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Presentation by Frits de Wolf during the Circular and Biobased Products Symposium 2023 in Wageningen.

Item does not contain fulltext, INTRODUCTION: Cerebral small vessel disease is increasingly linked to dementia. METHODS: We systematically searched Medline, Embase, and Cochrane databases for prospective population-based studies addressing associations of white matter hyperintensities, covert brain infarcts (i.e., clinically silent infarcts), and cerebral microbleeds with risk of all-dementia or Alzheimer's disease and performed meta-analyses. RESULTS: We identified 11 studies on white matter hyperintensities, covert brain infarcts, or cerebral microbleeds with risk of all-dementia or Alzheimer's disease. Pooled analyses showed an association of white matter hyperintensity volume and a borderline association of covert brain infarcts with risk of all-dementia (hazard ratio: 1.39 [95% confidence interval: 1.00; 1.94], N = 3913, and 1.47 [95% confidence interval: 0.97; 2.22], N = 8296). Microbleeds were not statistically significantly associated with an increased risk of all-dementia (hazard ratio: 1.25 [95% confidence interval: 0.66; 2.38], N = 8739). DISCUSSION: White matter hyperintensities are associated with an increased risk of all-dementia and Alzheimer's disease in the general population. However, studies are warranted to further determine the role of markers of cerebral small vessel disease in dementia.

Item does not contain fulltext, INTRODUCTION: Inflammatory markers are often elevated in patients with dementia, including Alzheimer's disease (AD). However, it remains unclear whether inflammatory markers are associated with the risk of developing dementia. METHODS: We searched PubMed, Embase, and Cochrane library for prospective population-based studies reporting associations between inflammatory markers and all-cause dementia or AD. We used random effects meta-analyses to obtain pooled hazard ratios (HRs) and 95% confidence intervals of inflammatory markers (highest vs. lowest quantile) for all-cause dementia and AD. RESULTS: Fifteen articles from 13 studies in six countries reported data that could be meta-analyzed. C-reactive protein (HR = 1.37 [1.05; 1.78]), interleukin-6 (HR = 1.40 [1.13; 1.73]), alpha1-antichymotrypsin (HR = 1.54 [1.14; 2.80]), lipoprotein-associated phospholipase A2 activity (HR = 1.40 [1.03; 1.90]), and fibrinogen were each associated with all-cause dementia, but neither was significantly associated with AD. DISCUSSION: Several inflammatory markers are associated with an increased risk of all-cause dementia; however, these markers are not specific for AD. Whether inflammatory markers closely involved in AD pathology are associated with the risk of AD remains to be elucidated.

Item does not contain fulltext, OBJECTIVE: Little is known about the impact of acute hepatitis C virus (HCV) co-infection on HIV-1 disease progression. We investigated CD4 cell count and HIV RNA concentration changes after HCV infection in individuals chronically infected with HIV-1. METHODS: We selected individuals that had the last negative and first positive HCV RNA test less than 1 year apart. Bivariate linear mixed-effects regression was used to model trends in HIV RNA level and CD4 cell count from 2 years before the last negative HCV RNA test until the first of the following dates: start of anti-HCV medication, change in combination antiretroviral therapy (cART) status, and end of follow-up. RESULTS: At the estimated time of HCV co-infection, of 89 individuals, 63 (71%) were cART-treated and 26 (29%) were not on cART. In persons on cART, median CD4 cell count declined from 587 to 508 cells per cubic millimeter (P < 0.0001) during the first 5 months after HCV infection and returned to 587 cells per cubic millimeter after 2.2 years. Also, the probability of an HIV RNA >50 copies per milliliter peaked to 18.6% at HCV co-infection, with lower probabilities 6 months before (3.5%, P = 0.006 compared with peak probability) and after (2.9%, P = 0.009). In persons not on cART, no significant impact of HCV co-infection on trends in the HIV RNA level or CD4 cell count was observed. CONCLUSIONS: Acute HCV infection in cART-treated, chronically HIV-infected patients was associated with a temporary decrease in CD4 cell counts and increased risk of HIV viremia >50 copies per milliliter. This may increase the risk of further HIV transmission.

