RETRO-TAS, a Retrospective Observational Study of Trifluridine/Tipiracil in Chemorefractory Metastatic Colorectal Cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) is an oral antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue that inhibits cell proliferation following its incorporation into DNA, and tipiracil that helps maintain the blood concentration of trifluridine by inhibiting the enzyme thymidine phosphorylase which inactivates trifluridine. It is approved as a third-line treatment option for patients with metastatic colorectal cancer (mCRC) and is administered at 35 mg/m2 two times daily from day 1 to 5 and from day 8 to 12 every 28 days. The aim of this investigator-initiated retrospective study (RETRO-TAS; NCT04965870) was to document real-world data on the clinical efficacy of FTD/TPI in patients with chemorefractory mCRC. METHODS: The clinical characteristics of patients with mCRC treated with FTD/TPI in 8 Cancer Centres were collected to assess physician's choice in the third or beyond line of treatment as well as the duration of treatment, dose modification, and toxicity. In addition, other important prognostic features related to mCRC such as molecular profile, performance status (PS), and primary site were analyzed. Statistical analysis for progression-free survival (PFS), overall survival (OS), 6-/8-month PFS rate and disease control rate (DCR) along with Cox regression model, Kaplan-Meier curves, and log-rank tests were carried out by using Stata/MP 16.0 for Windows. RESULTS: From October 2018 to October 2021, a total of 200 patients with mCRC and a median age of 67.0 (IQR 58.0, 75.0) years were treated with FTD/TPI. Τhe median follow-up time was 14 months (IQR 7, 23), 158 PDs and 106 deaths were reported at the time of this analysis. Of all the patients, 58% were males and 58% had mCRC at diagnosis. The molecular analysis identified mutations in KRAS (52%), NRAS (5%), HER2 (3.5%), BRAF (3.5%), and MSI (9%). Previous treatments included radical surgery in 51.5% and adjuvant chemotherapy in 39.5% of patients. FTD/TPI was administered in the third- (70.5%), fourth- (17.0%), or fifth-line (12.5%) treatment setting. Serious adverse events related to FTD/TPI included neutropenia (2%), anaemia (1%), thrombocytopenia (0.5%), diarrhoea (0.5%), nausea (0.5%), and fatigue (4%). A reduction of FTD/TPI dose, delay of next cycle initiation, and shorter duration were reported in 25%, 31%, and 14.5% of patients, respectively. Of all the patients 71.5% received FTD/TPI as monotherapy, 24.5% in combination with bevacizumab, and 4.0% with an anti-EGFR agent. The median FTD/TPI treatment duration was 119.5 days and 81% of patients discontinued treatment due to progressive disease. The DCR recorded by investigators' assessment was 45.5%. The median PFS was 4.8 and the median OS was 11.4 months. The 6- and the 8-month PFS rate was 41.4% and 31.5%, respectively. In the multivariate analysis, PS > 1 and presence of liver and lung metastasis were adversely associated with PFS and OS whereas mutational status and tumor sidedness were not. CONCLUSIONS: RETRO-TAS is a real-world observational study that confirms and adds on the findings of the pivotal RECOURSE Phase III study in relation to the efficacy of FTD/TPI in the third-line setting and in all subgroups of patients regardless of mutational status and sidedness.

Safety and efficacy of everolimus initiation from the first month after liver transplantation: A systematic review and meta-analysis.

INTRODUCTION: Everolimus, a selective inhibitor of mamalian target of rapamycin (mTORi), is considered to be an alternative immunosuppressive regimen in the liver transplantation (LT) setting. However, most of the transplant centers avoid its early use (i.e., during the first month) after LT mainly due to safety issues. METHODS: We searched for all articles published between 01/2010 and 7/2022 to evaluate the effectiveness and safety of initial/early administration of everolimus after LT. RESULTS: Seven studies (three randomized controlled trials and four prospective cohort studies) were included: initial/early everolimus-including therapy (group 1) was used in 512 (51%) and calcineurin inhibitor (CNI) based therapy (group 2) in 494 (49%) patients. No significant difference was found between group 1 and group 2 patients regarding the rates of biopsy-proven acute rejection episodes (Odds Ratio [OR]: 1.27, 95% CI: .67-2.41, p = .465) and hepatic artery thrombosis (OR: .43, 95% CI: .09-2.02, p = .289). Everolimus was associated with higher rates of dyslipidemia (14.2% vs. 6.8%, p = .005) and incisional hernia (29.2% vs. 10.1%, p < .001). Finally, no difference was found between the two groups regarding recurrence of hepatocellular carcinoma (Risk Rates [RR]: 1.22 95%CI: .66-2.29, p = .524) and mortality (RR: .85 95%CI: .48-1.50, p = .570). CONCLUSION: Use of initial/early everolimus seems to be effective with a satisfactory safety profile, making its administration a reasonable therapeutic option in the LT setting.

