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June 27, 2007 EUROPEAN JOURNAL OF MEDICAL RESEARCH 109 D.75 (Poster) 12h pharmacokinetic assessments of ART plasma concentrations in a cohort of HIV-positive pediatric patients Königs C. 1 , von Hentig N. 2 , Scheuplein M. 1 , Beuckmann K. 1 , Kurowski M. 3 , Funk M. 4 , Linde R. 1 , Kreuz W. 1 1 JW Goethe University, Department for Pediatrics, Hemostasis and Immundeficiency Treatment and Research Unit, Frankfurt, Germany, 2 JW Goethe University, Department for Pharmacology, Frankfurt, Germany, 3 HIV Lab, Berlin, Germany, 4 Paul-Ehrlich-Institut, Langen, Germany Therapeutic drug monitoring (TDM) is getting more and more common in modern antiretroviral therapy (ART). In pediatric patients, ART is often started in the first twelve months of life and probably a life-long therapy is needed. Very limited information on plasma concentration of antiretroviral substances in children is available. Early pharmacokinetic (PK) data from pediatric cohorts suggests the need for TDM in this population. In the Frankfurt pediatric cohort more than 60 pharmacokinetic analyses have been performed over a full dosing interval (i.e. 12 or 24 hrs). Patients were monitored following a standard protocol. PKs were performed after initiation of ART or change of regiment. Parents or patients documented ART intake three days prior to PK. On the PK day, blood was drawn in a fasting state, children had breakfast and took their medication according to recommendations in the out-patient unit. Serum samples were drawn at 1, 2, 3, 4, 6, 8 and12 hrs after intake (for once daily regiments also 24hrs). Additionally plasma concentrations of single time points were taken when patients had routine checks at the out-patient unit. All protease inhibitors and non-nucleoside reverse transcriptase inhibitors were examined. Results showed a great inter patient variability in plasma Cmin, Cmax and AUC for all antiretroviral substances tested. Most pediatric patients – especially very young children – had plasma levels below the range observed in an adult population. Only some of the patients, who were ten years and older, reached levels close to those seen in the adult populations. Some extremely high plasma concentrations were seen for some substances including EFV and LPV/r and correlated with side effects. In conclusion, TDM in a pediatric cohort under ART shows very different results to those seen in adults. Most observed plasma concentrations are much lower than in the adult population. Studies are needed to monitor plasma levels of antiretroviral drugs in children and to correlate the findings with clinical outcome. D.76 (Poster) Ritonavir (RTV) als häufigster Kombinationspartner der ART – Bedeutung des Therapeutischen Drug Monitorings (TDM) für eine individualisierte Therapie Bemman R. 1 , Threin A. 2 , Schirmer D. 1 , Leyh M. 1 , Winzer R. 1 , Heinz W. 1 , Guhl C. 1 , Schnaitmann E. 2 , Klinker H. 1 , Langmann P. 3 1 Medizinische Klinik und Poliklinik II der Universität Würzburg, Schwerpunkt Infekiologie, Würzburg, Germany, 2 Schwerpunktpraxis, Schwabstr. 57-59, Stuttgart, Germany, 3 Praxis für Gastroenterologie und Infektiologie, Karlstadt, Germany Hintergrund: RTV wird bei allen PI-basierten Therapien in einer Dosis von 100–200mg/d als „boost“ eingesetzt. Durch Hemmung des CYP-Systems ergibt die Kombination mit RTV jedoch häufig eine Vielzahl von Interaktionen innerhalb der ART und anderer Begleitmedikamente. Fragestellung: Anhand der Auswertung der RTV-Plasmaspiegel an einem größeren Patientenkollektiv sollte der Einfluss einer nicht-antiretroviralen Begleitmedikation, der Einfluss einer chronischen Lebererkrankung, das Auftreten von Nebenwirkungen, sowie die Varianz der RTV-Konzentrationen in unterschiedlichen PI-Kombinationen untersucht werden. Methodik: Von 321 Patienten wurden insgesamt 341 RTV- Plasmaspiegel mittels HPLC mit UV-Detektion gemessen. Die retrospektive Auswertung wurde anhand der Angaben auf dem Einsendebogen durchgeführt. Zur statistischen Analyse wurde der Mann Whitney Test herangezogen. Ergebnisse: Die RTV Plasmaspiegel nach einer Dosis von 0,1-0,6g/d lagen in Abhängigkeit vom Zeitintervall der Spiegelmessung nach der Medikamenten-einnahme bei 111ng/ml bis 6880ng/ml. Bei 3% der Patienten wurden 1 bis 4 Begleitmedikamente