Contains fulltext : 152131.PDF (publisher's version ) (Open Access), 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 i

Item does not contain fulltext, Genetically engineered protein polymers (GEPP) are a class of multifunctional materials with precisely controlled molecular structure and property profile. Representing a promising alternative for currently used materials in biomedical applications, GEPP offer multiple benefits over natural and chemically synthesized polymers. However, producing them in sufficient quantities for preclinical research remains challenging. Here, we present results from an in vitro cellular response study of a recombinant protein polymer that is soluble at low pH but self-organizes into supramolecular fibers and physical hydrogels at neutral pH. It has a triblock structure denoted as C2S(H)48C2, which consists of hydrophilic collagen-inspired and histidine-rich silk-inspired blocks. The protein was successfully produced by the yeast Pichia pastoris in laboratory-scale bioreactors, and it was purified by selective precipitation. This efficient and inexpensive production method provided material of sufficient quantities, purity and sterility for cell culture study. Rheology and erosion studies showed that it forms hydrogels exhibiting long-term stability, self-healing behavior and tunable mechanical properties. Primary rat bone marrow cells cultured in direct contact with these hydrogels remained fully viable; however, proliferation and mineralization were relatively low compared to collagen hydrogel controls, probably because of the absence of cell-adhesive motifs. As biofunctional factors can be readily incorporated to improve material performance, our approach provides a promising route towards biomedical applications.

Contains fulltext : 125527.pdf (publisher's version ) (Open Access), 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/mm(3) within 12 months of starting cART; ii) achieving viral load (VL) suppression

Contains fulltext : 128541.pdf (publisher's version ) (Closed access), BACKGROUND AND OBJECTIVE: HIV-associated Pneumocystis jirovecii pneumonia (PJP) remains one of the commonest opportunistic infections in Western countries. Although it has been suggested that racial differences in PJP incidence exist, early studies report conflicting results. This study aimed to investigate differences in PJP incidence in a developed country among patients originating from sub-Saharan Africa compared with other regions of origin. DESIGN AND METHODS: A retrospective observational cohort study was performed among 13,844 HIV-infected patients from the Dutch ATHENA cohort. The main outcome measure was occurrence of PJP. RESULTS: A total number of 1055 PJP infections were diagnosed. Patients originating from sub-Saharan Africa had a significantly lower risk of having PJP at the time of HIV diagnosis after adjustment of confounders compared with patients from Western origin [Western Europe, Australia and New Zealand; adjusted odds ratio (aOR) 0.21 (95% confidence interval (CI) 0.15-0.29)]. Other factors associated with higher PJP risk were increasing age [aOR 1.01 per year (95% CI 1.00-1.02)], a low CD4 count at HIV diagnosis [CD4 <50 versus >350 cells/mul aOR 123.3 (95% CI 77.8-195.5)] and a high plasma HIV-RNA (>100,000 copies/ml) at HIV diagnosis [aOR 1.41 (95% CI 1.19-1.66)]. Moreover, a clearly lower risk for PJP acquisition later during follow-up was observed among sub-Saharan Africans versus Western patients [adjusted hazard ratio 0.60 (95% CI 0.39-0.90)]. CONCLUSION: Among HIV-infected patients living in the Netherlands, PJP occurrence is substantially lower in patients originating from sub-Saharan Africa, as compared to Western patients. Differences in genetic susceptibility may partially explain the lower PJP incidence in these patients.

