Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/µL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

Impact of the COVID-19 pandemic on antibiotic prescribing in high-prescribing primary care physicians in Switzerland.

OBJECTIVES: The aim of this study was to evaluate antibiotic prescribing of medium-to-high prescribing primary care physicians being followed up after the completion of a Swiss national intervention trial of antibiotic prescription audit and feedback in the first SARS-CoV-2 pandemic year. METHODS: We used health insurer based claims data to calculate monthly antibiotic prescription rates per 100 consultations (primary endpoint) and applying interrupted time series (ITS) analysis methods, we estimated the immediate (step change) and sustained effects (slope) of the SARS-CoV-2 epidemic in 2020 on antibiotic prescribing compared to the pre-pandemic trial period from 2017-2019. RESULTS: We analysed data of 2945 of 3426 physicians (86.0%) from the trial with over 4 million consultations annually, who were in 2020 still in practice. Consultations dropped by 43% during the first pandemic year compared with 2017. Median monthly antibiotic prescription rates per 100 consultations in 2017 were 8.44 (Interquartile range [IQ] 6.32-11.50) and 8.35 (6.34-11.74) in the intervention and control groups, respectively, and increased to 15.63 (10.69-23.81) and 16.31 (10.65-24.72) per 100 consultations in 2020. ITS-derived incidence rate ratios for overall antibiotic prescriptions were 2.32 (95% CI 2.07-2.59) for the immediate pandemic effect, and 0.96 (0.95-0.98) for the sustained effect (change in slope in 2020 compared with 2017-2019). DISCUSSION: The SARS-CoV-2 pandemic had a major impact on antibiotic prescription patterns in primary care in Switzerland. For future viral pandemics, intervention plans with timely activation steps to minimize unjustified antibiotic consumption in primary care should be prepared.

Bridging the gap: identifying factors impacting mRNA severe acute respiratory syndrome coronavirus 2 vaccine booster response in people with HIV-1.

OBJECTIVES: This study aimed to investigate the association of demographic and clinical characteristics, including HIV-specific parameters with the antibody response to a third dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in people with HIV-1 (PWH). DESIGN: Post hoc analysis of data collected during the observational extension of the COrona VaccinE tRiAL pLatform trial (COVERALL-2) nested into the Swiss HIV Cohort Study (SHCS). METHODS: Serological measurements were conducted on a total of 439 PWH who had received a third dose of either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Antibody reactivity was assessed using the multifactorial ABCORA immunoassay that defines SARS-CoV-2 seroconversion and predicts neutralization activity. The association between log transformed antibody reactivity and various baseline factors, including vaccine type, demographics, immune and viral status, smoking status, comorbidities, infection history, and co-medication with chemotherapy and immunosuppressive drugs, was investigated using a multivariable linear regression model. RESULTS: Antibody response to third SARS-CoV-2 vaccination was significantly lower among PWH with CD4 + cell count less than 350 cells/µl [ratio of means 0.79; 95% confidence interval (CI) 0.65-0.95]. Having a detectable HIV-1 viral load at least 50 copies/ml and being on concurrent chemotherapy was associated with an overall lower humoral immune response (ratio of means 0.75; 95% CI 0.57-1.00 and 0.34; 95% CI 0.22-0.52, respectively). CONCLUSION: The study highlights the importance of optimal antiretroviral treatment for PWH, emphasizing the need for timely intervention to enhance the vaccine immunogenicity in this population. Moreover, it underscores the significance of sequential mRNA vaccination and provides important evidence for informing vaccine guidelines.

Cost-effectiveness of risk-based low-dose computed tomography screening for lung cancer in Switzerland.

