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Summary: Allogeneic haematopoietic cell transplantation (allo‐HCT) remains an option for tyrosine kinase inhibitor‐resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high‐risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry‐based study of 1686 CML patients undergoing first allo‐HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo‐HCT was 46 years (IQR 36–55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse‐free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non‐relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft‐versus‐host disease (GvHD)‐free/relapse‐free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types. [ABSTRACT FROM AUTHOR]

This article examines the occurrence of liver complications in patients with myelofibrosis who undergo allogeneic hematopoietic stem cell transplantation (HSCT). The study found that liver adverse events (AEs) were more common than expected, with 64% of patients experiencing liver AEs within the first 100 days after HSCT. The most common liver AEs were caused by the conditioning regimen. Risk factors for liver toxicity included worse performance status, higher comorbidity index, and higher prognostic scoring system score. The study also found that hyperbilirubinemia and hepatic graft-versus-host disease were associated with increased mortality. The text emphasizes the importance of monitoring liver complications in HSCT patients and suggests using imaging and biopsies to determine the cause and guide treatment. The study included various factors in the analysis and was approved by the appropriate ethics committee. [Extracted from the article]

Patients were transplanted with a median time to allo-HCT of 15.1 months (IQR, 9.8-27.9) for CEL, NOS patients, and 22.2 months (IQR, 11.5-55.8; I p i = 0.01) for HES. Helbig et al. reported on 10 patients with CEL, NOS with a median age of 62 (23-73 years), frequently with an aggressive clinical course, five of whom developed acute transformation within two years from the time of diagnosis.6 Here, only one patient in the chronic phase successfully underwent allo-SCT. Keywords: allogeneic stem cell transplant; chronic eosinophilic leukaemia; conditioning; hypereosinophilic syndrome; non-relapse mortality EN allogeneic stem cell transplant chronic eosinophilic leukaemia conditioning hypereosinophilic syndrome non-relapse mortality 209 213 5 06/27/22 20220701 NES 220701 Hypereosinophilic syndrome (HES) and chronic eosinophilic leukaemia (CEL), not otherwise specified (NOS) are rare haematological disorders.1 Allogeneic haematopoietic cell transplantation (allo-HCT) has been reported in single case reports or small case series only for both refractory HES or CEL, NOS and outcomes remain ill-defined.1-3 HES normally demonstrates a male predominance, likely underrecognized, with a variable clinical course. [Extracted from the article]

Supplemental Digital Content is Available in the Text. Background: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. Methods: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. Results: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm3. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm3. Discussion: Starting ART with a CD4 cell count of ≥500 cells/mm3 makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline. Methods: Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART, <100 CD4 cells/mm3, or AIDS) among therapy-naïve MSM HIV-1 seroconverters in the Netherlands. These models make different assumptions about the censoring process. Results: All 3 models estimated lower median CD4 cell counts 9 months after seroconversion in later calendar years (623, 582, and 541 cells/mm3 for 1984–1995 [n = 111], 1996–2002 [n = 139], and 2003–2007 seroconverters [n = 356], respectively, shared-parameter model). Only the 2 joint-models found a trend for a steeper decline of CD4 cell counts with seroconversion in later calendar years (overall p-values 0.002 and 0.06 for the pattern-mixture and the shared-parameter model, respectively). In the shared-parameter model the median decline from 9 to 48 months was 276 cellsmm3 for 1984–1995 seroconverters and 308 cells/mm3 for 2003–2007 seroconverters (difference in slope, p = 0.045). Conclusion: Mixed-effects models underestimate the CD4 cell decline prior to starting ART. Joint-models suggest that CD4 cell count declines more rapidly in patients infected between 2003 and 2007 compared to patients infected before 1996. [ABSTRACT FROM AUTHOR]