verabreicht. Bei Patienten mit einem Therapieversagen (n=40) waren die RTV-Plasmaspiegel mit 865±1156ng/ml nicht niedriger als bei den Patienten mit einem Therapieansprechen. Bei n=39 Patienten mit einer chronischen Lebererkrankung zeigten die RTV-Spiegel mit 946±1268ng/ml eine etwas größere Schwankungsbreite als bei Patienten ohne eine begleitende Lebererkrankung. Bei Vorliegen von Nebenwirkungen waren die RTV-Spiegel (489±415ng/ml) nicht erhöht. In der Kombination mit anderen PI waren RTV-Plasmaspiegel in der Kombination mit IDV (n=66) von 1209±1224ng/ml, mit APV (n=37) von 527±934ng/ml, mit ATV (n=72) von 383±395ng/ml und mit SQV (n=47) von 1551±2013ng/ml nachweisbar. Es zeigte sich eine deutliche Dosisabhängigkeit. Bei einer RTV Dosis von 0,1g/d lagen die RTV-Spiegel bei 111–688ng/ml, während die RTV-Talspiegel bei 0,2g/d im Bereich von 98–1209ng/ml schwankten. Diskussion: Die RTV Plasmaspiegel zeigen eine große Schwankungsbreite. Dabei ist eine Abhängigkeit von der verabreichten Dosis nachweisbar. Im Rahmen der individualisierten Therapie ist bei Verwendung einer nicht „fixen“ RTV-Kombination häufig unter TDM eine Anpassung der RTV-Dosierung möglich. D.77 (Poster) Safety of long-term Lopinavir plasma-levels in patients with liver dise Langmann P. 1 , Hubert C. 2 , Winzer R. 2 , Heinz W. 2 , Guhl C. 2 , Threin A. 3 , Schnaitmann E. 3 , Klinker H. 2 1 Praxis für Gastroenterologie und Infektiologie, Karlstadt, Germany, 2 Medizinische Klinik und Poliklinik II der Universität Würzburg, Schwerpunkt Infekiologie, Würzburg, Germany, 3 Schwerpunktpraxis, Schwabstr. 57-59, Stuttgart, Germany Objective: Chronic liver disease is often found in HIV infected patients. LPV as first choice protease inhibitor is often used over long time periods. Therapeutic Drug Monitoring (TDM) is an important tool in patient care but the knowledge of LPV-plasma-levels in patients with chronic liver disease remain uncertain. With this retrosepective analysis we investigated whether there are differences in LPV-plasma-levels between patients with and without chronic liver diseases over a long-time period.
110 EUROPEAN JOURNAL OF MEDICAL RESEARCH June 27, 2007 Methods: Over the time course, LPV-plasma-levels in consecutive patients with chronic liver disease (n=30) and consecutive patients without liver disease (n=38) were evaluated. LPV-plasma-levels were determined with a HPLC-based method. CD4-cell count and HI-viral load were also correlated with liver disease. Statistical analysis was done by multivariate analysis using the SPSS Software. Results: The LPV plasma-levels of n=450 samples from 30 patients with liver disease (Hepatitis B: n=17, Hepatitis C: n=16, Alcoholic liver disease: n=7) were determined over 18.7±16,3 months (1 - 48.5 months). A median of 10 samples per patient was eligible (2 - 50 samples). All patients received 400 mg LPV bid with various nuke-back-bones. There were no significant differences according to liver disease in LPVplasma levels (mean Ctrough without: 5.917±4.811 ng/ml, mean Ctrough with liver-disease: 6.564±4.517 ng/ml, p > 0.05). The intraindividual and interindividual variation of LPV-plasma levels, CD-4 increase, and HI-virus suppression in patients with and without liver disease were comparable. Conclusion: In this clinical setting no differences in LPVplasma levels between patients with and without chronic liver disease could be demonstrated. LPV-therapy in patients with chronic liver disease is safe. TDM is a helpful tool in patients with impaired liver function for dose adjustment. D.78 (Poster) A weight adapted nelfinavir (NFV) containing ART may decrease pill-burden Winzer R. 1 , Hillenbrand H. 2 , Galle P.R. 1 , Löhr H. 3 , Böcher W. 1 1 I. Medizinische Klinik der Universität Mainz, Mainz, Germany, 2 Schwerpunktpraxis, Berlin, Germany, 3 Praxis für Gastroenterologie, Wiesbaden, Germany Background: ART consisting of 2 NRTI + PI or NNRTI is standard today. Most antiretroviral drugs are dosed without consideration of individual patients weight. However, weight based dosing might reduce pill burden and increase treatment adherence, an important factor of treatment response.Thus, we compared a weight adapted NFV containing therapy (25mg/kg/d) with one with standard dosage (2500mg/d) in respect to pharmacokinetic, virological and immunological