High Burden of COVID-19-Associated Pulmonary Aspergillosis in Severely Immunocompromised Patients Requiring Mechanical Ventilation.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a frequent superinfection in critically ill patients with COVID-19 and is associated with increased mortality rates. The increasing proportion of severely immunocompromised patients with COVID-19 who require mechanical ventilation warrants research into the incidence and impact of CAPA during the vaccination era. METHODS: We performed a retrospective, monocentric, observational study. We collected data from adult patients with severe COVID-19 requiring mechanical ventilation who were admitted to the intensive care unit (ICU) of University Hospitals Leuven, a tertiary referral center, between 1 March 2020 and 14 November 2022. Probable or proven CAPA was diagnosed according to the 2020 European Confederation for Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) criteria. RESULTS: We included 335 patients. Bronchoalveolar lavage sampling was performed in 300 (90%), and CAPA was diagnosed in 112 (33%). The incidence of CAPA was 62% (50 of 81 patients) in European Organisation for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) host factor-positive patients, compared with 24% (62 of 254) in host factor-negative patients. The incidence of CAPA was significantly higher in the vaccination era, increasing from 24% (57 of 241) in patients admitted to the ICU before October 2021 to 59% (55 of 94) in those admitted since then. Both EORTC/MSGERC host factors and ICU admission in the vaccination era were independently associated with CAPA development. CAPA remained an independent risk factor associated with mortality risk during the vaccination era. CONCLUSIONS: The presence of EORTC/MSGERC host factors for invasive mold disease is associated with increased CAPA incidence and worse outcome parameters, and it is the main driver for the significantly higher incidence of CAPA in the vaccination era. Our findings warrant investigation of antifungal prophylaxis in critically ill patients with COVID-19.

Evaluation and implementation of optimized antimicrobial dosing strategies in obese and underweight patients.

PURPOSE: We aimed to develop and implement dosing recommendations for antimicrobials in obese and underweight patients within an academic hospital, and assess their impact on antibiotic prescribing. METHODS: A multi-step approach project was performed. First, obese and underweight patient prevalence and antimicrobial prescription frequency was determined in a point prevalence study. Second and third, a literature review and e-survey provided dosing evidence. Fourth, a consensus meeting was organized to formulate dosing recommendations. Fifth, these were implemented in our clinical validation service as six clinical rules continuously screening patients' records for potentially inappropriate prescriptions (PIPs). Uptake was evaluated by documenting the number of advices and acceptance rate. Last, an interrupted time series analysis (ITS) compared pre- and post-implementation periods to measure the impact of the intervention on residual PIPs/day. A residual PIP was defined as a PIP which persisted up to 48 h. RESULTS: First, 41% of 15.896 hospitalized patients received antimicrobials over 20 days; of which 12% were obese and 9% underweight. Antibiotics were predominantly prescribed according to standard dosing regimens, adjusted to renal function. Next, six dosing recommendations, derived from literature, survey, and consensus, were implemented. In the fifth step, during an 18-week period, 219 advices were given, with 86% acceptance rate. Last, in the ITS analysis, at preintervention, a median of 75% residual PIPs/day existed, reduced to 0% postintervention. Use of clinical rules resulted in a significant immediate 84% relative reduction in residual PIPs (95% CI 0.55-0.94). CONCLUSION: After conducting a literature review, e-survey, and seeking consensus from a panel of experts, dosing recommendations for antimicrobial treatment in both obese and underweight patients were developed. These recommendations have been successfully implemented into clinical practice, addressing the specific needs of these patient populations.

A Pathology-based Case Series of Influenza- and COVID-19-associated Pulmonary Aspergillosis: The Proof Is in the Tissue.

