Luuk Gras - Academia.edu (original) (raw)

Papers by Luuk Gras

Research paper thumbnail of The Effect on Treatment Comparisons of Different Measurement Frequencies in Human Immunodeficiency Virus Observational Databases

Data collected in a routine clinical setting are frequently used to compare antiretroviral treatm... more Data collected in a routine clinical setting are frequently used to compare antiretroviral treatments for human immunodeficiency virus (HIV). Differences in the frequency of measurement of HIV RNA levels and CD4-positive T-lymphocyte cell counts introduce a possible source of bias into estimates of the difference in effectiveness between treatments. The authors investigated the size of this bias when survival analysis

Research paper thumbnail of Reliability of expert interpretation of retinal photographs for the diagnosis of toxoplasma retinochoroiditis

British Journal of Ophthalmology, 2002

Aims: To measure agreement and estimate sensitivity and specificity of uveitis experts' inter... more Aims: To measure agreement and estimate sensitivity and specificity of uveitis experts' interpretation of retinal photographs for the diagnosis of toxoplasma retinochoroiditis.Methods: The authors collated 96 retinal photographs from patients presenting with symptomatic posterior uveitis to ophthalmology clinics within a defined geographical area. Five uveitis experts independently ranked each photograph as definite, probable, possible, or not toxoplasma retinochoroiditis. They measured

Research paper thumbnail of Clinical experience with the combined use of lopinavir/ritonavir and rifampicin

Aids, 2009

Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated... more Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse

Research paper thumbnail of Association between prenatal treatment and clinical manifestations of congenital toxoplasmosis in infancy: a cohort study in 13 European centres

Acta paediatrica (Oslo, Norway : 1992), 2005

To determine the effectiveness of prenatal treatment for clinical manifestations of congenital to... more To determine the effectiveness of prenatal treatment for clinical manifestations of congenital toxoplasmosis. 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. 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 ag...

Research paper thumbnail of Increased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015

Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivu... more 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. 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. 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 compa...

Research paper thumbnail of Changes in HIV RNA and CD4 cell count following acute HCV infection in chronically HIV-infected individuals

Journal of acquired immune deficiency syndromes (1999), Jan 31, 2014

Little is known about the impact of acute HCV co-infection on HIV-1 disease progression. We inves... more Little is known about the impact of acute 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. We selected individuals that had a 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 cART status and end of follow-up. At the estimated time of HCV co-infection, out 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/mm (p<0.0001) during the first 5 months after HCV infection and returned to 587 cells/mm after 2.2 years. Also, the probability of an HIV RNA >50 copies/ml peaked to 18.6% at HCV co-infection , with ...

Research paper thumbnail of Changes in First-Line cART Regimens and Short-Term Clinical Outcome between 1996 and 2010 in The Netherlands

PLoS ONE, 2013

Objectives: Document progress in HIV-treatment in the Netherlands since 1996 by reviewing changin... more 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.

Research paper thumbnail of Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice

Journal of Antimicrobial Chemotherapy, 2007

Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little ... more Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for atazanavir. 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. 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. TDM of atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia.

Research paper thumbnail of Efavirenz Dose Reduction Is Safe in Patients With High Plasma Concentrations and May Prevent Efavirenz Discontinuations

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2009

To establish whether efavirenz dose reduction in patients with high plasma concentrations prevent... more To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations. HIV-infected patients with a high efavirenz plasma concentration (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations. One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression. Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy.

