Automated surveillance of non-ventilator-associated hospital-acquired pneumonia (nvHAP): a systematic literature review.

BACKGROUND: Hospital-acquired pneumonia (HAP) and its specific subset, non-ventilator hospital-acquired pneumonia (nvHAP) are significant contributors to patient morbidity and mortality. Automated surveillance systems for these healthcare-associated infections have emerged as a potentially beneficial replacement for manual surveillance. This systematic review aims to synthesise the existing literature on the characteristics and performance of automated nvHAP and HAP surveillance systems. METHODS: We conducted a systematic search of publications describing automated surveillance of nvHAP and HAP. Our inclusion criteria covered articles that described fully and semi-automated systems without limitations on patient demographics or healthcare settings. We detailed the algorithms in each study and reported the performance characteristics of automated systems that were validated against specific reference methods. Two published metrics were employed to assess the quality of the included studies. RESULTS: Our review identified 12 eligible studies that collectively describe 24 distinct candidate definitions, 23 for fully automated systems and one for a semi-automated system. These systems were employed exclusively in high-income countries and the majority were published after 2018. The algorithms commonly included radiology, leukocyte counts, temperature, antibiotic administration, and microbiology results. Validated surveillance systems' performance varied, with sensitivities for fully automated systems ranging from 40 to 99%, specificities from 58 and 98%, and positive predictive values from 8 to 71%. Validation was often carried out on small, pre-selected patient populations. CONCLUSIONS: Recent years have seen a steep increase in publications on automated surveillance systems for nvHAP and HAP, which increase efficiency and reduce manual workload. However, the performance of fully automated surveillance remains moderate when compared to manual surveillance. The considerable heterogeneity in candidate surveillance definitions and reference standards, as well as validation on small or pre-selected samples, limits the generalisability of the findings. Further research, involving larger and broader patient populations is required to better understand the performance and applicability of automated nvHAP surveillance.

Anticholinergic and Sedative Medications Are Associated With Neurocognitive Performance of Well Treated People With Human Immunodeficiency Virus.

Background: We previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation. Methods: A medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome. Results: A total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference -0.26 to -0.14, P < .001 and P = .06) and binary (odds ratio [OR], ≥1.67; P < .05) models. Their combined use was associated with deficits in overall neurocognitive functions in both models (mean z-score difference -0.12, P = .002 and OR = 1.54, P = .03). These associations were unchanged in a subgroup analysis of participants without depression (n = 824). Conclusions: Anticholinergic and sedative medications contribute to NCI. Clinicians need to consider these drugs when assessing NCI in PWH.

Decreasing Incidence and Determinants of Bacterial Pneumonia in People With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bacterial pneumonia is a leading reason for hospitalization among people with HIV (PWH); however, evidence regarding its drivers in the era of potent antiretroviral therapy is limited. METHODS: We assessed risk factors for bacterial pneumonia in the Swiss HIV Cohort Study using marginal models. We further assessed the relationship between risk factors and changes in bacterial pneumonia incidence using mediation analysis. RESULTS: We included 12927 PWH with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100779 person-years. Bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 person-years in 2008 to 6.8 cases/1000 person-years in 2018. Older age, lower education level, intravenous drug use, smoking, lower CD4-cell count, higher HIV load, and prior pneumonia were significantly associated with higher bacterial pneumonia incidence. Notably, CD4 cell counts 350-499 cells/µL were significantly associated with an increased risk compared to CD4 ≥ 500 cells/µL (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.89). Decreasing incidence over the last decade can be explained by increased CD4-cell counts and viral suppression and decreased smoking frequency. CONCLUSIONS: Improvements in cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.

Immunophenotypic characterization of TCR γδ T cells and MAIT cells in HIV-infected individuals developing Hodgkin's lymphoma.

