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Many countries around the world use health technology assessment (HTA) to inform reimbursement and pricing decisions. HTA is often split into two steps, called assessment and appraisal. While the term HTA itself has been defined by international consortia, there is heterogeneity in the way different stakeholders use the terms assessment and appraisal. This creates ambiguity regarding which activities are included in technology assessment. With the new EU HTA Regulation, the HTA community should urgently seek to clarify the distinction between assessment and appraisal, as the regulation aims to centralize the clinical part of technology assessment at the European level. Failure to clarify this terminology will put the ambition of the regulation such as increased efficiency and reduction in duplication at risk. In this article, we argue that the distinction between assessment and appraisal should be seen as a science/value dichotomy. We discuss the transition from centralized assessment activities to country-level appraisal, which should culminate in a categorization of the overall added benefit in a local context. Finally, we touch on the important dimension of uncertainty always present in medical decision making.

Background: This work aimed to determine the role and action points for the involvement of medical societies in the European Health Technology Assessment (EU HTA) Methods: An online pre-convention survey was developed addressing four areas related to the EU HTA: (i) medical societies’ role; (ii) role of clinical guidelines; (iii) interface with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS); and (iv) approaching ‘best-available evidence’ (BAE). A descriptive analysis of questionnaire outcomes was conducted to inform the European Access Academy (EAA) Fall Convention 2023. Within the working groups (WGs), action points were identified and prioritised. Results: A total of 57 experts from 15 countries responded to the survey. The WGs were attended by (i) 11, (ii) 10, (iii) 12, and (iv) 12 experts, respectively, representing a variety of national backgrounds and stakeholder profiles. The most relevant action points identified were as follows: (i) incorporation of clinical context into population, intervention, comparator, outcomes (PICO) schemes, (ii) timely provision of up-to-date therapeutic guidelines, (iii) ensuring the inclusion of MCBS insights into the EU HTA process, and (iv) considering randomized controlled trials (RCTs) as the gold standard and leveraging regulatory insights if development programs only include single-arm trials. Conclusions: The involvement of medical societies is a critical success factor for the EU HTA. The identified key action points foster the involvement of patient associations and medical societies.

Abstract 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.

Abstract 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.

Abstract 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.

Abstract 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.

Abstract Background Late 2019, a new highly contagious coronavirus SARS-CoV-2 has emerged in Wuhan, China, causing within 2 months a pandemic with the highest disease burden in elderly and people with pre-existing medical conditions. The pandemic has highlighted that new and more flexible clinical trial approaches, such as trial platforms, are needed to assess the efficacy and safety of interventions in a timely manner. The two existing Swiss cohorts of immunocompromised patients (i.e., Swiss HIV Cohort Study (SHCS) and Swiss Transplant Cohort Study (STCS)) are an ideal foundation to set-up a trial platform in Switzerland leveraging routinely collected data. Within a newly founded trial platform, we plan to assess the efficacy of the first two mRNA SARS-CoV-2 vaccines that reached market authorization in Switzerland in the frame of a pilot randomized controlled trial (RCT) while at the same time assessing the functionality of the trial platform. Methods We will conduct a multicenter randomized controlled, open-label, 2-arm sub-study pilot trial of a platform trial nested into two Swiss cohorts. Patients included in the SHCS or the STCS will be eligible for randomization to either receiving the mRNA vaccine Comirnaty® (Pfizer/BioNTech) or the COVID-19 mRNA Vaccine Moderna®. The primary clinical outcome will be change in pan-lg antibody response (pan-Ig anti-S1-RBD; baseline vs. 3 months after first vaccination; binary outcome, considering ≥ 0.8 units/ml as a positive antibody response). The pilot study will also enable us to assess endpoints related to trial conduct feasibility (i.e., duration of RCT set-up; time of patient recruitment; patient consent rate; proportion of missing data). Assuming vaccine reactivity of 90% in both vaccine groups, we power our trial, using a non-inferiority margin such that a 95% two-sided confidence interval excludes a difference in favor of the reference group of more than 10%. A sample size of 380 (190 in each treatment arm) is required for a statistical power of 90% and a type I error of 0.025. The study is funded by the Swiss National Science Foundation (National Research Program NRP 78, “COVID-19”). Discussion This study will provide crucial information about the efficacy and safety of the mRNA SARS-CoV-2 vaccines in HIV patients and organ transplant recipients. Furthermore, this project has the potential to pave the way for further platform trials in Switzerland. Trial registration ClinicalTrials.gov NCT04805125 . Registered on March 18, 2021

