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Biomedical subjects

Jan Gerstoft

Publications and source records attributed to Jan Gerstoft.

50 records · Page 3Linked to original sources
PubMed2003

Impaired production of cytokines is an independent predictor of mortality in HIV-1-infected patients.

OBJECTIVES: With regard to the natural history of HIV-1 infection this study investigated whether whole-blood culture cytokine production was associated with mortality in HIV-1-infected patients. DESIGN AND METHODS: One hundred and seven HIV-1-infected patients stratified according to the Centers for Disease Control and Prevention criteria and 65 controls participated. The 24-h phytohaemagglutinin and lipopolysaccharide-stimulated whole-blood culture production of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL) receptor antagonist (-ra), IL-1beta, IL-12, IL-10, IL-2 and soluble (s) IL-2 receptor (-r)alpha were studied and progression was evaluated using Kaplan-Meier method and Cox proportional-hazards models. RESULTS: Compared with controls, asymptomatic patients had increased production of IL-1beta and IL-12 (both P< 0.05), unchanged production of TNF-alpha, IFN-gamma and IL-1ra and notably reduced production of IL-10, IL-2 and sIL2-ralpha (all P< 0.05). HIV progression led to a progressive decline in whole-blood culture production of TNF-alpha, IFN-gamma, IL-1ra, IL-1beta, IL-12, IL-10 and IL-2 (all P< 0.0001). Low production of these cytokines were all associated with increased mortality risk in the patients (log-rank test, all P < 0.01, univariate Cox, all P< 0.001). Furthermore, low production of TNF-alpha, IL-1beta, IL-12 and IL-10 independently predicted mortality after adjusting for other known prognostic variables (multivariate Cox, all P< 0.05). CONCLUSIONS: Preserved capacity of blood cells to produce cytokines was associated with prolonged survival in HIV-1-infected patients indicating a clinical significance of impaired cytokine production in HIV-1 infection.

Adult↗
PubMed2003

A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6.

The chemokine-like, secreted protein product of the U83 gene from human herpesvirus 6, here named vCCL4, was chemically synthesized to be characterized in a complete library of the 18 known human chemokine receptors expressed individually in stably transfected cell lines. vCCL4 was found to cause calcium mobilization as efficiently as the endogenous chemokine ligand CCL2 through the CCR2 receptor, whereas the virally encoded chemokine did not affect any of the other 17 human chemokine receptors tested. Mutual cross-desensitization between CCL2 and vCCL4 was demonstrated in the CCR2-transfected cells. The affinity of vCCL4 for the CCR2 receptor was 79 nm as determined in competition binding against radioactively labeled CCL2. In the murine pre-B lymphocyte cell line L1.2 stably transfected with the CCR2 receptor, vCCL4 acted as a relatively low potency but highly efficacious chemoattractant being equally or more efficacious in causing cell migration than CCL2 and CCL7 and considerably more efficacious than CCL8 and CCL13. It is concluded that human herpesvirus 6 encodes a highly selective and efficacious CCR2 agonist, which will attract CCR2 expressing cells, for example macrophages and monocytes, conceivably for the virus to infect and to establish latency in. It is suggested that vCCL4 during reactivation of the virus in for example monocyte-derived microglia could perhaps be involved in the pathogenesis of the CCR2-dependent disease, multiple sclerosis.

Amino Acid Sequence↗
PubMed2003

Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus.

The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.

Adolescent↗
PubMed2003

Natural history of hyperlactataemia in human immunodeficiency virus-1-infected patients during highly active antiretroviral therapy.

A study on the course of hyperlactataemia during highly active antiretroviral therapy (HAART) and the association between hyperlactataemia and antiretroviral drugs was conducted at the outpatient department, Rigshopitalet, Copenhagen. Lactate levels were monitored in 848 patients during a study period of 1 y. Longitudinal analysis was performed on all human immunodeficiency virus-1-infected patients who had plasma lactate > 2.1 mM. Hyperlactataemia was found in 178 patients (21%), of whom 7 patients needed treatment modification, owing to symptomatic hyperlactataemia in 3 and neuropathy in 4 patients, while 171 remained on unchanged therapy. Lactate levels increased in 20 patients during the study period, but the increases were modest with a mean of 0.6 mM (range 0.1-1.7 mM). The association between antiretroviral drugs and hyperlactataemia was studied using logistic regression in 263 patients with data on their treatment regimen available in electronic form. Only stavudine and ritonavir were significantly associated with hyperlactataemia, with odds ratios of 5.1 and 2.6, respectively. In conclusion, symptomatic hyperlactataemia is uncommon, while asymptomatic hyperlactataemia is a frequent and apparently benign condition unlikely to progress to lactic acidosis. A significant association between stavudine and hyperlactataemia was confirmed. The unexpected association between ritonavir and hyperlactataemia will need confirmation in future studies.

Acidosis, Lactic↗
PubMed2003

Prevalence of drug resistance mutations and non-B subtypes in newly diagnosed HIV-1 patients in Denmark.