Throughout Europe, computed tomography (CT) screening for lung cancer is in a phase of clinical implementation or reimbursement evaluation. To efficiently select individuals for screening, the use of lung cancer risk models has been suggested, but their incremental (cost-)effectiveness relative to eligibility based on pack-year criteria has not been thoroughly evaluated for a European setting. We evaluate the cost-effectiveness of pack-year and risk-based screening (PLCOm2012 model-based) strategies for Switzerland, which aided in informing the recommendations of the Swiss Cancer Screening Committee (CSC). We use the MISCAN (MIcrosimulation SCreening ANalysis)-Lung model to estimate benefits and harms of screening among individuals born 1940 to 1979 in Switzerland. We evaluate 1512 strategies, differing in the age ranges employed for screening, the screening interval and the strictness of the smoking requirements. We estimate risk-based strategies to be more cost-effective than pack-year-based screening strategies. The most efficient strategy compliant with CSC recommendations is biennial screening for ever-smokers aged 55 to 80 with a 1.6% PLCOm2012 risk. Relative to no screening this strategy is estimated to reduce lung cancer mortality by 11.0%, with estimated costs per Quality-Adjusted Life-Year (QALY) gained of €19 341, and a €1.990 billion 15-year budget impact. Biennial screening ages 55 to 80 for those with 20 pack-years shows a lower mortality reduction (10.5%) and higher cost per QALY gained (€20 869). Despite model uncertainties, our estimates suggest there may be cost-effective screening policies for Switzerland. Risk-based biennial screening ages 55 to 80 for those with ≥1.6% PLCOm2012 risk conforms to CSC recommendations and is estimated to be more efficient than pack-year-based alternatives.

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2).

Background: After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. Methods: In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. Results: Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). Conclusions: People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov).

Prognosis and prediction of antibiotic benefit in adults with clinically diagnosed acute rhinosinusitis: an individual participant data meta-analysis.

BACKGROUND: A previous individual participant data meta-analysis (IPD-MA) of antibiotics for adults with clinically diagnosed acute rhinosinusitis (ARS) showed a marginal overall effect of antibiotics, but was unable to identify patients that are most likely to benefit from antibiotics when applying conventional (i.e. univariable or one-variable-at-a-time) subgroup analysis. We updated the systematic review and investigated whether multivariable prediction of patient-level prognosis and antibiotic treatment effect may lead to more tailored treatment assignment in adults presenting to primary care with ARS. METHODS: An IPD-MA of nine double-blind placebo-controlled trials of antibiotic treatment (n=2539) was conducted, with the probability of being cured at 8-15 days as the primary outcome. A logistic mixed effects model was developed to predict the probability of being cured based on demographic characteristics, signs and symptoms, and antibiotic treatment assignment. Predictive performance was quantified based on internal-external cross-validation in terms of calibration and discrimination performance, overall model fit, and the accuracy of individual predictions. RESULTS: Results indicate that the prognosis with respect to risk of cure could not be reliably predicted (c-statistic 0.58 and Brier score 0.24). Similarly, patient-level treatment effect predictions did not reliably distinguish between those that did and did not benefit from antibiotics (c-for-benefit 0.50). CONCLUSIONS: In conclusion, multivariable prediction based on patient demographics and common signs and symptoms did not reliably predict the patient-level probability of cure and antibiotic effect in this IPD-MA. Therefore, these characteristics cannot be expected to reliably distinguish those that do and do not benefit from antibiotics in adults presenting to primary care with ARS.

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV.

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers.

Best practice guidance for antibiotic audit and feedback interventions in primary care: a modified Delphi study from the Joint Programming Initiative on Antimicrobial resistance: Primary Care Antibiotic Audit and Feedback Network (JPIAMR-PAAN).

