within one week before and after primary mRNA vaccination. We used multivariate regression to evaluate the association between work shifts around primary vaccination and anti-S antibody levels. We adjusted for confounders already known to influence vaccine efficacy (e.g. age, sex, immunosuppression, and obesity) and for variables significant at the 0.05 alpha level in the univariate analyses. RESULTS: The survey response rate was 43% (n = 638). Ninety-eight responders were excluded due to unknown vaccination dates, different vaccines, or administration of the second dose shortly (within 14 days) after or before serologic follow-up. Of the 540 healthcare workers included in our analysis, 175 (32.4%) had worked at least one late or night shift within seven days before and/or after primary vaccination. In the univariate analyses, working late or night shifts was associated with a nonsignificant -15.1% decrease in serum anti-S antibody levels (p = 0.090). In the multivariate analysis, prior infection (197.2% increase; p <0.001) and immunisation with the mRNA-1273 vaccine (63.7% increase compared to the BNT162b2 vaccine; p <0.001) were the strongest independent factors associated with increased anti-S antibody levels. However, the impact of shift work remained statistically nonsignificant (-13.5%, p = 0.108). CONCLUSION: Working late or night shifts shortly before or after mRNA vaccination against COVID-19 does not appear to significantly impact serum anti-S antibody levels. This result merits consideration since it supports flexible vaccination appointments for healthcare workers, including those working late or night shifts.

Development of a physiologically-based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs.

There is growing interest in the use of long-acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half-life complicates the conduct of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration-time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.

Effect of obesity on the exposure of long-acting cabotegravir and rilpivirine: a modelling study.

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in-silico trials using physiologically based pharmacokinetic (PBPK) modelling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections. METHODS: Our PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/overweight (body mass index (BMI) < 30 kg/m2) and in obese (BMI ≥30 kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60 kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (AUC) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25 kg/m2). RESULTS: Obesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35 kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40 kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration but this was less frequent with the monthly administration. CONCLUSIONS: Morbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment.

Deciphering factors linked with reduced SARS-CoV-2 susceptibility in the Swiss HIV Cohort Study.

BACKGROUND: Factors influencing susceptibility to SARS-CoV-2 remain to be resolved. Using data of the Swiss HIV Cohort Study (SHCS) on 6,270 people with HIV (PWH) and serologic assessment for SARS-CoV-2 and circulating-human-coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection. METHODS: We analyzed SARS-CoV-2 PCR-tests, COVID-19 related hospitalizations, and deaths reported to the SHCS between January 1, 2020 and December 31, 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in pre-pandemic (2019) and pandemic (2020) bio-banked plasma and compared to HIV-negative individuals. We applied logistic regression, conditional logistic regression, and Bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and Ab responses to SARS-CoV-2 in PWH. RESULTS: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High pre-pandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses upon infection. We observed a robust protective effect of smoking on SARS-CoV-2-infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14), which occurred even in previous smokers, and was highest for heavy smokers. CONCLUSIONS: Our findings of two independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2.

Antiretroviral Drug Exposure and Response in Obese and Morbidly Obese People With Human Immunodeficiency Virus (HIV): A Study Combining Modelling and Swiss HIV Cohort Data.

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS: Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and nonobese individuals. RESULTS: The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with nonobese (BMI: 18.5-25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than nonobese PWH. CONCLUSIONS: The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs.

Evaluation of the clinical relevance of the Biofire© FilmArray pneumonia panel among hospitalized patients.

PURPOSE: Panel PCR tests provide rapid pathogen identification. However, their diagnostic performance is unclear. We assessed the performance of the Biofire© FilmArray pneumonia (PN)-panel against standard culture in broncho-alveolar lavage (BAL) samples. METHODS: Setting: University Hospital Basel (February 2019 to July 2020), including hospitalized patients with a BAL (± pneumonia). We determined sensitivity and specificity of the PN-panel against standard culture. Using univariate logistic regression, we calculated odds ratios (OR) for pneumonia according to PN-panel and culture status, stratifying by chronic pulmonary disease. We calculated ORs for pneumonia for different pathogens to estimate the clinical relevance. RESULTS: We included 840 adult patients, 60% were males, median age was 68 years, 35% had chronic pulmonary disease, 21% had pneumonia, and 36% had recent antibiotic use. In 1078 BAL samples, bacterial pathogens were detected in 36% and 16% with PN-panel and culture, respectively. The overall sensitivity and specificity of the PN-panel was high, whereas the positive predictive value was low. The OR of pneumonia was 1.1 (95% CI 0.7-1.6) for PN-panel-positive only; 2.6 (95% CI 1.3-5.3) for culture-positive only, and 1.6 (95% CI 1.0-2.4) for PN-panel and culture-positive. The detection rate of Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis in the PN-panel was high but not associated with pneumonia. CONCLUSION: While sensitivity and specificity of PN-panel are high compared to culture, pathogen detection did not correlate well with a pneumonia diagnosis. Patients with culture-positive BAL had the highest OR for pneumonia-thus the impact of the PN-panel on clinical management needs further evaluation in randomized controlled trials.

