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Biomedical subjects

R Hemmer

Publications and source records attributed to R Hemmer.

At least 19 recordsLinked to original sources
PubMed2006

Antiviral efficacy and resistance in patients on antiretroviral therapy in Kigali, Rwanda: the real-life situation in 2002.

Our study aimed to complete the published data on ARV therapy in Africa by describing the baseline situation in Rwanda before the launch of a large ARV programme (ESTHER). Prescription habits, frequency and reasons for treatment interruptions but also antiviral efficay, resistance to ARVs and genotypic variability of the viruses present in Rwanda were analysed. Among the 233 patients included in the study, it appeared that a vast majority (91%) were under triple therapy and that half of them had experienced at least one treatment interruption caused mainly by drug shortage or financial difficulties. Among 60 blood samples analysed, 26 were in virological failure with a viral load above 1000 RNA copies/ml and 11 presented major drug resistance mutations. Finally, virological failure could mainly be explained by the high frequency of treatment interruptions but also by the emergence of drug resistance mutations. Consequently the major objective for the ESTHER programme to improve the situation in Rwanda will be to reduce the drug shortage and facilitate the financial accessibility of the treatments.

Anti-HIV Agents↗
PubMed2004

Simple DNA extraction method for dried blood spots and comparison of two PCR assays for diagnosis of vertical human immunodeficiency virus type 1 transmission in Rwanda.

Dried blood spots (DBS) on filter paper facilitate the collection, transport, and storage of blood samples for laboratory use. A rapid and simple DNA extraction procedure from DBS was developed and evaluated for the diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in children by an in-house nested-PCR assay on three genome regions and by the Amplicor HIV-1 DNA prototype assay version 1.5 (Roche Molecular Systems). A total of 150 samples from children born to HIV-1-infected mothers were collected in Kigali, Rwanda, in parallel as DBS and as peripheral blood mononuclear cell (PBMC) pellets. The results obtained on DBS by the two PCR assays were compared to the results of nested PCR on PBMCs. Of 150 PBMC samples, 10 were positive, 117 were negative, and 23 were indeterminate for HIV-1 infection. In DNA extracted from filter papers and amplified by using the in-house nested PCR, 9 of these 10 positive samples (90%) were found to be positive, and 1 was found to be indeterminate (only the pol region could be amplified). All of the negative samples and all of the 23 indeterminate samples tested negative for HIV-1 infection. When we used the Amplicor DNA test on DBS, all of the 10 PBMC-positive samples were found to be positive and all of the 23 indeterminate samples were found to be negative. Of the PBMC-negative samples, 115 were found to be negative and 2 were found to be indeterminate. We conclude that this simple rapid DNA extraction method on DBS in combination with both detection methods gave a reliable molecular diagnosis of HIV-1 infection in children born to HIV-infected mothers.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Financial situation of people living with HIV in Europe.

The objective was to investigate the financial situation of people living with HIV in Europe. Two surveys using an anonymous questionnaire were organized in Europe among people living with HIV, the first in 1996-97 and the second in 1998-99. One thousand one hundred and sixty-one people from the 1996-97 survey and 899 from the 1998-99 survey were included. Four hundred and fifty-seven (42%) of the 1996-97 participants reported that their income had decreased since HIV diagnosis. The latter participants reported significantly more often difficulties in paying for housing (27% vs 20%), food (18% vs 12%) and transport (17% vs 12%) compared to 1998-99 participants. In multiple regression analysis, severity of HIV disease, not being on highly active antiretroviral therapy (HAART), younger age, lower education level and living in the South of Europe were associated with having financial difficulties. We concluded that since the introduction of HAART, the financial situation of persons living with HIV in Europe has improved, but a relatively large percentage of them still have financial difficulties.

Adult↗
PubMed2001

HIV-associated hematologic disorders are correlated with plasma viral load and improve under highly active antiretroviral therapy.