BACKGROUND: Primary care is a critical partner for antimicrobial stewardship efforts given its high human antibiotic usage. Peer comparison audit and feedback (A&F) is often used to reduce inappropriate antibiotic prescribing. The design and implementation of A&F may impact its effectiveness. There are no best practice guidelines for peer comparison A&F in antibiotic prescribing in primary care. OBJECTIVE: To develop best practice guidelines for peer comparison A&F for antibiotic prescribing in primary care in high income countries by leveraging international expertise via the Joint Programming Initiative on Antimicrobial Resistance-Primary Care Antibiotic Audit and Feedback Network. METHODS: We used a modified Delphi process to achieve convergence of expert opinions on best practice statements for peer comparison A&F based on existing evidence and theory. Three rounds were performed, each with online surveys and virtual meetings to enable discussion and rating of each best practice statement. A five-point Likert scale was used to rate consensus with a median threshold score of 4 to indicate a consensus statement. RESULTS: The final set of guidelines include 13 best practice statements in four categories: general considerations (n = 3), selecting feedback recipients (n = 1), data and indicator selection (n = 4), and feedback delivery (n = 5). CONCLUSION: We report an expert-derived best practice recommendations for designing and evaluating peer comparison A&F for antibiotic prescribing in primary care. These 13 statements can be used by A&F designers to optimize the impact of their quality improvement interventions, and improve antibiotic prescribing in primary care.

Antibody Response After Third Vaccination With mRNA-1273 or BNT162b2: Extension of a Randomized Controlled SARS-CoV-2 Noninferiority Vaccine Trial in Patients With Different Levels of Immunosuppression (COVERALL-2).

Extension of the COVERALL (COrona VaccinE tRiAL pLatform) randomized trial showed noninferiority in antibody response of the third dose of Moderna mRNA-1273 vaccine (95.3% [95% confidence interval {CI}, 91.9%-98.7%]) compared to Pfizer-BioNTech BNT162b2 vaccine (98.1% [95% CI, 95.9%-100.0%]) in individuals with different levels of immunosuppression (difference, -2.8% [95% CI, -6.8% to 1.3%]).

Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

BACKGROUND: Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. METHODS: Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. RESULTS: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/µL (10-56/µL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively. CONCLUSIONS: We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

Effect of Antibiotic Prescription Audit and Feedback on Antibiotic Prescribing in Primary Care: A Randomized Clinical Trial.

Importance: Antibiotics are commonly prescribed in primary care, increasing the risk of antimicrobial resistance in the population. Objective: To investigate the effect of quarterly audit and feedback on antibiotic prescribing among primary care physicians in Switzerland with medium to high antibiotic prescription rates. Design, Setting, and Participants: This pragmatic randomized clinical trial was conducted from January 1, 2018, to December 31, 2019, among 3426 registered primary care physicians and pediatricians in single or small practices in Switzerland who were among the top 75% prescribers of antibiotics. Intention-to-treat analysis was performed using analysis of covariance models and conducted from September 1, 2021, to January 31, 2022. Interventions: Primary care physicians were randomized in a 1:1 fashion to undergo quarterly antibiotic prescribing audit and feedback with peer benchmarking vs no intervention for 2 years, with 2017 used as the baseline year. Anonymized patient-level claims data from 3 health insurers serving roughly 50% of insurees in Switzerland were used for audit and feedback. The intervention group also received evidence-based guidelines for respiratory tract and urinary tract infection management and community antibiotic resistance information. Physicians in the intervention group were blinded regarding the nature of the trial, and physicians in the control group were not informed of the trial. Main Outcomes and Measures: The claims data used for audit and feedback were analyzed to assess outcomes. Primary outcome was the antibiotic prescribing rate per 100 consultations during the second year of the intervention. Secondary end points included overall antibiotic use in the first year and over 2 years, use of quinolones and oral cephalosporins, all-cause hospitalizations, and antibiotic use in 3 age groups. Results: A total of 3426 physicians were randomized to the intervention (n = 1713) and control groups (n = 1713) serving 629 825 and 622 344 patients, respectively, with a total of 4 790 525 consultations in the baseline year of 2017. In the entire cohort, a 4.2% (95% CI, 3.9%-4.6%) relative increase in the antibiotic prescribing rate was noted during the second year of the intervention compared with 2017. In the intervention group, the median annual antibiotic prescribing rate per 100 consultations was 8.2 (IQR, 6.1-11.4) in the second year of the intervention and was 8.4 (IQR, 6.0-11.8) in the control group. Relative to the overall increase, a -0.1% (95% CI, -1.2% to 1.0%) lower antibiotic prescribing rate per 100 consultations was found in the intervention group compared with the control group. No relevant reductions in specific antibiotic prescribing rates were noted between groups except for quinolones in the second year of the intervention (-0.9% [95% CI, -1.5% to -0.4%]). Conclusions and Relevance: This randomized clinical trial found that quarterly personalized antibiotic prescribing audit and feedback with peer benchmarking did not reduce antibiotic prescribing among primary care physicians in Switzerland with medium to high antibiotic prescription rates. Trial Registration: ClinicalTrials.gov Identifier: NCT03379194.

