Biomedical subjects

Muriel Vray

Publications and source records attributed to Muriel Vray.

15 recordsLinked to original sources

PubMed2006

Molecular epidemiology of hepatitis B virus in Dakar, Sénégal.

Using DNA chip technology and real-time quantitative PCR, molecular profile of HBV strains infecting blood donors and patients in Dakar, Sénégal was studied. All HBsAg-positive blood donors (n = 175) and all patients who presented with chronic hepatitis B (n = 29) between 1st June 2003 and 31st July 2003 were studied. One patient, a blood donor, was coinfected by HCV, and nine patients had anti-HDV antibodies. Few persons in either group were HBeAg-positive. Viral load values were relatively low but correlated with biochemical abnormalities. Patients were infected mainly by genotype E (72%). Patients infected by genotype A (28%) tended to be younger than other patients. There was no significant difference between the blood donors and the patients with hepatitis B as regards virological markers, including viral load, when the HBV genotype was taken into account. The BCP A1762T and G1764A mutations were found in four patients and one patient, respectively; the two mutations were never found in the same patient. The W28* mutation at position 1896 of the core was detected in 19 of the 32 genotyped patients, 18 (83%) of whom had genotype E infection. ALT levels were not influenced by HBV mutations. This study shows a low frequency of clinical signs in HBsAg-positive blood donors, a relatively low level of viral replication, and a high frequency of pre-core mutants in this West African population. These results underline the importance of molecular characterization of HBV infection as specific treatments become available in this region.

Adult↗

PubMed2006

Identification of hepatitis B virus subgenotype A3 in rural Gabon.

An hepatitis B virus (HBV) molecular survey was conducted in five remote villages in the equatorial forest in Gabon, Central Africa. Two hundred seventy out of 311 inhabitants (86.8%) were HBV-infected or had evidence of past HBV infection. Chronic hepatitis corresponding to hepatitis B surface antigen (HBsAg) positivity was suspected in 27 (8.6%) of the HBV-infected subjects. High HBV viral loads were detected mainly in children aged 4-7 years. The pre-S/S domains were sequenced in 13 cases and 12 strains belonged to HBV-A genotype. In one case we found evidence for recombination between genotypes A and E. Phylogenetic analysis revealed that Gabonese HBV strains were distinct from HBV-A subgenotypes (A1 and A2). These new HBV strains from Gabon clustered with previously reported HBV-A3 subgenotype strains from Cameroon and Democratic Republic of Congo. The analysis of the pre-S2 domain allowed us to determine two amino acid substitutions (N/152/S and N/174/T) specific to the Central African HBV-A3 subgenotype strains and one amino acid substitution (P/155/Q) unique to these new Gabonese HBV-A3 subgenotype isolates. Two full genome sequences of two new Gabonese HBV isolates are also presented and confirm the distinctive HBV-Gab-A3 cluster.

Adolescent↗

PubMed2006

Virological responses to atazanavir-ritonavir-based regimens: resistance-substitutions score and pharmacokinetic parameters (Reyaphar study).

OBJECTIVE: To assess the impact of baseline HIV-1 substitutions, individual pharmacokinetic (PK) parameters (Cmin, Cmax, area under the curve [AUC0-->24 h]) and genotype-inhibitory quotient (GIQ) on virological responses (VR) to atazanavir-ritonavir (300 mg/100 mg)-based highly active antiretroviral therapy (HAART) in 71 antiretroviral-experienced, atazanavir-naive patients in virological failure (VF) on HAART. METHODOLOGY: VR was defined as HIV RNA <1.7 log10 copies/ml at week 12 (W12). A clinically relevant genotype-substitutions score for atazanavir-ritonavir was developed and validated (Reyaphar substitutions score). Previously published substitutions scores were also tested. RESULTS: Patients had a median (Q1; O3) of 6 (3; 8) previous treatment lines during 9 (7; 11) years. Baseline (WO) values were as follows: 262 (187; 435) CD4+/microl, 3.9 (2.6; 4.9) log10 HIV-1 RNA copies/ml, 4 (2; 6) protease substitutions and 3 (1; 4) NRTI-related substitutions. Respective steady-state Cmin, Cmax and AUC0-->24 h were 300 (200; 700) ng/ml, 620 (430; 750) ng/ml and 78,000 (61,000; 94,000) ng.h/ml. At W12, 49% of the patients had VR with a median decrease of -1.2 (-0.5; -2.3) log10 HIV-1 RNA copies/ml. The Reyaphar score included 12 baseline protease substitutions from the International AIDS Society USA list that were associated with poorer VR: L10I/F/R/V, K20I/M/R, L241, M461/L, 154L/M/T/V, L63P, A71I/L/V/T, G73A/C/F/T, V771, V82A/F/S/T, 184V, L90M and the polymorphism substitution Q58E. Comparing <5 versus > or =5 Reyaphar substitutions, the W12-W0 HIV-1 RNA decrease was - 1.4 (-0.7; -2.3) versus -0.5 (-1.2; +0.5) log10 copies/ml (P=0.009) with VR in 63% versus 110% (P<10(-4)), respectively. This score predicted VF at W12 with 46% sensitivity, compared to 33% and 28% for the ANRS 2004 and 2005 scores. PK parameters alone were not associated with VR, but GIQ was associated with virological outcome (P=0.04). 150L, known to be correlated with atazanavir-specific resistance, emerged in 2 (8%) of the 24 failing patients with paired genotypes at WO and VF. CONCLUSIONS: These findings highlight the need to cross-validate genotype-based algorithms to interpret substitution impact on virological outcome using different patient databases before their implementation in routine clinical practice.