The relationship between HIV-1 replication and hematologic parameters was examined in two separate studies. The first study was a cross-sectional evaluation of 207 untreated patients. In this study, the proportion of patients with hematologic disorders increased with disease progression. There was a significant inverse correlation between HIV-1 plasma viral load and all hematologic values (r = -0.266 to -0.331). The second study was a longitudinal evaluation of patients on combination antiretroviral therapy (HAART) with hematologic alterations before treatment ( N = 27 with platelets <150,000/microl, 24 with hemoglobin <12 g/dl, 36 with neutrophils <2000/microl and 29 with leukocytes <3000/microl). Samples were analyzed every 3 months for 2 years. At 2 years, >50% of patients experienced a sustained virologic response, with viral loads <500 RNA copies/ml. Hematologic reconstitution occurred progressively for all blood cell lineages and became statistically significant after the sixth month of therapy ( p <.001). Mean values increased from 110 to 180 x 10(3)/microl for platelets, from 10.7 to 12.3 g/dl for hemoglobin (stabilizing finally at 11.4 g/dl), from 1,260 to 2,240/microl for neutrophils, and from 2,260 to 3,600/microl for leukocytes. In conclusion, hematologic disorders are corrected by combination antiretroviral therapy. This suggests a causative role of HIV-1 in hematologic disorders.

Adult↗
PubMed2001

Clinical outcome among HIV-infected patients starting saquinavir hard gel compared to ritonavir or indinavir.

OBJECTIVE: To compare the clinical response among patients who initiate protease inhibitor therapies with different virological potency. DESIGN: We analysed patients who started indinavir, ritonavir or saquinavir hard gel capsule (hgc) as part of at least triple therapy during prospective follow-up within the EuroSIDA study. METHODS: Changes in plasma viral load (pVL) and CD4 cell count from baseline were compared between treatment groups. Time to new AIDS-defining events and death were compared in Kaplan--Meier models, and Cox models were established to further assess differences in clinical progression (new AIDS/death). Adjustment was made for differences in baseline parameters, in particular pVL, CD4 cell count, and region of Europe. RESULTS: A total of 2708 patients (median follow-up: 30 months) were included, of which 556 started ritonavir (21%), 1342 indinavir (50%), and 810 saquinavir hgc (30%). The three groups were fairly evenly balanced at baseline regarding CD4 count, previous diagnosis of AIDS and pVL, After 12 months, the median changes in CD4 cell count were 90, 96 and 74 x 10(6) cells/l, respectively;P < 0.001, the proportions of patients with pVL < 500 copies/ml were 47, 54 and 41%; P < 0.001, and the proportions with clinical progression were 11.9, 9.2 and 11.9%, respectively; P = 0.20 (log-rank test). In multivariate models the relative risk of clinical progression for indinavir compared with saquinavir hgc was: 0.77 (0.60--0.99); P = 0.043, and for ritonavir 0.83 (0.62--1.11); P = 0.20. CONCLUSIONS: Saquinavir hgc was associated with an inferior long-term clinical response relative to indinavir, which was consistent with the observed differences in virological and immunological responses.

Administration, Oral↗
PubMed2001

Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy.

BACKGROUND: Azodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity. OBJECTIVE: A first phase I/II clinical study of ADA. METHODS: ADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage. RESULTS: Fifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 x 10(6) cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10 copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P < 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10 copies/ml compared with baseline and 5/ 11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47-243%), and viral load decrease of 1.04 log10 copies/ml (range 0.52-1.23). CONCLUSIONS: The maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Antiretroviral treatments used among adults with HIV infection in Europe.

International guidelines for the treatment of human immunodeficiency virus (HIV) infection change rapidly. They are mainly based on results from large-scale randomized clinical trials, but also on hypotheses. The objective of the study was to look at the use of antiretrovirals (ARVs) in different HIV treatment centres in Europe. Between August 1996 and September 1997 self-administered anonymous questionnaires were distributed to persons with HIV infection at inpatient and outpatient departments in 11 European countries; 1,366 people completed the questionnaire. Important differences in use of ARVs were noted between different centres. Zidovudine was the drug that was used predominantly in all countries and by 77% of all patients; the use of didanosine, zalcitabine and stavudine differed widely. Use of ARVs was found to be lower for people who reported intravenous drug use (compared to homosexual transmission), people with a low education level, and those with a monthly income lower than 992 Euro. The use of a protease inhibitor containing ARV treatment regimen was significantly lower in the centres in the south of Europe. Between 1996 and 1997, many persons with HIV infection in Europe received a suboptimal ARV treatment regimen. Use of ARVs should be improved for intravenous drug users, persons with lower educational level and lower income.