Research paper thumbnail of Mortality in Patients With Successful Initial Response to Highly Active Antiretroviral Therapy Is Still Higher Than in Non-HIV-Infected Individuals

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2005

Mortality in HIV-infected patients has decreased dramatically since the introduction of highly ac... more Mortality in HIV-infected patients has decreased dramatically since the introduction of highly active antiretroviral therapy (HAART). We analyzed progression to death in a population of 3678 antiretroviral treatment-naive patients from the ATHENA national observational cohort from 24 weeks after the start of HAART. Mortality was compared with that in the general population in the Netherlands matched by age and gender. Only log-transformed CD4 cell count (hazard ratio [HR] = 0.50, 95% confidence interval [CI]: 0.40 to 0.61 per unit increase) and plasma viral load (HR = 0.30, 95% CI: 0.15 to 0.60, HIV RNA level &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100,000 vs. &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 100,000 copies/mL) measured at 24 weeks and infection via intravenous drug use (IDU) (HR = 0.16, 95% CI: 0.10 to 0.26, non-IDU vs. IDU) were significantly associated with progression to death. For non-IDU patients with 600 x 10 CD4 cells/L and an HIV RNA level &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100,000 copies/mL at 24 weeks, mortality was predicted to be 5.3 (95% CI: 3.5 to 8.4) and 10.4 (95% CI: 6.4 to 17.4) times higher than in the general population for 25-year-old men and women, respectively, and 1.15 (95% CI: 1.08 to 1.25) and 1.29 (95% CI: 1.16 to 1.50) times higher for 65-year-old men and women, respectively. Hence, mortality in HIV-infected patients with a good initial response to HAART is still higher than in the general population.

Research paper thumbnail of Immunologic, Virologic, and Clinical Consequences of Episodes of Transient Viremia During Suppressive Combination Antiretroviral Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2008

To investigate immunologic, virologic, and clinical consequences of episodes of transient viremia... more To investigate immunologic, virologic, and clinical consequences of episodes of transient viremia in patients with sustained virologic suppression. From the AIDS Therapy Evaluation Project, Netherlands cohort, 4447 previously therapy-naive patients were selected who were on continuous combination antiretroviral therapy and had initial success (2 consecutive HIV RNA measurements &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 copies/mL). During episodes of viral suppression (RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 copies/mL), low-level viremia (RNA 50 to 1000 copies/mL), or high-level viremia (RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 copies/mL) after initial success, the occurrence of therapy changes, drug resistance, and clinical events was assessed. During 11,187 person-years of follow-up, 1281 (28.8%) patients had at least 1 RNA measurement &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50 copies/mL. Among 8069 episodes, there were 5989 (74.2%) episodes of suppression, 1711 (21.2%) episodes of low-level viremia, and 369 (4.6%) episodes of high-level viremia. Most episodes of low-level viremia consisted of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =2 RNA measurements (93.7%), were without clinical events or therapy changes (79.6%), and were without changes in CD4 cell counts. Therapy changes (52.3% of episodes) and resistance (23.3%) were frequently observed during high-level viremia. Episodes of low-level viremia are frequent and short lasting, and the low proportion of episodes with clinical events suggests that leaving therapy unchanged is a clinically acceptable strategy. In contrast, high-level viremia is associated with resistance and is often followed by therapy changes.

Research paper thumbnail of Estimation of the Incidence of Late Bladder and Rectum Complications After High-Dose (70–78 Gy) Conformal Radiotherapy for Prostate Cancer, Using Dose–Volume Histograms

International Journal of Radiation OncologyBiologyPhysics, 1998

Research paper thumbnail of 2104 Analysis of dose volume histogram parameters to estimate late bladder and rectum complications after high-dose (70–78 Gy) conformal radiotherapy for prostate cancer

International Journal of Radiation Oncology*Biology*Physics, 1997

Research paper thumbnail of Effect of prenatal treatment on the risk of intracranial and ocular lesions in children with congenital toxoplasmosis