Contains fulltext : 95624.pdf (publisher's version ) (Closed access), BACKGROUND: Therapeutic drug monitoring (TDM) is recommended in several international HIV treatment guidelines. The adherence of clinicians to these recommendations is unknown. The authors evaluated the adherence to the Dutch TDM guideline of 2005. METHODS: From the ATHENA cohort study, three scenarios were selected for which the guideline recommended TDM: 1) start of a combination of lopinavir/ritonavir + efavirenz or nevirapine (drug-drug interaction); 2) start of efavirenz (routine TDM); and 3) use of nelfinavir during pregnancy. For each scenario, we determined the proportion of patients for whom TDM was performed. Multivariable logistic regression modeling was used to identify determinants for the use of TDM. RESULTS: The adherence to the TDM guideline was 46.7% in patients who started lopinavir/ritonavir plus efavirenz or nevirapine; 9.5% for patients who started efavirenz; and 58.5% for patients who used nelfinavir during pregnancy. Patients treated in clinics that had a TDM assay available locally and patients treated in academic clinics were more likely to receive TDM. A higher baseline HIV viral load was another significant predictor for the performing TDM. CONCLUSION: The adherence of clinicians to the Dutch TDM guidelines varied from low to moderate for the three investigated TDM scenarios. This study identifies several determinants for the use of TDM, which may be useful information for those responsible for generating TDM guidelines.

Contains fulltext : 97513.pdf (publisher's version ) (Closed access), BACKGROUND: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 x 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE: To identify the optimal CD4 cell count at which cART should be initiated. DESIGN: Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 x 10(9) cells/L. SETTING: HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS: 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 x 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 x 10(9) cells/L and were included in the analysis. MEASUREMENTS: Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS: Compared with initiating cART at the CD4 cell count threshold of 0.500 x 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations: CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION: Initiation of cART at a threshold CD4 count of 0.500 x 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 x 10(9) cells/L.

Item does not contain fulltext, OBJECTIVE: To compare life expectancies between recently diagnosed HIV-infected patients and age and sex-matched uninfected individuals from the general population. DESIGN: : National observational HIV cohort in the Netherlands. METHODS: Four thousand, six hundred and twelve patients diagnosed with HIV between 1998 and 2007 and still antiretroviral therapy-naive as of 24 weeks after diagnosis were selected. Progression to death compared to the age and sex-matched general population was studied with a multivariate hazards model in 4174 (90.5%) patients without AIDS events at 24 weeks. Life expectancy and number of life years lost were calculated using the predicted survival distribution. RESULTS: During 17 580 person-years of follow-up since 24 weeks after diagnosis [median follow-up 3.3 years, interquartile range (IQR) 1.6-5.8], 118 deaths occurred, yielding a mortality rate of 6.7 [95% confidence interval (CI) 5.5-8.0] per 1000 person-years. Median CD4 cell counts at 24 weeks were 480 cells/microl (IQR 360-650). According to the model, the median number of years lived from age 25 was 52.7 (IQR 44.2-59.3; general population 53.1) for men and 57.8 (49.2-63.7; 58.1) for women without CDC-B event. The number of life years lost varied between 0.4 if diagnosed with HIV at age 25 and 1.4 if diagnosed at age 55; for patients with a CDC-B event this range was 1.8-8.0 years. CONCLUSION: The life expectancy of asymptomatic HIV-infected patients who are still treatment-naive and have not experienced a CDC-B or C event at 24 weeks after diagnosis approaches that of non-infected individuals. However, follow-up time is short compared to the expected number of years lived.

Contains fulltext : 87614.pdf (publisher's version ) (Closed access), OBJECTIVE: To obtain insight in the HIV-1 transmission networks among men having sex with men (MSM) in the Netherlands. DESIGN: A phylogenetic tree was constructed from polymerase sequences isolated from 2877 HIV-1 subtype B-infected patients monitored as part of the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide observational cohort. METHODS: For MSM with a known date of infection, the most similar sequences were selected as potential transmission pairs when they clustered with bootstrap value of at least 99%. Time from infection to onward transmission was estimated as the median time between dates of infection for each transmission pair. The source of infections with a resistant strain was traced using the entire phylogenetic tree. RESULTS: Of sequences from 403 MSM with a known date of infection between 1987 and 2007, 175 (43%) formed 63 clusters. Median time to onward transmission was 1.4 years (interquartile range 0.6-2.7). Twenty-four (6%) MSM carried a virus with resistance-related mutations, 13 of these were in eight clusters together with sequences from 28 other patients in the entire phylogenetic tree. Six clusters contained sequences obtained from 29 men all presenting the same resistance-related mutations. CONCLUSION: From our selection of likely transmission pairs, we conclude that onward transmission of HIV-1 from infected MSM in the Netherlands happens both during and after primary infection. Transmission of resistant strains from the antiretroviral therapy-treated population is limited, but strains with resistance-related mutations have formed subepidemics.

