F de Wolf

Publications (141)848.08 Total impact

• Article: Temporary antiretroviral treatment during primary HIV-1 infection has a positive impact on health-related quality of life: data from the Primo-SHM cohort study.

  Ml Grijsen, Gt Koster, Mga van Vonderen, M van Kasteren, Gj Kootstra, R Steingrover, F de Wolf, Jm Prins, Pt Nieuwkerk
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  ABSTRACT: OBJECTIVES: The aim of the study was to compare health-related quality of life (HRQL) over 96 weeks in patients receiving no treatment or 24 or 60 weeks of combination antiretroviral therapy (cART) during primary HIV-1 infection (PHI). METHODS: A multicentre prospective cohort study of PHI patients, with an embedded randomized trial, was carried out. HRQL was assessed with the Medical Outcomes Study Health Survey for HIV (MOS-HIV) and a symptom checklist administered at weeks 0, 8, 24, 36, 48, 60, 72, 84 and 96. Mixed linear models were used for the analysis of differences in HRQL among the three groups. RESULTS: A total of 112 patients were included in the study: 28 received no treatment, 45 received 24 weeks of cART and 39 received 60 weeks of cART. Over 96 weeks of follow-up, the groups receiving 24 and 60 weeks of cART had better cognitive functioning than the no-treatment group (P = 0.005). Patients receiving 60 weeks of cART had less pain (P = 0.004), better role functioning (P = 0.001), better physical functioning (P = 0.02) and a better physical health summary score (P = 0.006) than the groups receiving no treatment or 24 weeks of cART. Mental health was better in patients receiving 24 weeks of cART than in patients in the no-treatment group or the group receiving 60 weeks of cART (P = 0.02). At week 8, patients in the groups receiving 24 and 60 weeks of cART reported more nausea (P = 0.002), diarrhoea (P < 0.001), abdominal pain (P = 0.02), stomach pain (P = 0.049) and dizziness (P = 0.01) than those in the no-treatment group. These differences had disappeared by week 24. CONCLUSIONS: Temporary cART during PHI had a significant positive impact on patients' HRQL as compared with no treatment, despite the initial, short-term occurrence of more physical symptoms, probably related to drug toxicity.
  HIV Medicine 04/2012; 13(10):630-635. · 3.01 Impact Factor
• Article: Late presentation of HIV infection: a consensus definition.

  A Antinori, T Coenen, D Costagiola, N Dedes, M Ellefson, J Gatell, E Girardi, M Johnson, O Kirk, J Lundgren, A Mocroft, A D'Arminio Monforte, A Phillips, D Raben, J K Rockstroh, C Sabin, A Sönnerborg, F De Wolf
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  ABSTRACT: Across Europe, almost a third of individuals infected with HIV do not enter health care until late in the course of their infection. Surveillance to identify the extent to which late presentation occurs remains inadequate across Europe and is further complicated by the lack of a common clinical definition of late presentation. The objective of this article is to present a consensus definition of late presentation of HIV infection. Over the past year, two initiatives have moved towards a harmonized definition. In spring 2009, they joined efforts to identify a common definition of what is meant by a 'late-presenting' patient. Two definitions were agreed upon, as follows. Late presentation: persons presenting for care with a CD4 count below 350 cells/μL or presenting with an AIDS-defining event, regardless of the CD4 cell count. Presentation with advanced HIV disease: persons presenting for care with a CD4 count below 200 cells/μL or presenting with an AIDS-defining event, regardless of the CD4 cell count. The European Late Presenter Consensus working group believe it would be beneficial if all national health agencies, institutions, and researchers were able to implement this definition (either on its own or alongside their own preferred definition) when reporting surveillance or research data relating to late presentation of HIV infection.
  HIV Medicine 01/2011; 12(1):61-4. · 3.01 Impact Factor
• Article: The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