Background. The aim of this study was to investigate the association between immunodeficiency, viremia, and non-AIDS-defining malignancies (NADM). Methods. Patients starting combination antiretroviral therapy (cART) as of 1 January 1996 were selected from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. In Cox models, risk factors for NADM were investigated. These included age, sex, transmission route, smoking, alcohol abuse, prior AIDS diagnosis, duration of exposure to cART, and estimated duration of human immunodeficiency virus infection. CD41 cell count and viral load (VL) were considered as time-updated variables and as measures of cumulative exposure to CD41 cell counts of <200, <350, or <500 cells/mm³ and detectable VL >50, >400, and >1000 copies/mL, respectively. Results. In a cohort of 11,459 patients, 236 NADMs were diagnosed; 102 were caused by infection, and 134 were attributable to other causes. Median CD4+ cell count at NADM diagnosis was 340 cells/mm³ (range, 210- 540 cells/mm³). Median time to first NADM after starting cART was 5.0 years (range, 2.2-8.2 years). In multivariate models, cumulative exposure to CD41 cell counts ,200 cells/mm³ remained significant (hazard ratio [HR], 1.12; range, 1.03-1.22) for each additional year of exposure. In stratified analyses, cumulative exposure to CD4+ cell counts <200 cells/mm³ was associated with malignancies possibly caused by infection (HR, 1.16; range, 1.03-1.31]) but was not associated with other types of cancers. No significant effect of viremia was seen in either type of cancer. Conclusions. Cumulative exposure to CD4+ cell counts <200 cells/mm³ during cART was associated with an increased risk of infection-related non-AIDS-defining malignancies. [ABSTRACT FROM AUTHOR]

The article presents a study on the safety of dose reduction in patients with high plasma efavirenz and its ability to prevent toxicity-induced efavirenz discontinuations. It explores the results of the study using the human immunodefficiency virus (HIV)-positive patients with high plasma efavirenz level as subjects. It concludes that toxicity-induced continuation in patients with high efavirenz plasma concentrations can be prevented by dose reduction without compromising virological efficacy.

Background: HIV-1 RNA plasma concentration at viral set-point is associated not only with disease outcome but also with the transmission dynamics of HIV-1. We investigated whether plasma HIV-1 RNA concentration and CD4 cell count at viral set-point have changed over time in the HIV epidemic in the Netherlands. Methodology/Principal Findings: We selected 906 therapy-naïve patients with at least one plasma HIV-1 RNA concentration measured 9 to 27 months after estimated seroconversion. Changes in HIV-1 RNA and CD4 cell count at viral set-point over time were analysed using linear regression models. The ATHENA national observational cohort contributed all patients who seroconverted in or after 1996; the Amsterdam Cohort Studies (ACS) contributed seroconverters before 1996. The mean of the first HIV-1 RNA concentration measured 9-27 months after seroconversion was 4.30 log10 copies/ml (95% CI 4.17-4.42) for seroconverters from 1984 through 1995 (n = 163); 4.27 (4.16-4.37) for seroconverters 1996-2002 (n = 232), and 4.59 (4.52-4.66) for seroconverters 2003-2007 (n = 511). Compared to patients seroconverting between 2003-2007, the adjusted mean HIV-1 RNA concentration at set-point was 0.28 log10 copies/ml (95% CI 0.16-0.40; p<0.0001) and 0.26 (0.11-0.41; p = 0.0006) lower for those seroconverting between 1996-2002 and 1984-1995, respectively. Results were robust regardless of type of HIV-1 RNA assay, HIV-1 subtype, and interval between measurement and seroconversion. CD4 cell count at viral set-point declined over calendar time at approximately 5 cells/ mm³/year. Conclusion: The HIV-1 RNA plasma concentration at viral set-point has increased over the last decade of the HIV epidemic in the Netherlands. This is accompanied by a decreasing CD4 cell count over the period 1984-2007 and may have implications for both the course of the HIV infection and the epidemic. [ABSTRACT FROM AUTHOR]

The article investigates CD4 cell count changes in therapy-naive patients during seven years of highly active antiretroviral therapy in an observational cohort. It shows that restoration of CD4 cell counts is feasible within seven years of HAART in most HIV-infected patients, achieving sufficient suppression of viral replication.