Adult↗

PubMed2005

Plasma virion reverse transcriptase activity and heat dissociation-boosted p24 assay for HIV load in Burkina Faso, West Africa.

BACKGROUND: In resource-limited settings, the requirement for inexpensive, easy-to-perform viral load monitoring has increased with greater antiretroviral drug availability. OBJECTIVES: To evaluate feasibility, in Burkina Faso, of a simple assay for plasma HIV reverse transcriptase (RT) activity quantification compared to heat dissociation-boosted (HDB) p24 antigen and RNA-based quantifications in plasma samples from HIV-infected patients. METHODS: : Plasma viraemia was quantified by RT activity, HDB-p24 and RNA copies in 84 samples from 70 HIV-1 group M-infected patients (82% non-B subtype, 93% treatment naive), including serial samples from nine patients. RESULTS: RT activity detected 86% of plasma samples containing measurable RNA copies; corresponding to 0, 93 and 100% of samples with 1.7-4.0 log(10), 4.1-4.8 log(10) and 4.9-6.7 log(10) RNA copies/ml, respectively. HDB-p24 detected 77% of plasma samples containing measurable RNA copies; corresponding to 27, 80 and 86% of samples with 1.7-4.0 log(10), 4.1-4.8 log(10) and 4.9-6.7 log(10) RNA copies/ml, respectively. Measurement error based on one-way analysis of variance between RT activity and HDB-p24 values with RNA copies showed good agreement with RT activity (ME, <10%), however poorer agreement was obtained with HDB-p24 values (ME, >10%). Patient follow up showed a similar pattern of viraemia with RNA and RT activity assays. CONCLUSION: Field trials in Burkina Faso support the practical use of plasma RT activity assay as an affordable alternative for HIV viral load determination in regions where RNA detection remains difficult to perform. HDB-p24 use requires further evaluation before being considered as an alternative method in African HIV-infected patient follow up.

Burkina Faso↗

PubMed2005

Therapeutic immunization with a human immunodeficiency virus (HIV) type 1-recombinant canarypox vaccine in chronically HIV-infected patients: The Vacciter Study (ANRS 094).

This open single-arm study evaluated whether the administration of an HIV-recombinant canarypox vaccine (vCP1433) in highly active antiretroviral therapy (HAART)-treated patients chronically infected with HIV was safe, immunogenic and associated with prolongation of treatment discontinuation: 48 patients received four monthly vCP1433 injections and stopped HAART. Immunization was safe. HIV-p24-specific lymphoproliferative responses (LPR), significantly increased in the whole group after two injections but decreased thereafter, HIV-gag-specific CD8 T cells were boosted in 55% patients tested. Altogether, 11% patients with at least one HIV-specific LPR during immunization remained off therapy after 44 weeks of interruption. Detection of such LPR response at the time of treatment interruption was significantly associated with the probability of remaining off therapy. These results provide rationale for future randomized trials exploring this strategy.

AIDS Vaccines↗

PubMed2003

Clinically relevant interpretation of genotype for resistance to abacavir.

OBJECTIVE: To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir. METHODS: All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with a P value < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method. RESULTS: In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was -1.64 log(10) copies/ml while it was -0.69 log(10) and -0.19 log(10) in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score. CONCLUSIONS: We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.