Rationale: Invasive pulmonary aspergillosis has emerged as a frequent coinfection in severe coronavirus disease (COVID-19), similarly to influenza, yet the clinical invasiveness is more debated. Objectives: We investigated the invasive nature of pulmonary aspergillosis in histology specimens of influenza and COVID-19 ICU fatalities in a tertiary care center. Methods: In this monocentric, descriptive, retrospective case series, we included adult ICU patients with PCR-proven influenza/COVID-19 respiratory failure who underwent postmortem examination and/or tracheobronchial biopsy during ICU admission from September 2009 until June 2021. Diagnosis of probable/proven viral-associated pulmonary aspergillosis (VAPA) was made based on the Intensive Care Medicine influenza-associated pulmonary aspergillosis and the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) COVID-19-associated pulmonary aspergillosis consensus criteria. All respiratory tissues were independently reviewed by two experienced pathologists. Measurements and Main Results: In the 44 patients of the autopsy-verified cohort, 6 proven influenza-associated and 6 proven COVID-19-associated pulmonary aspergillosis diagnoses were identified. Fungal disease was identified as a missed diagnosis upon autopsy in 8% of proven cases (n = 1/12), yet it was most frequently found as confirmation of a probable antemortem diagnosis (n = 11/21, 52%) despite receiving antifungal treatment. Bronchoalveolar lavage galactomannan testing showed the highest sensitivity for VAPA diagnosis. Among both viral entities, an impeded fungal growth was the predominant histologic pattern of pulmonary aspergillosis. Fungal tracheobronchitis was histologically indistinguishable in influenza (n = 3) and COVID-19 (n = 3) cases, yet macroscopically more extensive at bronchoscopy in influenza setting. Conclusions: A proven invasive pulmonary aspergillosis diagnosis was found regularly and with a similar histological pattern in influenza and in COVID-19 ICU case fatalities. Our findings highlight an important need for VAPA awareness, with an emphasis on mycological bronchoscopic work-up.

Pre-clinical In Vitro Models of Vascular Graft Coating in the Prevention of Vascular Graft Infection: A Systematic Review.

OBJECTIVE: Vascular graft infection (VGI) is a feared complication. Prevention is of the utmost importance and vascular graft coatings (VGCs) could offer a potential to do this, with in vitro research a first crucial step. The aim of this study was to summarise key features of in vitro models investigating coating strategies to prevent VGI in order to provide guidance for the setup of future translational research. DATA SOURCES: A comprehensive search was performed in MEDLINE, Embase, and Web of Science. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. For each database, a specific search strategy was developed. Quality was assessed with the Toxicological data Reliability Assessment Tool (ToxRTool). In vitro models using a VGC and inoculation of the graft with a pathogen were included. The type of graft, coating, and pathogen were summarised. The outcome assessment in each study was evaluated. RESULTS: In total, 4 667 studies were identified, of which 45 papers met the inclusion criteria. The majority used polyester grafts (68.2%). Thirty-one studies (68.9%) included antibiotics, and nine studies (20%) used a commercial silver graft in their protocol. New antibacterial strategies (e.g., proteolytic enzymes) were investigated. A variety of testing methods was found and focused mainly on bacterial adherence, coating adherence and dilution, biofilm formation, and cytotoxicity. Ninety-three per cent of the studies (n = 41) were considered unreliable. CONCLUSION: Polyester is the preferred type of graft to coat on. The majority of coating studies are based on antibiotics; however, new coating strategies (e.g., antibiofilm coating) are coming. Many in vitro setups are available. In vitro studies have great potential, they can limit the use, but cannot replace in vivo studies completely. This paper can be used as a guidance document for future in vitro research.

Vascular Graft Infections With Candida: A Factor for Increased Mortality in in-situ Reconstructions.

BACKGROUND: The empiric antibiotic regimen started after deep cultures and explantation of the graft mostly do not cover antifungals. We retrospectively studied the outcome of candida compared to non-candida VGI and assessed whether these results could justify the addition of antifungals to the empiric antibiotics in the early postoperative period. METHODS: All patients treated for infected aorto(ilio)femoral graft with excision and reconstruction at the vascular department of University Hospitals Leuven between January 2010 and 2017 (n = 56) were studied retrospectively. Patients were allocated to the candida group (n = 10) or non-candida group (n = 46) according to the presence of Candida in deep culture isolates. RESULTS: All-cause mortality was significantly higher in the candida group compared to the non-candida group. All-cause 30-day mortality was 40% and 13% for both groups respectively (P = 0.066). At 5 years this was 90% and 46% respectively (P = 0.014). In the candida group 6 patients (60%) had to be revised in the operating room due to bleeding, compared to 5 patients (11%) in the non-candida group (P = 0.002).  Two patients (20%) and 5 patients (11%) had to be readmitted to the ICU, respectively. CONCLUSION: Survival of candida related VGI is significantly worse, especially in the first 5 postoperative months. This could justify the addition of an antifungal to the early empiric postoperative antibiotic cocktail, especially in patients with an aorto-enteric fistula. A cost-benefit analysis could be useful to evaluate the yield.