Impact of Very Small Aneurysm Size and Anterior Communicating Segment Location on Outcome after Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Very small anterior communicating artery aneurysms (vsACoA) of <5 mm in size are detected in a considerable number of patients with aneurysmal subarachnoid hemorrhage (aSAH). Single-center studies report that vsACoA harbor particular risks when treated. OBJECTIVE: To assess the clinical and radiological outcome(s) of patients with aSAH diagnosed with vsACoA after aneurysm treatment and at discharge. METHODS: Information on n = 1868 patients was collected in the Swiss Subarachnoid Hemorrhage Outcome Study registry between 2009 and 2014. The presence of a new focal neurological deficit at discharge, functional status (modified Rankin scale), mortality rates, and procedural complications (in-hospital rebleeding and presence of a new stroke on computed tomography) was assessed for vsACoA and compared with the results observed for aneurysms in other locations and with diameters of 5 to 25 mm. RESULTS: This study analyzed n = 1258 patients with aSAH, n = 439 of which had a documented ruptured ACoA. ACoA location was found in 38% (n = 144/384) of all very small ruptured aneurysms. A higher in-hospital bleeding rate was found in vsACoA compared with non-ACoA locations (2.8 vs 2.1%), especially when endovascularly treated (2.1% vs 0.5%). In multivariate analysis, aneurysm size of 5 to 25 mm, and not ACoA location, was an independent risk factor for a new focal neurological deficit and a higher modified Rankin scale at discharge. Neither very small aneurysm size nor ACoA location was associated with higher mortality rates at discharge or the occurrence of a peri-interventional stroke. CONCLUSION: Very small ruptured ACoA have a higher in-hospital rebleeding rate but are not associated with worse morbidity or mortality.

Cost-effectiveness of adding oseltamivir to primary care for influenza-like-illness: economic evaluation alongside the randomised controlled ALIC4E trial in 15 European countries.

BACKGROUND: Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries. METHODS: Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed. RESULTS: The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient). CONCLUSION: Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > €22,459) and cost-saving in adults/adolescents from a societal perspective.

Regional and national antimicrobial stewardship activities: a survey from the Joint Programming Initiative on Antimicrobial Resistance-Primary Care Antibiotic Audit and Feedback Network (JPIAMR-PAAN).

Background: Antibiotic overuse and misuse in primary care are common, highlighting the importance of antimicrobial stewardship (AMS) efforts in this setting. Audit and feedback (A&F) interventions can improve professional practice and performance in some settings. Objectives and methods: To leverage the expertise from international members of the Joint Programming Initiative on Antimicrobial Resistance - Primary care Antibiotic Audit and feedback Network (JPIAMR-PAAN). Network members all have experience of designing and delivering A&F interventions to reduce inappropriate antibiotic prescribing in primary care settings. We aim to introduce the network and explore ongoing A&F activities in member regions. An online survey was administered to all network members to collect regional information. Results: Fifteen respondents from 11 countries provided information on A&F activities in their country, and national/regional antibiotic stewardship programmes or policies. Most countries use electronic medical records as the primary data source, antibiotic appropriateness as the main outcome of feedback, and target GPs as the prescribers of interest. Funding sources varied across countries, which could influence the frequency and quality of A&F interventions. Nine out of 11 countries reported having a national antibiotic stewardship programme or policy, which aim to provide systematic support to ongoing AMS efforts and aid sustainability. Conclusions: The survey identified gaps and opportunities for AMS efforts that include A&F across member countries in Europe, Canada and Australia. JPIAMR-PAAN will continue to leverage its members to produce best practice resources and toolkits for antibiotic A&F interventions in primary care settings and identify research priorities.