Different COVID-19 outcomes among systemic rheumatic diseases: a nation-wide cohort study.

OBJECTIVES: To investigate coronavirus disease 2019 (COVID-19)-associated risk of hospitalization and death in RA, AS, PsA, SLE and SSc in comparison with the general population during the first year of the pandemic, and compare their overall mortality with 2019. METHODS: Interlinking nationwide electronic registries, we recorded confirmed COVID-19-associated infections, hospitalizations and deaths, and all-cause deaths between 1 March 2020 and 28 February 2021 in all adults with RA, AS, PsA, SLE and SSc under treatment (n = 74 970, median age 67.5, 51.2, 58.1, 56.2 and 62.2 years, respectively) and in random comparators from the general population matched (1:5) on age, sex and region of domicile. Deaths from all causes during 2019 were also recorded. RESULTS: Compared with the general population, incidence rates (IR) for COVID-19-associated hospitalization were higher in RA [IR ratio (IRR) 1.71(1.50-1.95)], SLE [2.0 (1.4-2.7)] and SSc [2.28 (1.29-3.90)], while COVID-19-associated death rates were higher in RA [1.91 (1.46-2.49)]. When focusing only on severe acute respiratory syndrome coronavirus 2-infected subjects, after adjusting for age and gender, the odds ratio for COVID-19 associated death was higher in RA [1.47 (1.11-1.94)] and SSc [2.92 (1.07-7.99)] compared with the general population. The all-cause mortality rate compared with the general population increased in RA during the first year of the pandemic (IRR 0.71) with reference to 2019 (0.59), and decreased in SSc (IRR 1.94 vs 4.36). CONCLUSION: COVID-19 may have a more severe impact in patients with systemic rheumatic disease than in the general population. COVID-19-related mortality is increased in subgroups of patients with specific rheumatic diseases, underscoring the need for priority vaccination and access to targeted treatments.

HIV continuum of care: bridging cross-sectional and longitudinal analyses.

OBJECTIVE: The aim of this study was to propose a unified continuum-of-care (CoC) analysis combining cross-sectional and longitudinal elements, incorporating time spent between stages. DESIGN: The established 90-90-90 target follows a cross-sectional four-stage CoC analysis, lacking information on timing of diagnosis, antiretroviral therapy (ART) initiation, and viral suppression durability. METHODS: Data were derived from the Athens Multicenter AIDS Cohort Study (AMACS). In the cross-sectional CoC, we added stratification of diagnosed people with HIV (PWH) by estimated time from infection to diagnosis; of those who ever initiated ART or achieved viral suppression by corresponding current status (in 2018); and cumulative incidence function (CIF) of ART initiation and viral suppression, treating loss-to-follow-up (LTFU) as competing event. Viral suppression was defined as viral load less than 500 copies/ml. Viral suppression durability was assessed by the CIF of viral load rebound. FINDINGS: About 89.1% of PWH in 2018 were diagnosed (range of diagnoses: 1980-2018). Median time to diagnosis was 3.5 years (IQR: 1.1-7.0). Among diagnosed, 89.1% were ever treated, of whom 86.7% remained on ART. CIF of ART initiation and LTFU before ART initiation were 80.9 and 6.0% at 5 years since diagnosis, respectively. Among treated, 89.4% achieved viral suppression, of whom 87.4% were currently virally suppressed. The CIF of viral load rebound was 24.2% at 5 years since first viral suppression but substantially reduced in more recent years. INTERPRETATION: The proposed analysis highlights time gaps in CoC not evident by the standard cross-sectional approach. Our analysis highlights the need for early diagnosis and identifies late presenters as a key population for interventions that could decrease gaps in the CoC.