Abstract Background Mother-to-child HIV transmission (MTCT) has substantially declined since the scale-up of prevention programs around the world, including Rwanda. To achieve full elimination of MTCT, it is important to understand the risk factors associated with residual HIV transmission, defined as MTCT at the population-level that still occurs despite universal access to PMTCT. Methods We performed a case control study of children born from mothers with HIV with known vital status at 18 months from birth, who were followed in three national cohorts between October and December 2013, 2014, and 2015 in Rwanda. Children with HIV were matched in a ratio of 1:2 with HIV-uninfected children and a conditional logistic regression model was used to investigate risk factors for MTCT. Results In total, 84 children with HIV were identified and matched with 164 non-infected children. The median age of mothers from both groups was 29 years (interquartile range (IQR): 24–33). Of these mothers, 126 (51.4 %) initiated antiretroviral therapy (ART) before their pregnancy on record. In a multivariable regression analysis, initiation of ART in the third trimester (Adjusted Odds Ratio [aOR]: 9.25; 95 % Confidence Interval [95 % CI]: 2.12–40.38) and during labour or post-partum (aOR: 8.87; 95 % CI: 1.92–40.88), compared to initiation of ART before pregnancy, increased the risk of MTCT. Similarly, offspring of single mothers (aOR: 7.15; 95 % CI: 1.15–44.21), and absence of postpartum neonatal ART prophylaxis (aOR: 7.26; 95 % CI: 1.66–31.59) were factors significantly associated with MTCT. Conclusions Late ART initiation for PMTCT and lack of postpartum infant prophylaxis are still the most important risk factors to explain MTCT in the era of universal access. Improved early attendance at antenatal care, early ART initiation, and enhancing the continuum of care especially for single mothers is crucial for MTCT elimination in Rwanda.

Abstract Background Negative pressure wound therapy (NPWT) is a widely used method of wound treatment. We performed a systematic review of randomised controlled trials (RCTs) comparing the patient-relevant benefits and harms of NPWT with standard wound therapy (SWT) in patients with wounds healing by secondary intention. Methods We searched for RCTs in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: July 2018) and screened reference lists of relevant systematic reviews and health technology assessments. Manufacturers and investigators were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome (e.g. wound closure). We assessed publication bias and, if feasible, performed meta-analyses, grading the results into different categories (hint, indication or proof of a greater benefit or harm). Results We identified 48 eligible studies of generally low quality with evaluable data for 4315 patients and 30 eligible studies with missing data for at least 1386 patients. Due to potential publication bias (proportion of inaccessible data, 24%), we downgraded our conclusions. A meta-analysis of all wound healing data showed a significant effect in favour of NPWT (OR 1.56, 95% CI 1.15 to 2.13, p = 0.008). As further analyses of different definitions of wound closure did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. A meta-analysis of hospital stay (in days) showed a significant difference in favour of NPWT (MD − 4.78, 95% CI − 7.79 to − 1.76, p = 0.005). As further analyses of different definitions of hospital stay/readmission did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. There was neither proof (nor indication nor hint) of greater benefit or harm of NPWT for other patient-relevant outcomes such as mortality and adverse events. Conclusions In summary, low-quality data indicate a greater benefit of NPWT versus SWT for wound closure in patients with wounds healing by secondary intention. The length of hospital stay is also shortened. The data show no advantages or disadvantages of NPWT for other patient-relevant outcomes. Publication bias is an important problem in studies on NPWT, underlining that all clinical studies need to be fully reported.

Abstract Background Currently, there is limited evidence on the effectiveness of second-line antiretroviral therapy (ART) in sub-Saharan Africa. To address this challenge, outcomes of second-line protease inhibitor (PI) based ART in Rwanda were assessed. Methods A two-stage cluster sampling design was undertaken. 49 of 340 health facilities linked to the open-source electronic medical record (EMR) system of Rwanda were randomly sampled. Data sampling criteria included adult HIV positive patients with documented change from first to second-line ART regimen. Retention in care and treatment failure (viral load above 1000 copies/mL) were evaluated using multivariable Cox proportional hazards and logistic regression models. Results A total of 1688 patients (60% females) initiated second-line ART PI-based regimen by 31st December 2016 with a median follow-up time of 26 months (IQR 24–36). Overall, 92.5% of patients were retained in care; 83% achieved VL ≤ 1000 copies/ml, 2.8% were lost to care and 2.2% died. Defaulting from care was associated with more recent initiation of ART- PI based regimen, CD4 cell count ≤500 cells/mm3 at initiation of second line ART and viral load > 1000 copies/ml at last measurement. Viral failure was associated with younger age, WHO stage III&IV at ART initiation, CD4 cell count ≤500 cells/mm3 at switch, atazanavir based second-line ART and receiving care at a health center compared to hospital settings. Conclusions A high proportion of patients on second-line ART are doing relatively well in Rwanda and retained in care with low viral failure rates. However, enhanced understandings of adherence and adherence interventions for less healthy individuals are required. Routine viral load measurement and tracing of loss to follow-up is fundamental in resource limited settings, especially among less healthy patients.