International Journal of Epidemiology, 2001

The aim of prenatal treatment for infection with Toxoplasma gondii is to prevent neurological or ... more The aim of prenatal treatment for infection with Toxoplasma gondii is to prevent neurological or visual impairment in infected children either by preventing mother to child transmission of infection, or, once fetal infection has occurred, by limiting cell damage caused by the parasite. 1,2,pp.173-75 In this report, we present results on the effect of prenatal treatment on lesions attributable to parasite-induced cell damage in children with confirmed congenital toxoplasmosis. The lesions most commonly associated with congenital toxoplasmosis are intracranial calcification or hydrocephalus, which are usually detected during infancy, and retinochoroiditis, which may appear at any age. 2 Intracranial and/or ocular lesions were detected before school age in 33% (28/85) of congenitally infected children followed in three population-based cohort studies. 3-5 Of the 28 with lesions, 3 (4%) had severe neurological impairment. Retinochoroidal lesions have been reported in 16% (14/85) children at 1-6 years old, 3-5 of whom up to half may have permanent visual impairment, due to the size of the lesion and involvement of the macular area. 3-6 Information is lacking on the risk of developmental impairment in children with intracranial or ocular lesions. However, many appear to develop normally 6,7 and a small study comparing 17 congenitally infected children and their siblings raises the possibility that impairment may be worse in those with ocular than intracranial lesions (R Eaton, New England Neonatal Screening Program, personal communication).

Research paper thumbnail of Baseline Lipid Levels Rather Than the Presence of Reported Body Shape Changes Determine the Degree of Improvement in Lipid Levels After Switching to Atazanavir

HIV Clinical Trials, 2009

To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiven... more To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiveness of ATV in maintaining virus suppression. Retrospective cohort study in patients with viral suppression, comparing patients switching to ATV with those continuing combination antiretroviral therapy (cART). Outcome measures were 48-week total (TC), high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) changes, stratified for dyslipidemia and lipodystrophy and virological failure (time to first of two consecutive detectable HIV RNA). 225 patients switched to ATV (193 [85.8%] RTV boosted), and 3120 continued cART. In patients with baseline TC &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;6.2 mmol/L, those switching had greater mean (95% CI) TC decreases compared to those continuing cART (-1.26 [-1.63 to -0.89] and -0.54 [-0.64 to -0.44] mmol/L, p = .002). Likewise greater TG changes were observed in patients with high (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;2.3 mmol/L) baseline TG (-1.44 [-2.05 to -0.83] and -0.54 [-0.70 to -0.38] mmol/L, p = .002). Effects were seen irrespective of presence of lipodystrophy. Patients switching to ATV had virological failure more often (17/224 [7.8%]) than those continuing cART (73/3100 [2.4%], p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). Patients with virological suppression, including those with lipodystrophy, may benefit from switching to ATV with lipid profile improvement, especially if baseline lipid levels are high. This should be balanced against a possible higher virological failure risk.

Research paper thumbnail of Duration of the IgM response in women acquiring Toxoplasma gondii during pregnancy: implications for clinical practice and cross-sectional incidence studies

Epidemiology and Infection, 2004

We followed up a cohort of 446 toxoplasma-infected pregnant women to determine the median and var... more We followed up a cohort of 446 toxoplasma-infected pregnant women to determine the median and variability of the duration of positive toxoplasma-IgM (immunoglobulin M) results measured by an immunofluorescence test (IFT) and an immunosorbent agglutination assay (ISAGA). IgM antibodies were detected for longer using the ISAGA test [median 12 . 8 months, interquartile range (IQR) 6 . 9-24 . 9] than the IFT (median 10 . 4, IQR 7 . 1-14 . 4), but the variability between individuals in the duration of IgM positivity was greatest for the ISAGA test. IgM-positive results persisted beyond 2 years in a substantial minority of women (27 . 1% ISAGA, 9 . 1% IFT). Variation in the duration of the IgM response measured by ISAGA and IFT limit their usefulness for predicting the timing of infection in pregnant women. However, measurement of IgM and IgG antibodies in a cross-sectional serosurvey offers an efficient method for estimating the incidence of toxoplasma infection.