Algorithms↗

PubMed2003

Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal.

OBJECTIVES: To study the effectiveness, adherence and tolerance of a once-a-day highly active antiretroviral therapy regimen in adults in Senegal. DESIGN AND METHODS: In a prospective, open-label one-arm study, 40 treatment-naive HIV-1-infected patients took the following three drugs once a day at bedtime: didanosine, lamivudine and efavirenz. The primary endpoint was the percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months. The analysis was done on an intent-to treat basis. RESULTS: Eighty-five per cent of patients were at Centers for Disease Control and Prevention stage B or C and the plasma HIV RNA level was 5.4 +/- 0.4 log(10) copies/ml at baseline. The percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months was 95% [95% confidence interval (CI), 83-99]. The proportions of patients with plasma HIV-1 RNA below 50 copies/ml at months 3, 6, 9, 12 and 15 were 26% (n = 39; 95% CI, 12-39), 78% (n = 40; 95% CI, 65-90), 70% (n = 40; 95% CI, 56-84), 77% (n = 39; 95% CI, 64-90) and 69% (n = 39; 95% CI, 55-84), respectively. The CD4 cell count was 164 +/- 75 x 106/l at baseline and increased by a mean of 199 +/- 101 x 106/l at month 15. Permanent treatment discontinuation was never necessary for serious adverse effects. Adherence was excellent, as shown by plasma drug concentrations and according to the results of the questionnaire. CONCLUSIONS: The once-daily regimen of didanosine, lamivudine and efavirenz was safe, easy-to-take and demonstrated strong antiretroviral and immunologic effects in African patients with advanced HIV infection.

Adult↗

PubMed2003

Assessing the severity of migraine: development of the MIGSEV scale.

OBJECTIVES: To identify items that serve to assess the severity of migraine with a high level of clinical and psychometric relevance and to combine these into a unitary severity scale. BACKGROUND: Severity of migraine is an important determinant of patient quality of life and of health care resource utilization. Despite this, no validated method exists for measuring migraine severity. METHODS: After selection from the medical literature items of potential relevance to the severity of migraine, consensus meetings led to a choice of items which subsequently were refined further on the basis of patient interviews. The psychometric properties of those items then were assessed in a survey involving 287 migraineurs. The methods used to test reliability and validity included test-retest, calculation of Cronbach alpha coefficient, analysis of factorial structure using principal components analysis, a comparison of the agreement between doctors' and patients' assessments, and correlation with a validated quality-of-life questionnaire. The most pertinent items revealed by the factorial analysis were combined in a unitary scale. RESULTS: Seven items reflecting severity were identified by expert consensus. These were intensity of pain, tolerability, disability in daily activities, presence of nausea or vomiting, resistance to treatment, duration of attacks, and frequency of attacks. Principal components analysis identified 3 dimensions accounting for 65% of the overall variance related to intensity of attacks, resistance to treatment, and frequency of attacks. The internal consistency and the reproducibility of the items appeared quite satisfactory, and variations in these items were correlated with quality-of-life scores. The 4 items related to intensity of attacks were combined into a single scale with 3 response modalities. CONCLUSIONS: The 3 dimensions identified by this investigation appeared medically relevant and to have good psychometric properties. The items on the intensity dimension can be used to generate a simple scale for assessing migraine attack severity.

Adult↗

PubMed2003

Predictors of the virological response to a change in the antiretroviral treatment regimen in HIV-1-infected patients enrolled in a randomized trial comparing genotyping, phenotyping and standard of care (Narval trial, ANRS 088).