Introduction: Antibiotic consumption is highest in primary care, and antibiotic overuse furthers antimicrobial resistance. In our recently published pilot-RCT, we used monthly aggregated claims data to provide personalized antibiotic prescription feedback to general practitioners (GPs). The pilot-RCT has shown that personalized prescription feedback is a feasible and promising low-cost intervention to reduce antibiotic prescribing. Here, we describe the rationale and design of the follow-up RCT with 3426 GPs in Switzerland. We now have access to pseudonymized patient-level data from routinely collected health insurance data of the three largest health insurers in Switzerland. Methods and analysis: 1713 GPs randomized to the intervention group received once evidence-based treatment guidelines at the beginning, including region-specific antibiotic resistance information from the community and personalized feedback of their antibiotic prescribing, followed by quarterly personalized prescription feedback for two years. The first and the last mailings were sent out in December 2017 and September 2019, respectively. The 1713 GPs randomized to the control group were not notified about the study and they received no guidelines and no prescription feedback. The personalized prescription feedbacks and the analyses of the primary and secondary outcomes are entirely based on pseudonymized patient-level data from routinely collected health insurance data. The primary outcome is prescribed antibiotics per 100 patient consultations during the second year of intervention. The secondary outcomes include antibiotic use during the entire two-year trial period, use of broad-spectrum antibiotics, hospitalization rates (all-cause and infection-related), and antibiotic use in different age groups. If the feedback intervention proves to be efficacious, the intervention could be continued systemwide. Ethics and dissemination: The trial is publicly funded by the Swiss National Science Foundation (SNSF, grant number 407240_167066). The trial was approved by the ethics committee ''Ethikkommission Nordwest-und Zentralschweiz'' (EKNZ Project-ID 2017-00888). Results will be disseminated in peer-reviewed journals and international conferences.

Abstract Background The available evidence on the benefits and harms of novel drugs and therapeutic biologics at the time of approval is reported in publicly available documents provided by the US Food and Drug Administration (FDA). We aimed to create a comprehensive database providing the relevant information required to systematically analyze and assess this early evidence in meta-epidemiological research. Methods We designed a modular and flexible database of systematically collected data. We identified all novel cancer drugs and therapeutic biologics approved by the FDA between 2000 and 2016, recorded regulatory characteristics, acquired the corresponding FDA approval documents, identified all clinical trials reported therein, and extracted trial design characteristics and treatment effects. Herein, we describe the rationale and design of the data collection process, particularly the organization of the data capture, the identification and eligibility assessment of clinical trials, and the data extraction activities. Discussion We established a comprehensive database on the comparative effects of drugs and therapeutic biologics approved by the FDA over a time period of 17 years for the treatment of cancer (solid tumors and hematological malignancies). The database provides information on the clinical trial evidence available at the time of approval of novel cancer treatments. The modular nature and structure of the database and the data collection processes allow updates, expansions, and adaption for a continuous meta-epidemiological analysis of novel drugs. The database allows us to systematically evaluate benefits and harms of novel drugs and therapeutic biologics. It provides a useful basis for meta-epidemiological research on the comparative effects of innovative cancer treatments and continuous evaluations of regulatory developments.

Abstract Background Several studies found mid-regional pro-adrenomedullin (ProADM), the prohormone of the cardiovascular protein adrenomedullin, to be strongly associated with short-term mortality, mostly in the inpatient setting. We evaluated associations of ProADM levels with 10-year mortality in community-dwelling primary care patients with respiratory tract infections. Methods This is a post-hoc analysis using clinical and biomarker data of 134 primary care patients with respiratory tract infections. ProADM was measured on admission and after 7 days in batch-analysis. 10-year follow-up data was collected by GP, patient and relative tracing through phone interviews. We calculated Cox regression models and area under the receiver operating characteristics curves to assess associations of ProADM with 10-year all-cause mortality. Results During the 10-year follow-up 6% of included patients died. Median baseline ProADM blood levels (nmol/l) were significantly higher in non-survivors compared to survivors (0.5, IQR 0.4–1.3; vs. 0.2, IQR 0.1–0.5; p = 0.02) and showed a significant association with 10-year all-cause mortality in an age-adjusted cox regression model (HR: 2.5, 95%-CI: 1.0–6.1, p = 0.04). ProADM levels on day 7 showed similar results. Conclusions This posthoc analysis found an association of elevated ProADM blood levels and 10-year all-cause mortality in a primary care cohort with respiratory tract infections. Due to the methodological limitations including incomplete data regarding follow-up information and biomarker measurement, this study warrants validation in future larger studies. Trial registration Current Controlled Trials, SRCTN73182671