The aim of this study was to monitor the prevalence of drug resistance mutations in newly diagnosed HIV-1 positive individuals in Denmark. In addition we assessed the prevalence of non-B subtypes based on phylogenetic analysis of the pol gene. Plasma samples from 104 newly diagnosed HIV-1 positive patients were obtained in the year 2000. The entire protease gene and 320 amino acids of the reverse transcriptase gene were genotyped. Sequences were obtained from 97 patients. No subjects displayed primary resistance mutations in the protease gene, whereas all carried 1 or more secondary mutations. Resistance mutations in the RT-gene associated with NRTI-resistance were found in 1 patient, who was infected with zidovudine resistant HIV-1 harbouring the M41L mutation in combination with T215S and L210S. The T215S mutation has been showed to be associated with reversion of zidovudine resistance. The T215S mutation was found in 1 additional patient. The subtype distribution was subtype B 59%, C 18%, A 8%, CRF02_AG 5%, CRF01_AE 4%, D 3% and G 2%. We found 2 patients (2%) with mutations associated with resistance in the RT-gene and none in the protease gene indicating a low prevalence of resistant HIV-1 in Denmark in the year 2000.

Adolescent↗
PubMed2003

K65R with and without S68: a new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine.

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.

Anti-HIV Agents↗
PubMed2003

A randomized trial comparing initial HAART regimens of nelfinavir/nevirapine and ritonavir/saquinavir in combination with two nucleoside reverse transcriptase inhibitors.

BACKGROUND: A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance. METHODS: Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-naive HIV-infected patients allocated to a regimen of nelfinavir and nevirapine (1250/200 mg twice daily; n = 118) or ritonavir and saquinavir (400/400 mg twice daily; n = 115), both in combination with two nucleoside reverse transcriptase inhibitors. The primary end-point was HIV RNA < or = 20 copies/ml after 48 weeks (missing value = failure). Patients remained under follow-up also in case of switch from the randomized therapy. RESULTS: At baseline, the median CD4 cell counts were 126 (range: 0-942) (nelfinavir/nevirapine) and 150 (0-642) (ritonavir/saquinavir) cells/mm3, and HIV RNA measurements 5.0 copies/ml (1.3-6.4) in both groups. A total of 102 (86%) and 101 (88%) were antiretroviral-naive. 44% discontinued randomized therapy; P = 0.13. Of these, 80 and 73% switched therapy due to adverse events; P = 0.99. At week 48, 69 and 56%, respectively, had a HIV RNA < or = 20 copies/ml; P = 0.037. CONCLUSION: A regimen of nelfinavir/nevirapine had a favourable virological effect and tolerability over a 48-week period compared with ritonavir/saquinavir, when administered in combination with two nucleoside reverse transcriptase inhibitors. However, more extensive follow-up is required to determine the long-term consequences of triple class HAART regimens, including the development of broad drug resistance.

Adult↗
PubMed2002

Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy.

BACKGROUND: The safety of interrupting maintenance therapy for previous opportunistic infections other than Pneumocystis carinii pneumonia among patients with HIV infection who respond to potent antiretroviral therapy has not been well documented. OBJECTIVE: To assess the safety of interrupting maintenance therapy for cytomegalovirus (CMV) end-organ disease, disseminated Mycobacterium avium complex (MAC) infection, cerebral toxoplasmosis, and extrapulmonary cryptococcosis in patients receiving antiretroviral therapy. DESIGN: Observational study. SETTING: Seven European HIV cohorts. PATIENTS: 358 patients taking potent antiretroviral therapy (> or =3 drugs) who interrupted maintenance therapy at a CD4 lymphocyte count greater than 50 x 10(6) cells/L. MEASUREMENTS: Recurrence of opportunistic infection after interruption of maintenance therapy. RESULTS: 379 interruptions of maintenance therapy were identified: 162 for CMV disease, 103 for MAC infection, 75 for toxoplasmosis, and 39 for cryptococcosis. During 781 person-years of follow-up, five patients had relapse. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted when the CD4 lymphocyte count was less than 100 x 10(6) cells/L or when only one recent measurement exceeded this value. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted once CD4 counts were greater than 100 x 10(6) cells/L for 10 and 8 months, respectively. One relapse (toxoplasmosis) was diagnosed after maintenance therapy interruption at a CD4 lymphocyte count greater than 200 x 10(6) cells/L for 15 months. The overall incidences of recurrent CMV disease, MAC infection, toxoplasmosis, and cryptococcosis were 0.54 per 100 person-years (95% CI, 0.07 to 1.95 per 100 person-years), 0.90 per 100 person-years (CI, 0.11 to 3.25 per 100 person-years), 0.84 per 100 person-years (CI, 0.02 to 4.68 per 100 person-years), and 0.00 per 100 person-years (CI, 0.00 to 5.27 per 100 person-years), respectively. CONCLUSION: Maintenance therapy against previous infection with CMV, MAC, Toxoplasma gondii, or Cryptococcus neoformans in patients with HIV infection can be interrupted after sustained CD4 count increases to greater than 200 (or possibly 100 to 200) x 10(6) cells/L for at least 6 months after the start of potent antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2002

Skeletal muscle mitochondrial function and exercise capacity in HIV-infected patients with lipodystrophy and elevated p-lactate levels.