Research paper thumbnail of Discontinuation of Nevirapine Because of Hypersensitivity Reactions in Patients with Prior Treatment Experience, Compared with Treatment-Naive Patients: The ATHENA Cohort Study

Clinical Infectious Diseases, 2008

Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell count... more Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;250 cells/microL and in male individuals with CD4 cell counts &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;400 cells/microL 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. 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, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;250 cells/microL; for male patients, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;400 cells/microL) 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. 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). 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.

Research paper thumbnail of Cost-effectiveness of a nurse-based intervention (AIMS) to improve adherence among HIV-infected patients: design of a multi-centre randomised controlled trial

BMC Health Services Research, 2013

Background: Non-adherence to HIV-treatment can have a negative impact on patients' treatment succ... more 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.

Research paper thumbnail of Prediction of congenital toxoplasmosis by polymerase chain reaction analysis of amniotic fluid

BJOG: An International Journal of Obstetrics & Gynaecology, 2005

Objective To determine the accuracy of polymerase chain reaction (PCR) analysis of amniotic fluid... more Objective To determine the accuracy of polymerase chain reaction (PCR) analysis of amniotic fluid for fetal toxoplasmosis according to clinical predictors of outcome and study centre. Design Prospective cohort study.

Research paper thumbnail of Immune restoration and onset of new AIDS-defining events with combination antiretroviral therapy in HIV type-1-infected immigrants in the Netherlands

Antiviral Therapy, 2010

We investigated differences in immune restoration and onset of new AIDS-defining events on combin... more We investigated differences in immune restoration and onset of new AIDS-defining events on combination antiretroviral therapy (cART) among HIV type-1 (HIV-1)-infected patients of different regional origin now living in the Netherlands. Treatment-naive adults reaching plasma viral load (pVL)&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;400 copies/ml within 9 months of starting cART were selected from the Netherlands ATHENA cohort. CD4(+) T-cell response on cART was determined over 7 years using mixed models. CD4(+) T-cell counts were excluded from the analyses at the first of two consecutive measurements of pVL≥400 copies/ml following prior suppression to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;400 copies/ml. Multivariate analyses included gender, age, CD4(+) T-cell count and pVL prior to cART, hepatitis coinfection, HIV-1 transmission and region of origin (Western Europe/North America [WN], sub-Saharan Africa [SSA], Southeast Asia [SEA], Latin America/Caribbean [LAC] or other). For 6,057 selected patients (WN 3,947, SSA 989, SEA 237, LAC 695 and other 189), median follow-up was 3.2 years (WN 3.3, SSA 2.9, SEA 3.2, LAC 2.7 and other 2.7). CD4(+) T-cell increase in the first 6 months of cART was lower in males than females (-26 cells/mm(3); P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) and in patients from SSA compared with WN (-36 cells/mm(3); P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). Because men from SSA started with lower CD4(+) T-cell counts than men from WN, they continued to lag behind and had lower absolute CD4(+) T-cell counts after 7 years of cART. Furthermore, cumulative tuberculosis incidence after 7 years of cART was higher in SSA compared with WN (4.5% versus 0.5%, hazard ratio 5.08, 95% confidence interval 2.22-11.60). HIV-1-infected immigrants from SSA have blunted immune restoration on fully suppressive cART and should be identified at an earlier disease stage. Our results call for more intensive screening for both latent and active tuberculosis in these patients.

Research paper thumbnail of The Effect on Treatment Comparisons of Different Measurement Frequencies in Human Immunodeficiency Virus Observational Databases

Data collected in a routine clinical setting are frequently used to compare antiretroviral treatm... more Data collected in a routine clinical setting are frequently used to compare antiretroviral treatments for human immunodeficiency virus (HIV). Differences in the frequency of measurement of HIV RNA levels and CD4-positive T-lymphocyte cell counts introduce a possible source of bias into estimates of the difference in effectiveness between treatments. The authors investigated the size of this bias when survival analysis

Research paper thumbnail of Reliability of expert interpretation of retinal photographs for the diagnosis of toxoplasma retinochoroiditis

