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April 1995 - present
Publications
Publications (92)
Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research tow...
Background: Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; Stribild®) is a recommended integrase inhibitor-based regimen in treatment guidelines from the US Department of Health and Human Services and the British HIV Association. The purpose of this analysis was to determine the change in...
Introduction of highly active antiretroviral therapy (HAART) in 1996 changed the situation with human immunodeficiency virus (HIV) infection management. HIV-infected patients remain at an increased risk of hematologic malignances for which hematopoietic stem cell transplantation (HSCT) is considered standard therapy. Chemotherapy (CT), including hi...
The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, Februa...
Background:
Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify t...
Introduction:
Facing the rapid scale-up of antiretroviral treatment (ART) programs in resource-limited settings, monitoring of treatment outcome is essential in order to timely detect and tackle drawbacks [1].
Methods:
In a prospective cohort study, 300 consecutive patients starting first-line ART were enrolled between 2009 and2010 in a large HI...
Women and men are different—and this fundamental observation extends to their susceptibility and response to different diseases,
including autoimmune and infectious diseases. Apart from cultural and behavioral differences between the sexes that play a
prominent role in the exposure to pathogens, increasing data show that women and men also differ i...
The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations. We analysed three endpoints: myocardial infarction...
No consensus exists on how to define abnormally rapid deterioration in renal function (Rapid Progression, RP). We developed an operational definition of RP in HIV-positive persons with baseline estimated glomerular filtration rate (eGFR) >90 ml/min/1.73 m2 (using Cockcroft Gault) in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) st...
With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in pe...
The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infe...
Background:
Chronic hepatitis E virus (HEV) infections have recently been described in HIV-infected patients. Only few data are available for sub-Saharan Africa, where HIV and HEV are highly co-endemic, and where liver pathology is common in HIV-infected individuals.
Objectives:
To assess the prevalence of HEV viremia, anti-HEV antibodies, and s...
Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5'-NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tr...
Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome...
Background:
In Africa, success of antiretroviral treatment (ART) seems to lag behind in children compared with adults, and high therapeutic failure rates have been reported. We aimed to identify prevalence and determinants of virological failure in HIV-infected children treated under programmatic conditions.
Methods:
All patients <18 years on AR...
Regulatory T cells represent a specialized subpopulation of T lymphocytes that may modulate spontaneous HIV-1 disease progression by suppressing immune activation or inhibiting antiviral T cell immune responses. While the effects of classical CD25(hi) FoxP3(+) Treg during HIV-1 infection have been analyzed in a series of recent investigations, very...
Methods Peripheral blood and individual lymph nodes of a large cohort of HIV+ patients (n=131) at different disease stages, including 15 long-term nonprogressors and 21 elite controllers , was analyzed to determine the frequency, phenotype and function of Tregs. Results A significantly increased relative frequency of Tregs within the CD4+ compartme...
HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIV-related B cell dysfunctions...
An efficient synthesis of (S)- or (R)-3-(benzyloxy-methyl)-cyclopent-3-enol was developed by appling an enzyme-catalyzed kinetic-resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)- and (R)-cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this p...
Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 un...
Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses.
In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randoml...
Recently, it has been shown that human ejaculate enhances human immunodeficiency virus 1 (HIV-1) infectivity. Enhancement of infectivity is conceived to be mediated by amyloid filaments from peptides that are proteolytically released from prostatic acid phosphatase (PAP), termed Semen-derived Enhancer of Virus Infection (SEVI). The aim of this stud...
Despite the major successes of combination antiretroviral therapy (cART), HIV cannot be cured and treatment needs to be taken life-long. The major barrier to a cure is the persistence of long-lived latently infected T cells, residual replication and anatomical reservoirs. Gene therapy is a strategy that is currently being pursued as one approach to...
AIDS-related lymphomas (ARLs) significantly contribute to mortality in HIV-infected patients. Optimal chemotherapy treatment and the use of rituximab remain controversial. The aim of the present cohort study was to analyze the outcome of HIV-infected patients diagnosed with ARL, with regard to the use of rituximab, clinical characteristics and hist...
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 b...
