Muriel Vray

Modelling in Ecomomic Evaluation: An Unavoidable Fact of Life

The role of modelling in economic evaluation is explored by discussing, with examples, the uses of models. The expanded use of pragmatic clinical trials as an alternative to models is discussed. Some suggestions for good modelling practice are made.

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 × 106cells/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.

Evaluation of the Roche Cobas TaqMan and Abbott RealTime extraction-quantification systems for HIV-1 subtypes.

Objectives:We conducted a comparison of the Abbott Molecular RealTime (Rungis, France) and Roche Diagnostics Cobas Taqman (Meylan, France) automated nucleic acid extraction and real-time polymerase chain reaction (PCR) amplification systems for their capacity to quantify HIV RNA of various subtypes. The systems were tested on culture supernatants belonging to HIV-1 group M (n = 29), HIV-1 group O (n = 8), and HIV-2 (n = 7). We also tested 88 plasma samples from patients infected with HIV-1 group M (B-D [n = 7], A-CRF01 [n = 16], CRF02 [n = 49], and other strains [n = 16]). Results:The Abbott RealTime system quantified all 29 HIV-1 group M supernatants. One of these samples was not detected by the Roche Cobas TaqMan system. The Abbott RealTime system quantified 7 HIV-1 group O strains. Neither technique cross-reacted with HIV-2. The 79% intraclass correlation coefficient for the 88 plasma samples was barely acceptable, but 4 plasma samples were underestimated by more than 1 log by the Roche Cobas TaqMan system. Similar values were obtained for subtype B and D strains with the tests, indicating that the primers and probes are suitable for these strains. In contrast, the large differences observed with other subtypes, particularly CRF02, show the importance of primer and probe selection. Conclusion:The limitation of real-time PCR to span the entire diversity of HIV must be taken into account during treatment monitoring, resistance studies, and clinical trials.

Comparative RNA Quantification of HIV-1 Group M and Non-M With the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 v2.0 and Abbott Real-Time HIV-1 PCR Assays

Background: A new version of the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 assay (CA/CTM v2.0) has been introduced to overcome the underquantification observed with the first version. Methods: We compared the Roche Cobas CA/CTM v2.0 and Abbott RealTime HIV-1 assays for HIV-1 group M and non-M viral load measurement. Results: We found a good correlation (r = 0.96) between the 2 techniques for the 260 HIV-1 group M plasma samples tested. The Roche Cobas assay gave significantly higher values than the Abbott assay, and 51 samples (20%) yielded differences greater than 0.5 log10 copies per milliliter. Conversely, 2 samples were more than 0.5 log10 copies per milliliter higher with the Abbott assay than with the Roche Cobas assay. Among the 84 samples with undetectable viral load in the Abbott assay (detection limit 40 copies/mL), 17 (20%) were detectable with the CA/CTM v2.0 assay (detection limit 20 copies/mL), with values ranging from 41 to 897 copies per milliliter. Extrapolation of the Abbott curves led to 10/17 (59%) of these samples being quantifiable. HIV-1 groups O and P were similarly quantified by the two techniques. Conclusion: The results of the Roche Cobas CA/CTM v2.0 and Abbott RealTime HIV-1 assays correlate well. The new version of the CA/CTM assay shows improved sensitivity. Nevertheless, the 2 assays differ by more than 0.5 log10 copies per milliliter for some samples.

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.

Assessment of Migraine Severity Using the Migsev Scale: Relationship to Migraine Features and Quality of Life

We have recently developed an instrument to describe and categorize severity of migraine attacks from patient self-report, the MIGSEV questionnaire. We have now performed a large prospective survey using this tool to evaluate migraine severity in 2979 patients consulting for headache in France, included by 1164 general practitioners, 174 neurologists and 82 gynaecologists. The objective of the study was to determine the prevalence of severity grades in a large population who consults for migraine, to test the concordance between severity calculated from physician-derived and patient-derived data, and to test the relevance of the concept of severity as applied to diagnosis, other measures of the burden of migraine, and to health-related quality of life. Severe attacks were reported in around one-fifth of the sample. Physician- and patient-derived data provided concordant estimates of severity in 71% of cases, the discordant cases representing principally an underestimate by the physician of headache severity. Migraine severity was associated with frequent, long-lasting and treatment-resistant attacks, and with poor quality of life. The MIGSEV questionnaire is proposed as a simple measure of severity for the diagnosis and management of migraineurs, suitable for use both by physicians and patients.

