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Market uptake of pegylated interferons for the treatment of hepatitis C in Europe : meeting abstract
(2008)
Introduction and Objectives Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease with life threatening sequelae such as end-stage liver cirrhosis and liver cancer. It is estimated that the infection annually causes about 86,000 deaths, 1.2 million disability adjusted life years (DALYs), and ¼ of the liver transplants in the WHO European region. Presently, only antiviral drugs can prevent the progression to severe liver disease. Pegylated interferons combined with ribavirin are considered as current state-of-the-art treatment. Objective of this investigation was to assess the market uptake of these drugs across Europe in order to find out whether there is unequal access to optimised therapy. Material and Methods We used IMS launch and sales data (April 2000 to December 2005) for peginterferons and ribavirin for 21 countries of the WHO European region. Market uptake was investigated by comparing the development of country-specific sales rates. For market access analysis, we converted sales figures into numbers of treated patients and related those to country-specific hepatitis C prevalence. To convert sales figures into patient figures, the amount of active pharmaceutical ingredients (API) sold was divided by average total patient doses (ATPD), derived by a probability tree-based calculation algorithm accounting for genotype distribution, early stopping rules, body weight, unscheduled treatment stops and dose reductions Ntotal=APIPegIFNalpha-2a/ATPDPegIFNalpha-2a+APIPegIFN&alpha-2b/ATPDPegIFNalpha-2b For more concise result presentation the 21 included countries were aggregated into four categories: 1. EU founding members (1957): Belgium, France, Germany, Italy and Netherlands; 2. Countries joining EU before 2000: Austria (1995), Denmark (1973), Finland (1995), Greece (1981), Republic of Ireland (1973), Spain (1986), Sweden and UK (1973) 3. Countries joining EU after 2000: Czech Republic (2004), Hungary (2004), Poland (2004) and Romania (2007); 4. EU non-member states: Norway, Russia, Switzerland and Turkey. Results Market launch and market uptake of the investigated drugs differed considerably across countries. The earliest, most rapid and highest increases in sales rates were observed in the EU founding member states, followed by countries that joined the EU before 2000, countries that joined the EU after 2000, and EU non-member states. Most new EU member states showed a noticeable increase in sales after joining the EU. Market access analysis yielded that until end of 2005, about 308 000 patients were treated with peginterferon in the 21 countries. Treatment rates differed across Europe. The number of patients ever treated with peginterferon per 100 prevalent cases ranged from 16 in France to less than one in Romania, Poland, Greece and Russia. Discussion Peginterferon market uptake and prevalence adjusted treatment rates were found to vary considerably across 21 countries in the WHO European region suggesting unequal access to optimised therapy. Poor market access was especially common in low-resource countries. Besides budget restrictions, national surveillance and prevention policy should be considered as explanations for market access variation. Although our results allowed for the ranking of countries in order of market access, no final conclusions on over- or undertreatment can be drawn, because the number of patients who really require antiviral treatment is unknown. Further research based on pan-European decision models is recommended to determine the fraction of not yet successfully treated but treatable patients among those ever diagnosed with HCV. ...
Purpose of the study: There is a clinical need for antiretroviral therapy (ART) regimens that simplify dosing and make adherence easier for specific patient groups such as former intravenous drug users (IVDU) receiving opiate substitution. Availability of tenofovir DF (TDF) and other once-daily (OD) agents could offer a viable OD regimen. The 3OD study was designed to evaluate the use of OD HAART in IVDU patients.
Methods: 3OD was a single-arm, multicentre, 48-weeks trial to assess efficacy, tolerability and adherence to a OD TDF-containing HAART regimen in former IVDU patients receiving opiate substitution. Of 67 patients enrolled, 27 were antiretroviral treatment naïve, 10 were virologically suppressed (<400 copies/mL), and 30 were re-starting HAART without prior virological failure. Opiate substitution was adjusted according to subject symptoms of opiate overdosing or withdrawal. Various methods were used to assess adherence: besides pill count, patients were asked to fill in a MASRI (Medication Adherence Self-Report Inventory) questionnaire and an electronic log pad diary. Calculation of adherence by pill count assumed that unreturned pills had been taken by the subjects.