Within-host genetic diversity of extended-spectrum beta-lactamase-producing Enterobacterales in long-term colonized patients.

Despite recognition of the immediate impact of infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales (ESBL-PE) on human health, essential aspects of their molecular epidemiology remain under-investigated. This includes knowledge on the potential of a particular strain to persist in a host, mutational events during colonization, and the genetic diversity in individual patients over time. To investigate long-term genetic diversity of colonizing and infecting ESBL-Klebsiella pneumoniae species complex and ESBL-Escherichia coli in individual patients over time, we performed a ten-year longitudinal retrospective study and extracted clinical and microbiological data from electronic health records. In this investigation, 76 ESBL-K. pneumoniae species complex and 284 ESBL-E. coli isolates were recovered from 19 and 61 patients. Strain persistence was detected in all patients colonized with ESBL-K. pneumoniae species complex, and 83.6% of patients colonized with ESBL-E. coli. We frequently observed isolates of the same strain recovered from different body sites associated with either colonization or infection. Antimicrobial resistance genes, plasmid replicons, and whole ESBL-plasmids were shared between isolates regardless of chromosomal relatedness. Our study suggests that patients colonized with ESBL-producers may act as durable reservoirs for ongoing transmission of ESBLs, and that they are at prolonged risk of recurrent infection with colonizing strains.

Body mass index trends and its impact of under and overweight on outcome among PLHIV on antiretroviral treatment in rural Tanzania: A prospective cohort study.

INTRODUCTION: Increased body weight is an important risk factor for cardiovascular disease and is increasingly reported as a health problem in people living with HIV (PLHIV). There is limited data from rural sub-Saharan Africa, where malnutrition usually presents with both over- and undernutrition. We aimed to determine the prevalence and risk factors of underweight and overweight/obesity in PLHIV enrolled in a cohort in rural Tanzania before the introduction of integrase inhibitors. METHODS: This nested study of the prospective Kilombero and Ulanga Antiretroviral Cohort included adults aged ≥19 years initiated on antiretroviral therapy between 01/2013 and 12/2018 with follow-up through 06/2019. Body Mass Index (BMI) was classified as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), or overweight/obese (≥25.0 kg/m2). Stratified piecewise linear mixed models were used to assess the association between baseline characteristics and follow-up BMI. Cox proportional hazard models were used to assess the association between time-updated BMI and death/loss to follow-up (LTFU). RESULTS: Among 2,129 patients, 22,027 BMI measurements (median 9 measurements: interquartile range 5-15) were analysed. At baseline, 398 (19%) patients were underweight and 356 (17%) were overweight/obese. The majority of patients were female (n = 1249; 59%), and aged 35-44 years (779; 37%). During the first 9 months, for every three additional months on antiretroviral therapy, BMI increased by 2% (95% confidence interval 1-2%, p<0.0001) among patients underweight at baseline and by 0.7% (0.5-0.6%, p<0.0001) among participants with normal BMI. Over a median of 20 months of follow-up, 107 (5%) patients died and 592 (28%) were LTFU. Being underweight was associated with >2 times the hazard of death/LTFU compared to participants with normal BMI. CONCLUSION: We found a double burden of malnutrition, with underweight being an independent predictor of mortality. Monitoring and measures to address both states of malnutrition among PLHIV should be integrated into routine HIV care.

Impact of Obesity on the Drug-Drug Interaction Between Dolutegravir and Rifampicin or Any Other Strong Inducers.

Background: Obesity is increasingly prevalent among people with HIV. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions (DDIs) and, thus, the related recommendations for dose adjustment. Virtual clinical DDI studies were conducted using physiologically based pharmacokinetic (PBPK) modeling to compare the magnitude of the DDI between dolutegravir and rifampicin in nonobese, obese, and morbidly obese individuals. Methods: Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m2), obese (BMI 30-40 kg/m2), and morbidly obese (BMI 40-50 kg/m2) individuals. Results: Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. Conclusions: The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m2.