BACKGROUND: Despite successful combined antiretroviral therapy (cART), the risk of non-AIDS defining cancers (NADCs) remains higher for HIV-infected individuals than the general population. The reason for this increase is highly disputed. Here, we hypothesized that T-cell receptor (TCR) γδ cells and/or mucosal-associated invariant T (MAIT) cells might be associated with the increased risk of NADCs. γδ T cells and MAIT cells both serve as a link between the adaptive and the innate immune system, and also to exert direct anti-viral and anti-tumor activity. METHODS: We performed a longitudinal phenotypic characterization of TCR γδ cells and MAIT cells in HIV-infected individuals developing Hodgkin's lymphoma (HL), the most common type of NADCs. Cryopreserved PBMCs of HIV-infected individuals developing HL, matched HIV-infected controls without (w/o) HL and healthy controls were used for immunophenotyping by polychromatic flow cytometry, including markers for activation, exhaustion and chemokine receptors. RESULTS: We identified significant differences in the CD4+ T cell count between HIV-infected individuals developing HL and HIV-infected matched controls within 1 year before cancer diagnosis. We observed substantial differences in the cellular phenotype mainly between healthy controls and HIV infection irrespective of HL. A number of markers tended to be different in Vδ1 and MAIT cells in HIV+HL+ patients vs. HIV+ w/o HL patients; notably, we observed significant differences for the expression of CCR5, CCR6 and CD16 between these two groups of HIV+ patients. CONCLUSION: TCR Vδ1 and MAIT cells in HIV-infected individuals developing HL show subtle phenotypical differences as compared to the ones in HIV-infected controls, which may go along with functional impairment and thereby may be less efficient in detecting and eliminating malignant cells. Further, our results support the potential of longitudinal CD4+ T cell count analysis for the identification of patients at higher risk to develop HL.

Prevalence of Potential Drug-Drug Interactions in Patients of the Swiss HIV Cohort Study in the Era of HIV Integrase Inhibitors.

BACKGROUND: Prevalence of potential drug-drug interactions (PDDIs) between antiretroviral drugs (ARVs) and co-medications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of human immunodeficiency virus (HIV) integrase inhibitors (INIs), characterized by more favorable interaction profiles. METHODS: The prevalence of PDDIs in treated HIV-positive individuals was assessed for the period 01-12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged), or of weak clinical significance (yellow flagged). RESULTS: In 9298 included individuals, median age was 51 years (IQR, 43-58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and nonnucleoside reverse transcriptase inhibitor (NNRTIs) (32%)-based regimens. In the entire cohort, 68% received ≥1 co-medication, 14% had polypharmacy (≥5 co-medications) and 29% had ≥1 PDDI. Among individuals with co-medication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber-mostly with cardiovascular drugs-and 20% yellow-flagged PDDIs) compared to 59% in 2008. Two percent had red-flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared with 2008, fewer individuals received boosted ARVs (-24%) and NNRTIs (-13%) but the use of co-medications was higher. CONCLUSIONS: Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for co-medications in this aging population impeded lower rates of PDDIs.

The Role of Human Immunodeficiency Virus (HIV) Asymptomatic Status When Starting Antiretroviral Therapy on Adherence and Treatment Outcomes and Implications for Test and Treat: The Swiss HIV Cohort Study.

BACKGROUND: Since the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We explored the impact of asymptomatic status on adherence and clinical outcomes. METHODS: PLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure. RESULTS: Of 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1-4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 [95% confidence interval {CI}, .93-1.15]). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 [95% CI, .76-1.00]) and less likely to develop resistance (14% vs 27%, P < .001) than symptomatic PLHIV. CONCLUSIONS: Despite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.

Predictors of Virological Failure and Time to Viral Suppression of First-Line Integrase Inhibitor-Based Antiretroviral Treatment.

BACKGROUND: Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens. METHODS: We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations. RESULTS: We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio [mHR], 2.2; 95% confidence interval [CI], 1.3-3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1-3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3-.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2-.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6-.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0-1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome. CONCLUSIONS: Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts.

Cohort-Derived Machine Learning Models for Individual Prediction of Chronic Kidney Disease in People Living With Human Immunodeficiency Virus: A Prospective Multicenter Cohort Study.

BACKGROUND: It is unclear whether data-driven machine learning models, which are trained on large epidemiological cohorts, may improve prediction of comorbidities in people living with human immunodeficiency virus (HIV). METHODS: In this proof-of-concept study, we included people living with HIV in the prospective Swiss HIV Cohort Study with a first estimated glomerular filtration rate (eGFR) >60 mL/minute/1.73 m2 after 1 January 2002. Our primary outcome was chronic kidney disease (CKD)-defined as confirmed decrease in eGFR ≤60 mL/minute/1.73 m2 over 3 months apart. We split the cohort data into a training set (80%), validation set (10%), and test set (10%), stratified for CKD status and follow-up length. RESULTS: Of 12 761 eligible individuals (median baseline eGFR, 103 mL/minute/1.73 m2), 1192 (9%) developed a CKD after a median of 8 years. We used 64 static and 502 time-changing variables: Across prediction horizons and algorithms and in contrast to expert-based standard models, most machine learning models achieved state-of-the-art predictive performances with areas under the receiver operating characteristic curve and precision recall curve ranging from 0.926 to 0.996 and from 0.631 to 0.956, respectively. CONCLUSIONS: In people living with HIV, we observed state-of-the-art performances in forecasting individual CKD onsets with different machine learning algorithms.