Adolescent↗
PubMed2001

Variant human immunodeficiency virus type 1 proteases and response to combination therapy including a protease inhibitor.

The objective of this observational study was to assess the genetic variability in the human immunodeficiency virus (HIV) protease gene from HIV type 1 (HIV-1)-positive (clade B), protease inhibitor-naïve patients and to evaluate its association with the subsequent effectiveness of a protease inhibitor-containing triple-drug regimen. The protease gene was sequenced from plasma-derived virus from 116 protease inhibitor-naïve patients. The virological response to a triple-drug regimen containing indinavir, ritonavir, or saquinavir was evaluated every 3 months for as long as 2 years (n = 40). A total of 36 different amino acid substitutions compared to the reference sequence (HIV-1 HXB2) were detected. No substitutions at the active site similar to the primary resistance mutations were found. The most frequent substitutions (prevalence, >10%) at baseline were located at codons 15, 13, 12, 62, 36, 64, 41, 35, 3, 93, 77, 63, and 37 (in ascending order of frequency). The mean number of polymorphisms was 4.2. A relatively poorer response to therapy was associated with a high number of baseline polymorphisms and, to a lesser extent, with the presence of I93L at baseline in comparison with the wild-type virus. A71V/T was slightly associated with a poorer response to first-line ritonavir-based therapy. In summary, within clade B viruses, protease gene natural polymorphisms are common. There is evidence suggesting that treatment response is associated with this genetic background, but most of the specific contributors could not be firmly identified. I93L, occurring in about 30% of untreated patients, may play a role, as A71V/T possibly does in ritonavir-treated patients.

Adult↗
PubMed2001

Comparison of DNA sequencing and a line probe assay for detection of human immunodeficiency virus type 1 drug resistance mutations in patients failing highly active antiretroviral therapy.

The resistance of human immunodeficiency virus type 1 (HIV-1) to drugs is a major cause of antiretroviral treatment failure. We have compared direct sequencing to a line probe assay (LiPA) for the detection of drug resistance-related mutations in 197 clinical samples, and we have investigated the sequential appearance of mutations under drug pressure. For 26 patients with virological failure despite the use of two nucleoside analogues and one protease inhibitor (indinavir [n = 6], ritonavir [n = 10], and saquinavir [n = 10]), genotypic resistance assays were carried out retrospectively every 3 months for up to 2 years by using direct sequencing (TruGene; Visible Genetics) and a LiPA for detection of mutations in the reverse transcriptase (INNO-LiPA HIV-1 RT; Innogenetics) and the protease (INNO-LiPA HIV Protease, prototype version; Innogenetics) genes. Comparison of the results from both assays found rare major discrepancies (<1% of codons analyzed). INNO-LiPA detected more wild-type-mutant mixtures than sequencing but suffered from a high rate of codon hybridization failures for the reverse transcriptase. LiPA detected earlier and more frequently than sequencing the transient mixed virus population that contained I84V, which appears before V82A in the protease sequence. Mutations M461, G48V, and L90M were often transient and drug pressure related. In conclusion, direct sequencing and LiPAs give concordant results for most clinical isolates. LiPAs are more sensitive for the detection of mixed virus populations. Mutation I84V appears in minor populations in the early steps of the pathways of resistance to indinavir and ritonavir. The fact that some mutations can be found only transiently and in minor virus populations highlights the importance of a low detection limit for resistance assays.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Comparative estrogenicity of estradiol, ethynyl estradiol and diethylstilbestrol in an in vivo, male sheepshead minnow (Cyprinodon variegatus), vitellogenin bioassay.