Intramuscular cabotegravir and rilpivirine concentrations after switching from efavirenz-containing regimen.

AIMS: Intramuscular cabotegravir/rilpivirine (IM CAB/RPV) are metabolized by UGT1A1/CYP3A4. Efavirenz induces both enzymes; therefore, switching from an efavirenz-containing regimen to IM CAB/RPV could possibly result in suboptimal levels. Due to their long dosing interval, clinical studies with IM CAB/RPV are challenging. We used physiologically based pharmacokinetics (PBPK) modelling to simulate the switch from efavirenz to IM CAB/RPV. METHODS: First, we developed the drug models and verified the performance of the PBPK model to predict the pharmacokinetics of IM cabotegravir, IM rilpivirine and efavirenz by comparing the simulations against observed clinical data. Second, we verified the ability of the model to predict the effect of residual induction with observed data for the switch from efavirenz to dolutegravir or rilpivirine. Finally, we generated a cohort of 100 virtual individuals (20-50 years, 50% female, 18.5-30 kg/m2 ) to simulate IM CAB/RPV concentrations after discontinuing efavirenz in extensive and slow metabolizers of efavirenz. RESULTS: IM CAB concentrations were predicted to decrease by 11% (95% confidence interval 7-15%), 13% (6-21%) and 8% (0-18%) at day 1, 7 and 14 after efavirenz discontinuation. CAB concentrations were predicted to remain above the minimal efficacy threshold (i.e., 664 ng/mL) throughout the switch period both in extensive and slow metabolizers of efavirenz. Similarly, IM RPV concentrations were modestly decreased with the lowest reduction being 10% (6-14%) on day 7 post last efavirenz dose. CONCLUSION: Our simulations indicate that switching from an efavirenz-containing regimen to IM CAB/RPV does not put at risk of having a time window with suboptimal drug levels.

Sex-specific differences in myocardial injury incidence after COVID-19 mRNA-1273 booster vaccination.

AIMS: To explore the incidence and potential mechanisms of oligosymptomatic myocardial injury following COVID-19 mRNA booster vaccination. METHODS AND RESULTS: Hospital employees scheduled to undergo mRNA-1273 booster vaccination were assessed for mRNA-1273 vaccination-associated myocardial injury, defined as acute dynamic increase in high-sensitivity cardiac troponin T (hs-cTnT) concentration above the sex-specific upper limit of normal on day 3 (48-96 h) after vaccination without evidence of an alternative cause. To explore possible mechanisms, antibodies against interleukin-1 receptor antagonist (IL-1RA), the SARS-CoV-2-nucleoprotein (NP) and -spike (S1) proteins and an array of 14 inflammatory cytokines were quantified. Among 777 participants (median age 37 years, 69.5% women), 40 participants (5.1%; 95% confidence interval [CI] 3.7-7.0%) had elevated hs-cTnT concentration on day 3 and mRNA-1273 vaccine-associated myocardial injury was adjudicated in 22 participants (2.8% [95% CI 1.7-4.3%]). Twenty cases occurred in women (3.7% [95% CI 2.3-5.7%]), two in men (0.8% [95% CI 0.1-3.0%]). Hs-cTnT elevations were mild and only temporary. No patient had electrocardiographic changes, and none developed major adverse cardiac events within 30 days (0% [95% CI 0-0.4%]). In the overall booster cohort, hs-cTnT concentrations (day 3; median 5, interquartile range [IQR] 4-6 ng/L) were significantly higher compared to matched controls (n = 777, median 3 [IQR 3-5] ng/L, p < 0.001). Cases had comparable systemic reactogenicity, concentrations of anti-IL-1RA, anti-NP, anti-S1, and markers quantifying systemic inflammation, but lower concentrations of interferon (IFN)-λ1 (IL-29) and granulocyte-macrophage colony-stimulating factor (GM-CSF) versus persons without vaccine-associated myocardial injury. CONCLUSION: mRNA-1273 vaccine-associated myocardial injury was more common than previously thought, being mild and transient, and more frequent in women versus men. The possible protective role of IFN-λ1 (IL-29) and GM-CSF warrant further studies.

Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates.

BACKGROUND: People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized. OBJECTIVE: The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers. RESULTS: The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1. CONCLUSIONS: Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.

