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Biomedical subjects

Peter Reiss

Publications and source records attributed to Peter Reiss.

At least 37 records · Page 2Linked to original sources
PubMed2005

Dynamics of cytomegalovirus (CMV)-specific T cells in HIV-1-infected individuals progressing to AIDS with CMV end-organ disease.

BACKGROUND: Since cytomegalovirus (CMV) infection can cause serious clinical complications in immunocompromised individuals, we assessed cellular immune requirements for protection against CMV end-organ disease (CMV-EOD) in human immunodeficiency virus type 1 (HIV-1) infection. METHODS: Longitudinal samples from HIV-1-infected patients in the Amsterdam cohort were analyzed. Dynamics of CMV-specific CD8(+) and CD4(+) T cell responses were analyzed by 4-color fluorescence analysis using major histocompatibility class I CMV peptide-tetramers and by intracellular staining for perforin, granzyme B, and interferon (IFN)- gamma after stimulation with CMV-specific stimuli. CMV load was measured in parallel. RESULTS: In individuals progressing to acquired immunodeficiency syndrome with CMV-EOD, CMV-specific IFN- gamma -producing CD4(+) T cells disappeared during the year before onset of CMV-EOD. This disappearance was accompanied by a sharp increase in CMV load before onset of disease. Despite increasing CMV-specific CD8(+) T cell counts, decreasing CMV-specific IFN- gamma -producing CD8(+) T cell counts were found over time. In contrast, the percentage of CMV-specific perforin- and granzyme B-expressing CD8(+) T cells increased. CONCLUSIONS: Our data indicate that insufficient help of CD4(+) T cells may cause loss of IFN- gamma -producing CD8(+) T cells and loss of control of CMV dissemination. Increasing CMV-infected cell counts in the face of high CMV-specific perforin- and granzyme B-expressing CD8(+) T cell counts may explain the immune pathological characteristics of CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed2005

Increased multinucleoside drug resistance and decreased replicative capacity of a human immunodeficiency virus type 1 variant with an 8-amino-Acid insert in the reverse transcriptase.

Resistance to antiretroviral drugs is generally conferred by specific amino acid substitutions, rather than insertions or deletions, in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). The exception to these findings is the amino acid insertions found in the beta3-beta4 loop of the RT enzyme in response to treatment with nucleoside reverse transcriptase inhibitors. This insert consists most commonly of two amino acids, but we describe in detail the evolution of a variant with an 8-amino-acid (aa) insert in a patient treated with zidovudine (ZDV) and 2'-3'-dideoxycytidine (ddC). The 24-nucleotide insert is a partial duplication of local sequences but also contains a sequence segment of unknown origin. Extensive sequence analysis of longitudinal patient samples indicated that the HIV-1 population prior to the start of therapy contained not the wild-type amino acid 215T in RT but a mixture with 215D and 215C. Treatment with ZDV and subsequent ZDV-ddC combination therapy resulted in the evolution of an HIV-1 variant with a typical ZDV resistance genotype (41L, 44D, 67N, 69D, 210W, 215Y), which was slowly replaced by the insert-containing variant (41L, 44D, insert at position 69, 70R, 210W, 215Y). The latter variant demonstrated increased resistance to a wide range of drugs, indicating that the 8-aa insert augments nucleoside analogue resistance. The gain in drug resistance of the insert variant came at the expense of a reduction in replication capacity when assayed in the absence of drugs. We compared these data with the resistance and replication properties of 133 insert-containing sequences of different individuals present in the ViroLogic database and found that the size and actual sequence of the insert at position 69 influence the level of resistance to nucleoside analogues.

Adult↗
PubMed2005

Predictors of hypertension and changes of blood pressure in HIV-infected patients.

OBJECTIVE: We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals. METHODS: International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP > or =140 and/or diastolic BP > or =90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline. RESULTS: 73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2-6) were recorded over a median follow-up of 2.3 years (IQR: 1.5-2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences > or =5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2-76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors (P=0.75), protease inhibitors (P=0.92) as well as type of antiretroviral treatment at baseline (P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated < or =10 months and >10 months compared with no exposure; P=0.005). CONCLUSIONS: Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.

Adult↗
PubMed2005

Adverse effects of antiretroviral therapy for HIV infection: a review of selected topics.