An exploratory study of ascitic fluid lactate as prognostic factor of mortality in cirrhotic patients with spontaneous bacterial peritonitis.

BACKGROUND: The diagnostic value of ascitic fluid lactate (AF lactate) was previously evaluated in spontaneous bacterial peritonitis (SBP) but its prognostic value was not established. AIM: To assess the prognostic value of AF lactate in SBP. METHODS: We prospectively studied 63 consecutive patients with SBP. Fifty patients with acute-on-chronic liver failure (ACLF) or acute decompensation (AD) (ACLF/AD group) without SBP and 30 with stable decompensated cirrhosis (DC) were included as controls. In SBP, mortality was recorded at 30, 90 and 180 days. RESULTS: Arterial and AF lactate were significantly higher in SBP compared to other groups. Analyzing the SBP group alone, AF lactate accurately differentiated survivors from nonsurvivors in all time points. The prognostic performance of AF lactate was improved over time, with the area under the receiver operating characteristic computed at 0.894, 0.927 and 0.934 at 30, 90 and 180 days, respectively. The cutoff level of 2 mmol/L was associated with 100, 100 and 94.7% sensitivity, 57.9, 73.3 and 80% specificity, 61, 80.5 and 87.8% positive predictive value and 100, 100 and 90.9% negative predictive value, respectively. Arterial lactate, neutrophil-to-lymphocyte ratio (NLR) and Model for End-Stage Liver Disease (MELD) score predicted outcomes less accurately than AF lactate. Patients with AF lactate >2 mmol/L had a worse prognosis compared to patients with ≤2 mmol/L (log-rank P < 0.001). No case with AF lactate ≤2 mmol/L died within 90 days postSBP diagnosis. In Cox multivariate analysis at all time points, only AF lactate and NLR were independent predictors of mortality. CONCLUSION: An AF lactate level of 2 mmol/L has a high ability to differentiate survivors from nonsurvivors in the first 180 days postSBP. Its prognostic value outperformed arterial-lactate, NLR and MELD.

All-cause mortality in systemic rheumatic diseases under treatment compared with the general population, 2015-2019.

OBJECTIVES: To compare current all-cause mortality rates in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) versus general population. METHODS: In this population-based, retrospective cohort study, anonymised data on 11 186 586 citizens, including all patients with RA (42 735, 79% female), AS (9707, 43% female), PsA (13 779, 55% female), SLE (10 440, 89% female) and SSc (2277, 88% female), (median age of 64/47/54/53/59 years at study entry, respectively), under prescribed treatment between 2015 and 2019, were extracted from the electronic database covering nearly 99% of the Greek population. RESULTS: After 1:5 (patients:general population) matching for gender/age, we found that survival was worse in SSc, followed by SLE and inflammatory arthritis. Compared with the general population HRs for death increased from the first 3 years to 5 years of observation possibly due to increases in disease duration: RA (from 0.63 to 1.13 (95% CI: 1.05 to 1.22), AS (from 0.62 to 1.01, (95% CI: 0.76 to 1.33)), PsA (from 0.68 to 1.06, (95% CI: 0.88 to 1.28)), SLE (from 1.52 to 1.98, (95% CI: 1.67 to 2.33)) and SSc (from 2.27 to 4.24, (95% CI: 3.19 to 5.63)). In both SLE and SSc mortality was increased in men than women and in patients younger than 50 years. CONCLUSIONS: Survival rates over 5 years in inflammatory arthritis under treatment are currently becoming comparable (AS/PsA) or slightly higher (RA) than those of the general population. However, all-cause mortality is almost twofold and fourfold higher in SLE and SSc, respectively, being even higher for male and younger patients.

HIV continuum of care: expanding scope beyond a cross-sectional view to include time analysis: a systematic review.