Acute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletely contained to a viral setpoint. Accumulating evidence supports a role for natural killer (NK) cells in the early control of HIV infection; however, little...
Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cas...
Despite the tremendous advances in antiretroviral combination therapy over the last decade, eradication of HIV from the infected organism is still an elusive goal. Lifelong therapy is associated with potential long-term toxicity, adherence problems, and development of drug resistance. Thus, gene therapy approaches targeting viral eradication are st...
There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection.
Peripheral blood of a large cohort of HIV-infected patients (n = 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine
the frequency and phenotype of Tregs...
A first case of clinical tenofovir (TDF) HBV resistance in an HIV/HBV coinfected patient who developed an acute flare of hepatitis B is reported. The clinical course was accompanied by signs of acute liver failure after being on successful HBV treatment with tenofovir and persistently undetectable HBV-DNA viral load for over five years.
Circulating plasmacytoid dendritic cells (pDC) decline during HIV-1 infection, but at the same time they express markedly higher levels of interferon alpha (IFNalpha), which is associated with HIV-1 disease progression. Here we show an accumulation of pDC in lymph nodes (LN) of treatment-naïve HIV-1 patients. This phenomenon was associated with ele...
Persistent levels of IL-10 play a central role in progressive immune dysfunction associated with chronic viral infections such as HIV, but the underlying mechanisms are poorly understood. Because IL-10 affects the phenotypic and functional properties of DCs, which are responsible for initiating adaptive immune responses, we investigated whether IL-...
Background. Limited data exist describing the clinical outcome and immunological response primed during simultaneously acquired acute hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection. We present detailed clinical and immunological analysis of 3 individuals after concomitant infection with acute HCV and primary HIV. Methods...
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 S...
Humans tailor virus-specific immune responses through modulated expression of 12 different interferon (IFN)-alpha subtypes. However, exacerbated expression of certain IFN-alpha subtypes causes immunopathology in the context of autoimmune conditions and chronic viral infections. We showed that progression to AIDS is associated with elevated expressi...
The diversity of HIV-1 and human genetics complicates our ability to determine the impact of treatment during primary HIV-1 infection on disease outcome. Here, we show, in a small group infected with virtually identical HIV-1 strains and treated during primary HIV-1 infection, that patients expressing protective human leucocyte antigen alleles had...
Awarding the Nobel prize in physiology or medicine to Francoise Barre-Sinoussi and Luc Montagnier for the discovery of HIV-1, the causative agent of AIDS ([1][1]), is timely given the harm that the virus continues to inflict on the people of the world.
While these awardees fully deserve the award
To investigate whether HIV-infected patients on a stable and fully suppressive combination antiretroviral therapy (cART) regimen could safely be monitored less often than the current recommendations of every 3 months.
Two thousand two hundred and forty patients from the EuroSIDA study who maintained a stable and fully suppressed cART regimen for 1...
Background: Only a small minority of HIV infected patients control virus replication spontaneously and remain stable over long periods of time in the absence of therapy . Within LTNP subjects with complete virologic control (elite controllers, EC) and with low viral loads (intermediate controllers, IC) can be differentiated. Little is known about t...
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 ha...
Carrier-mediated transport across cell membranes is an important determinant of activity, resistance, and toxicity of chemotherapeutic agents including antiretroviral (ARV) drugs (ARDs). The organic cation transporters (OCTs) 1 and 2 have been implicated in the translocation of different cationic drugs but so far were insufficiently tested for inte...
A novel prophylactic AIDS vaccine candidate, consisting of single-stranded DNA for HIV-1 subtype C gag, protease, and part of reverse transcriptase genes, enclosed within a recombinant adeno-associated virus serotype-2 protein capsid (tgAAC09) induced T cell responses and antibodies in nonhuman primates. In this randomized, dose escalation phase I...
The aim of this study was to investigate the frequency of CYP2B6 polymorphisms (according to ethnicity) and the influence of heterozygosity and homozygosity on plasma concentrations of efavirenz and nevirapine.
Following written informed consent, 225 Caucasians and 146 Blacks were recruited from the German Competence Network for HIV/AIDS. Plasma co...