Shaping a research agenda to ensure a successful European health technology assessment: insights generated during the inaugural convention of the European access academy.

OBJECTIVES: Key challenges for a joint European Health Technology Assessment (HTA) include consolidated approaches towards the choice of adequate comparator(s), selection of endpoints that are relevant to patients with a given disease, dealing with remaining uncertainties as well as transparent and consistent management of related processes. We aimed to further crystallize related core domains within these four areas that warrant further research and scrutiny. METHODS: Building on the outcomes of a previously conducted questionnaire survey, four key areas, processes, uncertainty, comparator choice and endpoint selection, were identified. At the inaugural convention of the European Access Academy dedicated working groups were established defining and prioritizing core domains for each of the four areas. The working groups consisted of ~ 10 participants each, representing all relevant stakeholder groups (patients/ clinicians/ regulators/ HTA & payers/ academia/ industry). Story books identifying the work assignments were shared in advance. Two leads and one note taker per working group facilitated the process. All rankings were conducted on an ordinal Likert Response Scale scoring from 1 (low priority) to 7 (high priority). RESULTS: Identified key domains include for processes: i) address (resource-) challenge of multiple PICOs (Patient/ Intervention/ Comparator/ Outcomes), ii) time and capacity challenges, iii) integrating all involved stakeholders, iv) conflicts and aligning between different multi-national stakeholders, v) interaction with health technology developer; for uncertainty: i) early and inclusive collaboration, ii) agreement on feasibility of RCT and acceptance of uncertainty, iii) alignment on closing evidence gaps, iv) capacity gaps; for comparator choice: i) criteria for the choice of comparator in an increasingly fragmented treatment landscape, ii) reasonable number of comparators in PICOs, iii) shape Early Advice so that comparator fulfils both regulatory and HTA needs, iv) acceptability of Indirect Treatment Comparisons (ITC), v) ensure broad stakeholder involvement in comparator selection; for endpoint selection: i) approaching new endpoints; ii) patient preferences on endpoints; iii) position of HTA and other stakeholders; iv) long-term generation and secondary use of data; v) endpoint challenges in RCTs. CONCLUSIONS: The implementation of a joint European HTA assessment is a unique opportunity for a stronger European Health Union. We identified 19 domains related to the four key areas, processes, uncertainty, comparator choice and endpoint selection that urgently need to be addressed for this regulation to become a success.

CD4:CD8 Ratio and CD8 Cell Count and Their Prognostic Relevance for Coronary Heart Disease Events and Stroke in Antiretroviral Treated Individuals: The Swiss HIV Cohort Study.

INTRODUCTION: HIV infection leads to a persistent expansion of terminally CD8 T cells and CD8 T suppressor cells, a marker of chronic immune activation leading to a low CD4:CD8 ratio that may persist in the presence of potent antiretroviral therapy and regained CD4 helper cells. It remains unclear whether a low CD4:CD8 ratio is associated with cardiovascular diseases. METHODS: We conducted an observational cohort study to investigate the association of immune depression and activation as characterized by the proxy of the CD4:CD8 ratio on the hazard of coronary heart disease (CHD) and stroke among treated individuals living with HIV, while accounting for viral load and known risk factors for cardiovascular diseases and exposure to abacavir or protease inhibitors. We used Cox proportional hazard models with time-dependent cumulative and lagged exposures to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4, CD8, and CD4:CD8 immunological markers were not associated with an increased hazard for CHD. CD8 cell count lagged at 12 months above 1000 cells per µL increased the hazard of stroke, after adjusting for sociodemographics, cardiovascular risk factors, and exposure to specific types of antiretroviral drugs. CONCLUSIONS: This analysis of treated HIV-positive individuals within a large cohort with long-term follow-up does not provide evidence for a prognostic role of immune dysregulation regarding CHD. However, increased CD8 cell count may be a moderate risk factor for stroke. Early detection and treatment of HIV-positive individuals are crucial for an optimal immune restoration and a limited CD8 cells expansion.