  M. Ray, R. Logan, J. A. Sterne, S. Hernandez-Diaz, J. M. Robins, C. Sabin, L. Bansi, A. van Sighem, F. de Wolf, D. Costagliola, [......], S. Moreno, A. Justice, J. Goulet, S. Lodi, A. Phillips, R. Seng, L. Meyer, S. Perez-Hoyos, P. Garcia de Olalla, M. A. Hernan
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  ABSTRACT: OBJECTIVE: To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. DESIGN: A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. RESULTS: Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41-0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22-0.37) for less than 100 cells/microl, 0.33 (0.25-0.44) for 100 to less than 200 cells/microl, 0.38 (0.28-0.52) for 200 to less than 350 cells/microl, 0.55 (0.41-0.74) for 350 to less than 500 cells/microl, and 0.77 (0.58-1.01) for 500 cells/microl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49-0.67) for less than 1 year since initiation to 0.21 (0.14-0.31) for 5 years or more (P value for trend <0.001). CONCLUSION: We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.
  AIDS. 01/2010; 24(1):123-37.
• Article: Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

  J. A. Sterne, M. May, D. Costagliola, F. de Wolf, A. N. Phillips, R. Harris, M. J. Funk, R. B. Geskus, J. Gill, F. Dabis, [......], A. C. Justice, B. Ledergerber, G. Fatkenheuer, R. S. Hogg, A. D. Monforte, M. Saag, C. Smith, S. Staszewski, M. Egger, S. R. Cole
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  ABSTRACT: BACKGROUND: The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. METHODS: We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. FINDINGS: Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). INTERPRETATION: Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.
  Lancet. 01/2009; 373(9672):1352-63.
• Article: Prognosis of patients treated with cART from 36 months after initiation, according to current and previous CD4 cell count and plasma HIV-1 RNA measurements

  E. Lanoy, M. May, A. Mocroft, A. Phillip, A. Justice, G. Chene, H. Furrer, T. Sterling, A. D. Monforte, L. Force, J. Gill, R. Harris, R. S. Hogg, J. Rockstroh, M. Saag, P. Khaykin, F. de Wolf, J. A. Sterne, D. Costagliola
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  ABSTRACT: OBJECTIVES: CD4 cell count and plasma viral load are well known predictors of AIDS and mortality in HIV-1-infected patients treated with combination antiretroviral therapy (cART). This study investigated, in patients treated for at least 3 years, the respective prognostic importance of values measured at cART initiation, and 6 and 36 months later, for AIDS and death. METHODS: Patients from 15 HIV cohorts included in the ART Cohort Collaboration, aged at least 16 years, antiretroviral-naive when they started cART and followed for at least 36 months after start of cART were eligible. RESULTS: Among 14 208 patients, the median CD4 cell counts at 0, 6 and 36 months were 210, 320 and 450 cells/microl, respectively, and 78% of patients achieved viral load less than 500 copies/ml at 6 months. In models adjusted for characteristics at cART initiation and for values at all time points, values at 36 months were the strongest predictors of subsequent rates of AIDS and death. Although CD4 cell count and viral load at cART initiation were no longer prognostic of AIDS or of death after 36 months, viral load at 6 months and change in CD4 cell count from 6 to 36 months were prognostic for rates of AIDS from 36 months. CONCLUSIONS: Although current values of CD4 cell count and HIV-1 RNA are the most important prognostic factors for subsequent AIDS and death rates in HIV-1-infected patients treated with cART, changes in CD4 cell count from 6 to 36 months and the value of 6-month HIV-1 RNA are also prognostic for AIDS.
  AIDS. 01/2009; 23(16):2199-208.
• Article: Steady-state nevirapine plasma concentrations are influenced by pregnancy.

  J F J B Nellen, M Damming, M H Godfried, K Boer, M E van der Ende, D M Burger, F de Wolf, F W N M Wit, J M Prins
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  ABSTRACT: 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. 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. 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). 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.
  HIV Medicine 05/2008; 9(4):234-8. · 3.01 Impact Factor
• Article: Steady‐state nevirapine plasma concentrations are influenced by pregnancy

  JFJB Nellen, M Damming, MH Godfried, K Boer, ME Van Der Ende, DM Burger, F De Wolf, FWNM Wit, JM Prins
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  ABSTRACT: 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.ResultsSteady-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.
  HIV Medicine 03/2008; 9(4):234 - 238. · 3.01 Impact Factor
• Article: Therapeutic drug monitoring of the HIV protease inhibitor atazanavir in clinical practice.