An in vivo bioasssay for vitellogenin (VTG) synthesis was developed to screen individual chemicals or mixtures of chemicals for potentially estrogenic effects in a marine teleost model. An enzyme-linked immunosorbent assay (ELISA) was used to quantitate VTG synthesis in male sheepshead minnows (Cyprinodon variegatus) exposed to five concentrations of the natural estrogen (17beta-estradiol), a synthetic, steroidal pharmaceutical estrogen (17alpha-ethynyl estradiol), or a synthetic, non-steroidal, pharmaceutical estrogen (diethystilbestrol) for 16 days. At an exposure concentration of 20 ng/l, only diethystilbestrol elicited a vitellogenic response. At all test concentrations greater than 100 ng/l, VTG appeared in the plasma in a dose-dependent manner for the three estrogen treatments. Liver VTG mRNA measurements were also made, exhibiting no clear correlations between quantities, nor temporal appearance of the message and mature protein were apparent. This assay is short-term, relatively inexpensive, shows a direct response, and easily quantitated.

Journal Article↗
PubMed1998

Haptoglobin polymorphism, iron metabolism and mortality in HIV infection.

BACKGROUND: Three phenotypes of the antioxidant protein haptoglobin are known: Hp 1-1, Hp 2-1 and Hp 2-2. OBJECTIVES: To investigate the outcome of HIV infection according to haptoglobin type. DESIGN AND METHODS: Haptoglobin phenotypes were determined using starch gel electrophoresis in serum obtained from 653 HIV-infected Caucasians in the AIDS reference centers of Gent (n = 184), Antwerp (n = 309), and Luxembourg (n = 160). Survival was compared between haptoglobin types using Kaplan-Meier curves. Plasma HIV-1 RNA was quantified by reverse transcriptase PCR. Serum iron, transferrin saturation, ferritin, and vitamin C were assayed to evaluate iron-driven oxidative stress in 184 HIV-infected patients and 204 controls. RESULTS: The haptoglobin type distribution amongst the patients (17.6% Hp 1-1, 49.9% Hp 2-1, 32.5% Hp 2-2) corresponded to that of the controls. Kaplan-Meier curves showed a higher mortality for the Hp 2-2 group (P = 0.0001; adjusted mortality risk ratio, 1.78; 95% confidence interval, 1.25-2.54). Median survival time was 11.0 years (Hp 1-1 and Hp 2-1) versus 7.33 years (Hp 2-2). Plasma HIV-1 RNA levels prior to antiviral therapy and their increase over 1 year were highest in Hp 2-2 patients (P = 0.03 and 0.003, respectively). The Hp 2-2 type was associated with higher serum iron, transferrin saturation, and ferritin levels and with low vitamin C concentrations. Furthermore, ferritin concentrations were higher in HIV-infected patients than in controls (P < 0.0001). CONCLUSION: HIV-infected patients carrying the Hp 2-2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.

Adult↗
PubMed1996

Comparative pathogenesis of human WA1 and Babesia microti isolates in a Syrian hamster model.

The pathogenesis of a newly recognized, molecularly and antigenically distinct human babesial isolate (WA1) and Babesia microti, the common cause of human babesiosis in the United States, were compared in a Syrian hamster model. A group of 33 adult female hamsters were inoculated intraperitoneally with either WA1-infected, B. microti-infected, or uninfected hamster erythrocytes. All WA1-infected animals became parasitemic by postinoculation (PI) day 3 or 4 and were severely lethargic and dyspneic by PI days 6 to 10. Death often occurred spontaneously by PI day 10, with parasitemia of 12 to 90%. Hamsters inoculated with B. microti became parasitemic by PI day 7 and developed peak parasitemia (42 to 60%) by PI day 14 that subsequently decreased to low or undetectable values. Although the B. microti-infected hamsters developed severe anemia, they generally remained asymptomatic. Postmortem examination of WA1-infected hamsters revealed intravascular aggregates of large mononuclear inflammatory cells that occasionally occluded small to medium veins, pulmonary leukoclastic phlebitis, thrombosis, and multifocal coagulative necrosis in the heart, spleen, lung, and liver. No vascular lesions or areas of coagulative necrosis were detected in any B. microti-infected or control hamsters. The results of this study suggest that marked leukocytosis followed by acute necrotizing phlebitis resulting in disseminated intravascular coagulation, thromboembolism, and infarction may be central to the pathogenesis of WA1 infections.