Efficacy and safety of single-dose 40 mg/kg oral praziquantel in the treatment of schistosomiasis in preschool-age versus school-age children: An individual participant data meta-analysis.

BACKGROUND: Better knowledge of the efficacy and safety of single-dose 40 mg/kg oral praziquantel in preschool-age children is required, should preventive chemotherapy programs for schistosomiasis be expanded to include this age group. METHODOLOGY: We analyzed individual participant-level data from 16 studies (13 single-arm or cohort studies and three randomized trials), amounting to 683 preschool-age children (aged <6 years) and 2,010 school-age children (aged 6-14 years). Children had a documented Schistosoma mansoni or S. haematobium infection, were treated with single 40 mg/kg oral praziquantel, and assessed between 21 and 60 days post-treatment. Efficacy was expressed as arithmetic mean and individual egg reduction rate (ERR) and meta-analyzed using general linear models and mixed models. Safety was summarized using reported adverse events (AEs). PRINCIPAL FINDINGS: Preschool-age children had significantly lower baseline Schistosoma egg counts and more losses to follow-up compared to school-age children. No difference in efficacy was found between preschool- and school-age children using a general linear model of individual-participant ERR with baseline log-transformed egg count as covariate and study, age, and sex as fixed variables, and a mixed model with a random effect on the study. Safety was reported in only four studies (n = 1,128 individuals); few AEs were reported in preschool-age children 4 and 24 hours post-treatment as well as at follow-up. Three severe but not serious AEs were recorded in school-age children during follow-up. CONCLUSIONS/SIGNIFICANCE: There is no indication that single-dose 40 mg/kg oral praziquantel would be less efficacious and less safe in preschool-age children compared to school-age children, with the caveat that only few randomized comparisons exist between the two age groups. Preventive chemotherapy might therefore be extended to preschool-age children, with proper monitoring of its efficacy and safety.

Impact of Genetic and Nongenetic Factors on Body Mass Index and Waist-Hip Ratio Change in HIV-Infected Individuals Initiating Antiretroviral Therapy.

OBJECTIVE: There is limited data on abdominal obesity and the influence of genetics on weight change after antiretroviral therapy (ART) initiation. We assessed body mass index (BMI) and waist hip ration (WHR) change over time in the Swiss HIV Cohort study (SHCS). METHODS: Mixed-effects models characterizing BMI and WHR change over time in 1090 SHCS participants initiating ART between 2005 and 2015 were developed and used to quantify the influence of demographics, clinical factors, and genetic background. RESULTS: Individuals with CD4 nadir <100 cells/µL gained 6.4 times more BMI than individuals with ≥200, and 2.8 times more WHR than individuals with ≥100 (P < .001) during the first 1.5 and 2.5 years after ART initiation, respectively. The risk of being overweight or obese after 1.5 years increased with CD4 nadir <100 cells/µL compared to 100-199 (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.63-2.74) and ≥200 (OR, 1.69; 95% CI, 1.26-2.32), persisting after 10 years of ART. The risk of abdominal obesity after 2.5 years increased with CD4 nadir <100 compared to ≥100 (OR, 1.35; 95% CI, 1.17-1.54 [in men]; OR, 1.36; 95% CI, 1.18-1.57 [in women]), persisting after 10 years of ART. No significant differences were found across antiretroviral drug classes or genetic scores. CONCLUSIONS: The risk of general and abdominal obesity increased with CD4 nadir <100 cells/µL. Based on our results, including the genetic background would not improve obesity predictions in HIV-infected individuals.

Emergence of Drug Resistance in the Swiss HIV Cohort Study Under Potent Antiretroviral Therapy Is Observed in Socially Disadvantaged Patients.