In the current era of HIV treatment, the toxicity profiles of antiretroviral drugs have increasingly emerged as a basis for selecting initial antiretroviral regimens as well as a reason for switching therapy in treatment-experienced patients. In this respect, an intensive research effort involving clinical research as well as basic science research over the past six years, has focused on the cluster of metabolic and body composition abnormalities that have come to be termed the 'lipodystrophy syndrome'. These data have now provided a clear and clinically relevant understanding of the individual profiles of drugs within the nucleoside analogue reverse transcriptase inhibitor , HIV protease inhibitor and non-nucleoside analogue reverse transcriptase inhibitor drug classes, and have provided a rational basis for assessing and monitoring these adverse effects in clinical practice. In this review, current and emerging drug toxicities are considered with an emphasis on lipodystrophy complications.

Adenine↗
PubMed2005

Are specific antiretrovirals associated with an increased risk of discontinuation due to toxicities or patient/physician choice in patients with hepatitis C virus coinfection?

BACKGROUND: Liver damage associated with hepatitis C (HCV) may influence the likelihood of experiencing discontinuation due to toxicities or patient/physician choice (TOXPC) in patients taking combination antiretroviral therapy (cART). Little information to address this concern is available from clinical trials as patients with HCV are often excluded. AIMS: To compare incidence rates of discontinuation due to TOXPC associated with specific antiretrovial drugs in patients with or without HCV. PATIENTS/METHODS: A total of 4929 patients from EuroSIDA under follow-up from January 1999 on a specific nucleoside pair (zidovudine/lamivudine, didanosine/stavudine, stavudine/lamivudine, or other) with a third drug (abacavir, nelfinavir, indinavir, nevirapine, efavirenz, lopinavir/ritonavir or other boosted-protease inhibitor (PI)-containing regimen) and with known HCV serostatus were studied for the incidence of discontinuation of any nucleoside pair or third drug due to TOXPC. Incidence rate ratios were derived from Poisson regression models. RESULTS: In total 1358 patients had HCV (27.5%). During 12 799 person-years of follow-up there were 2141 discontinuations due to TOXPC for nucleoside pairs and 2501 for third drugs. The incidence of discontinuation due to TOXPC was consistently higher in patients with HCV after stratification by nucleoside pair or third drug. After adjustment for CD4+ count, gender, exposure group, time on HAART, region and treatment regimen, there were few differences in the rate of discontinuation due to TOXPC in those with HCV compared with those without for any nucleoside pairs or third drugs. Similar results were seen when concentrating on discontinuation due to toxicities alone. CONCLUSIONS: Although patients with HCV generally had higher rates of discontinuation due to TOXPC compared with patients without HCV, there was little evidence to suggest that this was associated with any specific nucleoside pair or third drug used as part of cART. Our results do not suggest that any specific component of cART is more poorly tolerated in patients with HCV or that the presence of HCV should influence the choice between antiretrovirals used as part of a cART regimen.

Anti-HIV Agents↗
PubMed2005

Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy.

BACKGROUND: Studies have suggested that HIV-1 may develop thymidine analogue mutations (TAMs) by one of two distinct pathways - the TAM1 pathway (including mutations 41L, 210W and 215Y) or the TAM2 pathway (including mutations 67N, 70R and 219E/Q) - under the pressure of a not fully suppressive thymidine-analogue-containing regimen. METHODS: Frozen plasma samples stored in the EuroSIDA repository were selected and sent to two central laboratories for genotypic analysis. We considered 733 patients with at least one genotypic test showing > or =1 TAMs (the first of these tests in chronological order was used). TAM1 and TAM2 genotypic profiles were defined in accordance with previous literature. Statistical modelling involved logistic regression and linear regression analysis for censored data. RESULTS: The observed frequencies of patterns classifiable as TAM1 or TAM2 profiles were markedly higher than the probabilities of falling into these classifications by chance alone. The chance of detecting a TAM2 profile increased by 25% per additional year of exposure to zidovudine. We found that mutations 67N and 184V were not associated with a particular TAM profile. In the presence of TAM2 profiles, the adjusted mean difference in the 6-month viral reduction was 0.96 log10 copies/ml (95% confidence interval: 0.20; 1.73) higher in patients who started stavudine-containing regimens instead of zidovudine-containing regimens. CONCLUSIONS: This study provides evidence that the suggested TAM clustering is a real phenomenon and that it may be driven by which thymidine analogue the patients has used. In patients with TAM2-resistant viruses, stavudine appears to retain greater viral activity than zidovudine.

Anti-HIV Agents↗
PubMed2004

Causes of death in HIV infection: the key determinant to define the clinical response to anti-HIV therapy.

Studies have shown an increased risk of new AIDS/death among injecting drug users (IDU) starting highly active antiretroviral therapy (HAART). Of 3872 patients starting HAART in the EuroSIDA study, 819 were IDU (21.2%). During 14 769 person-years of follow-up, 499 patients progressed to new AIDS/death. Compared with homosexual individuals, IDU had an increased incidence of new AIDS/death, but only for non-HIV deaths. There is an urgent need to define and standardize causes of death in observational studies.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1.

BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (-4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.

Adult↗
PubMed2004

Chelating ligands for nanocrystals' surface functionalization.

A new family of ligands for the surface functionalization of CdSe nanocrystals is proposed, namely alkyl or aryl derivatives of carbodithioic acids (R-C(S)SH). The main advantages of these new ligands are as follows: they nearly quantitatively exchange the initial surface ligands (TOPO) in very mild conditions; they significantly improve the resistance of nanocrystals against photooxidation because of their ability of strong chelate-type binding to metal atoms; their relatively simple preparation via Grignard intermediates facilitates the development of new bifunctional ligands containing, in addition to the anchoring carbodithioate group, a second function, which enables the grafting of molecules or macromolecules of interest on the nanocrystal surface. To give an example of this approach, we report, for the first time, the grafting of an electroactive oligomer from the polyaniline family-aniline tetramer-on CdSe nanocrystals after their functionalization with 4-formyldithiobenzoic acid. The grafting proceeds via a condensation reaction between the aldehyde group of the ligand and the terminal primary amine group of the tetramer. The resulting organic/inorganic hybrid exhibits complete extinction of the fluorescence of its constituents, indicating efficient charge or energy transfer between the organic and the inorganic semiconductors.

Journal Article↗
PubMed2004

Rate of viral rebound according to specific drugs in the regimen in 2120 patients with HIV suppression.

BACKGROUND: It is currently unclear whether the tendency for viral rebound in patients with viral load < 50 copies/ml differs according to the specific drug regimen being used. METHODS: To follow 2120 patients in EuroSIDA who had attained < 50 copies/ml on highly active antiretroviral therapy (HAART), without previously virologically failing HAART. RESULTS: The rate of viral rebound (two consecutive values > 400 copies/ml) was 4.9/100 person-years [95% confidence interval (CI), 4.0-5.8] for patients who were naive pre-HAART and 8.0/100 person-years (95% CI, 7.0-9.0) for those who were experienced with nucleoside analogue reverse transcriptase inhibitors (NRTI) pre-HAART. The rate of rebound was significantly higher in those taking nelfinavir than in those taking efavirenz, both in patients who were naive pre-HAART and those who were NRTI experienced [adjusted rate ratios, 2.83 (95% CI, 1.51-5.31) and 2.86 (95% CI, 1.65-5.00), respectively]. Among patients who were naive pre-HAART, those on abacavir had no evidence of a raised risk of viral rebound (adjusted rate ratio 1.17; 95% CI, 0.51-2.69), but in those with pre-HAART NRTI experience the rate was markedly raised (adjusted rate ratio, 4.48; 95% CI, 2.51-8.00). A similar picture was seen when comparing those on nevirapine with those on efavirenz, although the elevated rate ratio in pre-HAART experienced patients was of lower magnitude (adjusted rate ratio, 1.93). There was no strong evidence that rebound rates differed significantly for any NRTI pairs compared with zidovudine/lamivudine. CONCLUSION: Viral rebound rates in patients who have attained < 50 copies/ml appear to differ according to the specific drugs being used.

Adult↗
PubMed2004

Markedly diminished lipolysis and partial restoration of glucose metabolism, without changes in fat distribution after extended discontinuation of protease inhibitors in severe lipodystrophic human immunodeficient virus-1-infected patients.

Treatment for HIV-1 infection is often complicated by a lipodystrophy syndrome associated with insulin resistance and an elevated rate of lipolysis. In eight HIV-1 infected men with lipodystrophy syndrome, we studied the effects of replacement of protease inhibitor (PI) by abacavir on insulin sensitivity and lipolysis by hyperinsulinemic euglycemic clamp and on fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan. Glucose metabolism and lipolysis were assessed by tracer dilution employing [6,6-(2)H(2)]glucose and [(2)H(5)]glycerol, respectively. Data are expressed as mean +/- sd or 95% confidence interval (CI), as appropriate. There were no significant changes in fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan at wk 36 and wk 96. The fasting total glucose production decreased from 16.1 +/- 2.5 at study entry by 1.1 (range, -2.1 to -0.1) to 15.0 +/- 1.5 micromol/kg.min after PI withdrawal at wk 36 (n = 8). In an analysis restricted to the patients on treatment at wk 96 (n = 6), the decrease was 0.9 (range, -2.1 to 0.3) micromol/kg.min. During insulin infusion, glucose oxidation (as percent of total glucose disposal) increased from 36.8 +/- 12.7% by 11.0% (range, 1.3-20.8) to 47.9 +/- 13.9% in the wk 36 analysis. In the analysis restricted to the patients on treatment at wk 96 (n = 6) the increase was 7.7 (-4.0 to 19.4)%. Fasting lipolysis decreased from 2.7 +/- 0.6 micromol/kg.min by 0.9 (-1.6 to -0.2) to 1.8 +/- 0.3 micromol/kg.min in the wk-96 analysis (n = 6). The replacement of the studied PIs by abacavir in severe lipodystrophic HIV-1-infected patients results in a marked reduction of lipolysis. In contrast, fasting glucose production and insulin-stimulated glucose oxidation improve moderately, whereas insulin-stimulated glucose disposal and fat distribution do not change.