OBJECTIVE Asthma is associated with bronchial hyperresponsiveness, assessed by bronchial provocation tests such as the mannitol test. We aimed to assess the data on sensitivity and specificity of the mannitol test in diagnosing asthma. DATA SOURCES We searched electronically the Medline, Embase and Central databases from 1997 to 2019. STUDY SELECTION Inclusion criteria were the assessment of the validity of the mannitol test. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). Data were extracted according to a prespecified list and analysed qualitatively. RESULTS A total of 27 studies (4589 individuals, age 6–85 years, cross-sectional [n = 18] and case-controlled [n = 9] study design) were included. Overall sensitivity and specificity ranged from 8% (95% confidence interval [CI] 1–27) to 100% (95% CI 93–100) and 75% (95% CI 67–82) to 100% (95% CI 85–100). Excluding case-controlled design, studies conducted in a clinical setting showed a range from 19% (95% CI 14–27) to 91% (95% CI 59–100) for sensitivity and from 75% (95% CI 67–82) to 100% (95% CI 80–100) for specificity. Heterogeneity was high owing to differences in the populations examined and the methods used. CONCLUSIONS Studies on the accuracy of the mannitol test were heterogeneous. Overall specificity was higher than sensitivity and therefore the mannitol test seems to be a suitable diagnostic tool to confirm asthma. However, the high level of heterogeneity among the included studies makes a conclusive statement on the accuracy of the mannitol test difficult and further research is needed. As bronchial provocation tests can be especially useful in patients with an intermediate probability of asthma diagnosis, further studies are needed that include subjects with asthma symptoms but intermediate probability of asthma diagnosis.

BACKGROUND The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer’s disease is inconclusive. AIMS OF THE STUDY. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is

BACKGROUND Surgical registries are becoming increasingly popular. In addition, Swiss legislation requires data on therapeutic outcome quality. The Swiss Association of Surgeons (Schweizerische Gesellschaft Chirurgie, SGC-SCC) has already agreed on a first minimum data set. However, in the long run the scope and content of the registry should be evidence-based and not only accepted by professional stakeholders. The MIDAS study aims at providing such evidence for the example population of patients undergoing emergency or elective hip surgery. Five relevant aspects are considered: (1) choice of instruments for assessing health related quality of life (HRQoL); (2) optimal time-point for assessment; (3) use of proxy assessments; (4) choice of pre-surgery risk factors; and (5) assessment of peri- and postoperative variables. METHODS MIDAS is a longitudinal observational multicentre study. All patients suffering from a femoral neck fracture or from arthritis of the hip joint with an indication for prosthetic joint replacement surgery will be offered participation. The study is based on a combination of routine data from clinical standard practice with specifically documented data to be reported by the treating clinician and data to be collected in cooperation with the patient – in particular patient-reported outcome measures (PROMs). The latter include the Health Utility Index Mark 3 (HUI3) and Euro-Qol-5D (EQ-5D) as generic instruments, Hip Disability and Osteoarthritis Outcome Score (HOOS) as a disease specific instrument for the assessment of HRQoL, and two performance-based functional tests. Data will be collected at baseline, during hospitalisation/at discharge and at three routine follow-up visits. All patients will be asked to name a person for assessing proxy-perceived HRQoL. DISCUSSION To the best of our knowledge, this is the first study explicitly addressing questions about the design of a national surgical registry in an empirical manner. The study aims at providing a scientific base for decisions regarding scope and content of a potential national Swiss surgical registry. We designed a pragmatic study to envision data collection in a national registry with the option of specifying isolated research questions of interest. One focus of the study is the use of PROMs, and we hope that our study and their results will inspire also other surgical registries to take this important step forward. Trial registration Registered at the “Deutsches Register Klinischer Studien (DRKS)”, the German Clinical Trials Registry, since this registry meets the scope and methodology of the proposed study. Registration no.: DRKS00012991

OBJECTIVES The aims of this study were to (a) identify and assess the quality of reporting of published cost-effectiveness studies of bariatric surgery, (b) assess their transferability to Switzerland, and (c) adapt transferable cost-effectiveness results to Switzerland. METHODS A systematic literature search was performed in Medline, Embase and other databases. Two reviewers independently undertook screening, extraction, assessment of reporting quality utilising the Consolidated Health Economic Evaluation Reporting Standards, transferability, adaptation of cost data and recalculation of cost-effectiveness results. Cost data were adapted in three steps: correction for different levels of resource utilisation, for different prices of healthcare services and for change in costs over time. RESULTS Fifteen studies fulfilled criteria for adaptation of cost data to Switzerland. Four out of fifteen adapted studies with a long time-horizon for patients with a body mass index (BMI) >35kg/m2 indicated bariatric surgery to be a cost-saving (dominant) approach compared with conventional treatment. Other studies for patients with BMI >35kg/m2 showed cost-effective results, with incremental cost-effectiveness ratios (ICERs) below CHF 50,000 per quality adjusted life-year (QALY) gained. Two studies assessed cost-effectiveness for patients with BMI