parameters. Method: In this prospective, open-label monocenter trial over 48 weeks, patients on stable NFV containing ART (>3months) were sex and weight-related randomised either to a weight adapted (group A: 25mg/kg/d, n=14) or standard dosage (group B: 2500mg/d, n=14) NFV containing ART in combination with 2 NRTIs. Pharmacokinetic examinations were carried out at baseline, week 4 and week 12, virological and immunological parameters were done every 3 months. Data were analysed with Kruskal-Wallis test. Results: In total, 28 patients (m/f: 17/11; average age: 43±9years) were randomised; 23 patients reached week 48 (one screening-failure, one lost to-follow up at week 24, one virological therapy failure at week 36, two study unrelated deaths after week 36). Even though both groups were well matched regarding their body-mass-index (A: 22.83 ± 4.09kg/m 2 , B: 23.95 ± 3.49kg/m 2 ) there were no significant differences concerning most pharmacokinetic parameters (Ctroughbaseline: 1540./.820ng/ml, p1- log-raise) week 48, B: one virological failure week 36) and immunological treatment responses (CD4-increaseweek48: 30./.56cells/; p = 1.0) did not differ between both groups, although the administered NFV dosages and pill burden were significantly reduced in treatment group A (A: 24.05 ± 2.12mg/kg/d, B: 36.16 ± 8.58mg/kg/d; p = 0.001). Summary: In this study, there were no significant differences in the treatment response to weight adapted (25mg/kg/d) or standard dosage (2500mg/d) NFV containing antiretroviral therapy. Thus, a reduction of pill burden and treatment adherence seems reasonable under the conditions of therapeutical drug monitoring. D.79 (Poster) Anticonvulsants in patients on antiretroviral therapy: Case report and literature review Thaler J. 1 , Emmelkamp J. 1 , Bode J. 1 , Oette M. 1 , Strzelczyk A. 2 1 Universitätsklinikum Düsseldorf, Hepatologie, Gastroenterologie und Infektiologie, Düsseldorf, Germany, 2 Universität Marburg, Neurologie, Marburg, Germany Objective: To give an overview on published literature on the use of anticonvulsants in patients on antiretroviral therapy and to provide recommendations on their concurrent use. Background: In patients with HIV infection seizures are a relatively common occurrence. Seizures may be a result of HIV infection of the CNS, a manifestation of an opportunistic infection or a result of mass lesions. As they are likely to recur in HIV-seropositive patients anticonvulsive treatment is generally advisable for a first seizure without a recognisable and reversible cause. For the clinicians caring for HIV-seropositive patients anticonvulsants and antiretrovirals impose therapeutic dilemmas as they may interact through multiple mechanisms including enhanced or inhibited liver metabolism, competition for protein binding and increased viral replication. Case report: A 40 year-old patient with HIV Infection presented with a first seizure due to a primary CNS lymphoma. As the patient was under HAART, carbamazepine could not be adminstered because of significant pharmacological interactions. As with use of valproic acid a seizure control could not be obtained, levetiracetam was introduced because of little or no known interaction with HAART but had to be removed because of a disabling tremor. Finally the introduction of lamotrigine was well tolerated and lead to seizure control. Methods: A systematic literature review was performed to identify literature on the concurrent use of anticonvulsants and antiretrovirals. Using a standardized assessment form, information was extracted from each publication and systematically reported. Results and conclusions: There is only limited data available regarding interactions for the use of anticonvulsants in patients on antiretroviral therapy resulting in an urgent need for controlled trials examining pharmacokinetic and pharmacodynamic interactions between anticonvulsants and antiretrovirals. Valproic acid and newer anticonvulsants including gabapentine, lamotrigine and levetiracetam may be considered of reasonable choice compared to first-generation agents. However, close monitoring for anticonvulsant-antiretroviral interactions is advisable because of the potential for toxicity, poor seizure control and incomplete viral suppression.
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