Aim: To determine the effectiveness of prenatal treatment for clinical manifestations of congenital toxoplasmosis.Methods: We prospectively identified 255 live-born infants with congenital toxoplasmosis using prenatal or neonatal screening. We determined the effect of prenatal treatment on the risks of intracranial or ocular lesions in infancy, accounting for gestational age at maternal seroconversion.Results: Prenatal treatment within 4 wk of seroconversion reduced the risk of intracranial lesions compared with no treatment (odds ratio, OR 0.28; 95% CI: 0.08-0.75), but there was no significant effect when initiated after 4 wk (OR 0.76; 95% CI: 0.35-1.59; overall p-value 0.19). Compared to spiramycin alone, no treatment doubled the risk of intracranial lesions (OR 2.33; 95% CI: 1.04-5.50), but the risk did not differ with pyrimethamine-sulphonamide treatment (overall p-value 0.52). There was no consistent relationship between the type or timing of treatment and the risk of ocular lesions. Gestational age at maternal seroconversion was inversely associated with the risk of intracranial but not ocular lesions.Conclusion: Only early versus no prenatal treatment for intracranial lesions showed a statistically significant benefit. A large randomized controlled trial and/or meta-analysis of individual patient data from cohort studies is required to confirm these findings. [ABSTRACT FROM AUTHOR]

In HIV-negative patients, radiotherapy (RT) decreases CD4+ T-cell counts. We studied the effects of RT in HIV-1 positive patients.HIV-1 positive patients with a subsequent diagnosis of a solid tumor were selected from the Dutch national observational HIV cohort, Aids Therapy Evaluation in the Netherlands (ATHENA). The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was the time from baseline to reaching CD4 cell counts higher than those at baseline. Kaplan-Meier estimates of the percentage of patients reaching the endpoint were calculated.Ninety patients were included of whom 36 received RT and 54 did not. Median duration of RT was 46 [interquartile range (IQR) 30-63] days. Median first CD4 cell count after stopping RT was 150 (IQR 30-270) × 106/L lower compared with baseline. In 13 of the 36 patients receiving RT, CD4 cell counts recovered to baseline, after a median of 469 (IQR 345-595) days. In 35 of the 54 patients without RT, the CD4 cell count recovered to baseline or higher, after a median of 112 (IQR 42-182) days. After 3 years, in 39% of patients who had RT compared with 71% of patients without RT, CD4 cell counts recovered to baseline or higher (P < 0.0001). In a Cox regression adjusted for potential confounders, RT was associated with a longer (hazard ratio 0.29; 95% confidence interval 0.13 to 0.63) and combination antiretroviral therapy use with a shorter time to return to baseline [hazard ratio 2.46 (95% confidence interval 1.11 to 5.48)].RT resulted in a significant and prolonged decrease in CD4 cell counts. [ABSTRACT FROM AUTHOR]

Background. Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts >250 cells/μL and in male individuals with CD4 cell counts >400 cells/μL are based on findings in treatment-naive patients. It is unclear whether these guidelines also apply to treatment-experienced patients switching to NVP-based combination therapy. Methods. Patients in the ATHENA cohort study who had used NVP-based combination therapy were included. We identified patients who discontinued NVP-based combination therapy because of hypersensitivity reactions (HSRs; rash and/or hepatotoxicity) within 18 weeks after starting such therapy. We grouped patients according to their CD4 cell count at the start of NVP-based combination therapy (current CD4 cell count) as having a high CD4 cell count (for female patients, >250 cells/μL; for male patients, >400 cells/μL) or a low CD4 cell count. Treatment-experienced patients were further subdivided according to the last available CD4 cell count before first receipt of antiretroviral therapy (ART; pre-ART CD4 cell count) using the same criteria. Risk factors for HSR were assessed using multivariate logistic regression. Results. Of 3752 patients receiving NVP-based combination therapy, 231 patients (6.2%) discontinued NVP therapy because of HSRs. Independent risk factors included female sex and Asian ethnicity. Having an undetectable viral load (VL) at the start of NVP therapy was associated with reduced risk of developing an HSR (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.38-0.71). Pretreated patients with low pre-ART and high current CD4 cell counts and a detectable VL when switching to NVP-based combination therapy had a significantly higher risk of developing an HSR, compared with treatment-naive patients who started NVP therapy with low CD4 cell counts (adjusted OR, 1.87; 95% CI, 1.11-3.12); pretreated patients with low pre-ART CD4 cell counts who switched to NVP therapy with a high current CD4 cell count and an undetectable VL did not have an increased risk of developing an HSR (adjusted OR, 1.03; 95% CI, 0.66-1.61). Conclusions. Treatment-experienced patients who start NVP-based combination therapy with low pre-ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of HSRs, compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds. [ABSTRACT FROM AUTHOR]