INTRODUCTION: The continuum of care (CoC) model has been used to describe the main pillars of HIV care. This study aims to systematically review methods and elucidate gaps in the CoC analyses, especially in terms of the timing of the progression through steps, recognized nowadays as a critical parameter for an effective response to the epidemic. METHODS: A PubMed and EMBASE databases search up to December 2019 resulted in 1918 articles, of which 209 were included in this review; 84 studies presented in major HIV conferences were also included. Studies that did not provide explicit definitions, modelling studies and those reporting only on metrics for subpopulations or factors affecting a CoC stage were excluded. Included articles reported results on 1 to 6 CoC stages. RESULTS: Percentage treated and virally suppressed was reported in 78%, percentage diagnosed and retained in care in 58%, percentage linked to care in 54% and PLHIV in 36% of the articles. Information for all stages was provided in 23 studies. Only 6 articles use novel CoC estimates: One presents a dynamic CoC based on multistate analysis techniques, two base their time-to-next-stage estimates on a risk estimation method based on the cumulative incidence function, weighted for confounding and censoring and three studies estimated the HIV infection time based on mathematical modelling. CONCLUSION: A limited number of studies provide elaborated time analyses of the CoC. Although time analyses lack the straightforward interpretation of the cross-sectional CoC, they provide valuable insights for the timely response to the HIV epidemic. A future goal would be to develop a model that retains the simplicity of the cross-sectional CoC but also incorporates timing between stages.

A survey of methodologies on causal inference methods in meta-analyses of randomized controlled trials.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have been considered as the highest level of evidence in the pyramid of the evidence-based medicine. However, the causal interpretation of such results is seldom studied. METHODS: We systematically searched for methodologies pertaining to the implementation of a causally explicit framework for meta-analysis of randomized controlled trials and discussed the interpretation and scientific relevance of such causal estimands. We performed a systematic search in four databases to identify relevant methodologies, supplemented with hand-search. We included methodologies that described causality under counterfactuals and potential outcomes framework. RESULTS: We only identified three efforts explicitly describing a causal framework on meta-analysis of RCTs. Two approaches required individual participant data, while for the last one, only summary data were required. All three approaches presented a sufficient framework under which a meta-analytical estimate is identifiable and estimable. However, several conceptual limitations remain, mainly in regard to the data generation process under which the selected RCTs rise. CONCLUSIONS: We undertook a review of methodologies on causal inference methods in meta-analyses. Although all identified methodologies provide valid causal estimates, there are limitations in the assumptions regarding the data generation process and sampling of the potential RCTs to be included in the meta-analysis which pose challenges to the interpretation and scientific relevance of the identified causal effects. Despite both causal inference and meta-analysis being extensively studied in the literature, limited effort exists of combining those two frameworks.

Natural history of grade 1 ascites in patients with liver cirrhosis.

BACKGROUND: No evidence is available on the natural history of grade 1 ascites and its progression to grade 2/3 in patients with liver cirrhosis. The aim of the current study was to address this issue, to assess the development of main comorbid disorders closely related to ascites progression, and to identify the predictive factors for survival in this setting. METHODS: Consecutive Caucasian cirrhotic patients with grade 1 ascites were retrospectively analyzed. None of patients was under treatment with diuretics at diagnosis. Control groups consisted of 145 cirrhotics with grade 2/3 ascites and 175 cirrhotics without ascites. RESULTS: Diuretics were initiated in 58 patients with grade 1 ascites at baseline by the attending physician. At the last follow up, 29 patients had no ascites, 33 patients had grade 1 and 38 patients had grade 2/3 ascites. No variable was found to be an independent predictor of grade 2/3 ascites. Seven patients developed spontaneous bacterial peritonitis while under treatment with diuretics; at that time only 1 patient had grade 1 ascites. The mortality rate was similar among all examined groups. CONCLUSIONS: This study suggests that the presence of grade 1 ascites does not constitute a precursor of grade 2/3 ascites in patients with cirrhosis. Thus, patients with grade 1 ascites do not require specific treatment with diuretics.

Human Immunodeficiency Virus Continuum of Care in 11 European Union Countries at the End of 2016 Overall and by Key Population: Have We Made Progress?