Antecedentes: El período inmediato después del inicio del síndrome coronario agudo (SCA) representa un estadio crítico de la cardiopatía coronaria con un alto riesgo de eventos recurrentes y muertes. En los pacientes que presentan SCA los efectos a corto plazo del tratamiento precoz con estati-nas sobre resultados relevantes para el paciente son inciertos. Objetivos: Evaluar los efectos beneficiosos y perjudiciales de las estatinas administradas de forma precoz en pacientes con SCA a partir de ensayos controlados aleatorios (ECA). Estrategia de búsqueda: Se hicieron búsquedas en CENTRAL, MEDLINE, EMBASE y CINAHL (hasta el 1 febrero 2010). No se aplicó ninguna restricción en cuanto al idioma. La búsqueda se complementó al establecer contacto con especialistas en el campo, examinar las listas de referencias de las revisiones y los artículos editoriales sobre el tema y al buscar en los registros de ensayos. Criterios de selección: ECA que compararon estatinas con placebo o atención habitual, iniciaron el tratamiento con estatina en el transcurso de los 14 días después del inicio del SCA, tuvieron un seguimiento de al menos 30 días e informaron al menos un resultado clínico. Obtención y análisis de los datos: Dos autores evaluaron de forma independiente la calidad de los estudios y extrajeron los datos. Con un modelo de efectos aleatorios, se agruparon los efectos del tratamiento y se calcularon los cocientes de riesgos (CR) para todos los resultados en los grupos de tratamiento y control. Resultados principales: Dieciocho estudios (14 303 pacientes) compararon el tratamiento precoz con estatina versus placebo o atención habitual en pacientes con SCA. En comparación con el placebo o la atención habitual, el tratamiento precoz con estatina no redujo el resultado primario combinado de muerte, infarto de miocardio (IM) no mortal y accidente cerebrovascular al mes (cociente de riesgos [cR] 0,93; intervalo de confianza [IC] del 95%: 0,80 a 1,08) ni a los cuatro meses (CR 0,93; IC del 95%: 0,81 a 1,06) de seguimiento. No hubo reducciones estadísticamente significativas en el riesgo de las estatinas para muerte total, IM total, accidente cerebrovascular total, muerte cardiovascular, procedimientos de revascularización e insuficiencia cardíaca aguda al mes ni a los cuatro meses, aunque hubo tendencias favorables relacionadas con el uso de las estatinas para cada una de estas variables de evaluación. La incidencia de episodios de angina inestable se redujo significativamente a los cuatro meses después del SCA (CR 0,76; IC del 95%: 0,59 a 0,96). Hubo nueve pacientes con miopatía (niveles elevados de creatinquinasa > 10 veces el límite superior de lo normal) en los pacientes tratados con estatina (0,13%) versus uno (0,015%) en los grupos control. La toxicidad muscular grave estuvo limitada principalmente a los pacientes tratados con simvastatina 80 mg. Conclusiones de los autores: Según las pruebas disponibles, el inicio del tratamiento con estatinas en el transcurso de 14 días después del SCA no reduce la muerte, el infarto de miocardio ni el accidente cerebrovascular hasta los cuatro meses, pero reduce la ocurrencia de angina inestable a los cuatro meses después del SCA.

T-cell response plays an important role in SARS-CoV-2 immunogenicity. For people living with HIV (PWH) and solid organ transplant (SOT) recipients there is limited evidence on the reliability of commercially available T-cell tests. We assessed 173 blood samples from 81 participants (62 samples from 35 PWH; 111 samples from 46 SOT recipients [lung and kidney]) with two commercial SARS-CoV-2 Interferon-γ (IFN-γ) release assays (IGRA; SARS-CoV-2 IGRA by Euroimmun, and IGRA SARS-CoV-2 by Roche). The reliability between the tests was judged as low (Cohen's kappa [κ] = 0.20; overall percent agreement [OPA] = 66%). A high proportion of tests were invalid (22% Euroimmun; 8% Roche). When excluding these invalid tests, the agreement was higher (κ = 0.43; OPA = 90%). The low reliability between the two T-cell tests indicates that results should be interpreted with caution in SOT recipients and PWH and that SARS-CoV-2 T-cell tests need to be optimized and further validated for use in vulnerable patient populations.

Introduction The emphasis on aesthetic outcomes and quality of life (QoL) has motivated surgeons to develop skin-sparing or nipple-sparing mastectomy (SSM/ NSM) for breast cancer treatment or prevention. During the same operation, a so-called immediate breast reconstruction is performed. The breast can be reconstructed by positioning of a breast implant above (prepectoral) or below (subpectoral) the pectoralis major muscle or by using the patients’ own tissue (autologous reconstruction). The optimal positioning of the implant prepectoral or subpectoral is currently not clear. Subpectoral implant-based breast reconstruction (IBBR) is still standard care in many countries, but prepectoral IBBR is increasingly performed. This heterogeneity in breast reconstruction practice is calling for randomised clinical trials (RCTs) to guide treatment decisions.Methods and analysis International, pragmatic, multicentre, randomised, superiority trial. The primary objective of this trial is to test whether prepectoral IBBR provides better QoL with respect to long-term (24 months) physical well-being (chest) compared with subpectoral IBBR for patients undergoing SSM or NSM for prevention or treatment of breast cancer. Secondary objectives will compare prepectoral versus subpectoral IBBR in terms of safety, QoL and patient satisfaction, aesthetic outcomes and burden on patients. Total number of patients to be included: 372 (186 per arm).Ethics and dissemination This study will be conducted in compliance with the Declaration of Helsinki. Ethical approval has been obtained for the lead investigator’s site by the Ethics Committee ‘Ethikkommission Nordwest- und Zentralschweiz‘ (2020–00256, 26 March 2020). The results of this study will be published in a peer-reviewed medical journal, independent of the results, following the Consolidated Standards of Reporting Trials standards for RCTs and good publication practice. Metadata describing the type, size and content of the datasets will be shared along with the study protocol and case report forms on public repositories adhering to the FAIR (Findability, Accessibility, Interoperability, and Reuse) principles.Trial registration number NCT04293146.