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia. [ABSTRACT FROM AUTHOR]

The BEEHIVE (Bridging the Evolution and Epidemiology of HIV in Europe) project aims to analyse nearly-complete viral genomes from >3000 HIV-1 infected Europeans using high-throughput deep sequencing techniques to investigate the virus genetic contribution to virulence. Following the development of a computational pipeline, including a new de novo assembler for RNA virus genomes, to generate larger contiguous sequences (contigs) from the abundance of short sequence reads that characterise the data, another area that determines genome sequencing success is the quality and quantity of the input RNA. A pilot experiment with 125 patient plasma samples was performed to investigate the optimal method for isolation of HIV-1 viral RNA for long amplicon genome sequencing. Manual isolation with the QIAamp Viral RNA Mini Kit (Qiagen) was superior over robotically extracted RNA using either the QIAcube robotic system, the m Sample Preparation Systems RNA kit with automated extraction by the m2000 sp system (Abbott Molecular), or the MagNA Pure 96 System in combination with the MagNA Pure 96 Instrument (Roche Diagnostics). We scored amplification of a set of four HIV-1 amplicons of ∼1.9, 3.6, 3.0 and 3.5 kb, and subsequent recovery of near-complete viral genomes. Subsequently, 616 BEEHIVE patient samples were analysed to determine factors that influence successful amplification of the genome in four overlapping amplicons using the QIAamp Viral RNA Kit for viral RNA isolation. Both low plasma viral load and high sample age (stored before 1999) negatively influenced the amplification of viral amplicons >3 kb. A plasma viral load of >100,000 copies/ml resulted in successful amplification of all four amplicons for 86% of the samples, this value dropped to only 46% for samples with viral loads of <20,000 copies/ml. [ABSTRACT FROM AUTHOR]

Background: The HIV-1 subtype B epidemic amongst men who have sex with men (MSM) is resurgent in many countries despite the widespread use of effective combination antiretroviral therapy (cART). In this combined mathematical and phylogenetic study of observational data, we aimed to find out the extent to which the resurgent epidemic is the result of newly introduced strains or of growth of already circulating strains.Methods and Findings: As of November 2011, the ATHENA observational HIV cohort of all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who were diagnosed between 1981 and 1995 were included in the cohort if they were still alive in 1996. The ten most similar sequences to each ATHENA sequence were selected from the Los Alamos HIV Sequence Database, and a phylogenetic tree was created of a total of 8,320 sequences. Large transmission clusters that included ≥10 ATHENA sequences were selected, with a local support value ≥ 0.9 and median pairwise patristic distance below the fifth percentile of distances in the whole tree. Time-varying reproduction numbers of the large MSM-majority clusters were estimated through mathematical modeling. We identified 106 large transmission clusters, including 3,061 (52%) ATHENA and 652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the cohort in the Netherlands (2,128 of 4,288) were included in 91 large MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority clusters were already circulating before 1996, when cART was introduced, and have persisted to the present. Overall, 1,226 (35%) of the 3,460 diagnoses among MSM since 1996 were found in these 54 long-standing clusters. The reproduction numbers of all large MSM-majority clusters were around the epidemic threshold value of one over the whole study period. A tendency towards higher numbers was visible in recent years, especially in the more recently introduced clusters. The mean age of MSM at diagnosis increased by 0.45 years/year within clusters, but new clusters appeared with lower mean age. Major strengths of this study are the high proportion of HIV-positive MSM with a sequence in this study and the combined application of phylogenetic and modeling approaches. Main limitations are the assumption that the sampled population is representative of the overall HIV-positive population and the assumption that the diagnosis interval distribution is similar between clusters.Conclusions: The resurgent HIV epidemic amongst MSM in the Netherlands is driven by several large, persistent, self-sustaining, and, in many cases, growing sub-epidemics shifting towards new generations of MSM. Many of the sub-epidemics have been present since the early epidemic, to which new sub-epidemics are being added. [ABSTRACT FROM AUTHOR]