BACKGROUND: The rate of acquired human immunodeficiency virus type 1 (HIV-1) drug resistance (ADR) has fallen dramatically since introduction of combined antiretroviral therapy (cART) in Switzerland. However, clinical experience indicates that there are still patients at risk of newly acquiring drug resistance despite having access to cART. Here, we characterized risk factors for ADR, to improve patient care and prevent emergence of drug resistance and treatment failure. METHODS: We performed a case-control study to identify risk factors for ADR in all patients starting their first cART in the Swiss HIV Cohort Study (SHCS) since 1996. The SHCS is highly representative and includes >75% of patients receiving ART in Switzerland. To this end, we implemented a systematic medical chart review to obtain more detailed information on additional parameters, which are not routinely collected in the SHCS. The collected data were analyzed using univariable and multivariable conditional logistic regression. RESULTS: We included in our study 115 cases and 115 matched controls. Unemployment (multivariable odds ratio [mOR], 2.9 [95% confidence interval {CI}, 1.3-6.4]; P = .008), African origin (mOR, 3.0 [95% CI, 1.0-9.2]; P = .047), comedication with anti-infectives (mOR, 3.7 [95% CI, 1.0-12.6]; P = .045), and symptoms of mental illness (mOR, 2.6 [95% CI, 1.2-5.5]; P = .012) were associated with ADR in the multivariable model. CONCLUSIONS: Although ADR has become very rare with cART due to new potent therapies, patients in socially challenging life situations or presenting with mental health issues are at higher risk for drug resistance. Prompt identification and adequate support of these patients before ADR will prevent treatment failure and HIV-1 transmission.

Antibodies against HPV16E6 oncoprotein in the Swiss HIV cohort study: Kinetics and anal cancer risk prediction.

Our aim was to describe HPV16E6 antibody kinetics prior to anal cancer in people living with HIV/AIDS (PLWHA) and evaluate the possible contribution of HPV16E6 serology to anal cancer risk prediction. For 91 persons diagnosed with anal cancer in the Swiss HIV Cohort Study (1989-2017), serial serum/plasma samples were tested for HPV16E6 antibodies using multiplex serology, supplemented with samples from 1,356 participants without anal cancer. Anal cancer incidence was estimated for PLWHA from 40 years-old in the cART era, stratified by HPV16E6 serostatus. HPV16E6 seroprevalence was 23.3% in samples <2 years prior to anal cancer diagnosis and decreased with increasing time prior to cancer: 16.7% at 2-4 years, 4.4% at 5-9, and 7.0% at ≥10 years. Of 25 individuals with anal cancer who were HPV16E6-seropositive at any time during follow-up, the majority (n = 18) remained seropositive in all samples after seroconversion, whereas for seven cases, seropositivity was transitory. Among individuals with anal cancer, HPV16E6 seroprevalence was marginally higher in women vs. men who have sex with men (adjusted OR = 4.3, 95% CI: 1.1, 17.2) and in older participants (adjusted OR = 6.2, 95% CI: 1.1, 34.8 for cases diagnosed at ≥55 vs. <45 years). Anal cancer incidence was 402/100,000 person-years in HPV16E6-positive vs. 82/100,000 in HPV16E6-negative PLWHA (incidence rate ratio = 4.9, 95% CI: 1.3, 13.1). In conclusion, HPV16E6 serology, despite its low sensitivity, allows characterization of a group of individuals with very high anal cancer incidence and may have a place in secondary prevention in groups at high risk for anal cancer such as PLWHA.

Effectiveness of Transmitted Drug Resistance Testing Before Initiation of Antiretroviral Therapy in HIV-Positive Individuals.

BACKGROUND: For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS: We included individuals from the HIV-CAUSAL Collaboration who enrolled <6 months of HIV diagnosis between 2006 and 2015, were ART-naive, and had measured CD4 count and HIV-RNA. Follow-up started at the date when all inclusion criteria were first met (baseline). We compared 2 strategies: (1) TDR testing within 3 months of baseline versus (2) no TDR testing. We used inverse probability weighting to estimate the 5-year proportion and hazard ratios (HRs) of virological suppression (confirmed HIV-RNA <50 copies/mL), and of AIDS or death under both strategies. RESULTS: Of 25,672 eligible individuals (82% males, 52% diagnosed in 2010 or later), 17,189 (67%) were tested for TDR within 3 months of baseline. Of these, 6% had intermediate- or high-level TDR to any antiretroviral drug. The estimated 5-year proportion virologically suppressed was 77% under TDR testing and 74% under no TDR testing; HR 1.06 (95% confidence interval: 1.03 to 1.19). The estimated 5-year risk of AIDS or death was 6% under both strategies; HR 1.03 (95% confidence interval: 0.95 to 1.12). CONCLUSIONS: TDR prevalence was low. Although TDR testing improved virological response, we found no evidence that it reduced the incidence of AIDS or death in first 5 years after diagnosis.

