Antibody and T-cell response to bivalent booster SARS-CoV-2 vaccines in people with compromised immune function (COVERALL-3).

BACKGROUND: Bivalent mRNA vaccines, designed to combat emerging SARS-CoV-2 variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months post vaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/ml (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a five-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with HIV or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare.

Evaluation of the 2023 Duke-International Society of Cardiovascular Infectious Diseases Criteria in a Multicenter Cohort of Patients With Suspected Infective Endocarditis.

BACKGROUND: Since publication of Duke criteria for infective endocarditis (IE) diagnosis, several modifications have been proposed. We aimed to evaluate the diagnostic performance of the Duke-ISCVID (International Society of Cardiovascular Infectious Diseases) 2023 criteria compared to prior versions from 2000 (Duke-Li 2000) and 2015 (Duke-ESC [European Society for Cardiology] 2015). METHODS: This study was conducted at 2 university hospitals between 2014 and 2022 among patients with suspected IE. A case was classified as IE (final IE diagnosis) by the Endocarditis Team. Sensitivity for each version of the Duke criteria was calculated among patients with confirmed IE based on pathological, surgical, and microbiological data. Specificity for each version of the Duke criteria was calculated among patients with suspected IE for whom IE diagnosis was ruled out. RESULTS: In total, 2132 episodes with suspected IE were included, of which 1101 (52%) had final IE diagnosis. Definite IE by pathologic criteria was found in 285 (13%), 285 (13%), and 345 (16%) patients using the Duke-Li 2000, Duke-ESC 2015, or the Duke-ISCVID 2023 criteria, respectively. IE was excluded by histopathology in 25 (1%) patients. The Duke-ISCVID 2023 clinical criteria showed a higher sensitivity (84%) compared to previous versions (70%). However, specificity of the new clinical criteria was lower (60%) compared to previous versions (74%). CONCLUSIONS: The Duke-ISCVID 2023 criteria led to an increase in sensitivity compared to previous versions. Further studies are needed to evaluate items that could increase sensitivity by reducing the number of IE patients misclassified as possible, but without having detrimental effect on specificity of Duke criteria.

Evaluation of the 2023 Duke-ISCVID and 2023 Duke-ESC Clinical Criteria for the Diagnosis of Infective Endocarditis in a Multicenter Cohort of Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: The Duke criteria for infective endocarditis (IE) diagnosis underwent revisions in 2023 by the European Society of Cardiology (ESC) and the International Society for Cardiovascular Infectious Diseases (ISCVID). This study aims to assess the diagnostic accuracy of these criteria, focusing on patients with Staphylococcus aureus bacteremia (SAB). METHODS: This Swiss multicenter study conducted between 2014 and 2023 pooled data from three cohorts. It evaluated the performance of each iteration of the Duke criteria by assessing the degree of concordance between definite S. aureus IE (SAIE) and the diagnoses made by the Endocarditis Team (2018-23) or IE expert clinicians (2014-17). RESULTS: Among 1344 SAB episodes analyzed, 486 (36%) were identified as cases of SAIE. The 2023 Duke-ISCVID and 2023 Duke-ESC criteria demonstrated improved sensitivity for SAIE diagnosis (81% and 82%, respectively) compared to the 2015 Duke-ESC criteria (75%). However, the new criteria exhibited reduced specificity for SAIE (96% for both) compared to the 2015 criteria (99%). Spondylodiscitis was more prevalent among patients with SAIE compared to those with SAB alone (10% vs 7%, P = .026). However, when patients meeting the minor 2015 Duke-ESC vascular criterion were excluded, the incidence of spondylodiscitis was similar between SAIE and SAB patients (6% vs 5%, P = .461). CONCLUSIONS: The 2023 Duke-ISCVID and 2023 Duke-ESC clinical criteria show improved sensitivity for SAIE diagnosis compared to 2015 Duke-ESC criteria. However, this increase in sensitivity comes at the expense of reduced specificity. Future research should aim at evaluating the impact of each component introduced within these criteria.

18F-fluorodeoxyglucose uptake patterns in positron emission tomography/computed tomography caused by inflammation and/or infection after graft surgery for thoracic aortic dissection.