Summary of results: Overall, 55% (n = 37, ITT, M = F) of patients had viral load <400 copies/mL at week 48. Using an ITT, M = E analysis, 90% (37/41) of patients reached undetectable VL (<400 copies/mL), 56% (23/41 patients) had plasma HIV-1 RNA concentrations <50 copies/mL at week 48. Only 30 patients (45%) completed the full study and the follow-up period. In 51% of patients, TDF adherence was >100% using pill count. MASRI showed adherence rates of 80–100% in 83–85% of patients; however, 15 patients never entered any data. Diary data were entered by 57 patients; diary data were entered for fewer days than patients received treatment (mean difference 113 days, calculated from treatment start and stop dates).
Conclusion: TDF in combination with other OD antiretrovirals in former IVDU patients showed comparable efficacy to that seen in the average HIV-1 infected population. However, measurement of adherence to self-administered HAART via pill count, MASRI or diary may be misleading in this population.
It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and beta-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-µm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.
Background: In Germany, 17% of 59,000 persons living with HIV/AIDS are female. Accordingly, the research focus in clinical studies as well as in cohort analyses has been almost exclusively on HIV-positive men. As a consequence, there is an urgent need to characterize and evaluate the outcome of HAART in HIV-positive women and to identify special requirements of this particular patient population.
Methods: Cross-sectional multicentre (n = 31 centres) evaluation to observe characteristics of 1,557 HIV-positive women receiving medical care in Germany between June 2007 and March 2008. Data acquisition was performed using standardized questionnaires.
Summary of results: Of 1,557 HIV-positive women studied, 1,191 (77%) received HAART. Mean age was 40 years and average time of known HIV-infection was 9 years. Risk of HIV transmission was: 40% heterosexual intercourse in Germany, 36% heterosexual intercourse in a high prevalence country; 17% IDU; 7% other reasons for transmission. 46% of the women had a migration background. Mean time on antiretroviral treatment was 7 years. 53% of the female participants had been treated with >2 HAART-regimens. 47% of the study subjects received a PI-based regimen, 33% a NNRTI-based regimen; 20% were on other combinations. The most commonly used PI and NNRTI were lopinavir/r and nevirapine, respectively. Only 48% of all women under HAART achieved a viral load <40 copies/ml. There was a significant difference between the PI-treated group with 44% patients <40 copies/ml and the NNRTI-treated group with 56% <40 copies/ml (p = 0.003).
Conclusion: We found that HIV-positive women depicted an inferior virological response to HAART compared to those previously published in German cohort analyses dominated by men (response rates >75%). Possible differences in adherence or drug resistance may have impacted these results and are currently being evaluated in ongoing sub-analyses. Of note, the lack of a study arm with male patients is a limitation of this investigation. However, this is partly off-set by the fact that there are good comparative data in the male population found in other cohorts. We conclude that our results are in discordance to the popular assumption that there are no gender specific differences in virological treatment outcome of HAART.