OBJECTIVE: To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed. METHODS: The Narval trial was designed to compare phenotyping, genotyping and standard of care for the choice of antiretroviral therapy in patients in whom a protease inhibitor (PI)-containing regimen had failed. Virological success was defined as viral load below 200 copies/ml at week 12. Baseline variables including demographic, clinical and biological characteristics, HIV reverse transcriptase and protease mutations, the randomization arm, the drugs prescribed, as well as adherence to treatment and plasma concentrations of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) at week 12 were tested in the model. Variables that were significantly associated with virological success in univariate analysis were included in a logistic regression model. RESULTS: Five-hundred-and-forty-one patients were randomized. Virological success at week 12 was obtained in 200 patients. In multivariate analysis, the following factors were significantly associated with virological success: prescription of efavirenz to NNRTI-naive patients (OR=4.37; 95% CI: 2.76-6.90), randomization to the genotyping arm (OR=2.13, 1.20-3.79), prescription of lamivudine (OR=1.69, 1.01-2.83) and prescription of abacavir to abacavir-naive patients (OR=1.66, 1.02-2.72). Factors significantly associated with virological failure were prescription of nelfinavir (OR=0.30, 0.13-0.68), a high baseline viral load (OR=0.37, 0.28-0.50), the presence of at least five PI mutations (OR=0.42, 0.26-0.66), the presence of at least three thymidine analogue mutations (OR=0.61, 0.39-0.97) and at least 30 months of prior PI exposure (OR=0.64, 0.41-0.99). CONCLUSIONS: These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response. Genotyping was found to be beneficial, while this was not the case for phenotyping. This work was presented at the XI International HIV Drug Resistance Workshop, Sevilla, Spain, July 3-6 2002 (Abstract N(o)133); and at the XIV International Conference on AIDS, Barcelona, Spain, July 7-11 2002 (Abstract N(o)ThOrB138).

Adult↗

PubMed2002

Extended venous thromboembolism prophylaxis after total hip replacement: a comparison of low-molecular-weight heparin with oral anticoagulant.

BACKGROUND: Oral anticoagulants and low-molecular-weight heparin are both recommended for venous thromboembolism prophylaxis after total hip replacement. To date, these regimens have not been compared by means of clinical end points in the extended prophylaxis setting. METHODS: We randomly assigned 1279 patients 3 days after total hip replacement surgery to fixed-dose subcutaneous low-molecular-weight heparin (reviparin sodium, 4200 anti-Xa IU) or adjusted-dose oral anticoagulant (international normalized ratio, 2-3; acenocoumarol) for a 6-week period. The primary end point was the failure rate, defined as the combined clinical events of a confirmed symptomatic thromboembolic event, a major hemorrhage, or death. All patients were followed up throughout the study interval. The primary objective was to compare the observed cumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group. RESULTS: In the intent-to-treat population, objectively documented symptomatic thromboembolic events occurred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.30; 95% confidence interval for the difference, -0.8% to 2.8%). Major bleeding occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.001). The failure rate was 24 (3.7%) of 643 patients compared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants (P =.001). CONCLUSIONS: A significantly higher benefit-risk ratio was observed for patients undergoing elective hip replacement who received extended out-of-hospital prophylaxis with low-molecular-weight heparin vs acenocoumarol. Low-molecular-weight heparin prophylaxis was at least as effective as oral anticoagulants, but with a marked improvement in safety.

Acenocoumarol↗

PubMed2002

Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial.

OBJECTIVE: To assess the respective value of phenotype versus genotype versus standard of care for choosing antiretroviral therapy in patients failing protease inhibitor-containing regimens. METHODS: Patients with plasma HIV-1 RNA exceeding 1000 copies/ml were randomly allocated to phenotyping, genotyping, or standard of care. RESULTS: Five-hundred and forty-one patients were randomized, 190 to phenotyping, 192 to genotyping and 159 to standard of care. The baseline median CD4 cell count (280 x 106 cells/l), the plasma HIV-1 RNA level (4.3 log10 copies/ml), and the number of drugs previously received (n = 6) were similar in the three arms. More patients in the standard-of-care arm received at least three new drugs (55% versus 20% in the other arms; P < 0.001) and a regimen containing drugs from the three different classes. Plasma HIV-1 RNA was < 200 copies/ml at week 12 in 35% of patients in the phenotyping arm, 44% in the genotyping arm and 36% in the standard-of-care arm (phenotyping versus standard of care, P = 0.918; genotyping versus standard of care, P = 0.120). In a secondary analysis of 179 patients experiencing a first protease inhibitor failure, the percentage of patients achieving HIV-1 RNA < 200 copies/ml was significantly higher in the genotyping arm (65%) than in the phenotyping (45%) and the standard-of-care arms (45%) (genotyping versus standard of care, P = 0.022). CONCLUSIONS: Overall, resistance assays did not demonstrate benefit over standard of care. In patients with the most limited protease inhibitor experience, a significant benefit was observed in the genotyping arm.

Anti-HIV Agents↗

PubMedDate not supplied

Methodology for small clinical trials.