The aim of the study was to investigate the incidence of abacavir-related hypersensitivity reaction (HSR) and associated deaths in EuroSIDA HIV-1-infected patients.
Poisson regression models were developed to compare incidence of abacavir discontinuation according to the line of therapy within which abacavir was received, geographical regions, cale...
The new antiviral CCR5 antagonists have proven to be highly efficient in treatment experienced patient populations with multiple drug failure. Maraviroc is the most advanced compound in clinical development representing this new class of entry inhibitors. The favourable toxicity-, resistance- and pharmacokinetic profile of the drug has been proven...
In 2008, the goal of antiretroviral therapy is the suppression of viral load to undetectable levels (<50 HIV-RNA copies/ml) even in heavily pretreated patients harboring multidrug-resistant viruses. This ambitious goal can be achieved by combining at least two fully active antiretroviral drugs with an optimized background regimen according to genot...
The role of hemoglobin levels as an independent prognostic marker of progression to AIDS and/or death in HIV-infected patients starting combination antiretroviral therapy (cART) was investigated. A total of 2,579 patients from the EuroSIDA cohort with hemoglobin, CD4 cell count, and HIV RNA viral load measured 6 months prior to starting cART was in...
Immune activation is a major characteristic of human immunodeficiency virus type 1 (HIV-1) infection and a strong prognostic
factor for HIV-1 disease progression. The underlying mechanisms leading to immune activation in viremic HIV-1 infection, however,
are not fully understood. Here we show that, following the initiation of highly active antiretr...
Drug toxicity and viral resistance limit the long-term efficacy of antiviral drug treatment for human immunodeficiency virus (HIV) infection. Thus, alternative therapies need to be explored. We tested the infusion of T lymphocytes transduced with a retroviral vector (M87o) that expresses an HIV entry-inhibitory peptide (maC46). Gene-modified autolo...
Antiviral drug therapy can effectively suppress HIV replication, but emerging viral resistance and drug toxicity limit long-term therapeutic efficacy. In addition, regeneration of the T helper cell repertoire is often incomplete. The current major challenges in the treatment of HIV infection are therefore the reconstitution of cellular immunity, an...
The safety and efficacy of adoptive T-cell transfer (ATT) was tested in the context of viral suppression in syngeneic twins discordant for human immunodeficiency virus type 1 (HIV-1) infection. Human leucocyte antigen-matched T cells of seven HIV-negative twins were obtained by lymphapheresis and immediately transfused into the HIV-infected sibling...
This paper provides an overview of the current knowledge on virological rebound during treatment interruption and its consequences in patients with chronic HIV-1 infection.
After interruption of antiretroviral therapy, plasma viremia inevitably returns to individual pretherapy set point levels in almost all patients with chronic HIV infection. This...
The objective was to evaluate the feasibility and efficacy of a short-term, multi-agent and dose intensive regimen in AIDS patients with Burkitt or Burkitt-like lymphoma (BL/BLL) and to compare its efficacy with that of a conventional regimen. This was a retrospective, multi-center cohort study of all HIV-1-infected patients diagnosed with BL/BLL b...
The immunological and virological impact of short-term treatment initiated during acute human immunodeficiency virus type
1 (HIV-1) infection was assessed prospectively in 20 subjects, 12 of whom initiated highly active antiretroviral therapy (HAART)
for 24 weeks and then terminated treatment. Treatment resulted in suppression of viremia, an increa...
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. Th...
Despite significant improvements of the survival of HIV-infected patients during HAART, treatment limitations such as the development of drug-resistant HIV strains and long-term toxicities call for innovative treatment strategies. In this study, a novel antiviral gene that effectively inhibits virus entry was tested in a phase I/II clinical trial....
Background. We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. Methods. We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS- free persons starting HAART who were enrolled in 12 cohorts from Europe a...
Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody...
Esophageal candidiasis (EC) remains one of the most common AIDS defining illnesses in patients with human immunodeficiency virus (HIV) in the era of highly active antiretroviral therapy (HAART), but little is known about factors associated with EC after starting HAART.
To describe changes in the use of antimycotic medication, the incidence of EC an...
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...