BACKGROUND: High uptake of antiretroviral treatment (ART) is essential to reduce human immunodeficiency virus (HIV) transmission and related mortality; however, gaps in care exist. We aimed to construct the continuum of HIV care (CoC) in 2016 in 11 European Union (EU) countries, overall and by key population and sex. To estimate progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, we compared 2016 to 2013 estimates for the same countries, representing 73% of the population in the region. METHODS: A CoC with the following 4 stages was constructed: number of people living with HIV (PLHIV); proportion of PLHIV diagnosed; proportion of those diagnosed who ever initiated ART; and proportion of those ever treated who achieved viral suppression at their last visit. RESULTS: We estimated that 87% of PLHIV were diagnosed; 92% of those diagnosed had ever initiated ART; and 91% of those ever on ART, or 73% of all PLHIV, were virally suppressed. Corresponding figures for men having sex with men were: 86%, 93%, 93%, 74%; for people who inject drugs: 94%, 88%, 85%, 70%; and for heterosexuals: 86%, 92%, 91%, 72%. The proportion suppressed of all PLHIV ranged from 59% to 86% across countries. CONCLUSIONS: The EU is close to the 90-90-90 target and achieved the UNAIDS target of 73% of all PLHIV virally suppressed, significant progress since 2013 when 60% of all PLHIV were virally suppressed. Strengthening of testing programs and treatment support, along with prevention interventions, are needed to achieve HIV epidemic control.

Vitamin D-related immunomodulation in patients with liver cirrhosis.

OBJECTIVE(S): Increasing evidence indicates that vitamin D status is linked to severity of liver cirrhosis and patients' survival. However, the potential role of vitamin D-related immunomodulation in hepatic decompensation and patients' mortality in relation to vitamin D deficiency remains unknown. The aim of the current study is to evaluate the association between vitamin D status and vitamin D binding protein (VDBP) levels with serum cytokine and lipopolysaccharide binding protein (LBP) and to examine their role on disease severity and cirrhotics' mortality. METHODS: One hundred consecutive Caucasian patients with liver cirrhosis were enrolled in the study. 25(OH)D, VDBP, and LBP concentrations were assessed by ELISA. Cytokine tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), IL-1ß, IL-8, IL-10, and IL-12 levels were determined by Cytometric Bead Array. RESULTS: 25(OH)D levels were inversely correlated with CP score, MELD, IL-6, and CP stage and VDBP levels with CP score, MELD, IL-6, IL-8, LBP, and CP stage. Cirrhotics with 25(OH)D deficiency and severe deficiency had significantly higher CP score, increased IL-6 levels and lower VDBP levels. In the multivariate analysis, the independent prognostic factors associated with patients' survival were CP stage B [hazard ratio = 6.75; 95% confidence interval (CI) 1.32, 34.43; P = 0.022], CP stage C (hazard ratio = 7.39; 95% CI 1.41, 38.81; P = 0.018), the presence of hepatocellular carcinoma (hazard ratio = 4.50; 95% CI 1.54, 13.13; P = 0.006) and 25(OH)D levels (hazard ratio = 0.87; 95% CI 0.80, 0.95; P = 0.002). CONCLUSION: The results show that vitamin D status and VDBP levels are associated with liver cirrhosis severity and patients' mortality, possibly through a proinflammatory immune response.

In Vitro Gene Transcription of Listeria monocytogenes after Exposure to Human Gastric and Duodenal Aspirates.

The aim of the present study was to assess, for the first time to our knowledge, Listeria monocytogenes CFU changes, as well as to determine the transcription of key virulence genes, namely, sigB, prfA, hly, plcA, plcB, inlA, inlB, inlC, inlJ, inlP, and lmo2672 after in vitro exposure to human gastric and duodenal aspirates. Furthermore, investigations of the potential correlation between CFU changes and gene regulation with factors influencing gastric (proton pump inhibitor intake and presence of gastric atrophy) and duodenal pH were the secondary study aims. Gastric and duodenal fluids that were collected from 25 individuals undergoing upper gastrointestinal endoscopy were inoculated with L. monocytogenes serotype 4b strain LQC 15257 at 9 log CFU·mL-1 and incubated at 37°C for 100 min and 2 h, respectively, with the time corresponding to the actual exposure time to gastric and duodenal fluids in the human gastrointestinal tract. Sampling was performed upon gastric fluid inoculation, after incubation of the inoculated gastric fluids, upon pathogen resuspension in duodenal fluids and after incubation of the inoculated duodenal fluids. L. monocytogenes CFU changes were assessed by colony counting, as well as reverse transcription quantitative PCR by using inlB as a target. Gene transcription was assessed by reverse transcription quantitative PCR. In 56% of the cases, reduction of the pathogen CFU occurred immediately after exposure to gastric aspirate. Upregulation of hly and inlC was observed in 52 and 58% of the cases, respectively. On the contrary, no upregulation or downregulation was noticed regarding sigB, prfA, plcA, plcB, inlA, inlB, inlJ, inlP, and lmo2672. In addition, sigB and plcA transcription was positively and negatively associated, respectively, with an increase of the pH value, and inlA transcription was negatively associated with the presence of gastric atrophy. Finally, a positive correlation between the transcriptomic responses of plcB, inlA, inlB, inlC, inlJ, inlP, and lmo2672 was detected. This study revealed that the CFU of the pathogen was negatively affected after exposure to human gastroduodenal aspirates, as well as significant correlations between the characteristics of the aspirates with the virulence potential of the pathogen.