Switch from a ritonavir to a cobicistat containing antiretroviral regimen and impact on tacrolimus levels in a kidney transplant recipient.

BACKGROUND: Solid-organ transplantation due to end-stage organ disease is increasingly performed in people living with HIV. Despite improved transplant outcomes, management of these patients remains challenging due to higher risk for allograft rejection, infection and drug-drug interactions (DDIs). Complex regimens for multi-drug resistant HIV-viruses may cause DDIs particularly if the regimen contains drugs such as ritonavir or cobicistat. CASE PRESENTATION: Here we report on a case of an HIV-infected renal transplant recipient on long-term immunosuppressive therapy with mycophenolate mofetil and tacrolimus dosed at 0.5 mg every 11 days due to the co-administration of a darunavir/ritonavir containing antiretroviral regimen. In the presented case the pharmacokinetic booster was switched from ritonavir to cobicistat for treatment simplification. A close monitoring of tacrolimus drug levels was performed in order to prevent possible sub- or supratherapeutic tacrolimus trough levels. A progressive decrease in tacrolimus concentrations was observed after switch requiring shortening of tacrolimus dosing interval. This observation was unexpected considering that cobicistat is devoid of inducing properties. CONCLUSIONS: This case highlights the fact that the pharmacokinetic boosters ritonavir and cobicistat are not fully interchangeable. Therapeutic drug monitoring of tacrolimus is warranted to maintain levels within the therapeutic range.

Exploring group differences in the response to a sexual risk reduction intervention to prevent hepatitis C virus reinfection in HIV-infected MSM: a mixed-methods study.

To prevent hepatitis C virus (HCV) reinfection, within the Swiss HCVree Trial, a preventive risk reduction intervention was implemented alongside curative treatment. Formative qualitative research identified three response patterns to the intervention. This mixed-methods study's aim was to cross-validate group differences in (a) the content of sexual risk reduction goals set during intervention and (b) the extent of their behavioural change in condomless anal intercourse with non-steady partners (nsCAI), sexualised and intravenous drug use at start and six-month post-intervention. Qualitative thematic analysis was used to summarise goal setting domains. Quantitative descriptive analysis was used to evaluate group differences based on assumptions of the group descriptions. Results largely confirmed assumptions on inter-group response differences in goal setting and behaviour: as expected group 1 Avoid risks showed the lowest HCV risk profile with changes in nsCAI. Group 2 Minimize-risks and Group 3 Accept-risks showed unchanged nsCAI. Group 3 had the highest HCV risk profile. Differences in their goal preferences (1: condom use; 2 reduction blood exposure; 3 safer dating) highlight diversity in attitudes to behavioural change. Our results improve understanding of variability in intervention responses such as changes in attitudes and behaviour. This provides evidence for intervention tailoring and outcome measurement.

A qualitative study on the perception of infection prevention and control measures among healthcare workers without patient contact during the SARS-CoV-2 pandemic.

We conducted a qualitative interview-based study to examine the perception of infection prevention and control (IPC) measures implemented during the COVID-19 pandemic among healthcare workers (HCWs) without patient contact in a tertiary academic care center. We compared these findings to those derived from interviews of HCWs with patient contact from the same institution using the same study design. The following main four themes were identified: (1) As for HCWs with patient contact, transparent communication strongly contributes to employees' sense of security. (2) Information on personal protective equipment (PPE) usage needs to be stratified according to different educational backgrounds and professions. (3) Consistency of IPC measures was positively perceived yet a desire for constant reminders to counteract the fatigue effect played a more significant role for HCWs without patient contact. (4) As compared to HCWs with patient contact, HCWs without patient contact preferred uniform digital training resources rather than more face-to-face training. This study shows that the needs of HCWs with and without patient contact differ and need to be considered in pandemic management.

Effect of SLCO1B1 c.521T>C polymorphism on the lipid response to statins in people living with HIV on a boosted protease inhibitor-containing regimen.