Hodgkin's disease (HD) is the most common non-acquired immunodeficiency syndrome (AIDS)-defining malignancy in human immunodeficiency virus (HIV)-infected patients. We analysed the outcome of patients with HIV-associated HD (HIV-HD) with respect to the use and efficacy of highly active antiretroviral therapy (HAART) and other prognostic factors. To...
Most people infected with HIV-1 cannot control viral replication despite the presence of virus-specific CD8+ T cells. It has been postulated that this inability is related to the failure of these cells to mature into fully differentiated effector cells. We tested this hypothesis by comparing the maturation phenotype of virus-specific CD8+ T cells i...
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 i...
DC-SIGNR is a C-type lectin that functions as a transreceptor for HIV-1. The exon 4 of the DC-SIGNR gene comprises a variable number of 69-bp tandem repeats, encoding for parts of the extracellular protein domain. Here, we analyzed the relevance of this gene polymorphism for the interindividual transmission of HIV-1 and the progression to AIDS. A c...
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, sa...
To date, most studies have focused on the characterization of HIV-1-specific cellular immune responses in the peripheral blood (PB) of infected individuals. Much less is known about the comparative magnitude and breadth of responses in the lymphoid tissue. This study analyzed HIV-1-specific CD8+ T cell responses simultaneously in PB and lymph nodes...
Objective: To describe the use of second line protease-inhibitor (PI) regimens across Europe and to determine factors associated with virological and immunological response.
Design: Analysis of data from 984 patients with a median follow-up of 21 months enrolled in EuroSIDA. Patients started their second PI-containing regimen at least 16 weeks afte...
Background
Predictors of virological response to highly active antiretroviral therapy (HAART) have never been systematically evaluated in a large continental multicenter cohort of unselected human immunodeficiency virus (HIV)–infected people.Objective
To determine the factors related to achieving and maintaining undetectable plasma HIV-1 RNA leve...
The role of the thymus in HIV-1 pathogenesis remains unclear. We developed an assay to quantify the number of recent thymic
emigrants in blood based on the detection of a major excisional DNA byproduct (termed α1 circle) of T cell receptor rearrangement.
By studying 532 normal individuals, we found that α1 circle numbers in blood remain high for th...
In a prospective multicenter study 68 out of 158 patients with HIV infection and malignant lymphoma were assigned to a risk-adapted induction therapy using the following algorithm: High-risk patients fulfilled 2 of 3 criteria: T4 lymphocytes < 50/μ:L; WHO activity index 3 or 4; pre-existing AIDS-defining opportunistic infection. Normal-risk patient...
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,...
Objectives:
To analyse the short-term kinetics of viral plasma RNA and CD4+ T cells numbers in patients with different initial CD4+ T-cell counts treated with different antiretroviral regimens.
Methods:
In 10 HIV-1 positive patients, in vivo kinetics of plasma HIV RNA and CD4+ T cells were studied during antiretroviral treatment. Lymphocyte subp...
Disseminated infections caused by Mycobacterium avium complex (DMAC) represent a frequent opportunistic disease in HIV-infected patients with advanced stages of immunodeficiency (CD4-count < 100/μl). Fever, weight loss, night sweats and anemia are the leading clinical symptoms. Antimycobacterial therapy is clearly indicated in symptomatic patients...
We studied seven cases of Kaposi's sarcomas (KS) obtained from patients with AIDS and one KS from a patient without HIV infection. Antigen expression was studied by immunocytochemistry and mRNA expression by in situ hybridisation. The markers tested were endothelial leukocyte adhesion molecule-1, thrombomodulin, and tissue factor. In all tumors (AI...
Follicular dendritic cells (FDC) contribute minimally to the total cell population of lymphatic tissue. In order to obtain higher numbers of viable FDC with only a small fraction of contaminating cells the following procedure was developed. Subsequent to the usual mechanical and enzymatical digestion of human tonsils, single cells were layered on t...
We have previously shown that in AIDS patients a predominant species of infectious virus can be found which is not neutralized by homologous serum. The presence of the infectious virus was associated with the lack of type-specific antibody directed against the V3 domains of these virions. In contrast to this lack of V3-specific antibody, the other...