BACKGROUND: To identify 18F-fluorodeoxyglucose (FDG) uptake patterns in positron emission tomography/computed tomography (PET/CT) caused by infection, inflammation, surgical material, and/or graft coating. METHODS AND RESULTS: Of 610 consecutive patients with thoracic aortic graft surgery, 60 patients with 187 PET/CT were retrospectively included. We quantified FDG uptake in all grafts using maximum standardized uptake value (SUVmax) alone and in relation to liver background (SUVratio) and determined the uptake pattern. Mixed linear regression models with random slope and intercept were applied for the analysis of SUVratio over time and generalized estimating equations to analyze the associations with anastomosis uptake. FDG uptake was frequently focal (90%), higher in infected than in noninfected grafts (mean SUVratio 2.19; 95% CI 2.05-2.32 vs. 1.63; 1.46-1.79, P < 0.001), and decreasing slowly over time (SUVratio per year since surgery -0.048; 95% CI -0.15- 0.051, P = 0.34), without a difference in slope between infected and noninfected grafts (P = 0.52). There was no evidence of an interaction between SUVratio and use of BioGlue® surgical adhesive (intercept P = 0.73, slope P = 0.71), or graft coating (gelatin and collagen, all P > 0.7). FDG uptake at the anastomosis was more frequent in noninfected grafts than in infected grafts (66% vs. 21%, odds ratio (OR) 11.34; 95% CI 3.61-35.66, P < 0.001). This effect was attenuated by the use of BioGlue® (OR 5.05; 95% CI 0.45-56.9, P = 0.19). CONCLUSIONS: FDG uptake in PET/CT after thoracic aortic graft surgery is higher in infected grafts than in noninfected grafts. In noninfected grafts, focal uptake is also frequent, mostly anastomosis-associated, not associated with graft coating, and possibly affected by the use of BioGlue®.

Improving antimicrobial treatment in terms of antimicrobial stewardship and health costs by an OPAT service.

PURPOSE: Outpatient parenteral antimicrobial therapy (OPAT) is a standard for antimicrobial therapy internationally. With this prospective cohort study, we aimed to assess the impact of an OPAT service as part of antimicrobial stewardship (AMS) and evaluate the safety and efficiency of the program while illuminating the financial benefit for the hospital. METHODS: Socio-demographic data, treatment regimen and outcomes were prospectively recorded for all patients assigned to the program of the OPAT unit of the University Hospital of Zurich between November 2018 and September 2022. RESULTS: In total, we recorded 303 OPAT assignments of which 260 resulted in effective OPAT episodes. The 260 OPAT episodes were further optimized toward the choice of antimicrobial agent (n = 18) and length of therapy (n = 6). Moreover, OPAT resulted in alteration of patient assessment and care led by AMS strategies in 247 of 260 episodes (95%). While the bed days saved per year increased consistently with time, a total of 3934 in-hospital treatment days were saved amounting to a cost saving of 9,835,000 CHF over 47 months. Adverse events were recorded in 46 cases whilst only two of these have been the reason for readmission during OPAT treatment. Clinical cure was noted in 77% (199/260) and was negatively associated with Charlson Comorbidity Index (CCI; OR per 1 unit higher 0.85 (95% CI 0.78-0.93)). CONCLUSION: This study demonstrates the impact of an OPAT service in the framework of AMS as well as its benefits for the hospital whilst preserving safety and efficacy for the patient's parenteral antimicrobial treatment.

Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success.

Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistance. Even antibiotic-susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations, and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic pH, abscess environment, and antibiotic exposure promoted persister formation in vitro and in vivo. Multiomics analysis identified molecular changes in S. aureus in response to acid stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters, including down-regulation of virulence and cell division and up-regulation of ribosomal proteins, nucleotide-, and amino acid-metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP levels and accumulation of insoluble proteins involved in transcription, translation, and energy production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype, including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted antipersister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult to treat.

Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

The 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis: Updating the Modified Duke Criteria.

The microbiology, epidemiology, diagnostics, and treatment of infective endocarditis (IE) have changed significantly since the Duke Criteria were published in 1994 and modified in 2000. The International Society for Cardiovascular Infectious Diseases (ISCVID) convened a multidisciplinary Working Group to update the diagnostic criteria for IE. The resulting 2023 Duke-ISCVID IE Criteria propose significant changes, including new microbiology diagnostics (enzyme immunoassay for Bartonella species, polymerase chain reaction, amplicon/metagenomic sequencing, in situ hybridization), imaging (positron emission computed tomography with 18F-fluorodeoxyglucose, cardiac computed tomography), and inclusion of intraoperative inspection as a new Major Clinical Criterion. The list of "typical" microorganisms causing IE was expanded and includes pathogens to be considered as typical only in the presence of intracardiac prostheses. The requirements for timing and separate venipunctures for blood cultures were removed. Last, additional predisposing conditions (transcatheter valve implants, endovascular cardiac implantable electronic devices, prior IE) were clarified. These diagnostic criteria should be updated periodically by making the Duke-ISCVID Criteria available online as a "Living Document."

Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.

Antibiotic prophylaxis before dental procedures to prevent infective endocarditis: a systematic review.

PURPOSE: Infective endocarditis (IE) is a severe bacterial infection. As a measure of prevention, the administration of antibiotic prophylaxis (AP) prior to dental procedures was recommended in the past. However, between 2007 and 2009, guidelines for IE prophylaxis changed all around the word, limiting or supporting the complete cessation of AP. It remains unclear whether AP is effective or not against IE. METHODS: We conducted a systematic review whether the administration of AP in adults before any dental procedure, compared to the non-administration of such drugs, has an effect on the risk of developing IE. We searched for studies in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OVID, and EMBASE. Two different authors filtered articles independently and data extraction was performed based on a pre-defined protocol. RESULTS: The only cohort study meeting our criteria included patients at high-risk of IE. Analysis of the extracted data showed a non-significant decrease in the risk of IE when high-risk patients take AP prior to invasive dental procedures (RR 0.39, p-value 0.11). We did not find other studies including patients at low or moderate risk of IE. Qualitative evaluation of the excluded articles reveals diversity of results and suggests that most of the state-of-the-art articles are underpowered. CONCLUSIONS: Evidence to support or discourage the use of AP prior to dental procedures as a prevention for IE is very low. New high-quality studies are needed, even though such studies would require big settings and might not be immediately feasible.

Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over >17 Years.

BACKGROUND: In people with human immunodeficiency virus (PWH), long-term telomere length (TL) change without/with suppressive antiretroviral therapy (ART) and the contribution of genetic background to TL are incompletely understood. METHODS: We measured TL change in peripheral blood mononuclear cells by quantitative polymerase chain reaction in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. We applied mixed-effects multilevel regression to obtain uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4/CD8 ratio. We assessed the effect of (1) individual antiretrovirals and (2) an individual TL-polygenic risk score ([TL-PRS] based on 239 single-nucleotide polymorphisms) on TL in 798 additional participants from our previous longitudinal studies. RESULTS: During untreated human immunodeficiency virus (HIV) infection (median observation, 7.7; interquartile range [IQR], 4.7-11] years), TL declined significantly (median -2.12%/year; IQR, -3.48% to -0.76%/year; P = .002). During suppressive ART (median observation, 9.8; IQR, 7.1-11.1 years), there was no evidence of TL decline or increase (median + 0.54%/year; IQR, -0.55% to + 1.63%/year; P = .329). The TL-PRS contributed to TL change (global P = .019) but particular antiretrovirals did not (all P > .15). CONCLUSIONS: In PWH, TL is associated with an individual PRS. Telomere length declined significantly during untreated chronic HIV infection, but no TL change occurred during suppressive ART.

Antibody Response in Immunocompromised Patients After the Administration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine BNT162b2 or mRNA-1273: A Randomized Controlled Trial.

BACKGROUND: BNT162b2 by Pfizer-BioNTech and mRNA-1273 by Moderna are the most commonly used vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Head-to-head comparison of the efficacy of these vaccines in immunocompromised patients is lacking. METHODS: Parallel, 2-arm (allocation 1:1), open-label, noninferiority randomized clinical trial nested into the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. People living with human immunodeficiency virus (PLWH) or solid organ transplant recipients (SOTR; ie, lung and kidney) from these cohorts were randomized to mRNA-1273 or BNT162b2. The primary endpoint was antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain (Elecsys Anti-SARS-CoV-2 immunoassay, Roche; cutoff ≥0.8 units/mL) 12 weeks after first vaccination (ie, 8 weeks after second vaccination). In addition, antibody response was measured with the Antibody Coronavirus Assay 2 (ABCORA 2). RESULTS: A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 PLWH and 71 SOTR). The percentage of patients showing an immune response was 92.1% (95% confidence interval [CI]: 88.4-95.8; 186/202) for mRNA-1273 and 94.3% (95% CI: 91.2-97.4; 198/210) for BNT162b2 (difference: -2.2%; 95% CI: -7.1 to 2.7), fulfilling noninferiority of mRNA-1273. With the ABCORA 2 test, 89.1% had an immune response to mRNA-1273 (95% CI: 84.8-93.4; 180/202) and 89.5% to BNT162b2 (95% CI: 85.4-93.7; 188/210). Based on the Elecsys test, all PLWH had an antibody response (100.0%; 341/341), whereas for SOTR, only 60.6% (95% CI: 49.2-71.9; 43/71) had titers above the cutoff level. CONCLUSIONS: In immunocompromised patients, the antibody response of mRNA-1273 was noninferior to BNT162b2. PLWH had in general an antibody response, whereas a high proportion of SOTR had no antibody response.