Contains fulltext : 81637.pdf (publisher's version ) (Closed access), BACKGROUND: This collaboration of seven observational clinical cohorts investigated risk factors for treatment-limiting toxicities in both antiretroviral-naive and experienced patients starting nevirapine-based combination antiretroviral therapy (NVPc). METHODS: Patients starting NVPc after 1 January 1998 were included. CD4 cell count at starting NVPc was classified as high (>400/microl/>250/microl for men/women, respectively) or low. Cox models were used to investigate risk factors for discontinuations due to hypersensitivity reactions (HSR, n = 6547) and discontinuation of NVPc due to treatment-limiting toxicities and/or patient/physician choice (TOXPC, n = 10,186). Patients were classified according to prior antiretroviral treatment experience and CD4 cell count/viral load at start NVPc. Models were stratified by cohort and adjusted for age, sex, nadir CD4 cell count, calendar year of starting NVPc and mode of transmission. RESULTS: Median time from starting NVPc to TOXPC and HSR were 162 days [interquartile range (IQR) 31-737] and 30 days (IQR 17-60), respectively. In adjusted Cox analyses, compared to naive patients with a low CD4 cell count, treatment-experienced patients with high CD4 cell count and viral load more than 400 had a significantly increased risk for HSR [hazard ratio 1.45, confidence interval (CI) 1.03-2.03] and TOXPC within 18 weeks (hazard ratio 1.34, CI 1.08-1.67). In contrast, treatment-experienced patients with high CD4 cell count and viral load less than 400 had no increased risk for HSR 1.10 (0.82-1.46) or TOXPC within 18 weeks (hazard ratio 0.94, CI 0.78-1.13). CONCLUSION: Our results suggest it may be relatively well tolerated to initiate NVPc in antiretroviral-experienced patients with high CD4 cell counts provided there is no detectable viremia.

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Contains fulltext : 70941.pdf (publisher's version ) (Closed access), OBJECTIVES: Optimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother-to-child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations. METHODS: We included all HIV-1-infected women for whom NVP plasma concentrations were available as part of routine patient care at two university hospitals. Plasma NVP concentrations were compared for pregnant (n=45) and non-pregnant (n=152) women. Univariate and multivariate linear regression analyses were used to identify and adjust for other confounding factors associated with NVP plasma concentrations. For pregnant women who had a plasma NVP concentration available both during and outside pregnancy, a paired analysis was performed. RESULTS: Steady-state NVP plasma concentrations were lower in pregnant women: 5.2 mg/L (interquartile range 3.9-6.8) vs. 5.8 mg/L (4.3-7.7) (P=0.08). After adjusting for confounders, both pregnancy (regression coefficient=-0.90 mg/L, P=0.046) and African descent (regression coefficient=+1.13 mg/L, P=0.005) influenced NVP concentrations significantly. The paired analysis showed mean concentrations of 4.8 mg/L during pregnancy and 5.8 mg/L outside pregnancy (paired t-test, P=0.073). CONCLUSIONS: Pregnancy has a moderate but significant lowering effect on NVP plasma concentrations. Being of African descent compensates for the lowering effect of pregnancy on NVP concentrations.