The comparative effectiveness of NRTI-sparing dual regimens in emulated trials using observational data from the Swiss HIV Cohort Study.

BACKGROUND: Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) cause side effects in some patients, prompting the use of either partly or fully NRTI-sparing regimens. METHODS: We used data from the Swiss HIV Cohort Study to estimate the effectiveness of two new dolutegravir dual regimens relative to the alternative NRTI-sparing dual regimens that our clinicians used previously. We emulated two trials by propensity score matching case patients on the dolutegravir regimen with control patients on an alternative regimen. We analysed the case control sets using a Bayesian Cox model and estimated effectiveness as the percentage still on their trial regimen without virological failure at 48 weeks. RESULTS: In a comparison of partly NRTI-sparing regimens, 58 cases treated with dolutegravir were matched to 17 controls treated with boosted darunavir (both with lamivudine or emtricitabine). The estimated difference in effectiveness was 15% (95% credible interval [CrI] 2-33) and 12% (95% CrI 0-26) in two sequential analyses 1 year apart. In a comparison of fully NRTI-sparing regimens, 54 cases treated with dolutegravir were matched to 32 controls treated with raltegravir (both with boosted darunavir). The estimated difference in effectiveness was 9% (95% CrI -1-21) and 5% (95% CrI -4-15) in the two sequential analyses. CONCLUSIONS: Estimates of relative effectiveness suggest that both dolutegravir regimens are not inferior to these alternative regimens. All four regimens seem suitable for patients needing an NRTI-sparing regimen: there were few virological failures and few treatment changes due to toxicity.

Inadequate Perioperative Prophylaxis and Postsurgical Complications After Graft Implantation Are Important Risk Factors for Subsequent Vascular Graft Infections: Prospective Results From the Vascular Graft Infection Cohort Study.

BACKGROUND: Reconstructive vascular surgery has become increasingly common. Vascular graft infections (VGIs) are serious complications, leading to increased morbidity and mortality. Previously described risk factors for VGIs include groin incisions, wound infections, and comorbidities. We aimed to identify modifiable predictors for VGIs as targets for infection prevention strategies. METHODS: Participants of the prospective Vascular Graft Infection Cohort (VASGRA) with surgery between 2013 and 2017 were included. The observation time was calculated from surgery until a confirmed VGI or the last follow-up. Variables were assessed by infection status, using non-parametric tests. Univariable and multivariable Cox proportional hazard regression models, adjusted for demographic factors, were applied to assess risk factors for a VGI. RESULTS: A total of 438 predominantly male (83.1%) patients with a median age of 71 years (interquartile range [IQR] 63 - 76) contributed to 554 person years of follow-up. Thereof, 39 (8.9%) developed a VGI, amounting to an incidence rate of 7.0/100 person years. We found incisional surgical site infections (adjusted hazard ratio [aHR] 10.09, 95% CI 2.88 - 35.34); hemorrhage (aHR 4.92, 1.28-18.94); renal insufficiency (aHR 4.85, 1.20 - 19.61); inadequate perioperative prophylaxis in patients with an established antibiotic treatment, compared to the additional application of perioperative prophylaxis (aHR 2.87, 95% CI 1.17 - 7.05); and procedure time increases of 1-hour intervals (aHR 1.22, 95% CI 1.08 - 1.39) to be risk factors for VGIs. CONCLUSIONS: We identified procedure time; inadequate perioperative prophylaxis, especially among patients with an established antibiotic treatment; and several postsurgical infectious and non-infectious complications as modifiable, predictive factors for VGIs and, therefore, as keys to improved surveillance programs and prevention strategies. CLINICAL TRIALS REGISTRATION: NCT01821664.

Tracing HIV-1 strains that imprint broadly neutralizing antibody responses.

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Increased Pathogen Identification in Vascular Graft Infections by the Combined Use of Tissue Cultures and 16S rRNA Gene Polymerase Chain Reaction.