In 1911 Eugen Bleuler (Bleuler, 1911) postulated that schizophrenia was a disorder resulting from inability to properly integrate mental processes. Around the same time, Carl Wernicke (Wernicke, 1894) proposed that psychosis might result from disruption of white matter tracts. Both of these statements can be considered early cornerstones of modern connectivity hypotheses developed towards the end of the twentieth century by such researchers as Karl Friston (1998) and Nancy Andreansen (1998). In the current work, the hypothesis that schizophrenia, rather than being a disorder or either anatomical or functional connectivity, is a disorder where both of these processes interact and influence the clinical presentation of patients, is examined. This is achieved through a detailed examination of a sample of chronic schizophrenia patients using a combination of functional and anatomical Magnetic Resonance Imaging techniques. The relationship of these measures to clinical symptoms is also explored. In the first study, anatomical connectivity at the whole-brain level is examined using Diffusion Tensor Imaging. The results of the study contribute to the previous literature on auditory hallucinations in schizophrenia and provide the first direct correlation between increased anatomical connectivity and increased severity of psychotic symptoms. The second study provides a thorough examination of the interhemispheric connectivity. This is achieved through a detailed examination of the corpus callosum using a combination of diffusivity and volumetric values. This is the first study to date where several anatomical methods are used in one sample. The results illustrate the importance of using different techniques to accurately characterize anatomical abnormalities observed in schizophrenia. In addition, contrary to previous research reports, the results of the current study imply that only specific sub-sections of the corpus callosum are affected by anatomical abnormalities. The pattern of these changes may influence clinical presentation of patients. Finally, functional connectivity at the whole-brain level is examined during resting-state using Independent Component Analysis. Similarly to the results of the anatomical examinations, it provides further supporting evidence that the pattern of disturbances observed in the current sample of schizophrenia patients examined herein reflects a combination of hypo- and hyperconnectivity. Moreover, the study further validates resting-state functional Magnetic Resonance Imaging as a reliable tool for examining functional abnormalities in schizophrenia.
Background This study was carried out to compare the HRQoL of patients in general practice with differing chronic diseases with the HRQoL of patients without chronic conditions, to evaluate the HRQoL of general practice patients in Germany compared with the HRQoL of the general population, and to explore the influence of different chronic diseases on patients HRQoL, independently of the effects of multiple confounding variables. Methods A cross-sectional questionnaire survey including the SF-36, the EQ-5D and demographic questions was conducted in 20 general practices in Germany. 1009 consecutive patients aged 15–89 participated. The SF-36 scale scores of general practice patients with differing chronic diseases were compared with those of patients without chronic conditions. Differences in the SF-36 scale/summary scores and proportions in the EQ-5D dimensions between patients and the general population were analyzed. Independent effects of chronic conditions and demographic variables on the HRQoL were analyzed using multivariable linear regression and polynomial regression models. Results The HRQoL for general practice patients with differing chronic diseases tended to show more physical than mental health impairments compared with the reference group of patients without. Patients in general practice in Germany had considerably lower SF-36 scores than the general population (P < 0.001 for all) and showed significantly higher proportions of problems in all EQ-5D dimensions except for the self-care dimension (P < 0.001 for all). The mean EQ VAS for general practice patients was lower than that for the general population (69.2 versus 77.4, P < 0.001). The HRQoL for general practice patients in Germany seemed to be more strongly affected by diseases like depression, back pain, OA of the knee, and cancer than by hypertension and diabetes. Conclusion General practice patients with differing chronic diseases in Germany had impaired quality of life, especially in terms of physical health. The independent impacts on the HRQoL were different depending on the type of chronic disease. Findings from this study might help health professionals to concern more influential diseases in primary care from the patient´s perspective.
The impact of European integration on the German system of pharmaceutical product authorization
(2008)
The European Union has evolved since 1965 into an influential political player in the regulation of pharmaceutical safety standards. The objective of establishing a single European market for pharmaceuticals makes it necessary for member-states to adopt uniform safety standards and marketing authorization procedures. This article investigates the impact of the European integration process on the German marketing authorization system for pharmaceuticals. The analysis shows that the main focal points and objectives of European regulation of pharmaceutical safety have shifted since 1965. The initial phase saw the introduction of uniform European safety standards as a result of which Germany was obliged to undertake “catch-up” modernization. From the mid-1970s, these standards were extended and specified in greater detail. Since the mid-1990s, a process of reorientation has been under way. The formation of the European Agency for the Evaluation of Medicinal Products (EMEA) and the growing importance of the European authorization procedure, combined with intensified global competition on pharmaceutical markets, are exerting indirect pressure for EU member-states to adjust their medicines policies. Consequently, over the past few years Germany has been engaged in a competition-oriented reorganization of its pharmaceutical product authorization system the outcome of which will be to give higher priority to economic interests.