Clinical features and etiology of pneumonia in acid-fast bacillus sputum smear-negative HIV-infected patients hospitalized in Asia and Africa.

Objectives:To determine the main causes of acid-fast bacillus sputum smear-negative pneumonia in Asian and African HIV-infected patients Design and setting:A prospective multicenter study (ANRS 1260) of consecutive hospitalized patients in tertiary hospitals in Phnom Penh, Ho Chi Minh City, Bangui and Dakar. Intervention:Use of the same clinical, radiological and biological methods at the four sites; regular quality controls of participating laboratories; final review of medical records by experts. Similar criteria used to establish diagnoses. Results:In all 462 patients were enrolled, 291 in Asia and 171 in Africa. The median CD4 cell count was 25 cells/μl. Radiological opacities were diffuse in 42% of patients and localized in 45%. Fiberoptic bronchoscopy was performed in 354 patients, at similar rates in the four sites. A definite and/or probable diagnosis was obtained in 375 patients (81%). Pneumocystis jiroveci pneumonia, bacterial pneumonia, AFB sputum smear-negative tuberculosis and other infections (fungi, parasites, atypical mycobacteria) were diagnosed in respectively 47, 30, 17 and 12% of Asian patients and 3, 48, 26 and 5% of African patients. Conclusion:In South-east Asia, acid-fast bacillus smear-negative pneumonia is caused by a wide variety of pathogens. When possible, fiberoptic bronchoscopy must be performed rapidly if clinical data are not highly suggestive of bacterial pneumonia, Pneumocystis jiroveci pneumonia or tuberculosis. In contrast, in Africa, bacterial pneumonia and tuberculosis are responsible for the large majority of cases. Fiberoptic bronchoscopy should be restricted to patients with clinical and/or radiological findings not suggestive of bacterial pneumonia or tuberculosis, antibiotic failure, and three consecutive negative sputum smears.

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 log10, 4.1–4.8 log10 and 4.9–6.7 log10 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 log10, 4.1–4.8 log10 and 4.9–6.7 log10 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.

Hepatitis B virus exposure during childhood in Cameroon, Central African Republic and Senegal after the integration of HBV vaccine in the expanded program on immunization.

Background: More than 2 billion people worldwide have been exposed to hepatitis B virus (HBV). To prevent these infections, Senegal and Cameroon integrated the HBV vaccine into their Expanded Program on Immunization (EPI) in 2005, as did the Central African Republic (CAR) in 2008. We evaluated the prevalence of HBV exposure and infection after the integration of the HBV vaccine in the EPI. Methods: An observational cross-sectional study was conducted among the hospitalized children 3 months to 6 years of age in Cameroon, CAR and Senegal. Plasma was collected for the detection of anti-HBc, anti-HBs and hepatitis B surface antigen in children with anti-HBc and anti-HBs. Results: Between April 2009 and May 2010, 1783 children were enrolled, 19.4% of whom were anti-HBc positive. The percentage of children with anti-HBc was 44.4% among the children younger than 6 months, decreasing after 6 months to reach 18.8% at 12 months. This decline was followed by a rapid increase in anti-HBc positivity rate in CAR observed as early as 12 months of age compared with Cameroon and Senegal, where the anti-HBc increased between 18 and 36 months of age, respectively. The prevalence of hepatitis B surface antigen–positive children was significantly higher in CAR than that in Cameroon and Senegal (5.1% versus 0.7% and 0.2%; P < 0.001). Socioeconomic level, age and country were factors associated with the presence of anti-HBc. Conclusions: Passive transfer of anti-HBc maternal antibodies versus HBV exposure could be differentiated as early as 12 months of age. The low prevalence of anti-HBc and hepatitis B surface antigen among children born after the integration of HBV vaccine in the EPI in Cameroon and Senegal suggests a positive impact of HBV vaccination.