Absorptiometry, Photon↗
PubMed2004

Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy.

INTRODUCTION: Mitochondrial toxicity resulting from mitochondrial DNA (mtDNA) depletion is suggested to be involved in the pathogenesis of lipodystrophy. METHODS: We cross-sectionally assessed lipodystrophy both clinically and radiographically in patients who, 4 years before, had been enrolled in a randomized comparative trial of stavudine- or zidovudine-based therapy. mtDNA content was measured in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue from the thigh and back. RESULTS: Twenty-eight of the 45 patients enrolled in the original trial were included. Despite comparable exposure to stavudine or zidovudine (51 and 50 months, respectively), lipoatrophy prevalence by intent-to-treat analysis was significantly greater in stavudine recipients (82 vs 9%, P=0.0001). Likewise, those allocated to stavudine had significantly less peripheral fat. In an analysis restricted to patients who had remained on randomly allocated nucleoside reverse transcriptase inhibitors (NRTIs), mtDNA in PBMCs decreased after the start of treatment in both groups (P<0.0001) (-73% for stavudine and -67% for zidovudine, P=0.11), resulting in significantly lower levels in patients with lipoatrophy (P=0.007). The mtDNA content in subcutaneous adipose tissue from the thigh, but not from the back, was significantly lower in patients allocated to stavudine compared to zidovudine (P=0.01). mtDNA in adipose tissue from either location did not differ significantly between those with or without lipoatrophy. DISCUSSION: This study objectively confirms that regimens containing stavudine are associated with a greater risk of lipoatrophy than those containing zidovudine. mtDNA in PBMCs markedly declined with both treatments and was lowest in patients with lipoatrophy. The lack of difference in mtDNA in adipose tissue from patients with as opposed to without lipoatrophy may have been masked by a relative preponderance of stromal and vascular tissue in the subcutaneous tissue samples from these patients, combined with compensatory mitochondrial proliferation in remaining adipocytes. However, our findings may also suggest that the different risk of lipoatrophy observed between NRTIs cannot solely be explained by differences in mtDNA depletion directly at the level of peripheral adipose tissue.

Adipose Tissue↗
PubMed2004

Baseline resistance and virological outcome in patients with virological failure who start a regimen containing abacavir: EuroSIDA study.

OBJECTIVES: To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort. PATIENTS AND METHODS: A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data. RESULTS: The baseline VL was 4.36 log10 RNA copies/ml [interquartile range (IQR): 3.65-4.99 log10 RNA copies/ml] and the median CD4 cell count was 210 cells/microl (IQR: 67-305 cells/microl). Our patients were pre-exposed to a median of seven antiretrovirals (2-12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0-8). Overall, the Kaplan-Meier estimate of the median month 6 VL decline was 0.86 log10 RNA copies/ml [95% confidence intervals (95% CI): 0.45-1.24]. The VL in those patients (n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15-0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05). CONCLUSIONS: Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.

Adult↗
PubMed2003

Combination antiretroviral therapy and the risk of myocardial infarction.

BACKGROUND: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction. METHODS: In this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction. Relative rates were calculated with Poisson regression models. Combination antiretroviral therapy was defined as any combination regimen of antiretroviral drugs that included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. RESULTS: Over a period of 36,199 person-years, 126 patients had a myocardial infarction. The incidence of myocardial infarction increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; P<0.001). Other factors significantly associated with myocardial infarction were older age, current or former smoking, previous cardiovascular disease, and male sex, but not a family history of coronary heart disease. A higher total serum cholesterol level, a higher triglyceride level, and the presence of diabetes were also associated with an increased incidence of myocardial infarction. CONCLUSIONS: Combination antiretroviral therapy was independently associated with a 26 percent relative increase in the rate of myocardial infarction per year of exposure during the first four to six years of use. However, the absolute risk of myocardial infarction was low and must be balanced against the marked benefits from antiretroviral treatment.

Adult↗