Contains fulltext : 70499.pdf (publisher's version ) (Closed access), OBJECTIVE: To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-naive patients initiating ART. DESIGN: Observational cohort study of patients initiating ART between January 2000 and December 2005. SETTING: The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States. STUDY PARTICIPANTS: A total of 13 546 antiretroviral-naive HIV-positive patients initiating ART with efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, or abacavir as third drugs in combination with a zidovudine and lamivudine nucleoside reverse transcriptase inhibitor backbone. MAIN OUTCOME MEASURES: Short-term (24-week) virologic failure (>500 copies/ml) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes). RESULTS: Compared with efavirenz as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; nevirapine (adjusted odds ratio = 1.87, 95% confidence interval (CI) = 1.58-2.22), lopinavir/ritonavir (1.32, 95% CI = 1.12-1.57), nelfinavir (3.20, 95% CI = 2.74-3.74), and abacavir (2.13, 95% CI = 1.82-2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with nevirapine (adjusted hazard ratio for composite outcome measure 1.27, 95% CI = 1.04-1.56) and abacavir (1.22, 95% CI = 1.00-1.48). CONCLUSION: Among antiretroviral-naive patients initiating therapy, between-ART regimen, differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.

Contains fulltext : 52795.pdf (publisher's version ) (Closed access), BACKGROUND: Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for atazanavir. METHODS: This is a retrospective cohort analysis on the use of TDM of atazanavir at three clinical sites in The Netherlands. Patients were divided into three groups: (i) all patients with evaluable data of plasma atazanavir concentrations and its relationship with hyperbilirubinaemia; (ii) patients who started atazanavir without documented evidence of protease inhibitor (PI) mutations; (iii) patients who started atazanavir with documented evidence of PI mutations. The genotypic inhibitory quotient (GIQ) was calculated by dividing the mean atazanavir plasma trough concentration by the number of PI mutations. RESULTS: A total of 108 patients were included; 70 (65.8%) were using atazanavir/ritonavir (300/100 mg once daily). No significant relationship was observed between atazanavir plasma trough concentration and antiviral response in patients starting atazanavir without PI mutations (group 2; n = 82). In contrast, a significant relationship was observed between atazanavir GIQ and treatment response in patients starting atazanavir while having PI mutations (group 3; n = 26). The cut-off value for GIQ most predictive of virological failure was 0.23 mg/L/mutation: patients (n = 8) with a GIQ equal to or below this value had 50% virological failure whereas patients (n = 18) with a GIQ above 0.23 mg/L/mutation had only 11% virological failure (chi(2): P = 0.030). Atazanavir plasma trough concentrations were significantly related with the occurrence of increased total bilirubin concentrations. CONCLUSIONS: TDM of atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia.