A public health value-based healthcare paradigm for HIV.

BACKGROUND: HIV patients face considerable acute and chronic healthcare needs and battling the HIV epidemic remains of the utmost importance. By focusing on health outcomes in relation to the cost of care, value-based healthcare (VBHC) proposes a strategy to optimize quality of care and cost-efficiency. Its implementation may provide an answer to the increasing pressure to optimize spending in healthcare while improving patient outcomes. This paper describes a pragmatic value-based healthcare framework for HIV care. METHODS: A value-based HIV healthcare framework was developed during a series of roundtable discussions bringing together 16 clinical stakeholder representatives from the Belgian HIV reference centers and 2 VBHC specialists. Each round of discussions was focused on a central question translating a concept or idea to the next level of practical implementation: 1) how can VBHC principles be translated into value-based HIV care drivers; 2) how can these value-based HIV care divers be translated into value-based care objectives and activities; and 3) how can value-based HIV care objectives and activities be translated into value-based care indicators. Value drivers were linked to concrete objectives and activities using a logical framework approach. Finally, specific, measurable, and acceptable structure, process and outcomes indicators were defined to complement the framework. RESULTS: Our framework identifies 4 core value areas where HIV care would benefit most from improvements: Prevention, improvement of the cascade of care, providing patient-centered HIV care and sustaining a state-of-the-art HIV disease management context. These 4 core value areas were translated into 12 actionable core value objectives. For each objective, example activities were proposed. Indicators are suggested for each level of the framework (outcome indicators for value areas and objectives, process indicators for suggested activities). CONCLUSIONS: This framework approach outlines how to define a patient- and public health centered value-based HIV care paradigm. It proposes how to translate core value drivers to practical objectives and activities and suggests defining indicators that can be used to track and improve the framework's implementation in practice.

Immunogenicity and Safety of the 9-Valent Human Papillomavirus Vaccine in Solid Organ Transplant Recipients and Adults Infected With Human Immunodeficiency Virus (HIV).

BACKGROUND: The burden of human papillomavirus (HPV) in human immunodeficiency virus (HIV)-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in persons living with HIV and particularly in SOT recipients have been sparse to date, included low numbers of participants, and none of them assessed the 9-valent HPV (9vHPV) vaccine. We investigated the immunogenicity with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and the safety of the 9vHPV vaccine in persons living with HIV and recipients of a kidney, lung, or heart transplant. METHODS: This is a phase III investigator-initiated study in 100 persons living with HIV (age 18-45 years) and 171 SOT recipients (age 18-55 years). The 9vHPV vaccine was administered at day 1, month 2, and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs). RESULTS: All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/mL in HIV-positive participants and from 17 to 170 mMU/mL in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine related. No patients died during the study. CONCLUSIONS: Immunogenicity of the 9vHPV vaccine is high in persons living with HIV but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups.

Pre-clinical in vivo Models of Vascular Graft Coating in the Prevention of Vascular Graft Infection: A Systematic Review.