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.

TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Patients with stage II-III colorectal cancer (CRC) treated with adjuvant chemotherapy, gain a 25% survival benefit. In the context of personalized medicine, there is a need to identify patients with CRC who may benefit from adjuvant chemotherapy. Molecular profiling could guide treatment decisions in these patients. Thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF could be included in the molecular profile under consideration. AIM: To investigate the association of TYMS gene polymorphisms, KRAS and BRAF mutations with survival of CRC patients treated with chemotherapy. METHODS: A retrospective study studied formalin-fixed paraffin-embedded tissues (FFPEs) of consecutive patients treated with adjuvant chemotherapy during January/2005-January/2007. FFPEs were analysed with PCR for the detection of TYMS polymorphisms, mutated KRAS (mKRAS) and BRAF (mBRAF). Patients were classified into three groups (high, medium and low risk) according to 5'UTR TYMS polymorphisms Similarly, based on 3'UTR polymorphism ins/loss of heterozygosity (LOH) patients were allocated into two groups (high and low risk of relapse, respectively). Cox regression models examined the associated 5-year survival outcomes. RESULTS: One hundred and thirty patients with early stage CRC (stage I-II: 55 patients; stage III 75 patients; colon: 70 patients; rectal: 60 patients) were treated with surgery and chemotherapy. The 5-year disease free survival and overall survival rate was 61.6% and 73.9% respectively. 5'UTR polymorphisms of intermediate TYMS polymorphisms (2RG/3RG, 2RG/LOH, 3RC/LOH) were associated with lower risk for relapse [hazard ratio (HR) 0.320, P = 0.02 and HR 0.343, P = 0.013 respectively] and death (HR 0.368, P = 0.031 and HR 0.394, P = 0.029 respectively). The 3'UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (P = 0.001) and death (P = 0.005). mBRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas mKRAS (39% of patients) not. CONCLUSION: Prospective validating studies are required to confirm whether 2RG/3RG, 2RG/LOH, 3RC/LOH, absence of ins/LOH and wild type BRAF may indicate patients at lower risk of relapse following adjuvant chemotherapy.

Are European HIV cohort data within EuroCoord representative of the diagnosed HIV population?

OBJECTIVE: HIV cohorts are an important source of clinical data for informing public health policies and programmes. However, the generalizability of cohort findings to the wider population of people diagnosed with HIV in each country remains unclear. In this work, we assessed the representativeness of six large national HIV cohorts within Europe. DESIGN AND METHODS: Individual-level cohort data were provided from national cohorts in France, Germany, Greece, Italy, Spain and the United Kingdom. Analysis focused on new HIV diagnoses reported to The European Surveillance System (TESSy) during three time periods (2000-2004, 2005-2009 and 2010-2013), to allow for temporal changes. Cohort and TESSy records were matched and compared by age, sex, transmission mode, region of origin and CD4+ cell count at diagnosis. The probability of being included in each cohort given demographic characteristics was estimated and used to generate weights inversely proportional to the probability of being included. RESULTS: Participating cohorts were generally representative of the national HIV-diagnosed population submitted to TESSy. However, people who inject drugs, those born in a country other than that reporting the data, those with low CD4 cell counts at diagnosis, and those more than 55 years were generally underrepresented in the cohorts examined. CONCLUSION: These European cohorts capture a representative sample of the HIV-diagnosed populations in each country; however some groups may be underrepresented.

HIV cascade of care in Greece: Useful insights from additional stages.