British Journal of Ophthalmology, 2002

Aims: To measure agreement and estimate sensitivity and specificity of uveitis experts' inter... more Aims: To measure agreement and estimate sensitivity and specificity of uveitis experts' interpretation of retinal photographs for the diagnosis of toxoplasma retinochoroiditis.Methods: The authors collated 96 retinal photographs from patients presenting with symptomatic posterior uveitis to ophthalmology clinics within a defined geographical area. Five uveitis experts independently ranked each photograph as definite, probable, possible, or not toxoplasma retinochoroiditis. They measured

Research paper thumbnail of Clinical experience with the combined use of lopinavir/ritonavir and rifampicin

Aids, 2009

Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated... more Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse

Research paper thumbnail of Association between prenatal treatment and clinical manifestations of congenital toxoplasmosis in infancy: a cohort study in 13 European centres

Acta paediatrica (Oslo, Norway : 1992), 2005

To determine the effectiveness of prenatal treatment for clinical manifestations of congenital to... more To determine the effectiveness of prenatal treatment for clinical manifestations of congenital toxoplasmosis. 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. 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 ag...

Research paper thumbnail of Increased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015

Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivu... more 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. 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. 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 compa...

Research paper thumbnail of Changes in HIV RNA and CD4 cell count following acute HCV infection in chronically HIV-infected individuals

Journal of acquired immune deficiency syndromes (1999), Jan 31, 2014

Little is known about the impact of acute HCV co-infection on HIV-1 disease progression. We inves... more Little is known about the impact of acute 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. We selected individuals that had a 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 cART status and end of follow-up. At the estimated time of HCV co-infection, out 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/mm (p<0.0001) during the first 5 months after HCV infection and returned to 587 cells/mm after 2.2 years. Also, the probability of an HIV RNA >50 copies/ml peaked to 18.6% at HCV co-infection , with ...

Research paper thumbnail of Changes in First-Line cART Regimens and Short-Term Clinical Outcome between 1996 and 2010 in The Netherlands

PLoS ONE, 2013

Objectives: Document progress in HIV-treatment in the Netherlands since 1996 by reviewing changin... more 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.

Research paper thumbnail of Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice

Journal of Antimicrobial Chemotherapy, 2007

Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little ... more Therapeutic drug monitoring (TDM) is being applied for a number of antiretroviral agents. Little is known about the use of TDM for atazanavir. 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. 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. TDM of atazanavir might be beneficial for patients with documented PI resistance or patients with hyperbilirubinaemia.

Research paper thumbnail of Efavirenz Dose Reduction Is Safe in Patients With High Plasma Concentrations and May Prevent Efavirenz Discontinuations

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2009

To establish whether efavirenz dose reduction in patients with high plasma concentrations prevent... more To establish whether efavirenz dose reduction in patients with high plasma concentrations prevents toxicity-induced efavirenz discontinuations. HIV-infected patients with a high efavirenz plasma concentration (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=4.0 mg/L) while using efavirenz 600 mg once daily as part of their highly active antiretroviral therapy regimen were selected from the AIDS Therapy Evaluation in The Netherlands cohort study. These patients were classified into 2 groups. The reduced-dose group contained all patients who underwent dose reduction after the high plasma concentration measurement; the standard-dose group consisted of patients who had no dose reduction. Kaplan-Meier and Cox proportional hazards analysis were used to assess the impact of dose reduction on toxicity-induced efavirenz discontinuations. One hundred eighty patients with high plasma efavirenz levels were included, 47 of them subsequently had their efavirenz dose reduced from 600 mg to 400 mg once-daily, which resulted in a 41% decrease in the median efavirenz plasma concentration. At week 48, the Kaplan-Meier estimated cumulative incidence of toxicity-induced efavirenz discontinuations was 11.5% in patients who continued the standard dose versus 2.3% in patients who had a dose reduction; P = 0.066 (log-rank test). Dose reduction was not associated with loss of virological suppression. Dose reduction may prevent toxicity-induced discontinuations in patients with high efavirenz plasma concentrations, whereas not compromising virological efficacy.