OBJECTIVES: It is unclear to what extent assessments of work ability differ between disability claimants, their treating physicians, and multidisciplinary medical expert teams. METHODS: We compared assessments of work ability for consecutive disability claimants referred to a multidisciplinary assessment center in Switzerland over a 4-year period. Assessments were made for the last job (LJ) prior to claiming a disability benefit and an alternative job (AJ) thought to suit the claimant’s physical and mental abilities. Mean differences (MD) in percentage work ability between assessments from claimants, physicians, and experts were then estimated in a linear regression model. RESULTS: The 3562 claims made during the study period were mostly due to musculoskeletal and depressive disorders. Assessments differed little between claimants and physicians [LJ MD 1.3% (95% confidence interval [95% CI] 0.5–2.2%); AJ MD 11% (95% CI 10–12%)]. Experts on average assessed a claimant’s work ability higher than either the claimant or physician, particularly in the AJ [MD between expert and claimant 57% (95% CI 56–58%) and between expert and physician 46% (95% CI 45–48%)]. CONCLUSIONS: Assessments of work ability differed substantially between experts in multidisciplinary medical teams and both claimants and their treating physicians. A careful evaluation of the disability assessment process is needed in an effort to reduce disagreement between expert teams and treating physicians and so improve acceptance of the process.

AIMS OF THE STUDY: To assess the cost-effectiveness of primarily surgical treatment (PST) versus primarily conservative treatment (PCT) in adults with intermediate severity, acute or subacute, lumbar radicular syndrome due to intervertebral disc herniation. METHODS: A decision analytic model from healthcare system and societal perspectives was used to compare outcomes and costs of PST with those of PCT (physiotherapy, epidural injection and medication). Treatment pathways and quality of life were obtained from published clinical trials. Costs were derived from Swiss health insurance claims data. Swiss clinical experts provided information on use of medication and physiotherapy. The main outcome of interest was incremental cost per quality-adjusted-life-year (QALY) gained over a period of 2 years. Costs and QALYs gained were discounted from the second year, at a rate of 2% per year. RESULTS: In the base-case analysis from a healthcare system perspective, over 2 years, PST compared with PCT led to 0.0634 additional QALYs per person, at an additional net cost of CHF 7198 per person. The corresponding incremental cost effectiveness ratio (ICER) amounted to CHF 113 396 per QALY gained. From a societal perspective the ICER was CHF 70 711 per QALY gained. ICERs were subject to substantial uncertainty because of limitations in available data. CONCLUSION: A PST approach, when compared with PCT, may be cost effective from a societal perspective based on a willingness-to-pay threshold of CHF 100 000 per QALY gained. However, it is less likely to be cost effective from the perspective of the Swiss healthcare system. More research is needed to understand the long-term economic implications among this patient group.

BackgroundLittle is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees.Methods and findingsWe used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements.ConclusionsPublication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.

We analysed potential drug-drug interactions (DDI) in ambulatory care in Switzerland based on claims data from three large health insurers in 2010 to identify physicians with peculiar prescription behaviour differing from peers of the same specialty.We analysed contraindicated or potentially contraindicated DDI from the national drug formulary and calculated for each physician the ratios of the number of patients with a potential DDI divided by the number of patients at risk and used a zero inflated binomial distribution to correct for the inflated number of observations with no DDI. We then calculated the probability that the number of caused potential DDI of physicians was unlikely (p-value < 0.05 and ≥ 0.01) and very unlikely (p-value