Developing and testing a Corona VaccinE tRiAL pLatform (COVERALL) to study Covid-19 vaccine response in immunocompromised patients.

BACKGROUND: The rapid course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic calls for fast implementation of clinical trials to assess the effects of new treatment and prophylactic interventions. Building trial platforms embedded in existing data infrastructures is an ideal way to address such questions within well-defined subpopulations. METHODS: We developed a trial platform building on the infrastructure of two established national cohort studies: the Swiss human immunodeficiency virus (HIV) Cohort Study (SHCS) and Swiss Transplant Cohort Study (STCS). In a pilot trial, termed Corona VaccinE tRiAL pLatform (COVERALL), we assessed the vaccine efficacy of the first two licensed SARS-CoV-2 vaccines in Switzerland and the functionality of the trial platform. RESULTS: Using Research Electronic Data Capture (REDCap), we developed a trial platform integrating the infrastructure of the SHCS and STCS. An algorithm identifying eligible patients, as well as baseline data transfer ensured a fast inclusion procedure for eligible patients. We implemented convenient re-directions between the different data entry systems to ensure intuitive data entry for the participating study personnel. The trial platform, including a randomization algorithm ensuring balance among different subgroups, was continuously adapted to changing guidelines concerning vaccination policies. We were able to randomize and vaccinate the first trial participant the same day we received ethics approval. Time to enroll and randomize our target sample size of 380 patients was 22 days. CONCLUSION: Taking the best of each system, we were able to flag eligible patients, transfer patient information automatically, randomize and enroll the patients in an easy workflow, decreasing the administrative burden usually associated with a trial of this size.

Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in people with HIV.

We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60 years, with CD4+ cell count superior to 350 cells/µl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations.

Incidence of Liver Resection Following the Introduction of Caseload Requirements for Liver Surgery in Switzerland.

BACKGROUND: Centralization of care is an established concept in complex visceral surgery. Switzerland introduced case load requirements (CR) in 2013 in five areas of cancer surgery. The current study investigates the effects of CR on indication and mortality in liver surgery. METHODS: This is a retrospective analysis of a complete national in-hospital data set including all admissions between January 1, 2005, and December 31, 2015. Primary outcome variables were the incidence proportion and the 60-day in-hospital mortality of liver resections. Incidence proportion was calculated as the overall yearly number of liver resections performed in relation to the population living in Switzerland before and after the introduction of CR. RESULTS: Our analysis shows an increase number of liver resections compared to the period before introduction of CR from 2005-2012 (4.67 resections/100,000) to 2013-2015 (5.32 resections/100,000) after CR introduction. Age-adjusted incidence proportion increased by 14% (OR 1.14 95 CI [1.07-1.22]). National in-hospital mortality remained stable before and after CR (4.1 vs 3.7%), but increased in high-volume institutions (3.6 vs 5.6%). The number of hospitals performing liver resections decreased after the introduction of CR from 86 to 43. Half of the resections were performed in institutions reaching the stipulated numbers (53% before vs 49% after introduction of CR). After implementation of CR, patients undergoing liver surgery had more comorbidities (88 vs 92%). CONCLUSION: The introduction of CR for liver surgery in Switzerland in 2013 was accompanied by an increase in operative volume with limited effects on centralization of care.