BACKGROUND: Aiming to eliminate HIV infection, UNAIDS has set a global "90-90-90" target by 2020. We sought to construct a 6-stages HIV Cascade of Care (CoC) in Greece, overall and by risk group, to assess risk-group and stage-specific progress in achieving the UNAIDS target. PATIENTS AND METHODS: Combining data from the HIV/AIDS surveillance system and a population-based HIV cohort study, the CoC included: i) number of people living with HIV (PLHIV) by end of 2013; ii) proportion of PLHIV ever diagnosed; iii) proportion of diagnosed linked-to-care iv) proportion of linked-to-care ever initiating antiretroviral therapy (ART); v) proportion of treated who retained-in-care vi) proportion of those retained-in-care who were virally suppressed (≤200 copies/mL) at their last visit (01/07/2012-31/12/2013). RESULTS: In 2013, 14147 PLHIV were in Greece. Overall, proportions of each stage in the cascade were: 78.4% diagnosed; 86% linked-to-care; 78.5% initiated ART; 86.4% retained-in-care, and 87.1% virally suppressed. Totally, 42.6% of all PLHIV were virally suppressed. The percentage diagnosed was lower among heterosexual men and women (heterosexuals) than in MSM (men who have sex with men) or PWID (people who inject drugs). Most MSM were linked to care (97.2% of diagnosed) while a substantial proportion of PWID were not (80.8% of diagnosed). Once treated, PWID remained in care in similar proportions to MSM. Unlike PWID, a high proportion of the retained in care MSM and heterosexuals achieved viral suppression. CONCLUSIONS: At the end of 2013, we identified gaps in the HIV CoC in Greece, which differed across risk groups. Targeted interventions are critical in optimizing early diagnosis and timely linkage. A 6-stage CoC, stratified by risk group, can inform strategic public health planning in improving HIV treatment outcomes.

Prognostic significance of vitamin D receptor (VDR) gene polymorphisms in liver cirrhosis.

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1ß and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1ß levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

Substantial Heterogeneity in Progress Toward Reaching the 90-90-90 HIV Target in the WHO European Region.

BACKGROUND: Achieving the UNAIDS 90-90-90 target by 2020 is expected to end the HIV epidemic by 2030. We report on progress in the WHO European Region in meeting this target. METHODS: The European Centre for Disease Prevention and Control (ECDC) sent questionnaires to 55 countries in 2016. We report estimates for 4 stages of the continuum of HIV care (living with HIV, diagnosed, treated, and virally suppressed), corresponding to the Joint United Nations Programme on HIV and AIDS (UNAIDS) target and explore differences by subregion and challenges with reporting data. FINDINGS: Forty-four countries provided data for ≥1 stage, and 29 for all 4 stages. Estimated HIV prevalence was 0.19% (range 0.02%-0.84%, n = 37 countries providing stage 1 data). The proportion diagnosed of people living with HIV ranged from 38% to 98% (n = 37 reporting number of people living with HIV and diagnosed). The proportion on ART of those diagnosed ranged from 27% to 96% (n = 40 reporting numbers diagnosed and treated), and viral suppression rates ranged from 32% to 97% (n = 31 providing numbers treated and virally suppressed). The overall continuum of care estimate for 29 countries with complete data was 81-84-88, which differed by subregion: 84-88-90, 84-69-62, and 57-45-57 for the western, central, and eastern subregions, respectively. Challenges in reporting data included absence of a single data source for all stages, shortage of expertise, and lack of financial and human resources. CONCLUSIONS: There is an urgent need to strengthen HIV testing programs throughout Europe, particularly in the eastern subregion, and to remove constraints hampering access to testing and care. Recent changes to treatment guidelines should help reduce the numbers diagnosed not treated.

Effect of immediate initiation of antiretroviral treatment on the risk of acquired HIV drug resistance.

OBJECTIVE: We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/µl and initiation with CD4 cell count less than 350 cells/µl. DESIGN: Cohort study based on routinely collected data from the HIV-CAUSAL collaboration. METHODS: For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics. RESULTS: In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/µl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/µl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/µl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2). CONCLUSION: Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

Lactate serum concentrations during treatment with nucleos(t)ide analogues in hepatitis B with or without cirrhosis.

OBJECTIVE: The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues. PATIENTS AND METHODS: One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy. RESULTS: None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class. CONCLUSION: None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.