OBJECTIVE: Vascular graft infection (VGI) remains an important complication with a high mortality and morbidity rate. Currently, studies focusing on the role of vascular graft coatings in the prevention of VGI are scarce. Therefore, the aims of this study were to survey and summarise key features of pre-clinical in vivo models that have been used to investigate coating strategies to prevent VGI and to set up an ideal model that can be used in future preclinical research. DATA SOURCES: A systematic review was conducted in accordance with the Preferred reporting items for Systematic Reviews and Meta-Analysis guidelines. A comprehensive search was performed in MEDLINE (PubMed), Embase, and Web of Science. REVIEW METHODS: For each database, a specific search strategy was developed. Quality was assessed with the Toxicological data Reliability Assessment Tool (ToxRTool). The type of animal model, graft, coating, and pathogen were summarised. The outcome assessment in each study was evaluated. RESULTS: In total, 4 667 studies were identified, of which 94 papers focusing on in vivo testing were included. Staphylococcus aureus was the organism most used (n = 65; 67.7%). Most of the graft types were polyester grafts. Rifampicin was the most frequently used antibiotic coating (n = 43, 48.3%). In the outcome assessment, most studies mentioned colony forming unit count (n = 88; 91.7%) and clinical outcome (n = 72; 75%). According to the ToxRTool, 21 (22.3%, n = 21/94) studies were considered to be not reliable. CONCLUSION: Currently published in vivo models are very miscellaneous. More attention should be paid to the methodology of these pre-clinical reports when transferring novel graft coatings into clinical practice. Variables used in pre-clinical reports (bacterial strain, duration of activity coating) do not correspond well to current clinical studies. Based on the results of this review, a proposal for a complete and comprehensive set up for pre-clinical invivo testing of anti-infectious properties of vascular graft coatings was defined.

COVID-19 and gastrointestinal endoscopy: What should be taken into account?

On March 11, 2020 the World Health Organization declared COVID-19 pandemic, leading to a subsequent impact on the entire world and health care system. Since the causing Severe Acute Respiratory Syndrome Coronavirus 2 houses in the aerodigestive tract, activities in the gastrointestinal outpatient clinic and endoscopy unit should be limited to emergencies only. Health care professionals are faced with the need to perform endoscopic or endoluminal emergency procedures in patients with a confirmed positive or unknown COVID-19 status. With this report, we aim to provide recommendations and practical relevant information for gastroenterologists based on the limited amount of available data and local experience, to guarantee a high-quality patient care and adequate infection prevention in the gastroenterology clinic.

Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial.

BACKGROUND: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. METHODS: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. RESULTS: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. CONCLUSIONS: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. CLINICAL TRIALS REGISTRATION: NCT00413218.

Increasing candidaemia incidence from 2004 to 2015 with a shift in epidemiology in patients preexposed to antifungals.

Candidaemia is an important health problem in immunocompromised patients with an epidemiology varying with region, period and patient population involved. The occurrence of candidaemia and the associated species distribution over a 12-year period at a large tertiary care centre in Belgium were analysed. The trend in incidence in the intensive care units (ICUs) and non-ICUs was investigated as well as the influence of antifungal exposure on the species distribution. From 2004 until 2015, 865 candidaemia episodes occurred in 826 patients at the University Hospitals Leuven. Candida albicans (59%) remained the most important cause of candidaemia, followed by C. glabrata (22.4%) and C. parapsilosis (8%). The mean incidence in the whole hospital was 1.48 per 10 000 patient days (PD). The incidence in ICUs increased reaching up to 10.7 per 10 000 PD whereas in the non-ICUs, the incidence decreased. Prior exposure to fluconazole and echinocandins was associated with candidaemia caused by less susceptible species. Candidaemia incidence increased in the whole hospital, driven by ICUs. Surveillance of candidaemia epidemiology on a local scale is of high value to guide empirical treatment strategies.

Outcome and Treatment of Nocardiosis After Solid Organ Transplantation: New Insights From a European Study.

BACKGROUND: Solid organ transplant (SOT) recipients are at risk of nocardiosis, a rare opportunistic bacterial infection, but prognosis and outcome of these patients are poorly defined. Our objectives were to identify factors associated with 1-year mortality after nocardiosis and describe the outcome of patients receiving short-course antibiotics (≤120 days). METHODS: We analyzed data from a multicenter European case-control study that included 117 SOT recipients with nocardiosis diagnosed between 2000 and 2014. Factors associated with 1-year all-cause mortality were identified using multivariable conditional logistic regression. RESULTS: One-year mortality was 10-fold higher in patients with nocardiosis (16.2%, 19/117) than in control transplant recipients (1.3%, 3/233, P < .001). A history of tumor (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8), invasive fungal infection (OR, 1.3; 95% CI, 1.1-1.5), and donor age (OR, 1.0046; 95% CI, 1.0007-1.0083) were independently associated with 1-year mortality. Acute rejection in the year before nocardiosis was associated with improved survival (OR, 0.85; 95% CI, 0.73-0.98). Seventeen patients received short-course antibiotics (median duration 56 [24-120] days) with a 1-year success rate (cured and surviving) of 88% and a 5.9% risk of relapse (median follow-up 49 [6-136] months). CONCLUSIONS: One-year mortality was 10-fold higher in SOT patients with nocardiosis than in those without. Four factors, largely reflecting general medical condition rather than severity and/or management of nocardiosis, were independently associated with 1-year mortality. Patients who received short-course antibiotic treatment had good outcomes, suggesting that this may be a strategy for further study.