Objectives To examine the dose-response relationship between cumulative exposure to kneeling and squatting as well as to lifting and carrying of loads and symptomatic knee osteoarthritis (OA) in a population-based case-control study. Methods In five orthopedic clinics and five practices we recruited 295 male patients aged 25 to 70 with radiographically confirmed knee osteoarthritis associated with chronic complaints. A total of 327 male control subjects were recruited. Data were gathered in a structured personal interview. To calculate cumulative exposure, the self-reported duration of kneeling and squatting as well as the duration of lifting and carrying of loads were summed up over the entire working life. Results The results of our study support a dose-response relationship between kneeling/squatting and symptomatic knee osteoarthritis. For a cumulative exposure to kneeling and squatting > 10.800 hours, the risk of having radiographically confirmed knee osteoarthritis as measured by the odds ratio (adjusted for age, region, weight, jogging/athletics, and lifting or carrying of loads) is 2.4 (95% CI 1.1-5.0) compared to unexposed subjects. Lifting and carrying of loads is significantly associated with knee osteoarthritis independent of kneeling or similar activities. Conclusions As the knee osteoarthritis risk is strongly elevated in occupations that involve both kneeling/squatting and heavy lifting/carrying, preventive efforts should particularly focus on these "high-risk occupations".
Infliximab is a monoclonal antibody directed against TNF-alpha. It has been approved for use in rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis and plaque-type psoriasis. In case reports, positive effects on pustular variants of psoriasis have also been reported. However, paradoxically, manifestation of pustular psoriasis and plaque-type psoriasis has been reported in patients treated with TNF antagonists including infliximab for other indications. Here, we report on 5 patients with chronic plaque-type psoriasis who developed palmoplantar pustulosis during or after discontinuation of infliximab therapy. In two of the five cases, manifestation of palmoplantar pustulosis was not accompanied by worsening of plaque-type psoriasis. Possibly, site-specific factors or a differential contribution of immunological processes modulated by TNF inhibitors to palmoplantar pustulosis and plaque-type psoriasis may have played a role.
Background Brain-computer interface methodology based on self-regulation of slow-cortical potentials (SCPs) of the EEG (electroencephalogram) was used to assess conditional associative learning in one severely paralyzed, late-stage ALS patient. After having been taught arbitrary stimulus relations, he was evaluated for formation of equivalence classes among the trained stimuli. Methods A monitor presented visual information in two targets. The method of teaching was matching to sample. Three types of stimuli were presented: signs (A), colored disks (B), and geometrical shapes (C). The sample was one type, and the choice was between two stimuli from another type. The patient used his SCP to steer a cursor to one of the targets. A smiley was presented as a reward when he hit the correct target. The patient was taught A-B and B-C (sample – comparison) matching with three stimuli of each type. Tests for stimulus equivalence involved the untaught B-A, C-B, A-C, and C-A relations. An additional test was discrimination between all three stimuli of one equivalence class presented together versus three unrelated stimuli. The patient also had sessions with identity matching using the same stimuli. Results The patient showed high accuracy, close to 100%, on identity matching and could therefore discriminate the stimuli and control the cursor correctly. Acquisition of A-B matching took 11 sessions (of 70 trials each) and had to be broken into simpler units before he could learn it. Acquisition of B-C matching took two sessions. The patient passed all equivalence class tests at 90% or higher. Conclusion The patient may have had a deficit in acquisition of the first conditional association of signs and colored disks. In contrast, the patient showed clear evidence that A-B and B-C training had resulted in formation of equivalence classes. The brain-computer interface technology combined with the matching to sample method is a useful way to assess various cognitive abilities of severely paralyzed patients, who are without reliable motor control.