  R M M Cleijsen, M E van de Ende, F P Kroon, F Verduyn Lunel, P P Koopmans, L Gras, F de Wolf, D M Burger
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  ABSTRACT: 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.
  Journal of Antimicrobial Chemotherapy 11/2007; 60(4):897-900. · 5.07 Impact Factor
• Article: Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

  JA. Sterne, MT. May, CA. Sabin, AN. Phillips, D. Costagliola, G Chene, AC. Justice, F. de Wolf, RS. Hogg, M. Battegay, A. d'Arminio Monforte, G. Fätkenheuer, S. Staszewski, JM. Gill, M. Egger, for the Antiretroviral Therapy Cohort Collaboration
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  ABSTRACT: BACKGROUND:: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. METHODS:: We analyzed data on 20,379 treatment-naive HIV-1-infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). RESULTS:: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count <25 cells/muL had persistently higher progression rates than individuals with a baseline CD4 count >350 cells/muL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). CONCLUSIONS:: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART.
  J Acquir Immune Defic Syndr. 01/2007; 46(5):607-15.
• Article: Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies

  R. Hogg, M. May, A. Phillips, D. Costagliola, J. Sterne, C. Sabin, F. De Wolf, B. Ledergerber, A. D’Arminio Monforte, A. Justice, J. Gill, G. Fusco, Staszewski S., J. Rockstroh, G. Chêne, M. Egger
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  ABSTRACT: BACKGROUND: No large clinical end-point trials have been conducted comparing regimens among human immunodeficiency virus type 1-positive persons starting antiretroviral therapy. We examined clinical progression according to initial regimen in the Antiretroviral Therapy Cohort Collaboration, which is based on 12 European and North American cohort studies. METHODS: We analyzed progression to death from any cause and to AIDS or death (AIDS/death), comparing efavirenz (EFV), nevirapine (NVP), nelfinavir, idinavir, ritonavir (RTV), RTV-boosted protease inhibitors (PIs), saquinavir, and abacavir. We also compared nucleoside reverse-transcriptase inhibitor pairs: zidovudine/lamivudine (AZT/3TC), stavudine (D4T)/3TC, D4T/didanosine (DDI), and others. RESULTS: A total of 17,666 treatment-naive patients, 55,622 person-years at risk, 1,617 new AIDS events, and 895 deaths were analyzed. Compared with EFV, the adjusted hazard ratio (HR) for AIDS/death was 1.28 (95% confidence interval [CI], 1.03-1.60) for NVP, 1.31 (95% CI, 1.01-1.71) for RTV, and 1.45 (95% CI, 1.15-1.81) for RTV-boosted PIs. For death, the adjusted HR for NVP was 1.65 (95% CI, 1.16-2.36). The adjusted HR for death for D4T/3TC was 1.35 (95% CI, 1.14-1.59), compared with AZT/3TC. CONCLUSIONS: Outcomes may vary across initial regimens. Results are observational and may have been affected by bias due to unmeasured or residual confounding. There is a need for large, randomized, clinical end-point trials.
  J Infect Dis. 01/2006; 194(5):612-22.
• Source

  Available from: Andrea M Rehman

  Article: Gender difference in HIV-1 RNA viral loads

  C. A. Donnelly, L. M. Bartley, A. C. Ghani, A. M. Le Fevre, G. P. Kwong, B. J. Cowling, A. I. van Sighem, F. de Wolf, R. A. Rode, R. M. Anderson
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  ABSTRACT: OBJECTIVES: To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. METHODS: Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). RESULTS: After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. CONCLUSIONS: The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.
  HIV Medicine 06/2005; 6(3):170-8. · 3.01 Impact Factor
• Article: Gender difference in HIV‐1 RNA viral loads

  CA Donnelly, LM Bartley, AC Ghani, AM Le Fevre, GP Kwong, BJ Cowling, AI Van Sighem, F De Wolf, RA Rode, RM Anderson
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  ABSTRACT: Objectives To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count.Methods Plasma viral load data were analysed for >30 000 HIV-infected patients attending clinics in the USA [HIV Insight™ (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ).ResultsAfter adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight™:−0.053 log10 HIV-1 RNA copies/mL, P=0.202; Athena: −0.005 log10 copies/mL, P=0.667; Plum:−0.072 log10 copies/mL, P=0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/μL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/μL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight™ and Plum databases.Conclusions The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.
  HIV Medicine 04/2005; 6(3):170 - 178. · 3.01 Impact Factor
• Article: Differential CD4 T-cell response in HIV-1-infected patients using protease inhibitor-based or nevirapine-based highly active antiretroviral therapy.