RIVM rapport:Increased surveillance of pathogens may for strengthen the prevention and control of infectious diseases. Infectious diseases cause a considerable burden of disease the Netherlands. Detailed characterization of pathogens will yield insight in changes of the pathogen itself, in changes in transmission patterns, and in changes in virulence and resistance. Therefore it is necessary to determine which pathogens should be studied, to what level of detail, and how they should be collected. In this report , the bacteria, viruses and parasites that give the the greatest burden of disease or present the greatest risk for the public health have been described in a standardized way. Several pathogens emerge from this study for which an increase in collection and characterization is desirable. Examples are: 1) Human papillomavirus, to improve assessment of the potential vaccine efficacy. 2) Influenza virus, to better characterize resistance to antiviral drugs. 3) Bordetella pertusis (whooping cough), to detect population changes that can influence vaccine efficacy. 4) Meticillin-resistance Staphylococcus aureus (MRSA), to reduce delays in contact-source tracing and containment. The pathogen surveillance in the Netherlands will be intensified on basis of this report. This enhanced surveillance will be executed in close co-operation with the peripheral microbiological laboratories., Verdere intensivering van de analyse van pathogenen in Nederland is nodig om preventie en bestrijding van infectieziekten te verbeteren. Infectieziekten veroorzaken een aanzienlijke ziektelast in Nederland. Daarnaast gaat van infectieziekten ook een grote dreiging uit voor de openbare gezondheidszorg. Detailkarakterisering van pathogenen geeft inzicht in mogelijke veranderingen van de pathogeen zelf, zoals veranderde virulentie of resistentie. Daarnaast levert het ook inzicht in mogelijk veranderde transmissieroutes. Wel is het noodzakelijk om goed af te wegen welke pathogenen gekarakteriseerd moeten worden, tot welk detailniveau, en hoe groot de steekproef van een bepaalde pathogeen moet zijn om een representatief beeld te krijgen. In dit rapport zijn de bacterien, virussen en parasieten die de grootste ziektelast veroorzaken of de grootste bedreiging vormen voor de openbare gezondheidszorg op een gestandariseerde manier beschreven. In deze beschrijving is in het bijzonder aandacht besteed aan de relevantie van de pathogenen voor de openbare gezondheidszorg. Uit deze inventariserende studie komen een aantal pathogenen naar voren waarvan het wenselijk is om die intensiever te verzamelen en te karateriseren. Voorbeelden hiervan zijn: 1) Humaan papillomavirus, om de potentiele vaccineffectiviteit beter te kunnen inschatten. 2) Influenzavirus, om resistentie tegen antivirale middelen beter in kaart te brengen. 3) Bordetella pertusis (kinkhoest), om populatieveranderingen, die mogelijk de vaccineffectiviteit verlagen, beter te kunnen waarnemen. 4) Meticilline resistente Staphylococcus aureus (MRSA), om bron-en-contact opsporing en inperkingsmaatregelen te versnellen. Dit rapport zal als basis dienen voor de intensivering van de kiemsurveillance van pathogenen in Nederland, die in samenwerking met de perifere microbiologische laboratoria uitgevoerd zal gaan worden.

Contains fulltext : 51011.pdf (publisher's version ) (Closed access), For 95 protease inhibitor-experienced HIV-1-infected patients, the genotypic inhibitory quotient (GIQ; trough level/number of mutations) was calculated for lopinavir. Three different sets of mutations showed equal predictive value. However, the use of cumulative numbers of mutations for calculation of the GIQ showed significantly better association with the virological response. Furthermore, the predictive value of the GIQ was no different from that of the number of mutations alone.

De Biobased-Productsdivisie van AFSG-Wageningen UR gebruikt micro-organismen om op commando polymeren te maken met een van a tot z ontworpen monomeervolgorde en blokstructuur

RIVM rapport:On august 1st 2003, a total of 8.496 HIV infected individuals were registered (78% male and 22% female). Men who have sex with men (MSM) form the largest group within the HIV/AIDS registration (51%), followed by the heterosexuals (27%). The latter group is increasing relatively in time, from 3% in 1985 to 38% in 2002. The number of patients from HIV endemic countries, in particular from sub-Saharan Africa, is also increasing, especially among women., Per 1 augustus 2003 zijn er in totaal 8.496 personen met HIV in Nederland geregistreerd (78% mannen en 22% vrouwen). De homo- en biseksuele mannen met HIV vormen de grootste groep in de HIV-registratie (51%), gevolgd door heteroseksueel geinfecteerden (27%). In de tijd is er een duidelijke toename te zien van deze laatste groep, van 3% in 1985 tot 38% in 2002. Het aandeel van personen uit HIV-endemische gebieden, met name uit sub-Sahara Afrika, neemt eveneens in de tijd toe, vooral bij de vrouwen.

Contains fulltext : 185695.pdf (publisher's version ) (Closed access), BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. METHODS: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. RESULTS: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. CONCLUSIONS: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.