Antibiotics are overused in children and adolescents with lower respiratory tract infection (LRTI). Serum-procalcitonin (PCT) can be used to guide treatment when bacterial infection is suspected. Its role in pediatric LRTI is unclear.Between 01/2009 and 02/2010 we randomized previously healthy patients 1 month to 18 years old presenting with LRTI to the emergency departments of two pediatric hospitals in Switzerland to receive antibiotics either according to a PCT guidance algorithm established for adult LRTI or standard care clinical guidelines. In intention-to-treat analyses, antibiotic prescribing rate, duration of antibiotic treatment, and number of days with impairment of daily activities within 14 days of randomization were compared between the two groups.In total 337 children, mean age 3.8 years (range 0.1-18), were included. Antibiotic prescribing rates were not significantly different in PCT guided patients compared to controls (OR 1.26; 95% CI 0.81, 1.95). Mean duration of antibiotic exposure was reduced from 6.3 to 4.5 days under PCT guidance (-1.8 days; 95% CI -3.1, -0.5; P = 0.039) for all LRTI and from 9.1 to 5.7 days for pneumonia (-3.4 days 95% CI -4.9, -1.7; P

BACKGROUND:Non-adherence is one of the strongest predictors of therapeutic failure in HIV-positive patients. Virologic failure with subsequent emergence of resistance reduces future treatment options and long-term clinical success. METHODS:Prospective observational cohort study including patients starting new class of antiretroviral therapy (ART) between 2003 and 2010. Participants were naïve to ART class and completed ≥1 adherence questionnaire prior to resistance testing. Outcomes were development of any IAS-USA, class-specific, or M184V mutations. Associations between adherence and resistance were estimated using logistic regression models stratified by ART class. RESULTS:Of 314 included individuals, 162 started NNRTI and 152 a PI/r regimen. Adherence was similar between groups with 85% reporting adherence ≥95%. Number of new mutations increased with increasing non-adherence. In NNRTI group, multivariable models indicated a significant linear association in odds of developing IAS-USA (odds ratio (OR) 1.66, 95% confidence interval (CI): 1.04-2.67) or class-specific (OR 1.65, 95% CI: 1.00-2.70) mutations. Levels of drug resistance were considerably lower in PI/r group and adherence was only significantly associated with M184V mutations (OR 8.38, 95% CI: 1.26-55.70). Adherence was significantly associated with HIV RNA in PI/r but not NNRTI regimens. CONCLUSION:Therapies containing PI/r appear more forgiving to incomplete adherence compared with NNRTI regimens, which allow higher levels of resistance, even with adherence above 95%. However, in failing PI/r regimens good adherence may prevent accumulation of further resistance mutations and therefore help to preserve future drug options. In contrast, adherence levels have little impact on NNRTI treatments once the first mutations have emerged.

We aimed to compare rates of virologic response and CD4 changes after combination antiretroviral (cART) initiation in individuals infected with B and specific non-B HIV subtypes.Using CASCADE data we analyzed HIV-RNA and CD4 counts for persons infected ≥1996, ≥15 years of age. We used survival and longitudinal modeling to estimate probabilities of virologic response (confirmed HIV-RNA 500 c/ml at 6 months or ≥1000 c/ml following response) and CD4 increase after cART initiation.2003 (1706 B, 142 CRF02_AG, 55 A, 53 C, 47 CRF01_AE) seroconverters were included in analysis. There was no evidence of subtype effect overall for response or failure (p = 0.075 and 0.317, respectively) although there was a suggestion that those infected with subtypes CRF01_AE and A responded sooner than those with subtype B infection [HR (95% CI):1.37 (1.01-1.86) and 1.29 (0.96-1.72), respectively]. Rates of CD4 increase were similar in all subtypes except subtype A, which tended to have lower initial, but faster long-term, increases.Virologic and immunologic response to cART was similar across all studied subtypes but statistical power was limited by the rarity of some non-B subtypes. Current antiretroviral agents seem to have similar efficacy in subtype B and most widely encountered non-B infections in high-income countries.

BACKGROUND: In HIV-infected patients, prediction of Cytomegalovirus (CMV) disease remains difficult. A protective role of mannan-binding lectin (MBL) and ficolins against CMV disease has been reported after transplantation, but the impact in HIV-infected patients is unclear. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we investigated associations between plasma levels of MBL/ficolins and CMV disease. We compared HIV-infected patients with CMV disease (cases) to CMV-seropositive patients without CMV disease (controls) matched for CD4 T-cells, sampling time, and use of combination antiretroviral therapy. MBL and M-ficolin, L-ficolin, and H-ficolin were quantified using ELISA. RESULTS: We analysed 105 cases and 105 matched controls. CMV disease was neither associated with MBL (odds ratio [OR] 1.03 per log(10) ng/mL increase (95% CI 0.73-1.45)) nor with ficolins (OR per log(10) ng/mL increase 0.66 (95% CI 0.28-1.52), 2.34 (95% CI 0.44-12.36), and 0.89 (95% CI 0.26-3.03) for M-ficolin, L-ficolin, and H-ficolin, respectively). We found no evidence of a greater association between MBL and CMV disease in patients with low CD4 counts; however in the multivariable analysis, CMV disease was more likely in patients with an increased HIV RNA (OR 1.53 per log(10) copies/mL; 95% CI 1.08-2.16), or a shorter duration of HIV-infection (OR 0.91 per year; 95% CI 0.84-0.98). CONCLUSIONS: CMV disease is not associated with low levels of MBL/ficolins, suggesting a lack of a protective role in HIV-infected patients.