Assessing Antibiotic Tolerance of Staphylococcus aureus Derived Directly from Patients by the Replica Plating Tolerance Isolation System (REPTIS).

Antibiotic-tolerant Staphylococcus aureus poses a great challenge to clinicians as well as to microbiological laboratories and is one reason for treatment failure. Antibiotic-tolerant strains survive transient antibiotic exposure despite being fully susceptible in vitro. Thus, fast and reliable methods to detect tolerance in the routine microbiology laboratory are urgently required. We therefore evaluated the feasibility of the replica plating tolerance isolation system (REPTIS) to detect antibiotic tolerance in Staphylococcus aureus isolates derived directly from patients suffering from different types of infections and investigated possible connections to clinical presentations and patient characteristics. One hundred twenty-five S. aureus isolates were included. Replica plating of the original resistance testing plate was used to assess regrowth in the zones of inhibition, indicating antibiotic tolerance. Bacterial regrowth was assessed after 24 and 48 h of incubation, and an overall regrowth score (ORS) was assigned. Regrowth scores were compared to the clinical presentation. Bacterial regrowth was high for most antibiotics targeting protein synthesis and relatively low for antibiotics targeting other cellular functions such as DNA replication, transcription, and cell wall synthesis, with the exception of rifampin. Isolates with a blaZ penicillinase had lower regrowth in penicillin and ampicillin. Low ORSs were more prevalent among isolates recovered from patients with immunosuppression or methicillin-resistant S. aureus (MRSA) isolates. In conclusion, REPTIS is useful to detect antibiotic tolerance in clinical microbiological routine diagnostics. Further studies should evaluate the impact of rapid detection of antibiotic tolerance as a clinical decision-making tool for tailored antibiotic treatments.

Decrease of condom use in heterosexual couples and its impact on pregnancy rates: the Swiss HIV Cohort Study (SHCS).

INTRODUCTION: Following the 'Swiss statement' in 2008 it became an option to omit the use of condoms in serodiscordant couples and to conceive naturally. We analysed its impact on condom use and pregnancy events. METHODS: In all, 3023 women (aged 18-49 years) participating in the Swiss HIV Cohort Study were included. Observation time was divided into pre- and post-Swiss statement phases (July 2005-December 2008 and January 2009-December 2019). We used descriptive statistics, Poisson interrupted time series analysis for pregnancy incidence, and logistic regression to identify predictors of live births, spontaneous and induced abortions. RESULTS: Condomless sex in sexually active women increased from 25% in 2005 to 75% in 2019, while pregnancy incidence did not. Women after 2008 experienced higher spontaneous abortion rates (12.1% vs. 17.2%, p = 0.02) while induced abortion and live birth rates did not change significantly. Spontaneous abortions were more common in older women [adjusted odds ratio (aOR) = 1.4, 95% CI: 1.2-1.7, p < 0.001], in women consuming alcohol (aOR = 2.8, 95% CI: 1.9-4.1, p < 0.001) and in those with non-suppressed viral load (aOR = 0.2, 95% CI: 0.1-0.4, p ≤ 0.001). Induced abortions were more likely in women with depression (aOR = 3.4, 95% CI: 1.8-6.3, p < 0.001) and non-suppressed viral load (aOR = 0.3, 95% CI: 0.2-0.7, p = 0.003). CONCLUSIONS: The publication of the Swiss statement resulted in more condomless sex in heterosexual women, but this did not result in a higher incidence of pregnancy. Maternal age and spontaneous abortion rates increased over time, while induced abortion rates were not significantly affected. Women living with HIV in Switzerland have an unmet need regarding family planning counselling.

Impact of a structured patient education programme on early diagnosis of prosthetic pulmonary valve endocarditis.