Background: Vascular graft infections (VGI) are difficult to diagnose and treat, and despite redo surgery combined with antimicrobial treatment, outcomes are often poor. VGI diagnosis is based on a combination of clinical, radiological, laboratory and microbiological criteria. However, as many of the VGI patients are already under antimicrobial treatment at the time of redo surgery, microbiological identification is often difficult and bacterial cultures often remain negative rendering targeted treatment impossible. We aimed to assess the benefit of 16S rRNA gene polymerase chain reaction (broad-range PCR) for better microbiological identification in patients with VGI. Methods: We prospectively analyzed the clinical, microbiological, and treatment data of patients enrolled in the observational Vascular Graft Cohort Study (VASGRA), University Hospital Zurich, Switzerland. The routine diagnostic work-up involved microbiological cultures of minced tissue samples, and the use of molecular techniques in parallel. Patient-related and microbiological data were assessed in descriptive analyses, and we calculated sensitivity, specificity, negative and positive predictive value for broad-range 16S rRNA gene PCR versus culture (considered as gold standard). Results: We investigated 60 patients (median age 66 years (Interquartile range [IQR] 59-75)) with confirmed VGI between May 2013 and July 2017. The prevalence of antimicrobial pretreatment at the time of sampling was high [91%; median days of antibiotics 7 days (IQR 1-18)]. We investigated 226 microbiological specimens. Thereof, 176 (78%) were culture-negative and 50 (22%) were culture-positive. There was a concordance of 70% (158/226) between conventional culture and broad-range PCR (sensitivity 58% (95% CI 43-72); specificity 74% (67-80%)). Among the group of 176 culture-negative specimens, 46 specimens were broad-range PCR-positive resulting in identification of overall 69 species. Among the culture and/or broad-range PCR-positive specimens (n = 96), 74 (77%) were monomicrobial and 22 (23%) polymicrobial, whereas the rate of polymicrobial samples was higher in broad-range PCR-positive specimens (93%). Conclusions: Combined cultures and broad-range 16S rRNA gene PCR from periprosthetic tissue and/or explanted vascular grafts increased the diagnostic accuracy in VGI, particularly in patients already under antimicrobial treatment at the time of redo surgery. Ideally, antimicrobial treatment should be withheld until surgical sampling in order to optimize microbiological diagnostics.Clinical trials.gov identifier: NCT01821664.

HIV-1 Drug Resistance Among Ugandan Adults Attending an Urban Out-Patient Clinic.

BACKGROUND: Little is known about prevalence of drug resistance among HIV-infected Ugandans, a setting with over 15 years of public sector access to antiretroviral therapy (ART) and where virological monitoring was only recently introduced. SETTING: This study was conducted in the adults' out-patient clinic of the Infectious Diseases Institute, Kampala, Uganda. METHODS: HIV genotyping was performed in ART-naive patients and in treatment-experienced patients on ART for ≥6 months with virological failure (≥1000 copies/mL). RESULTS: A total of 152 ART-naive and 2430 ART-experienced patients were included. Transmitted drug resistance was detected in 9 (5.9%) patients. After a median time on ART of 4.7 years [interquartile range: 2.5-8.7], 190 patients (7.8%) had virological failure with a median viral load of 4.4 log10 copies per milliliter (interquartile range: 3.9-4.9). In addition, 146 patients had a viral load between 51 and 999 copies per milliliter. Most patients with virological failure (142, 74.7%) were on first-line ART. For 163 (85.8%) ART-experienced patients, genotype results were available. Relevant drug-resistance mutations were observed in 135 (82.8%), of which 103 (63.2%) had resistance to 2 drug classes, and 11 (6.7%) had resistance to all drug classes available in Uganda. CONCLUSION: The prevalence of transmitted drug resistance was lower than recently reported by the WHO. With 92% of all patients virologically suppressed on ART, the prevalence of virological failure was low when a cutoff of 1000 copies per milliliter is applied, and is in line with the third of the 90-90-90 UNAIDS targets. However, most failing patients had developed multiclass drug resistance.

Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity.

Understanding pathways that promote HIV-1 broadly neutralizing antibody (bnAb) induction is crucial to advance bnAb-based vaccines. We recently demarcated host, viral, and disease parameters associated with bnAb development in a large HIV-1 cohort screen. By establishing comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in 4,281 individuals in the same cohort, we now show that the same four parameters that are significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influence HIV-1-binding antibody responses. However, the effects proved selective, shaping binding antibody responses in an antigen and IgG subclass-dependent manner. IgG response landscapes in bnAb inducers indicated a differentially regulated, IgG1-driven HIV-1 antigen response, and IgG1 binding of the BG505 SOSIP trimer proved the best predictor of HIV-1 neutralization breadth in plasma. Our findings emphasize the need to unravel immune modulators that underlie the differentially regulated IgG response in bnAb inducers to guide vaccine development.