  F van Leth, F W N M Wit, P Reiss, J K M E Schattenkerk, M E van der Ende, M M E Schneider, J W Mulder, P H J Frissen, F de Wolf, J M A Lange
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  ABSTRACT: To study the dynamics of CD4 T-lymphocyte counts (CD4 counts) after the initiation of either protease inhibitor (PI)-based or nevirapine (NVP)-based first-line highly active antiretroviral therapy (HAART). A retrospective cohort study of 1029 HIV-infected antiretroviral therapy-naive patients initiating either PI-based or NVP-based HAART was carried out. Patients were censored as soon as they experienced virological failure, or changed their original antiretroviral regimen for any reason. In total, 920 and 109 patients initiated PI- and NVP-based HAART, respectively. The patients in the PI group more often had AIDS (15 vs. 6% in the NVP group), had a lower median baseline CD4 count (234 vs. 250 cells/microL in the NVP group) and had higher median baseline plasma HIV-1 RNA levels (pVL) (5.0 vs. 4.7 log10 HIV-1 RNA copies/mL in the NVP group). After 96 weeks of follow-up, the mean increase from baseline in CD4 count, adjusted for baseline CD4 count, age, gender and baseline pVL, was 310 cells/microL in the PI group and 212 cells/microL in the NVP group (P=0.003). This difference was mainly attributable to the patients in the NVP group initiating HAART with a baseline CD4 count below 200 cells/microL. There were no differences between the PI and NVP groups with respect to the change in the number of CD4 cells as a proportion of the total number of lymphocytes. Patients successfully treated with NVP-based HAART have a smaller increase in absolute CD4 cells compared with those treated with PI-based HAART.
  HIV Medicine 04/2004; 5(2):74-81. · 3.01 Impact Factor
• Article: Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies.

  G Chêne, J A C Sterne, M May, D Costagliola, B Ledergerber, A N Phillips, F Dabis, J Lundgren, A D'Arminio Monforte, F de Wolf, R Hogg, P Reiss, A Justice, C Leport, S Staszewski, J Gill, G Fatkenheuer, M E Egger
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  ABSTRACT: We examined whether the initial virological and immunological response to highly active antiretroviral treatment (HAART) is prognostic in patients with HIV-1 who start HAART. We analysed 13 cohort studies from Europe and North America including 9323 adult treatment-naive patients who were starting HAART with a combination of at least three drugs. We modelled clinical progression from month 6 after starting HAART, taking into account CD4 count and HIV-1 RNA measured at baseline and 6 months. During 13408 years of follow-up 152 patients died and 874 developed AIDS or died. Compared with patients who had a 6-month CD4 count of fewer than 25 cells/microL, adjusted hazard ratios for AIDS or death were 0.55 (95%CI 0.32-0.96) for 25-49 cells/microL, 0.62 (0.40-0.96) for 50-99 cells/microL, 0.42 (0.28-0.64) for 100-199 cells/microL, 0.25 (0.16-0.38) for 200-349 cells/microL, and 0.18 (0.11-0.29) for 350 or more cells/microL at 6 months. Compared with patients who had a 6-month HIV-1 RNA of 100000 copies/mL or greater, adjusted hazard ratios for AIDS or death were 0.59 (0.41-0.86) for 10000-99999 copies/mL, 0.42 (0.29-0.61) for 500-9999 copies/mL, and 0.29 (0.21-0.39) for 6-month HIV-1 RNA of 500 copies/mL or fewer. Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations. The probability of progression at 3 years ranged from 2.4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum. At 6 months after starting HAART, the current CD4 cell count and viral load, but not values at baseline, are strongly associated with subsequent disease progression. Our findings should inform guidelines on when to modify HAART.
  The Lancet 09/2003; 362(9385):679-86. · 38.28 Impact Factor
• Source

  Available from: Hein Putter

  Article: A Bayesian approach to parameter estimation in HIV dynamical models.

  H Putter, S H Heisterkamp, J M A Lange, F de Wolf
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  ABSTRACT: In the context of a mathematical model describing HIV infection, we discuss a Bayesian modelling approach to a non-linear random effects estimation problem. The model and the data exhibit a number of features that make the use of an ordinary non-linear mixed effects model intractable: (i) the data are from two compartments fitted simultaneously against the implicit numerical solution of a system of ordinary differential equations; (ii) data from one compartment are subject to censoring; (iii) random effects for one variable are assumed to be from a beta distribution. We show how the Bayesian framework can be exploited by incorporating prior knowledge on some of the parameters, and by combining the posterior distributions of the parameters to obtain estimates of quantities of interest that follow from the postulated model.
  Statistics in Medicine 09/2002; 21(15):2199-214. · 1.88 Impact Factor
• Article: Surrogate markers for disease progression in treated HIV infection.

  A C Ghani, F de Wolf, N M Ferguson, C A Donnelly, R Coutinho, F Miedema, J Goudsmit, R M Anderson
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  ABSTRACT: To characterize the relationships among highly active antiretroviral therapy (HAART), HIV-1 RNA levels, immune system markers, and clinical outcome in a cohort of HIV-1-infected homosexual men. A total of 123 men enrolled in the Amsterdam cohort study of HIV-1 infection and AIDS with a documented seroconversion for HIV-1 antibodies and known date of seroconversion were included in this study. CD4 + /CD8 + T-cell counts and HIV-1 RNA levels in plasma were measured approximately every 6 months. Dates of starting and stopping antiretroviral therapy were also recorded. The relationship between HIV-1 RNA in plasma, CD4 + /CD8 + T-cell counts and HAART and their influence on clinical outcome were examined using a graphical chain modeling approach. Generalized estimating equations were used to examine correlations among the three disease markers. Hazards models with time-dependent covariates were used to examine the influence of HAART and the disease markers on progression to AIDS. HAART was significantly associated with reduced disease progression (relative hazard [RH] of AIDS, 0.20;, 95% confidence interval [CI], 0.05-0.85). The most recent HIV-1 RNA measurement and CD4 + T-cell count are independently associated with disease progression (adjusted RH for HIV-1 RNA 1.8 per log 10 increase; 95% CI, 1.2-2.6, p =.002; adjusted RH for CD4 + 0.48 per 100 x 10(6)/L increase; 95% CI, 0.40-0.58; p <.001). Depending on these measurements, HAART was no longer significantly associated with AIDS (adjusted RH, 0.81; 95% CI, 0.18-3.6; p =.78). HIV-1 RNA levels in plasma and CD4 + T-cell counts are currently considered as effective surrogate markers for the effect of HAART on disease progression in this cohort.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 11/2001; 28(3):226-31. · 4.43 Impact Factor
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  Available from: royalsocietypublishing.org

  Article: The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications.

  C Fraser, N M Ferguson, F de Wolf, R M Anderson
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  ABSTRACT: This paper develops a predictive mathematical model of cell infection, host immune response and viral replication that reproduces observed long-term trends in human immunodeficiency virus (HIV) pathogenesis. Cell activation induced by repeated exposure to many different antigens is proposed as the principal mechanism of providing target cells for HIV infection and, hence, of CD4+ T cell depletion, with regulation of the overall T cell pool size causing concomitant CD8 pool increases. The model correctly predicts the cross-patient variability in disease progression, the rate of which is found to depend on the efficacy of anti-HIV cytotoxic T lymphocyte responses, overall viral pathogenicity and random effects. The model also predicts a variety of responses to anti-viral therapy, including episodic residual viral replication and discordant responses and we find that such effects can be suppressed by increasing the potency of treatment.
  Proceedings of the Royal Society B: Biological Sciences 11/2001; 268(1481):2085-95. · 5.41 Impact Factor
• Source

  Available from: Pythia T Nieuwkerk

  Article: Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study.

  P T Nieuwkerk, M A Sprangers, D M Burger, R M Hoetelmans, P W Hugen, S A Danner, M E van Der Ende, M M Schneider, G Schrey, P L Meenhorst, H G Sprenger, R H Kauffmann, M Jambroes, M A Chesney, F de Wolf, J M Lange
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  ABSTRACT: 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. 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. 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. 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.
  Archives of Internal Medicine 10/2001; 161(16):1962-8. · 11.46 Impact Factor
• Article: [HIV-1 therapy in the Netherlands; virological and immunological response to antiretroviral therapy].

  M Jambroes, G J Weverling, P Reiss, S A Danner, S Jurriaans, J H ten Veen, M E van der Ende, M Schutten, M M Schneider, R Schuurman, J W Mulder, A C Kroes, J M Lange, F de Wolf
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  ABSTRACT: To evaluate the effect of treatment of HIV-1 infection with combination therapy consisting of since 1996 in the Netherlands available protease and reverse transcriptase inhibitors. Prospective cohort study. In an observational clinical cohort of HIV-1-infected individuals, the short-term successful treatment end point of antiviral therapy including at least one antiretroviral drug licensed in the Netherlands since July 1, 1996 (protease inhibitors and reverse transcriptase inhibitors), was HIV-1 RNA plasma levels < or = 500 copies/ml (virological success). Cox proportional hazard models were used to identify prognostic markers for therapy success. The study included 2,148 infected individuals with a median follow-up of 135 weeks of treatment; 1,049 had been pre-treated with antiretroviral drugs before starting their new regimen and 1,099 were treatment naive. Plasma HIV-1 RNA levels < or = 500 copies/ml at 24 weeks of treatment were seen in 61% of all patients. The chance of therapy success for naive patients was twice that for pre-treated patients (relative risk: 1.8; p < or = 0.001). Following the first 24 weeks, the chance of virological success was higher in the naive group (78% versus 63%; p < or = 0.001), and the number of naive patients failing therapy after initial success was smaller compared to pre-treated patients (22% versus 45%; p < or = 0.001). In the naive group, the CD4+ T-cell number increased from 239 to 440 (x 10(6) cells/l) in case of success, and decreased from 150 to 320 in case of treatment failure. HIV-1 related morbidity declined from 0.26 to 0.05 and mortality dropped from 0.07 to 0.03 per person-year of follow-up. Regimens were changed at least once in 76% of patients. Toxicity and therapy failure were the main reasons for regimen changes in naive and pre-treated patients, respectively. A combination of antiretroviral drugs, including at least one of the drugs licensed since 1996, led to a drop in HIV-1 plasma concentrations. Morbidity and mortality also decreased. The chance of a better immunological and virological response to the new drug regimens was greatest in therapy-naive patients.
  Nederlands tijdschrift voor geneeskunde 08/2001; 145(33):1591-7.
• Source

  Available from: Si La Yong

  Article: OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion.

  R M van Praag, J M Prins, M T Roos, P T Schellekens, I J Ten Berge, S L Yong, H Schuitemaker, A J Eerenberg, S Jurriaans, F de Wolf, C H Fox, J Goudsmit, F Miedema, J M Lange
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  ABSTRACT: Activation of resting T cells has been proposed to purge the reservoir of HIV-1-infected resting CD4+ T cells. We therefore treated three HIV-1-infected patients on antiretroviral therapy with OKT3, a CD3 monoclonal antibody, and recombinant human IL-2. Here we report the profound and partially long-lasting host responses induced by the OKT3 and IL-2 treatment. OKT3/IL-2 induced a strong but transient release of plasma cytokines and chemokines. The percentage CD4+ and CD8+ cells in the blood expressing the activation marker CD38 transiently increased to almost 100%, and in lymph nodes we "observed" a 10-fold increase in the number of dividing Ki67+ cells and increased numbers of apoptotic cells. Following OKT3/IL-2 treatment, a long-lasting depletion of CD4+ cells in the peripheral blood and lymph nodes occurred, suggesting the physical deletion of these cells. Increases in CD4+T cell numbers during the two year followup period were due mainly to increased memory cell numbers. CD8+ cells were also depleted in the blood, but less severely in lymph nodes, and returned to baseline levels within several weeks.
  Journal of Clinical Immunology 06/2001; 21(3):218-26. · 3.08 Impact Factor