Phylogenetic evidence for underreporting of male-to-male sex among human immunodeficiency virus-infected donors in the Netherlands and Flanders.

BACKGROUND: Separate transmission networks for human immunodeficiency virus (HIV) coexist. Molecular typing of viral genomes can provide insight in HIV transmission routes in donors for whom risk behavior-based donor selection failed. STUDY DESIGN AND METHODS: This study includes all HIV-infected Dutch and Flemish donors in the period 2005 to 2014 (n = 55). Part of the HIV polymerase (pol) gene was amplified, sequenced, and compared with more than 10,000 HIV strains obtained from HIV-infected Dutch and Flemish patients. The most likely transmission route was determined based on HIV phylogeny and the donor's self-reported risk behavior during the exit interview. RESULTS: HIV-infected donors were predominantly male (69%), were repeat donors (73%), were born in the Netherlands or Belgium (95%), and harbored HIV Subtype B (68%). Seventy-five percent of HIV-infected male donors were part of robust phylogenetic clusters linked to male-to-male sex, while only 24% of HIV-infected male donors reported male-to-male sex during posttest counseling. Sex between men and women accounted for 13% of HIV infections in male donors and 93% of HIV infections in female donors based on phylogenetic analysis. Only 40% of HIV-infected female donors had HIV Subtype B; 65% of female donors reported a foreign partner and indeed HIV sequences interspersed with sequences from HIV-endemic areas abroad, in particular sub-Saharan Africa. CONCLUSION: HIV typing helps to understand HIV transmission routes in donor populations. We found substantial underreporting of male-to-male sex among HIV-infected male donors. Donor education on HIV risk factors and the danger of window-period donations and a donor environment that encourages frank disclosure of sexual behavior will contribute to a decrease of HIV-infected donors.

Nocardia Infection in Solid Organ Transplant Recipients: A Multicenter European Case-control Study.

BACKGROUND: Nocardiosis is a rare, life-threatening opportunistic infection, affecting 0.04% to 3.5% of patients after solid organ transplant (SOT). The aim of this study was to identify risk factors for Nocardia infection after SOT and to describe the presentation of nocardiosis in these patients. METHODS: We performed a retrospective case-control study of adult patients diagnosed with nocardiosis after SOT between 2000 and 2014 in 36 European (France, Belgium, Switzerland, the Netherlands, Spain) centers. Two control subjects per case were matched by institution, transplant date, and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors for nocardiosis. RESULTS: One hundred and seventeen cases of nocardiosis and 234 control patients were included. Nocardiosis occurred at a median of 17.5 (range, 2-244) months after transplant. In multivariable analysis, high calcineurin inhibitor trough levels in the month before diagnosis (odds ratio [OR], 6.11; 95% confidence interval [CI], 2.58-14.51), use of tacrolimus (OR, 2.65; 95% CI, 1.17-6.00) and corticosteroid dose (OR, 1.12; 95% CI, 1.03-1.22) at the time of diagnosis, patient age (OR, 1.04; 95% CI, 1.02-1.07), and length of stay in the intensive care unit after SOT (OR, 1.04; 95% CI, 1.00-1.09) were independently associated with development of nocardiosis; low-dose cotrimoxazole prophylaxis was not found to prevent nocardiosis. Nocardia farcinica was more frequently associated with brain, skin, and subcutaneous tissue infections than were other Nocardia species. Among the 30 cases with central nervous system nocardiosis, 13 (43.3%) had no neurological symptoms. CONCLUSIONS: We identified 5 risk factors for nocardiosis after SOT. Low-dose cotrimoxazole was not found to prevent Nocardia infection. These findings may help improve management of transplant recipients.