Anemia↗
PubMed1995

Changes in survival over time after a first episode of Pneumocystis carinii pneumonia for European patients with acquired immunodeficiency syndrome. Multicentre Study Group on AIDS in Europe.

BACKGROUND: Factors associated with improved survival over time for patients with the acquired immunodeficiency syndrome (AIDS) who have Pneumocystis carinii pneumonia at diagnosis are not clearly defined. METHODS: An inception cohort of 2533 patients with AIDS, diagnosed from 1979 to 1989, from 52 centers in 17 European countries was studied. Survival 3 months and 3 years after diagnosis was estimated by Kaplan-Meier life tables. Independent predictors of survival were analyzed by construction of Cox proportional hazards models. RESULTS: Patients in whom AIDS and P carinii pneumonia had been diagnosed before 1988 had a poorer 3-month (ie, short-term) survival, whereas the survival 1 and 2 years after P carinii pneumonia was lower only for patients whose disease was diagnosed before 1987 compared with those with more recent diagnoses. Other variables associated with poorer outcome were greater age, infection via blood transfusion, diagnosis made in south Europe, and coexisting illnesses. After controlling for these prognostic markers in multivariate analysis, improvement in survival over time was still evident. For patients who survived the P carinii pneumonia episode, both zidovudine and secondary prophylaxis for P carinii pneumonia initiated around the time of diagnosis were associated with improved survival, and, after controlling for these treatment variables, no statistically significant improvement in survival over time was observed. CONCLUSIONS: Survival after an episode of P carinii pneumonia has improved within recent years. Increased awareness of early symptoms of P carinii pneumonia and better treatment of the pneumonia may have led to improvement in short-term survival over time, whereas the introduction of zidovudine and increased use of secondary P carinii pneumonia prophylaxis may have resulted in the recent increase in survival 1 and 2 years after the diagnosis. However, 3-year survival remained unchanged over time, implying that the underlying human immunodeficiency virus infection and other complications are not effectively controlled.

AIDS-Related Opportunistic Infections↗
PubMed1992

Prolonged clinically asymptomatic evolution after HIV-1 infection is marked by the absence of complement C4 null alleles at the MHC.

The length of time after which persons infected with HIV-1 progress to AIDS is variable. Certain alleles at the MHC have been shown to influence negatively the clinical outcome of HIV-1-infected persons and to be associated with special clinical manifestations. We investigated the MHC class I, class II and class III antigens in 54 Caucasian HIV-1-infected persons. The MHC profile of individuals with a prolonged period before AIDS is marked by a lower frequency of C4 null alleles.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Redirected targeting of LDL to human monocyte Fc gamma receptors with bispecific antibodies.

Recent studies indicate that low density lipoprotein (LDL)-immune complexes consisting of anti-LDL antibodies bound to LDL may contribute to macrophage foam cell development by uptake through immunoglobulin G (IgG) Fc receptors. As human mononuclear phagocytes possess three structurally and functionally distinct classes of IgG Fc receptors, we developed a system whereby the effects of LDL-immune complexes could be studied with respect to each type of IgG Fc receptor. Novel bispecific antibodies consisting of anti-Fc gamma receptor antibodies linked to anti-LDL antibodies were used to prepare bispecific LDL-immune complexes for targeting to specific Fc gamma receptors. In this report, the effects of bispecific LDL-immune complexes directed to Fc gamma receptor types I, II, and III were studied primarily with monocytes and were compared with the effects of similarly prepared bispecific complexes that targeted LDL to human leukocyte antigen (HLA) class I antigens. Each type of bispecific antibody was effective in targeting 125I-LDL to its respective site on the cell surface. Using fluorophore-labeled LDL and flow cytometry, bispecific complexes directed to Fc gamma receptor types I or II but not to HLA class I antigens caused a two- to sevenfold increase in cell-associated fluorescence relative to control cells treated with LDL in the absence of bispecific antibody. Uptake occurred in the presence of excess unlabeled LDL, acetylated LDL, and antioxidants. That the bispecific complexes triggered metabolic uptake was supported by studies of kinetics and temperature dependence. Using 125I-labeled complexes, metabolic degradation of LDL was demonstrated in association with each of the three types of Fc gamma receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