Background. Since 2000, incidence of sexually acquired hepatitis C virus (HCV)-infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods. From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands.Written questionnaires were administered, covering socio-demographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results. Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0-52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63-15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04-12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02-6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27-192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39-8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19-2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60-14.53) had significant effects on HCV acquisition. Conclusions. In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM. [ABSTRACT FROM AUTHOR]

The results of this large nationwide study show better virological responses to emtricitabine than to lamivudine as part of frequently used first-line combination antiretroviral regimens for therapy-naive HIV-1–infected patients.Background. Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART.Methods. This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score–adjusted models.Results. Therapy-naive HIV-1–infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11–2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25–3.52) in on-treatment analysis. Propensity score–adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61–3.42) with efavirenz and 2.01 (95% CI, 1.36–2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression.Conclusions. The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available. [ABSTRACT FROM PUBLISHER]

Temporary cART during primary HIV-infection (PHI) did not select for drug resistance mutations after treatment interruption and did not affect the subsequent virological response to long-term cART. Our data demonstrate that fear of drug resistance development is not a valid argument to refrain from temporary early treatment during PHI. [ABSTRACT FROM AUTHOR]

Objectives: Document progress in HIV-treatment in the Netherlands since 1996 by reviewing changing patterns of cART use and relating those to trends in patients' short-term clinical outcomes between 1996 and 2010. Design and Methods: 1996–2010 data from 10,278 patients in the Dutch ATHENA national observational cohort were analysed. The annual number of patients starting a type of regimen was quantified. Trends in the following outcomes were described: i) recovery of 150 CD4 cells/mm3 within 12 months of starting cART; ii) achieving viral load (VL) suppression ≤1,000 copies/ml within 12 months of starting cART; iii) switching from first-line to second-line regimen within three years of starting treatment; and iv) all-cause mortality rate per 100 person-years within three years of starting treatment. Results: Between 1996 and 2010, first-line regimens changed from lamivudine/zidovudine-based or lamivudine/stavudine-based regimens with unboosted-PIs to tenofovir with either emtricitabine or lamivudine with NNRTIs. Mortality rates did not change significantly over time. VL suppression and CD4 recovery improved over time, and the incidence of switching due to virological failure and toxicity more than halved between 1996 and 2010. These effects appear to be related to the use of new regimens rather than improvements in clinical care. Conclusion: The use of first-line cART in the Netherlands closely follows changes in guidelines, to the benefit of patients. While there was no significant improvement in mortality, newer drugs with better tolerability and simpler dosing resulted in improved immunological and virological recovery and reduced incidences of switching due to toxicity and virological failure. [ABSTRACT FROM AUTHOR]

Background: Non-adherence to HIV-treatment can have a negative impact on patients' treatment success rates, quality of life, infectiousness, and life expectancy. Few adherence interventions have shown positive effects on adherence and/or virologic outcomes. The theory- and evidence-based Adherence Improving self-Management Strategy (AIMS) is an intervention that has been demonstrated to improve adherence and viral suppression rates in a randomised controlled trial. However, evidence of its cost-effectiveness is lacking. Following a recent review suggesting that cost-effectiveness evaluations of adherence interventions for chronic diseases are rare, and that the methodology of such evaluations is poorly described in the literature, this manuscript presents the study protocol for a multi-centre trial evaluating the effectiveness and cost-effectiveness of AIMS among a heterogeneous sample of patients. Methods/design: The study uses a multi-centre randomised controlled trial design to compare the AIMS intervention to usual care from a societal perspective. Embedded in this RCT is a trial-based and model-based economic evaluation. A planned number of 230 HIV-infected patients are randomised to receive either AIMS or usual care. The relevant outcomes include changes in adherence, plasma viral load, quality of life, and societal costs.The time horizon for the trial-based economic evaluation is 12-15 months. Costs and effects are extrapolated to a lifetime horizon for the model-based economic evaluation.Discussion: The present multicentre RCT is designed to provide sound methodological evidence regarding the effectiveness and cost-effectiveness of a nurse-based counselling intervention (AIMS) to support treatment adherence among a large and heterogeneous sample of HIV-infected patients in the Netherlands. The objective of the current paper is to describe the trial protocol in sufficient detail to allow full evaluation of the quality of the study design. It is anticipated that, if proven cost-effective, AIMS can contribute to improved evidence-based counselling guidelines for HIV-nurses and other health care professionals. Trial registration: The study has been registered on clinicaltrials.gov (Identifier: NCT01429142). [ABSTRACT FROM AUTHOR]