BACKGROUND: Infective endocarditis is a major threat after prosthetic pulmonary valve replacement. Early diagnosis may improve outcomes. METHODS: A structured patient education programme for prevention and early diagnosis of infective endocarditis was developed at our institution since 2016. Time delay between onset of symptoms of prosthetic pulmonary valve endocarditis and its diagnosis (defined as initiation of appropriate high-dose intravenous antibiotic treatment) was compared for patients presenting before (cohort 1) and after (cohort 2) initiation of the patient education programme. RESULTS: Between 2008-2019, 26 patients (median age 24.9, range: 16.8-62.0 years, 73% male) were diagnosed with prosthetic pulmonary valve endocarditis, 13 patients (cohort 1) before (1.7 cases/year) and 13 patients (cohort 2) after June 2016 (3.7 cases/year). There were no differences in baseline characteristics or clinical presentation between the study cohorts. Overall, the median delay between onset of symptoms and diagnosis of infective endocarditis was 6 days (range: 0-133 days) with a significantly longer delay among patients in cohort 1, compared to cohort 2 (25 days, range: 5-133 days versus 3 days, range: 0-13 days, p < 0.0001). A delay of >7 days was documented in 11/13 patients (85%) in cohort 1 as compared to 1/13 (8%) in cohort 2 (p < 0.001). Need for urgent valve replacement or permanent deterioration of prosthetic valve function was higher in cohort 1, compared to cohort 2 (11/13, 85% versus 5/13, 39%; p = 0.041). CONCLUSIONS: Prosthetic pulmonary valve endocarditis is increasingly recognised. A structured patient education programme may improve early diagnosis and clinical outcomes.

Rapid Progression of Kidney Dysfunction in People Living With HIV: Use of Polygenic and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Risk Scores.

BACKGROUND: In people with human immunodeficiency virus (PWH), it is unknown whether genetic background associates with rapid progression of kidney dysfunction (ie, estimated glomerular filtration rate [eGFR] decrease of >5mL/min/1.73m2 per year for ≥3 consecutive years). METHODS: We obtained univariable and multivariable hazard ratios (HR) for rapid progression, based on the clinical D:A:D chronic kidney disease (CKD) risk score, antiretroviral exposures, and a polygenic risk score based on 14 769 genome-wide single nucleotide polymorphisms in white Swiss HIV Cohort Study participants. RESULTS: We included 225 participants with rapid progression and 3378 rapid progression-free participants. In multivariable analysis, compared to participants with low D:A:D risk, participants with high risk had rapid progression (HR =  1.82 [95% CI, 1.28-2.60]). Compared to the first (favorable) polygenic risk score quartile, participants in the second, third, and fourth (unfavorable) quartiles had rapid progression (HR = 1.39 [95% CI, 0.94-2.06], 1.52 [95% CI, 1.04-2.24], and 2.04 [95% CI, 1.41-2.94], respectively). Recent exposure to tenofovir disoproxil fumarate was associated with rapid progression (HR = 1.36 [95% CI, 1.06-1.76]). DISCUSSION: An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors.

Coronary Artery Disease-Associated and Longevity-Associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living With Human Immunodeficiency Virus: The Swiss HIV Cohort Study.

BACKGROUND: Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with human immunodeficiency virus (HIV) (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRSs) and by considering genetic variants associated with successful aging and longevity. METHODS: In the Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (ORs) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRSs. PRSs were built from CAD-associated single-nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. RESULTS: We included 269 patients with CAD events between 2000 and 2017 (median age, 54 years; 87% male; 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (ie, traditional and HIV-related) risk factors and PRSs, built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (P < .001). Participants with the most unfavorable clinical risk factor profile (top quintile) had an adjusted CAD-OR of 17.82 (95% confidence interval [CI], 8.19-38.76), compared with participants in the bottom quintile. Participants with the most unfavorable CAD-PRSs (top quintile) had an adjusted CAD-OR of 3.17 (95% CI, 1.74-5.79), compared with the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had an adjusted CAD-OR of 3.67 (95% CI, 2.00-6.73), compared with the bottom quintile. CONCLUSIONS: In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related, and genetic risk factors provided the most powerful CAD prediction.

Telomere Length, Traditional Risk Factors, Factors Related to Human Immunodeficiency Virus (HIV) and Coronary Artery Disease Events in Swiss Persons Living With HIV.

BACKGROUND: Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with human immunodeficiency virus (HIV; PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH. METHODS: We measured TL by quantitative polymerase chain reaction (PCR) in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 1 January 2000 to 31 December 2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses. RESULTS: We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR = 0.56 (95% confidence interval [CI], .35-.91) and OR = 0.54 (95% CI, .31-.96). Multivariable OR for current smoking was 1.93 (95% CI, 1.27-2.92), dyslipidemia OR = 1.92 (95% CI, 1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR = 1.82 (95% CI, 1.27-2.59), OR = 2.02 (95% CI, 1.34-3.04), OR = 3.42 (95% CI, 2.14-5.45), and OR = 1.66 (95% CI, 1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use. CONCLUSIONS: In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.