Item does not contain fulltext, OBJECTIVE: To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48. DESIGN: In a prospectively, randomized, open, single-centre study, antiretroviral-naive patients (CD4 cell count > or =200 cells/microl and a plasma HIV-1 RNA level 10,000 copies/ml) were assigned to a combination of zidovudine/lamivudine or stavudine/lamivudine. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (>500 copies/ml). RESULTS: Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indinavir was added in 89% (42/47) of the patients. Only one discontinuation occurred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log10 copies/ml to <500 copies/ml in 100% of patients and <50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA decreased from 4.98 log10 copies/ml at baseline to <500 copies/ml in 100% of patients and <50 copies/ml in 66.7% of the patients. On an intent-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudine and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/microl, with 150 cells/microl in the zidovudine/lamivudine arm, and from 290 cells/microl, with 310 cells/microl in the stavudine/lamivudine arm (P=0.0001). However, the percentage of CD4 cells did not differ in each group. In the zidovudine/lamivudine group 9/10 and 5/5, and in the stavudine/lamivudine g

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RIVM rapport:To obtain insight into the variation of the HIV-1 V3 neutralization domain of variants circulating in the Netherlands, 126 Dutch, 70 Curacao and 45 African serum samples from HIV-1 infected individuals were screened for antibody reactivity to a set of 16 to 17 mer synthetic peptides, representing the central part of the V3-loop of gp120 of HIV-1 variants circulating in the US, Europe and Africa. These peptides were used in an ELISA and antibody reactivity to the peptides was compared to the actual amino acid sequence of viral RNA circulating in a subset of the same serum samples. In conclusion, we found a relatively high genetic and antigenic homogeneity of the V3 gene of HIV infections in the Netherlands and Curacao during the years 1988-1990. Antibody reactivity to synthetic V3 peptides, as well as sequence analysis confirmed the prevalence of B subtype HIV-1 among the Dutch and Curacaon samples and the prevalence of A/D subtypes among the Tanzanian samples. Screening of HIV-1 positive serum samples for genetic typing by using a set of well defined synthetic V3 peptides appeared to be feasible. In combination with molecular analysis (V3 sequencing and/or hetroduplex mobility assay) of this method can be applied to obtain insight in changes in genetic and antigenic variation of HIV-1 in a population: changes within subtype B HIV-1 variants, as well as introduction of other (new) HIV-1 variants can this be surveyed. This is of importance to obtain insight in the (molecular) epidemiology of HIV-1 as well as with respect to the development and the eventual use of an HIV-1 vaccine., Doel van het onderzoek was om inzicht te verkrijgen in de antigene en genetische variatie van het in Nederland en Curacao circulerende humane immunodeficientie virus type 1 (HIV-1). De genetische variatie tussen HIV-1 isolaten is aanzienlijk. De genetische variatie doet zich vooral voor op een vijftal gebieden van het deel van het virale genoom, dat codeert voor het externe envelop eiwit gp120 van HIV-1. Van deze vijf gebieden is het derde variabele domein (V3) gelegen tussen aminozuur-positities 269 en 331 van gp120 het meest uitvoerig bestudeerd. Van de Nederlandse serummonsters reageerde 54.8% specifiek tegen een van de peptiden p108, p109 of p110, welke representatief zijn voor het genotype B. Voor wat betreft de monsters afkomstig uit Curacao werd een vergelijkbaar resultaat gevonden, met dit verschil dat ten opzichte van de Nederlandse monsters een relatief hoge frequentie van serum reactiviteit tegen p110 werd gevonden. Op grond van de serologische reactiviteit in het V3 gebied kan worden geconcludeerd dat in de periode 1988 - 1990 in Nederland en Curacao subtype B HIV-1 varianten het meest prevalent waren. De V3-loop reactiviteit bleek vergelijkbaar met die gemeten in de Amsterdamse cohortstudies onder homoseksuele mannen en druggebruikers. De resultaten van de specifieke antistofreactiviteit werd in het algemeen bevestigd door de resultaten van het V3 sequentie-onderzoek, maar subtiele sequentieverschillen tussen de V3 loop reactiviteit en circulerend viraal V3 werden in een aantal gevallen aangetoond. Aanbevolen wordt in 1995 een tweede survey uit te voeren, te meer daar inmiddels meer bekend is over verschillende subtypen van HIV-1 en recent het zogeheten subtype O is beschreven.