We show in human immunodeficiency virus–positive persons that the coronary artery disease effect of an unfavorable genetic background is comparable to previous studies in the general population, and comparable in size to traditional risk factors and antiretroviral regimens known to increase cardiovascular risk.Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection.Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort.Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD.Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. [ABSTRACT FROM AUTHOR]

Several studies reported an association between immunodeficiency and non-AIDS-defining diseases. We investigated whether nonstructured treatment interruptions and episodes of viremia during suppressive combination antiretroviral therapy were independently associated with non-AIDS diseases.Six thousand four hundred forty patients with viral suppression (<50 copies/mL) within 48 weeks of starting combination antiretroviral therapy were selected from the Dutch ATHENA cohort. In proportional hazards models, associations between treatment interruptions, viral suppression, low-level (50-400 copies/mL), and high-level viremia (>400), and serious non-AIDS diseases (cardiovascular disease, chronic renal failure, liver fibrosis/cirrhosis) were investigated by including time-updated cumulative exposure to either viremia and interruptions or HIV RNA >400 copies per milliliter.During 24,603 person-years, of which 88.5% occurred during viral suppression, 102 patients developed cardiovascular disease, 54 chronic renal failure, and 70 liver fibrosis/cirrhosis. Overall incidence of non-AIDS diseases ranged from 1.41 (95% confidence interval: 0.73 to 2.46) per 100 person-years for CD4 counts <200 to 0.71 (0.49 to 1.00) for CD4 ≥500 cells per cubic millimeter. Compared with viral suppression, high-level viremia was associated only with cardiovascular disease (relative hazard: 1.37, 1.04 to 1.81 per year longer), whereas interruptions and low-level viremia were not associated with non-AIDS diseases. Relative hazards for cumulative exposure to RNA >400 versus 400 copies per milliliter were 1.32 (1.01 to 1.73) for cardiovascular disease, 1.13 (0.66 to 1.92) for renal failure, and 0.86 (0.51 to 1.44) for fibrosis/cirrhosis.Lower CD4 counts are associated with increased risk of non-AIDS diseases, whereas high-level viremia seems to be independently associated with cardiovascular disease. However, the power to detect associations with viremia or interruptions may have been limited as most events occurred during viral suppression. [ABSTRACT FROM AUTHOR]

The article presents a study on the immunologic, virulogic and clinical consequences of episodes of transient viremia in HIV-1-infected patients with sustained virologic suppression. Results showed that episodes of low-level viremia are frequent and short lasting in such patient, and the low proportion of episodes with clinical events suggests that leaving combination antiretroviral therapy (cART) unchanged is a clinically accepted method.

Abstract: The paper reviews methodological difficulties that arise when using observational studies to evaluate the effect of prenatal screening and treatment. The principle of each difficulty is described and then illustrated by a clinical example of toxoplasmosis in pregnancy and its consequences. Methods to deal with these difficulties are described. Given the limitations of existing observational studies and lack of randomised controlled trials, a systematic review of cohort studies offers the best approach for exploring potential biases. [Copyright &y& Elsevier]

Cites a study regarding the mortality in HIV-infected patients. Decrease of the HIV-infected patients mortality; Analysis of the progression of death in antiretroviral treatment population; Association of CD4 cell count and infection via intravenous drug use to the death progression; Comparison of the mortality in HIV-infected patients with a good initial response to highly active antiretroviral therapy with the general population.