Research paper thumbnail of Mortality in Patients With Successful Initial Response to Highly Active Antiretroviral Therapy Is Still Higher Than in Non-HIV-Infected Individuals

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2005

Mortality in HIV-infected patients has decreased dramatically since the introduction of highly ac... more Mortality in HIV-infected patients has decreased dramatically since the introduction of highly active antiretroviral therapy (HAART). We analyzed progression to death in a population of 3678 antiretroviral treatment-naive patients from the ATHENA national observational cohort from 24 weeks after the start of HAART. Mortality was compared with that in the general population in the Netherlands matched by age and gender. Only log-transformed CD4 cell count (hazard ratio [HR] = 0.50, 95% confidence interval [CI]: 0.40 to 0.61 per unit increase) and plasma viral load (HR = 0.30, 95% CI: 0.15 to 0.60, HIV RNA level &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100,000 vs. &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or = 100,000 copies/mL) measured at 24 weeks and infection via intravenous drug use (IDU) (HR = 0.16, 95% CI: 0.10 to 0.26, non-IDU vs. IDU) were significantly associated with progression to death. For non-IDU patients with 600 x 10 CD4 cells/L and an HIV RNA level &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100,000 copies/mL at 24 weeks, mortality was predicted to be 5.3 (95% CI: 3.5 to 8.4) and 10.4 (95% CI: 6.4 to 17.4) times higher than in the general population for 25-year-old men and women, respectively, and 1.15 (95% CI: 1.08 to 1.25) and 1.29 (95% CI: 1.16 to 1.50) times higher for 65-year-old men and women, respectively. Hence, mortality in HIV-infected patients with a good initial response to HAART is still higher than in the general population.

Research paper thumbnail of Immunologic, Virologic, and Clinical Consequences of Episodes of Transient Viremia During Suppressive Combination Antiretroviral Therapy

JAIDS Journal of Acquired Immune Deficiency Syndromes, 2008

To investigate immunologic, virologic, and clinical consequences of episodes of transient viremia... more To investigate immunologic, virologic, and clinical consequences of episodes of transient viremia in patients with sustained virologic suppression. From the AIDS Therapy Evaluation Project, Netherlands cohort, 4447 previously therapy-naive patients were selected who were on continuous combination antiretroviral therapy and had initial success (2 consecutive HIV RNA measurements &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 copies/mL). During episodes of viral suppression (RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;50 copies/mL), low-level viremia (RNA 50 to 1000 copies/mL), or high-level viremia (RNA &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1000 copies/mL) after initial success, the occurrence of therapy changes, drug resistance, and clinical events was assessed. During 11,187 person-years of follow-up, 1281 (28.8%) patients had at least 1 RNA measurement &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50 copies/mL. Among 8069 episodes, there were 5989 (74.2%) episodes of suppression, 1711 (21.2%) episodes of low-level viremia, and 369 (4.6%) episodes of high-level viremia. Most episodes of low-level viremia consisted of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or =2 RNA measurements (93.7%), were without clinical events or therapy changes (79.6%), and were without changes in CD4 cell counts. Therapy changes (52.3% of episodes) and resistance (23.3%) were frequently observed during high-level viremia. Episodes of low-level viremia are frequent and short lasting, and the low proportion of episodes with clinical events suggests that leaving therapy unchanged is a clinically acceptable strategy. In contrast, high-level viremia is associated with resistance and is often followed by therapy changes.