Small clinical trials are trials in which the number of patients does not enable the objective of the study to be appropriately met with the usual methodological rules. This situation is common in the case of rare diseases, in paediatrics, in certain cancer pathologies or when the number of patients exposed to the treatment needs to be limited. The principal methodological problems are initially identified, and the classical methods (controlled, randomised, double-blind trial using parallel groups, crossover trial, factorial design, trial performed with several measures repeated over time, add-on design, randomised withdrawal design or early-escape design) and more uncommon methods (sequential approaches, meta-analyses, the 'N of 1' method and other methods that facilitate decision making or modelling) are then discussed. Subsequently, recommendations are made to ensure that the results obtained are not a matter of chance, and to increase the level of proof.

Clinical Trials as Topic↗

PubMedDate not supplied

[Methodology and quality control in EPIGRAM, a pharmacoepidemiological study of obesity in general practice].

The EPIGRAM pharmacoepidemiological study was conducted in general practitioners prescribing orlistat (Xenical) in order to describe, under real clinical conditions, the management of obese or overweight patients. A 1-year follow-up of a patient cohort treated with orlistat was also conducted. Quality criteria specific to the study were defined to ensure the scientific validity of the results; these criteria mainly involved the following items: independent scientific committee, sampling investigator's recruitment, study organisation and quality control of the collected data. On-site control visits of a sample of 13% of participating GPs revealed that 75% of the controlled data were documented in a source file of which 85% were consistent with the source data. Only 1% of the 130 000 controlled data (data were controlled only on visits for which information was available) gave rise to correction requests. Of the patients treated with orlistat on inclusion, 17% were lost to follow-up by their GP and 25% were contacted directly at the end of the study.

Adult↗

PubMedDate not supplied

[Results from the observational study EPIGRAM: management of excess weight in general practice and follow-up of patients treated with orlistat].

The EPIGRAM pharmacoepidemiological study was conducted in general practitioners (GPs) prescribing orlistat (Xenical) in order to describe, under real clinical conditions, the management of obese or overweight patients, as well as a 1-year follow-up of a patient cohort treated with orlistat. A total of 714 GPs participated in this study and recruited a total of 6801 patients. Forty percent were treated with orlistat, 76% were women and 63% presented with a comorbidity. With a mean body mass index of 33.1+/-5.1 kg/m2, 85% of the patients treated with orlistat were in agreement with the indications of this drug. Comparison of patients treated and not treated with orlistat did not allow identification of any key factor able to predict prescription of the treatment. Patients treated with orlistat on inclusion and reviewed at least once by their doctor were followed up for an average of 11 months and a maximum of 23 months. Between 64% and 77% of patients stopped treatment with orlistat during the follow-up period. The treatment cost was the main reason for definitive treatment discontinuation for more than 50% of the patients. The average weight loss was 5% and 9% after 3 and 12 months of treatment, respectively.

Adolescent↗

PubMedDate not supplied

The respective roles of controlled clinical trials and cohort monitoring studies in the pre- and postmarketing assessment of drugs.

The respective roles of controlled clinical trials and observational studies (cohort or case-control studies) in evaluating the efficacy, safety and usefulness of a drug were analysed. A randomised, controlled, double-blind study is the best method of estimating the efficacy of a treatment. It provides the least biased and most robust estimate of the causal relationship. In certain situations and on the basis of certain criteria, observational studies can have a proof-of-efficacy value. Randomised, controlled, pre- and postmarketing authorisation (MA) clinical studies identify the rarer adverse effects and compare them with those resulting from the reference treatment. Before the MA, the pooled safety data from different controlled trials can provide an estimation of relatively frequent adverse events and subjects at risk. However, an observational study is the most appropriate method of evaluating the safety of a drug in the currently used conditions. By definition, a drug influences the health of a population if it directly or indirectly improves its health. A drug would have a major role in public health if it reduced mortality or morbidity related to a particular disease or if it improved the quality of life of patients with this disease. Prior to marketing a product, modelling is the approach of choice to quantify the expected effect. Pragmatic, postmarketing trials and observational studies are the reference methods used to define the population affected, the efficacy and safety of the drug in a real situation and its usefulness for public health. In conclusion, randomised clinical trials remain the reference approach for evaluating efficacy, while observational studies have a confirmatory value. Observational studies are the most appropriate way of evaluating safety in the currently used conditions, as the clinical trial has limited indications. In the interests of public health, modelling is the pre-marketing approach of choice, while pragmatic trials and observational studies are the postmarketing reference approaches.

Cohort Studies↗