Introduction Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable by HIV-1 guidelines in first-line tenofovir/efavirenz (TDF/EFV) and TDF/nevirapine (NVP) combination antiretroviral therapy (cART). Data from trials on equivalence of 3TC and FTC are inconsistent. We examined the effectiveness of 3TC and FTC in the national HIV cohort in the Netherlands. Material and Methods Observational cohort study on cART naïve HIV-1 patients. Therapy was initiated as 3TC or FTC with TDF/EFV or TDF/NVP between 2002 and 2012. Patients with baseline resistance or prior cART experience were excluded. Main outcomes were Week 48 virological failure (VF) by on treatment analysis, time to HIV-RNA <400 copies/mL within 48 weeks and VF within 240 weeks after at least one HIV-RNA <400 copies/mL. Acquired resistance to reverse transcriptase was evaluated. Analyses were done by logistic regression and Cox proportional hazard models. Propensity score adjusted models and intention to treat evaluations were included as sensitivity analysis. Results A total of 4836 patients initiated 3TC/TDF/EFV ( n=546), FTC/TDF/EFV ( n=3391), 3TC/TDF/NVP ( n=207) or FTC/TDF/NVP ( n=692). Ninety-six patients were excluded for baseline resistance or prior cART experience. By Week 48, VF proportions were higher for 3TC/TDF/EFV (10.8%) compared to FTC/TDF/EFV (3.6%) and for 3TC/TDF/NVP (27.0%) compared to FTC/TDF/NVP (11.0%). The multivariable adjusted odds ratio (OR) on VF was 1.78 (95% CI 1.11-2.84; p=0.016) with 3TC/TDF/EFV compared to FTC/TDF/EFV and 2.09 (95% CI 1.25-3.52; p=0.005) with 3TC/TDF/NVP compared to FTC/TDF/NVP. Propensity score adjusted models and intention to treat analyses showed comparable results. The time to virological suppression within 48 weeks was not influenced by using 3TC or FTC in cART. If HIV-RNA <400 copies/mL was achieved on initial cART first, no differences in VF within 240 weeks were observed between 3TC and FTC with TDF/EFV ( p=0.090) or TDF/NVP ( P=0.255). Patients failing 3TC-containing cART had higher median HIV-RNA at VF compared to FTC containing cART ( p<0.001) and 89.8% had acquired resistance on 3TC compared to 81.2% on FTC. Conclusions Including FTC in cART is associated with better virological responses compared to 3TC. As cost constraints may call for the use of generic 3TC, a well-powered randomized trial to confirm the presumed equivalence of 3TC and FTC is needed. [ABSTRACT FROM AUTHOR]

Background: Non-adherence to HIV-treatment can have a negative impact on patients treatment success rates, quality of life, infectiousness, and life expectancy. Few adherence interventions have shown positive effects on adherence and/or virologic outcomes. The theory- and evidence-based Adherence Improving self-Management Strategy (AIMS) is an intervention that has been demonstrated to improve adherence and viral suppression rates in a randomised controlled trial. However, evidence of its cost-effectiveness is lacking. Following a recent review suggesting that cost-effectiveness evaluations of adherence interventions for chronic diseases are rare, and that the methodology of such evaluations is poorly described in the literature, this manuscript presents the study protocol for a multi-centre trial evaluating the effectiveness and cost-effectiveness of AIMS among a heterogeneous sample of patients.Methods/design: The study uses a multi-centre randomised controlled trial design to compare the AIMS intervention to usual care from a societal perspective. Embedded in this RCT is a trial-based and model-based economic evaluation. A planned number of 230 HIV-infected patients are randomised to receive either AIMS or usual care. The relevant outcomes include changes in adherence, plasma viral load, quality of life, and societal costs. The time horizon for the trial-based economic evaluation is 12-15 months. Costs and effects are extrapolated to a lifetime horizon for the model-based economic evaluation.Discussion: The present multicentre RCT is designed to provide sound methodological evidence regarding the effectiveness and cost-effectiveness of a nurse-based counselling intervention (AIMS) to support treatment adherence among a large and heterogeneous sample of HIV-infected patients in the Netherlands. The objective of the current paper is to describe the trial protocol in sufficient detail to allow full evaluation of the quality of the study design. It is anticipated that, if proven cost-effective, AIMS can contribute to improved evidence-based counselling guidelines for HIV-nurses and other health care professionals.Trial Registration: The study has been registered on clinicaltrials.gov (Identifier: NCT01429142). [ABSTRACT FROM AUTHOR]