Editor's Choice - Validation of the Management of Aortic Graft Infection Collaboration (MAGIC) Criteria for the Diagnosis of Vascular Graft/Endograft Infection: Results from the Prospective Vascular Graft Cohort Study.

OBJECTIVE: The timely management of vascular graft/endograft infection (VGEI) is crucial to a favourable outcome, yet can be challenging as there is no validated gold standard diagnostic test. Recently, a new case definition has been proposed by the Management of Aortic Graft Infection Collaboration (MAGIC) to close the diagnostic gap. The aim of this study was to validate the MAGIC criteria as a suggested diagnostic standard for the diagnosis of suspected VGEI in the prospective Vascular Graft Cohort study (VASGRA). METHODS: VASGRA is an open, prospective, observational cohort study. Prospective participants in VASGRA between 2013 and 2019 were included (257 patients; 137 with VGEI). The accuracy of the MAGIC criteria for a diagnosis of VGEI was evaluated retrospectively by calculating the sensitivity and specificity vs. the consensually adjudicated VASGRA infection status. RESULTS: The VASGRA cohort categorised 137 (53.3%) patients as "diseased" and 120 patients as "not diseased"; using the MAGIC criteria, 183/257 (71.2%) patients were considered to be "diseased". Thus, for the MAGIC criteria, a sensitivity of 99% (95% confidence interval [CI] 96-100) and a specificity of 61% (95% CI 52-70) were calculated. Considering suspected VGEI according to the MAGIC criteria as "not diseased" achieved congruent assessments of the VASGRA team and the MAGIC criteria, with a sensitivity of 93% and a specificity of 93%. The accuracy of the MAGIC criteria for the different graft locations were also compared. If the suspected VGEIs were assigned to the "not diseased" group, VGEIs of the thoracic aorta seemed to have a poorer sensitivity (86%; 95% CI 73-95) than the other graft locations. CONCLUSION: The current MAGIC criteria offer good sensitivity and specificity in the context of true infections but a reduced specificity for a possible VGEI.

Contribution of Genetic Background and Data Collection on Adverse Events of Anti-human Immunodeficiency Virus (HIV) Drugs (D:A:D) Clinical Risk Score to Chronic Kidney Disease in Swiss HIV-infected Persons With Normal Baseline Estimated Glomerular Filtration Rate.

BACKGROUND: In human immunodeficiency virus (HIV), the relative contribution of genetic background, clinical risk factors, and antiretrovirals to chronic kidney disease (CKD) is unknown. METHODS: We applied a case-control design and performed genome-wide genotyping in white Swiss HIV Cohort participants with normal baseline estimated glomerular filtration rate (eGFR >90 mL/minute/1.73 m2). Univariable and multivariable CKD odds ratios (ORs) were calculated based on the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) score, which summarizes clinical CKD risk factors, and a polygenic risk score that summarizes genetic information from 86 613 single-nucleotide polymorphisms. RESULTS: We included 743 cases with confirmed eGFR drop to <60 mL/minute/1.73 m2 (n = 144) or ≥25% eGFR drop to <90 mL/minute/1.73 m2 (n = 599), and 322 controls (eGFR drop <15%). Polygenic risk score and D:A:D score contributed to CKD. In multivariable analysis, CKD ORs were 2.13 (95% confidence interval [CI], 1.55-2.97) in participants in the fourth (most unfavorable) vs first (most favorable) genetic score quartile; 1.94 (95% CI, 1.37-2.65) in the fourth vs first D:A:D score quartile; and 2.98 (95% CI, 2.02-4.66), 1.70 (95% CI, 1.29-2.29), and 1.83 (95% CI, 1.45-2.40), per 5 years of exposure to atazanavir/ritonavir, lopinavir/ritonavir, and tenofovir disoproxil fumarate, respectively. Participants in the first genetic score quartile had no increased CKD risk, even if they were in the fourth D:A:D score quartile. CONCLUSIONS: Genetic score increased CKD risk similar to clinical D:A:D score and potentially nephrotoxic antiretrovirals. Irrespective of D:A:D score, individuals with the most favorable genetic background may be protected against CKD.