AIMS: We previously observed that some individuals on HIV boosted protease inhibitor-containing regimen do not achieve their lipid targets despite elevated statin concentrations. This study evaluated whether the common single polymorphism c.521T>C in SLCO1B1, associated with reduced statin uptake in the liver, could explain this observation. METHODS: People living with HIV in the Swiss HIV Cohort Study were eligible if they were on a boosted protease inhibitor concomitantly with a statin for at least 6 months and if their SLCO1B1 genotype was available. Furthermore, their lipids had to be documented before and after the introduction of the statin. The statin efficacy was defined as % change in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides levels after statin initiation compared to pretreatment levels. Lipid response was adjusted for differences in potency and dose between statins. RESULTS: In total, 88 people living with HIV were included, of whom 58, 28 and 2 carried the SLCO1B1 TT, TC and CC genotypes, respectively. The change in lipid levels after statin initiation tended to be lower in carriers of the polymorphism although the difference was not statistically significant (TT vs. TC/CC: total cholesterol: -11.7 vs. -4.8%; low-density lipoprotein- cholesterol: -20.6 vs. -7.4%; high-density lipoprotein-cholesterol: 1.6 vs. 0%; triglycerides: -11.5 vs. -7.9%). In the multiple linear regression, change in total cholesterol was inversely correlated with the total cholesterol level prestatin treatment (coefficient -6.60, 95% confidence interval: -9.63 to -3.56, P < .001). CONCLUSION: The lipid-lowering effect of statins tended to be attenuated by SLCO1B1 polymorphism and progressively declined as total cholesterol under the boosted protease inhibitor treatment decreased.

A systematic outbreak investigation of SARS-CoV-2 transmission clusters in a tertiary academic care center.

BACKGROUND: We sought to decipher transmission pathways in healthcare-associated infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within our hospital by epidemiological work-up and complementary whole genome sequencing (WGS). We report the findings of the four largest epidemiologic clusters of SARS-CoV-2 transmission occurring during the second wave of the pandemic from 11/2020 to 12/2020. METHODS: At the University Hospital Basel, Switzerland, systematic outbreak investigation is initiated at detection of any nosocomial case of SARS-CoV-2 infection, as confirmed by polymerase chain reaction, occurring more than five days after admission. Clusters of nosocomial infections, defined as the detection of at least two positive patients and/or healthcare workers (HCWs) within one week with an epidemiological link, were further investigated by WGS on respective strains. RESULTS: The four epidemiologic clusters included 40 patients and 60 HCWs. Sequencing data was available for 70% of all involved cases (28 patients and 42 HCWs), confirmed epidemiologically suspected in house transmission in 33 cases (47.1% of sequenced cases) and excluded transmission in the remaining 37 cases (52.9%). Among cases with identical strains, epidemiologic work-up suggested transmission mainly through a ward-based exposure (24/33, 72.7%), more commonly affecting HCWs (16/24, 66.7%) than patients (8/24, 33.3%), followed by transmission between patients (6/33, 18.2%), and among HCWs and patients (3/33, 9.1%, respectively two HCWs and one patient). CONCLUSIONS: Phylogenetic analyses revealed important insights into transmission pathways supporting less than 50% of epidemiologically suspected SARS-CoV-2 transmissions. The remainder of cases most likely reflect community-acquired infection randomly detected by outbreak investigation. Notably, most transmissions occurred between HCWs, possibly indicating lower perception of the risk of infection during contacts among HCWs.

Quantifying and Predicting Ongoing Human Immunodeficiency Virus Type 1 Transmission Dynamics in Switzerland Using a Distance-Based Clustering Approach.

BACKGROUND: Despite effective prevention approaches, ongoing human immunodeficiency virus 1 (HIV-1) transmission remains a public health concern indicating a need for identifying its drivers. METHODS: We combined a network-based clustering method using evolutionary distances between viral sequences with statistical learning approaches to investigate the dynamics of HIV transmission in the Swiss HIV Cohort Study and to predict the drivers of ongoing transmission. RESULTS: We found that only a minority of clusters and patients acquired links to new infections between 2007 and 2020. While the growth of clusters and the probability of individual patients acquiring new links in the transmission network was associated with epidemiological, behavioral, and virological predictors, the strength of these associations decreased substantially when adjusting for network characteristics. Thus, these network characteristics can capture major heterogeneities beyond classical epidemiological parameters. When modeling the probability of a newly diagnosed patient being linked with future infections, we found that the best predictive performance (median area under the curve receiver operating characteristic AUCROC = 0.77) was achieved by models including characteristics of the network as predictors and that models excluding them performed substantially worse (median AUCROC = 0.54). CONCLUSIONS: These results highlight the utility of molecular epidemiology-based network approaches for analyzing and predicting ongoing HIV transmission dynamics. This approach may serve for real-time prospective assessment of HIV transmission.