OBJECTIVE: To investigate the skeletal muscle mitochondrial function in HIV-infected patients with lipodystrophy or elevated p-lactate levels. DESIGN: Eight HIV patients treated with highly active antiretroviral therapy, with lipodystrophy or elevated p-lactate, and eight healthy controls were exposed to incremental exercise until exhaustion. METHODS: Blood samples and gas analysis were performed at rest, during exercise and in recovery. Oxygen consumption, workload and blood lactate were assessed. Before and immediately after exercise muscle biopsies were obtained, in which citrate synthase (CS), hydroxyacyl-coenzyme A dehydrogenase (HD), glycogen and nucleotides were measured. RESULTS: Maximal workload was significantly lower in patients compared with controls [171 Watt (88-206) versus 235 Watt (118-294) P = 0.05]. A trend towards lower maximal oxygen consumption (VO(2max)) was detected in patients [2136 ml/min (1221-2598) versus 2985 ml/min (1506-3959) P = 0.11]. Patients had significantly elevated levels of blood lactate at rest [1.55 mmol/l (1-2.5) versus 0.8 mmo/l (0.37-1.1) P < 0.01), but no significant difference in maximal blood-lactate values was found. The decline in blood lactate in the recovery period was similar between groups. There was no significant difference in CS, HD, glycogen or nucleotides. CONCLUSION: The significantly lower working capacity and the trend towards reduced VO(2max) in patients could be caused by mitochondrial dysfunction, but may also be caused by impaired physical fitness. The similar levels of nucleotides, CS, HD, and glycogen and the normal increase in blood lactate during exercise indicates a normal oxidative phosphorylation. No evidence of serious damage to skeletal muscle mitochondrial function was found.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2002

Blood infectivity in transmissible spongiform encephalopathies.

Blood infectivity in transmissible spongiform encephalopathies (TSE) is reviewed with special emphasis on transmission by blood transfusion in human beings. It is concluded that transmission by transfusion seems biologically plausible as regards variant Creutzfeld-Jakob Disease (vCJD), albeit present knowledge suggests that it is extremely uncommon. Precautionary measures against the putative risk of vCJD transmission by blood transfusion are discussed.

Animals↗
PubMed2002

Cell-associated HIV DNA measured early during infection has prognostic value independent of serum HIV RNA measured concomitantly.

Using data from the Danish AIDS Cohort of HIV-infected homosexual men established in the 1980s, the prognostic value of early HIV DNA loads was evaluated. In addition to DNA measurements, concomitant serum HIV RNA levels, CD4 cell counts and CCR5 genotypes were determined. The patients were divided into 3 groups, according to whether their cell-associated HIV DNA load was < or = 100, 500 or > or = 2,500 DNA copies/10(6) peripheral blood mononuclear cells. Clinical progression rates differed significantly between the groups (p < 0.005). Cell-associated HIV DNA load had prognostic value independent of serum HIV RNA (p < 0.02). However, when HIV DNA, HIV RNA and CD4 cell counts were all included in a Cox model, only serum HIV RNA had independent prognostic value. Patients heterozygous for the CCR5 delta 32 allele had significantly lower HIV DNA loads than those homozygous for the normal allele (p < 0.05). The interplay between HIV RNA and DNA levels is discussed, together with the possibility that cell-associated HIV DNA load is a marker of the HIV RNA peak seen shortly after primary HIV infection.

Cohort Studies↗
PubMedDate not supplied

Right ventricular volume and mass determined by cine magnetic resonance imaging in HIV patients with possible right ventricular dysfunction.

Impaired right ventricular (RV) function has been reported to occur in patients with HIV when studied by echocardiography. However, for accurate evaluation of RV function and morphology, first-pass radionuclide ventriculography (RNV) and cine magnetic resonance imaging (cine-MRI) are methods of choice. Studies of RV involvement in patients with HIV are of interest since pulmonary hypertension is a known serious complication of HIV recognized with increasing frequency. The aim of the present study was to characterize cardiac function and geometry in patients with HIV and reduced right ventricular ejection fraction (RVEF). To do so, we screened patients with RNV and performed an additional cine-MRI in those with reduced RVEF determined by RNV. Ninety patients with HIV were included. To evaluate the MRI measures exactly we included 18 age- and gender-matched healthy volunteers to establish reference values. RNV showed in 13 of the 90 patients a reduced RVEF with a standard cutoff value for RVEF of 0.50. Six of these agreed to have an additional MRI investigation performed. These 6 patients with HIV had an RVEF measured by RNV between 0.41-0.49. Measured by MRI the range of RVEF was 0.47-0.55 with 3 below the lower 95% reference limit according to the control group (lower reference limit: 0.49). None of the 6 patients with HIV had dilated right ventricle and only 1 had a marginally increased right ventricular mass index of 43 g/m(2) (reference: <41 g/m(2)). With use of MRI, a few patients with HIV may have a marginally reduced RVEF but normal RV dimensions and mass. Thus, RV dysfunction does not seem to constitute a major clinical problem in this antivirally treated HIV population.

Adult↗