Research paper thumbnail of Estimation of the Incidence of Late Bladder and Rectum Complications After High-Dose (70–78 Gy) Conformal Radiotherapy for Prostate Cancer, Using Dose–Volume Histograms

International Journal of Radiation OncologyBiologyPhysics, 1998

Research paper thumbnail of 2104 Analysis of dose volume histogram parameters to estimate late bladder and rectum complications after high-dose (70–78 Gy) conformal radiotherapy for prostate cancer

International Journal of Radiation Oncology*Biology*Physics, 1997

Research paper thumbnail of Effect of prenatal treatment on the risk of intracranial and ocular lesions in children with congenital toxoplasmosis

International Journal of Epidemiology, 2001

The aim of prenatal treatment for infection with Toxoplasma gondii is to prevent neurological or ... more The aim of prenatal treatment for infection with Toxoplasma gondii is to prevent neurological or visual impairment in infected children either by preventing mother to child transmission of infection, or, once fetal infection has occurred, by limiting cell damage caused by the parasite. 1,2,pp.173-75 In this report, we present results on the effect of prenatal treatment on lesions attributable to parasite-induced cell damage in children with confirmed congenital toxoplasmosis. The lesions most commonly associated with congenital toxoplasmosis are intracranial calcification or hydrocephalus, which are usually detected during infancy, and retinochoroiditis, which may appear at any age. 2 Intracranial and/or ocular lesions were detected before school age in 33% (28/85) of congenitally infected children followed in three population-based cohort studies. 3-5 Of the 28 with lesions, 3 (4%) had severe neurological impairment. Retinochoroidal lesions have been reported in 16% (14/85) children at 1-6 years old, 3-5 of whom up to half may have permanent visual impairment, due to the size of the lesion and involvement of the macular area. 3-6 Information is lacking on the risk of developmental impairment in children with intracranial or ocular lesions. However, many appear to develop normally 6,7 and a small study comparing 17 congenitally infected children and their siblings raises the possibility that impairment may be worse in those with ocular than intracranial lesions (R Eaton, New England Neonatal Screening Program, personal communication).

Research paper thumbnail of Baseline Lipid Levels Rather Than the Presence of Reported Body Shape Changes Determine the Degree of Improvement in Lipid Levels After Switching to Atazanavir

HIV Clinical Trials, 2009

To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiven... more To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiveness of ATV in maintaining virus suppression. Retrospective cohort study in patients with viral suppression, comparing patients switching to ATV with those continuing combination antiretroviral therapy (cART). Outcome measures were 48-week total (TC), high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) changes, stratified for dyslipidemia and lipodystrophy and virological failure (time to first of two consecutive detectable HIV RNA). 225 patients switched to ATV (193 [85.8%] RTV boosted), and 3120 continued cART. In patients with baseline TC &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;6.2 mmol/L, those switching had greater mean (95% CI) TC decreases compared to those continuing cART (-1.26 [-1.63 to -0.89] and -0.54 [-0.64 to -0.44] mmol/L, p = .002). Likewise greater TG changes were observed in patients with high (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;2.3 mmol/L) baseline TG (-1.44 [-2.05 to -0.83] and -0.54 [-0.70 to -0.38] mmol/L, p = .002). Effects were seen irrespective of presence of lipodystrophy. Patients switching to ATV had virological failure more often (17/224 [7.8%]) than those continuing cART (73/3100 [2.4%], p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). Patients with virological suppression, including those with lipodystrophy, may benefit from switching to ATV with lipid profile improvement, especially if baseline lipid levels are high. This should be balanced against a possible higher virological failure risk.

Research paper thumbnail of Duration of the IgM response in women acquiring Toxoplasma gondii during pregnancy: implications for clinical practice and cross-sectional incidence studies

Epidemiology and Infection, 2004

We followed up a cohort of 446 toxoplasma-infected pregnant women to determine the median and var... more We followed up a cohort of 446 toxoplasma-infected pregnant women to determine the median and variability of the duration of positive toxoplasma-IgM (immunoglobulin M) results measured by an immunofluorescence test (IFT) and an immunosorbent agglutination assay (ISAGA). IgM antibodies were detected for longer using the ISAGA test [median 12 . 8 months, interquartile range (IQR) 6 . 9-24 . 9] than the IFT (median 10 . 4, IQR 7 . 1-14 . 4), but the variability between individuals in the duration of IgM positivity was greatest for the ISAGA test. IgM-positive results persisted beyond 2 years in a substantial minority of women (27 . 1% ISAGA, 9 . 1% IFT). Variation in the duration of the IgM response measured by ISAGA and IFT limit their usefulness for predicting the timing of infection in pregnant women. However, measurement of IgM and IgG antibodies in a cross-sectional serosurvey offers an efficient method for estimating the incidence of toxoplasma infection.