Invasive aspergillosis after kidney transplant: case-control study.

BACKGROUND: Transplant recipients are at risk for invasive aspergillosis (IA), associated with a significant mortality rate. Renal transplant-specific risk factors have not been established. METHODS: Forty-one adult kidney transplant recipients diagnosed with proven or probable IA from 1995 through 2013 were identified by search of the computerized patient files in the University Hospitals Leuven. The control population in this 1:2 case-control study consisted of the 2 patients who received a kidney transplant immediately before and after each identified patient and did not develop IA (n = 82). RESULTS: Leukopenia after kidney transplant increased the risk of IA among all patients (odds ratio [OR], 2.345 [95% confidence interval {CI}, 1.084-5.071]). For early-onset infection (ie, occurred during the first 3 months after transplant), a longer duration of renal replacement therapy pretransplant and the occurrence of leukopenia were risk factors (OR per year, 1.192 [95% CI, 1.006-1.413] and OR, 3.346 [95% CI, 1.063-10.527], respectively), whereas donor cytomegalovirus seropositivity increased the risk for late-onset IA (ie, occurred >3 months after transplant) (OR, 3.677 [95% CI, 1.388-9.743]). Twelve-week mortality rate was 39%. Disseminated infection, leukopenia, and the height of the serum galactomannan index were associated with an increased risk of death (hazard ratio [HR], 5.080 [95% CI, 1.740-14.830]; HR, 3.198 [95% CI, 1.183-8.649]; and HR, 1.371 [95% CI, 1.123-1.674], respectively). CONCLUSIONS: Prolonged renal replacement therapy before kidney transplant increases the risk of IA early after transplant. The height of the serum galactomannan index predicts mortality.

The genealogical population dynamics of HIV-1 in a large transmission chain: bridging within and among host evolutionary rates.

Transmission lies at the interface of human immunodeficiency virus type 1 (HIV-1) evolution within and among hosts and separates distinct selective pressures that impose differences in both the mode of diversification and the tempo of evolution. In the absence of comprehensive direct comparative analyses of the evolutionary processes at different biological scales, our understanding of how fast within-host HIV-1 evolutionary rates translate to lower rates at the between host level remains incomplete. Here, we address this by analyzing pol and env data from a large HIV-1 subtype C transmission chain for which both the timing and the direction is known for most transmission events. To this purpose, we develop a new transmission model in a Bayesian genealogical inference framework and demonstrate how to constrain the viral evolutionary history to be compatible with the transmission history while simultaneously inferring the within-host evolutionary and population dynamics. We show that accommodating a transmission bottleneck affords the best fit our data, but the sparse within-host HIV-1 sampling prevents accurate quantification of the concomitant loss in genetic diversity. We draw inference under the transmission model to estimate HIV-1 evolutionary rates among epidemiologically-related patients and demonstrate that they lie in between fast intra-host rates and lower rates among epidemiologically unrelated individuals infected with HIV subtype C. Using a new molecular clock approach, we quantify and find support for a lower evolutionary rate along branches that accommodate a transmission event or branches that represent the entire backbone of transmitted lineages in our transmission history. Finally, we recover the rate differences at the different biological scales for both synonymous and non-synonymous substitution rates, which is only compatible with the 'store and retrieve' hypothesis positing that viruses stored early in latently infected cells preferentially transmit or establish new infections upon reactivation.

RegaDB: community-driven data management and analysis for infectious diseases.

SUMMARY: RegaDB is a free and open source data management and analysis environment for infectious diseases. RegaDB allows clinicians to store, manage and analyse patient data, including viral genetic sequences. Moreover, RegaDB provides researchers with a mechanism to collect data in a uniform format and offers them a canvas to make newly developed bioinformatics tools available to clinicians and virologists through a user friendly interface. AVAILABILITY AND IMPLEMENTATION: Source code, binaries and documentation are available on http://rega.kuleuven.be/cev/regadb. RegaDB is written in the Java programming language, using a web-service-oriented architecture.

Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe.

BACKGROUND: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program. METHODS: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy. RESULTS: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM. CONCLUSION: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring.