Publications (13)73.92 Total impact
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Article: Va2Va2 T cells are skewed towards a terminal differentiation phenotype in untreated HIV infection.
The Journal of Infectious Diseases 04/2013; · 6.41 Impact Factor -
Article: Resistance data in the ARTEN trial.
Antiviral therapy 01/2011; 16(7):1135; author's reply 1135-6. · 3.16 Impact Factor -
Article: Calculation of direct antiretroviral treatment costs and potential cost savings by using generics in the German HIV ClinSurv cohort.
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ABSTRACT: BACKGROUND/AIM OF THE STUDY: The study aimed to determine the cost impacts of antiretroviral drugs by analysing a long-term follow-up of direct costs for combined antiretroviral therapy, cART, -regimens in the nationwide long-term observational multi-centre German HIV ClinSurv Cohort. The second aim was to develop potential cost saving strategies by modelling different treatment scenarios. Antiretroviral regimens (ART) from 10,190 HIV-infected patients from 11 participating ClinSurv study centres have been investigated since 1996. Biannual data cART-initiation, cART-changes, surrogate markers, clinical events and the Centre of Disease Control- (CDC)-stage of HIV disease are reported. Treatment duration was calculated on a daily basis via the documented dates for the beginning and end of each antiretroviral drug treatment. Prices were calculated for each individual regimen based on actual office sales prices of the branded pharmaceuticals distributed by the license holder including German taxes. During the 13-year follow-up period, 21,387,427 treatment days were covered. Cumulative direct costs for antiretroviral drugs of €812,877,356 were determined according to an average of €42.08 per day (€7.52 to € 217.70). Since cART is widely used in Germany, the costs for an entire regimen increased by 13.5%. Regimens are more expensive in the advanced stages of HIV disease. The potential for cost savings was calculated using non-nucleotide-reverse-transcriptase-inhibitor, NNRTI, more frequently instead of ritonavir-boosted protease inhibitor, PI/r, in first line therapy. This calculation revealed cumulative savings of 10.9% to 19.8% of daily treatment costs (50% and 90% substitution of PI/r, respectively). Substituting certain branded drugs by generic drugs showed potential cost savings of between 1.6% and 31.8%. Analysis of the data of this nationwide study reflects disease-specific health services research and will give insights into the cost impacts of antiretroviral therapy, and might allow a more rational allocation of resources within the German health care system.PLoS ONE 01/2011; 6(9):e23946. · 4.09 Impact Factor -
Article: Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma.
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ABSTRACT: AIDS-related lymphoma contributes to significant morbidity and mortality among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART). We assessed the predictive role of cumulative HIV viremia and other risk factors in the development of AIDS-related non-Hodgkin lymphoma. Data from the Clinical Surveillance of HIV Disease (ClinSurv) study, an ongoing, observational, open cohort study of HIV-infected patients from different urban areas in Germany, were analyzed using a Cox proportional hazards model. In the Cox model, which comprised 6022 patients and 27,812 patient-years of follow-up while patients were receiving HAART from 1999 through 2006, cumulative HIV viremia was found to be independently associated with the risk of lymphoma (hazard ratio, [HR], 1.67 [95% confidence interval {CI}, 1.27-2.20]) (P < .001]). This association differed markedly between lymphoma subtypes. Although the association was more pronounced for Burkitt-type lymphoma (HR, 3.45 [95% CI, 1.52-7.85]) (P = .003), there was no association between cumulative HIV viremia and the incidence of primary central nervous system lymphoma (HR, 1.00 [95% CI, 0.39-2.57]) (P = .997). Other risk factors associated with an increased risk in a multivariable analysis included the latest CD4 T cell count as well as age per 10-year increment. Cumulative HIV viremia is an independent and strong predictor of AIDS-related lymphoma among patients receiving HAART. The influence of cumulative HIV viremia may differ between lymphoma subtypes.The Journal of Infectious Diseases 08/2009; 200(1):79-87. · 6.41 Impact Factor -
Article: Increased interferon alpha expression in circulating plasmacytoid dendritic cells of HIV-1-infected patients.
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ABSTRACT: The role of plasmacytoid dendritic cells (pDC) and interferon alpha (IFN alpha) in HIV-1 infection is still unclear. On one hand, HIV-1 disease is associated with a progressive decline of pDC, which displays reduced ability to produce IFN alpha after in vitro challenge. On the other hand, high IFN alpha serum levels in HIV-1-infected individuals have been proposed to promote immune hyper-activation and disease progression. We sought to determine whether disappearance of pDC in HIV-1 disease is due to homing in lymphoid tissues. We also studied IFN alpha and myxovirus resistance protein A (MxA) expression in unstimulated pDC and correlated these results with selected clinical and laboratory parameters. We found that pDC decline markedly in peripheral blood of patients progressing to disease but at the same time express much higher levels of IFN alpha and MxA compared to control individuals. On the other hand, we observed steady pDC counts in lymph nodes of HIV-1 patients. The frequency of circulating pDC correlated directly with CD4 cell counts and inversely with viral load. However, we found no correlation between IFN alpha and MxA expression levels, CD4 counts, and viral load. Circulating pDC decline sharply in the course of HIV-1 disease, but express high levels of IFN alpha, which may represent a hallmark of systemic immune dysfunction.JAIDS Journal of Acquired Immune Deficiency Syndromes 08/2008; 48(5):522-30. · 4.43 Impact Factor -
Article: Factor I-mediated processing of complement fragments on HIV immune complexes targets HIV to CR2-expressing B cells and facilitates B cell-mediated transmission of opsonized HIV to T cells.
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ABSTRACT: Our study demonstrates that binding of complement-opsonized HIV to complement receptor type 1 on human erythrocytes (E) via C3b fragments is followed by a rapid normal human serum-mediated detachment of HIV from E. The release was dependent on the presence of factor I indicating a conversion of C3b fragments to iC3b and C3d on the viral surface. This in turn resulted in an efficient binding of opsonized HIV to CR2-expressing B cells, thus facilitating B cell-mediated transmission of HIV to T cells. These data provide a new dynamic view of complement opsonization of HIV, suggesting that association of virus with E might be a transient phenomenon and the factor I-mediated processing of C3b to iC3b and C3d on HIV targets the virus to complement receptor type 2-expressing cells. Thus, factor I in concert with CR1 on E and factor H in serum due to their cofactor activity are likely to be important contributors for the generation of C3d-opsonized infectious HIV reservoirs on follicular dendritic cells and/or B cells in HIV-infected individuals.The Journal of Immunology 10/2006; 177(5):3469-76. · 5.79 Impact Factor -
Article: Detection of minor populations of drug-resistant HIV-1 in acute seroconverters.
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ABSTRACT: The transmission of drug-resistant HIV-1 is a major health concern. To date, most clinical studies have relied on sequencing techniques for genotypic analyses which do not allow quantification of minority viral populations below 25%. As minor populations of drug-resistant HIV-1 could impact the efficiency of antiretroviral therapy, this study was performed to determine the prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters. Forty-nine acute seroconverters from two clinical centers in Germany were included in the study. Individuals were identified between June 1999 and March 2003, and none had received antiretroviral therapy prior to sampling. Minor populations of drug-resistant variants were detected by quantitative real-time polymerase chain reaction using allele-discriminating oligonucleotides for three key resistance mutations: L90M (protease), K103N and M184V (reverse transcriptase). The approximate discriminative power was between 0.01 and 0.2%. Drug-resistant variants were detected in 10 of 49 patients (20.4%). The L90M mutation was found in one of 49 (2%), the K103N mutation in five of 49 (10.2%) and the M184V mutation in six of 49 (12.2%) patients, respectively. In five of the 10 individuals with detectable drug-resistant virus (50%), the detected population represented a minor viral quasi-species (< 25% of viruses) and was not detected by direct sequencing. The prevalence of minor populations of drug-resistant HIV-1 in acute seroconverters can be frequently detected and may impact the success of antiretroviral therapy.AIDS 12/2005; 19(16):1819-25. · 6.24 Impact Factor -
Article: Complement dependent trapping of infectious HIV in human lymphoid tissues.
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ABSTRACT: HIV-1 bound extracellularly to follicular dendritic cells (FDC) in germinal centers (GC) of lymphoid tissues (LT) represents the largest viral reservoir in HIV-infected individuals; however there is no direct evidence as to whether HIV trapped in human GC remains infectious. In the GC, complement receptors and Fc gamma receptors have been suggested to participate in trapping of HIV; therefore, the relative contribution of complement- and Fc gamma receptors in binding HIV on LT was investigated and the infectivity of this virus was tested. As it is difficult to isolate FDC without contaminations of productively infected cells, HIV was detached from LT of HIV positive individuals using antibodies blocking complement- and Fc gamma receptors. Isolated virus was tested in an infectivity assay. HIV detached from LT was quantified by HIV p24 ELISA, PCR and in an in vitro infectivity assay. Presence and accessibility of viral envelope proteins, complement factors and immunoglobulins on the surface of detached viral particles were evaluated through viral capture by respective antibodies. Although both C3d-fragments and IgG molecules were identified on the surface of HIV detached from LT, trapping of HIV was mediated solely by CR2-C3d interactions, whereas contribution of Fc gamma receptors was not detectable. Infectivity assays with HIV stripped from LT of HIV positive individuals revealed that in four out of ten patients HIV particles were infectious. These findings indicate that in the GC infectious virus is trapped on CR2-expressing FDC (or B cells). Reduction of this pool of HIV could be a therapeutic goal.AIDS 04/2005; 19(5):481-6. · 6.24 Impact Factor -
Article: Mycotic brain abscess caused by opportunistic reptile pathogen.
Emerging infectious diseases 03/2005; 11(2):349-50. · 6.17 Impact Factor -
Article: Delayed central nervous system virus suppression during highly active antiretroviral therapy is associated with HIV encephalopathy, but not with viral drug resistance or poor central nervous system drug penetration.
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ABSTRACT: HIV-1 encephalopathy (HIVE) is associated with high levels of viral RNA in the central nervous system (CNS). Highly active antiretroviral therapy (HAART) effectively reduces HIV replication in both plasma and cerebrospinal fluid (CSF). Some individuals, however, exhibit delayed CSF HIV RNA suppression in the presence of rapid plasma responses. We investigated the reasons for this discrepancy. CSF and plasma were collected prospectively in paired samples before and once or several times during HAART in 40 HIV-positive subjects. Ten had HIVE and 30 patients were neurologically asymptomatic or had non-HIVE neurological manifestations. The slopes of viral RNA decay during HAART were compared between the compartments. The presence of HIVE was defined by clinical standards and its severity categorized according to the Memorial Sloan Kettering score. CSF and plasma levels of antiretroviral drugs were measured. Viral drug resistance during HAART in CSF and plasma was analysed both genotypically and phenotypically. Slow CSF viral decay and a high degree of compartmental discordance (slopeCSF/slopeplasma) were both significantly correlated with HIVE (P < 0.00002). There was no correlation of a rapid CSF response with Centers for Disease Control and Prevention stage, CD4 cell count, or with the number of antiretroviral compounds and their known CSF penetration. Slow CSF viral decay was associated with neither low levels of antiretroviral drugs in the CSF or plasma, nor with viral drug resistance. None of the treatment-associated variables, but only the presence of HIVE, was associated with delayed virus elimination during HAART in the CSF. This suggests a distinct pattern of viral replication in the CNS in HIVE.AIDS 10/2003; 17(13):1897-906. · 6.24 Impact Factor -
Article: Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma.
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ABSTRACT: AIDS-related lymphoma (ARL) remains a frequent complication of HIV infection. We analyzed the outcome of patients with ARL with respect to the use and efficacy of highly active antiretroviral therapy (HAART) and to potential prognostic factors. This multicenter cohort study included patients with systemic ARL diagnosed between 1990-2001. We evaluated overall survival and the effects of several variables on overall survival using the Kaplan-Meier method and the extended Cox proportional hazards model. Response to HAART was used as a time-dependent variable and was defined as a CD4 cell count increase of >/= 100 x 106 cells/l and/or at least one viral load < 500 copies/ml during the first 2 years following diagnosis of ARL. Among 203 patients with ARL, median overall survival was 9.0 months [95% confidence interval (CI), 7.6-12.4 months]. In the univariate analyses, age < 60 years, no previous AIDS, CD4 cell counts >/= 200 x 106 cells/l, hemoglobin > 11 g/dl, Ann Arbor stages I-II and A, no extranodal lesion, response to HAART, and complete remission showed statistically significant association with prolonged overall survival. In the multivariate Cox model, the only factors independently associated with overall survival were response to HAART [relative hazard (RH), 0.32; 95% CI, 0.16-0.62], complete remission (RH, 0.24; 95% CI, 0.15-0.36), previous AIDS (RH, 1.92; 95%CI, 1.23-3.01) and extranodal involvement (RH, 2.85; 95% CI, 1.47-5.51). Efficacy of HAART was independently associated with prolonged survival in this large cohort of patients with ARL. Information on patient's response to HAART is crucial for the evaluation of future treatment strategies.AIDS 07/2003; 17(10):1521-9. · 6.24 Impact Factor -
Article: Effects of interleukin-2 plus highly active antiretroviral therapy on HIV-1 replication and proviral DNA (COSMIC trial).
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ABSTRACT: The effect of interleukin-2 (IL-2) in combination with antiretroviral therapy on HIV-1 replication and reservoirs was investigated. In a prospective, open-label trial, 56 asymptomatic HIV-1-infected subjects (CD4 T cell count > 350 x 10(6) cells/l) were randomized to highly active antiretroviral therapy (HAART: stavudine, lamivudine, nelfinavir, saquinavir) with or without IL-2 (9 megaunits daily for 5 days in 6-weekly intervals for a total of eight cycles). Productive and latent infection were analysed in peripheral blood, and residual virus replication in the lymphoid tissue and in the cerebrospinal fluid. The influence of IL-2 on viral rebound after treatment discontinuation was studied. Virus replication was detected in 21 of 31 on-treatment lymph nodes despite undetectable plasma viraemia. Viral RNA was found in resting as well as in proliferating cells. RNA-negative patients tended towards more rapid proviral DNA elimination. Supplementary IL-2 led to a greater increase in CD4 T cell counts than HAART alone (P < 0.001), resulting in normalization in approximately 90% of IL-2-treated patients compared with approximately 50% HAART-only subjects. IL-2 had no beneficial effect on virus replication and on proviral DNA in peripheral blood. Viral persistence during HAART is partly a result of continued low-level replication, calling for more active regimens. IL-2 accelerates the normalization of CD4 T cell counts but does not impact on virus production or latency.AIDS 07/2002; 16(11):1479-87. · 6.24 Impact Factor -
Article: Asymptomatic HIV infection is characterized by rapid turnover of HIV RNA in plasma and lymph nodes but not of latently infected lymph-node CD4+ T cells
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ABSTRACT: Objectives: To study the kinetics of plasma viraemia and HIV-infected lymph-node cells in stable asymptomatic HIV infection with high CD4+ T-cell counts. Methods: Nine asymptomatic HIV-infected patients with stable CD4+ T-cell counts (510-1350 × 106/l) were treated with a triple-drug combination. Plasma viraemia was determined at days 0, 3, 7, 10, 14, 21 and 28 of treatment [Roche polymerase chain reaction (PCR) and ultrasensitive PCR assay]. Sequential lymph-node biopsies were examined in four patients before and after 4 weeks of treatment. Productively infected cells were counted in lymph-node sections (in situ hybridization). The infection rates of FACS-sorted CD4+ lymph-node T cells and the expression of single-spliced, double-spliced and full-length HIV transcripts were determined. Results: HIV plasma RNA half-lives ranged from 1.4 to 2.7 days. Viral turnover varied between 0.07 and 7.54 × 108 copies per day. The number of productively infected lymph-node cells as well as the amount of extracellular virus in germinal centres was markedly reduced during treatment, paralleled by a clearance of single-spliced, double-spliced and full-length HIV transcripts from CD4+ lymph-node T cells. Plasma viraemia remained detectable with an ultrasensitive PCR assay in three out of four patients. The percentage of lymph-node CD4+ T cells harbouring proviral DNA decreased only slightly. Conclusions: The kinetics of HIV replication are rapid in stable asymptomatic infection, and the magnitude of replication varies considerably. Productively infected lymph-node cells and extracellular virus in germinal centres undergo a rapid turnover, whereas latently infected CD4+ T cells have a lower rate of turnover. The latter may contribute substantially to viral persistence during therapy.AIDS 07/1997; 11(9):1103-1110. · 6.24 Impact Factor
Top co-authors
Top Journals
Institutions
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2005
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Friedrich-Alexander Universität Erlangen-Nürnberg
- Department of Clinical and Molecular Virology
Erlangen, Bavaria, Germany
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2003
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Universität Hamburg
- Department of Neurological Surgery
Hamburg, Hamburg, Germany
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2002
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University Medical Center Hamburg - Eppendorf
Hamburg, Hamburg, Germany
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