Research paper thumbnail of Discontinuation of Nevirapine Because of Hypersensitivity Reactions in Patients with Prior Treatment Experience, Compared with Treatment-Naive Patients: The ATHENA Cohort Study

Clinical Infectious Diseases, 2008

Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell count... more Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;250 cells/microL and in male individuals with CD4 cell counts &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;400 cells/microL 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. 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, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;250 cells/microL; for male patients, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;400 cells/microL) 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. 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). 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.

Research paper thumbnail of Cost-effectiveness of a nurse-based intervention (AIMS) to improve adherence among HIV-infected patients: design of a multi-centre randomised controlled trial

BMC Health Services Research, 2013

Background: Non-adherence to HIV-treatment can have a negative impact on patients' treatment succ... more 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.

Research paper thumbnail of Prediction of congenital toxoplasmosis by polymerase chain reaction analysis of amniotic fluid

BJOG: An International Journal of Obstetrics & Gynaecology, 2005

Objective To determine the accuracy of polymerase chain reaction (PCR) analysis of amniotic fluid... more Objective To determine the accuracy of polymerase chain reaction (PCR) analysis of amniotic fluid for fetal toxoplasmosis according to clinical predictors of outcome and study centre. Design Prospective cohort study.

Research paper thumbnail of Immune restoration and onset of new AIDS-defining events with combination antiretroviral therapy in HIV type-1-infected immigrants in the Netherlands

Antiviral Therapy, 2010

We investigated differences in immune restoration and onset of new AIDS-defining events on combin... more We investigated differences in immune restoration and onset of new AIDS-defining events on combination antiretroviral therapy (cART) among HIV type-1 (HIV-1)-infected patients of different regional origin now living in the Netherlands. Treatment-naive adults reaching plasma viral load (pVL)&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;400 copies/ml within 9 months of starting cART were selected from the Netherlands ATHENA cohort. CD4(+) T-cell response on cART was determined over 7 years using mixed models. CD4(+) T-cell counts were excluded from the analyses at the first of two consecutive measurements of pVL≥400 copies/ml following prior suppression to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;400 copies/ml. Multivariate analyses included gender, age, CD4(+) T-cell count and pVL prior to cART, hepatitis coinfection, HIV-1 transmission and region of origin (Western Europe/North America [WN], sub-Saharan Africa [SSA], Southeast Asia [SEA], Latin America/Caribbean [LAC] or other). For 6,057 selected patients (WN 3,947, SSA 989, SEA 237, LAC 695 and other 189), median follow-up was 3.2 years (WN 3.3, SSA 2.9, SEA 3.2, LAC 2.7 and other 2.7). CD4(+) T-cell increase in the first 6 months of cART was lower in males than females (-26 cells/mm(3); P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) and in patients from SSA compared with WN (-36 cells/mm(3); P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). Because men from SSA started with lower CD4(+) T-cell counts than men from WN, they continued to lag behind and had lower absolute CD4(+) T-cell counts after 7 years of cART. Furthermore, cumulative tuberculosis incidence after 7 years of cART was higher in SSA compared with WN (4.5% versus 0.5%, hazard ratio 5.08, 95% confidence interval 2.22-11.60). HIV-1-infected immigrants from SSA have blunted immune restoration on fully suppressive cART and should be identified at an earlier disease stage. Our results call for more intensive screening for both latent and active tuberculosis in these patients.