BACKGROUND:New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis. METHODOLOGY/PRINCIPAL FINDINGS:The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995-1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate. CONCLUSIONS/SIGNIFICANCE:The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions.

BackgroundGood adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels.MethodsEligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA ResultsFrom January 2003 until May 2009, 37 individuals on EFV (28 suppressed and 9 not suppressed) and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56).ConclusionsThe investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.

Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland.HIV-infected patients aged ≥18 years who started ART 2004-2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells

The unparalleled success of combination antiretroviral therapy (cART) is based on the combination of three drugs from two classes. There is insufficient evidence whether simplification to ritonavir boosted protease inhibitor (PI/r) monotherapy in virologically suppressed HIV-infected patients is effective and safe to reduce cART side effects and costs.We systematically searched Medline, Embase, the Cochrane Library, conference proceedings and trial registries to identify all randomised controlled trials comparing PI/r monotherapy to cART in suppressed patients. We calculated in an intention to treat (loss-of follow-up, discontinuation of assigned drugs equals failure) and per-protocol analysis (exclusion of protocol violators following randomisation) and based on three different definitions for virological failure pooled risk ratios for remaining virologically suppressed.We identified 10 trials comparing 3 different PIs with cART based on a PI/r plus 2 reverse transcriptase inhibitors in 1189 patients. With the most conservative approach (viral load

BackgroundThere is insufficient evidence whether the benefit of adding angiotensin II receptor blockers (ARBs) to angiotensin-converting enzyme (ACE) inhibitors outweighs the increased risk of adverse effects in patients with heart failure.Methodology/principal findingsTwo independent reviewers searched and abstracted randomized controlled trials of ARBs and ACE inhibitors compared to ACE inhibitor therapy alone in patients with heart failure reporting mortality and hospitalizations having a follow-up of at least 6 months identified by a systematic literature search. Eight trials including a total of 18,061 patients fulfilled our inclusion criteria. There was no difference between patients treated with combination therapy and ACE inhibitor therapy alone for overall mortality, hospitalization for any reason, fatal or nonfatal MI. Combination therapy was, however, associated with fewer hospital admissions for heart failure (RR 0.81, 95%CI 0.72-0.91), although there was significant heterogeneity across trials (p-value for heterogeneity = 0.04; I(2) = 57% [95%CI 0-83%]). Patients treated with combination therapy had a higher risk of worsening renal function and symptomatic hypotension, and their trial medications were more often permanently discontinued. Lack of individual patient data precluded the analysis of time-to-event data and identification of subgroups which potentially benefit more from combination therapy such as younger patients with preserved renal function and thus at lower risk to experience worsening renal function or hyperkalemia.Conclusions/significanceCombination therapy with ARBs and ACE inhibitors reduces admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but does not reduce overall mortality or all-cause hospitalization and is associated with more adverse events. Thus, based on current evidence, combination therapy with ARBs and ACE inhibitors may be reserved for patients who remain symptomatic on therapy with ACE inhibitors under strict monitoring for any signs of worsening renal function and/or symptomatic hypotension.

CD4 cell count is a strong predictor of the subsequent risk of AIDS or death in HIV-infected patients initiating combination antiretroviral therapy (cART). It is not known whether the rate of CD4 cell decline prior to therapy is related to prognosis and should, therefore, influence the decision on when to initiate cART.We carried out survival analyses of patients from the 23 cohorts of the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) collaboration with a known date of HIV seroconversion and with at least two CD4 measurements prior to initiating cART. For each patient, a pre-cART CD4 slope was estimated using a linear mixed effects model. Our primary outcome was time from initiating cART to a first new AIDS event or death. We included 2,820 treatment-naïve patients initiating cART with a median (interquartile range) pre-cART CD4 cell decline of 61 (46-81) cells/microl per year; 255 patients subsequently experienced a new AIDS event or death and 125 patients died. In an analysis adjusted for established risk factors, the hazard ratio for AIDS or death was 1.01 (95% confidence interval 0.97-1.04) for each 10 cells/microl per year reduction in pre-cART CD4 cell decline. There was also no association between pre-cART CD4 cell slope and survival. Alternative estimates of CD4 cell slope gave similar results. In 1,731 AIDS-free patients with >350 CD4 cells/microl from the pre-cART era, the rate of CD4 cell decline was also not significantly associated with progression to AIDS or death (hazard ratio 0.99, 95% confidence interval 0.94-1.03, for each 10 cells/microl per year reduction in CD4 cell decline).The CD4 cell slope does not improve the prediction of clinical outcome in patients with a CD4 cell count above 350 cells/microl. Knowledge of the current CD4 cell count is sufficient when deciding whether to initiate cART in asymptomatic patients. Please see later in the article for the Editors' Summary.