Browsing by Author "Clumeck, Nathan"

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    Pharmacokinetics of Two Randomized Trials Evaluating the Safety and Efficacy of Indinavir, Saquinavir and Lopinavir in Combination with Low-Dose Ritonavir: The MaxCmin1 and 2 Trials
    (2007-08-10) Justesen, Ulrik S; Fox, Zoe; Pedersen, Court; Cahn, Pedro; Gerstoft, Jan; Clumeck, Nathan; Losso, Marcello; Peters, Barry; Obel, Niels; Castagna, Antonella; Dragsted, Ulrik B; Lundgren, Jens D; n behalf of the MaxCmin1 and 2 trial groups
    Abstract: Our objective was to identify possible differences in protease inhibitor plasma concentrations between and within three protease inhibitor regimens (indinavir, saquinavir and lopinavir all in combination with low-dose ritonavir) and to relate these differences to safety and efficacy. Data originated from pre-defined pharmacokinetic substudies within two randomized 48-week trials evaluating the safety and efficacy of three protease inhibitor regimens. At weeks 4 and 48, plasma was collected and minimum drug plasma concentrations, Cmin, were obtained. Out of 656 randomized patients, 283 patients had available Cmin at week 4. Indinavir, saquinavir and lopinavir Cmin were high when combined with low-dose ritonavir. No significant difference in the proportion of patients experiencing treatment failure could be found according to the Cmin within any treatment arm. A saquinavir Cmin > 2000 ng/ml was associated with an increased risk of gastrointestinal grade 3 or 4 adverse events and higher total cholesterol. Overall, there were no changes in Cmin from week 4 to week 48 in patients who remained on therapy. No association between treatment failure and the Cmin could be demonstrated. Associations between high Cmin and toxicity were identified in the saquinavir arm; therefore, dose reductions may be appropriate in certain patients with Cmin several times above the minimum effective concentration.
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    Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1–Infected Patients: The MaxCmin1 Trial
    (2003-09-01) Dragsted, Ulrik Bak; Gerstoft, Jan; Pedersen, Court; Peters, Barry; Duran, Adriana; Obel, Niels; Castagna, Antonella; Cahn, Pedro; Clumeck, Nathan; Bruun, Johan N; Benetucci, Jorge; Hill, Andrew; Cassetti, Isabel; Vernazza, Pietro; Youle, Mike; Fox, Zoe; MaxCmin1 Trial Group
    This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1–infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied
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    Ritonavir-Boosted Tipranavir Demonstrates Superior Efficacy to Ritonavir-Boosted Protease Inhibitors in Treatment-Experienced HIV-Infected Patients: 24-Week Results of the RESIST-2 Trial
    (2006-11-15) Cahn, Pedro; Villacian, Jorge; Lazzarin, Adriano; Katlama, Christine; Grinsztejn, Beatriz; Arasteh, Keikawus; López, Paulo; Clumeck, Nathan; Gerstoft, Jan; Stavrianeas, Nikolas; Moreno, Santiago; Antunes, Francisco; Neubacher, Dietmar; Mayers, Douglas
    Background. Tipranavir, a novel protease inhibitor, has demonstrated antiviral activity against protease inhibitor—resistant human immunodeficiency virus type 1 (HIV-1) isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-2) trial is an ongoing, open-label, phase III trial comparing ritonavir-boosted tipranavir (TPV/r) plus an optimized background regimen with an individually optimized, ritonavir-boosted protease inhibitor in treatment-experienced, HIV-1-infected patients. Methods. Patients at 171 sites in Europe and Latin America who had received ⩾2 previous protease inhibitor regimens, had triple-antiretroviral class experience, had an HIV-1 RNA level ⩾1000 copies/mL, and had genotypically demonstrated primary protease inhibitor resistance were eligible. After genotypic resistance tests were performed, a protease inhibitor and optimized background regimen were selected before randomization. Patients were randomized to receive either TPV/r or comparator protease inhibitor—ritonavir (CPI/r) and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed HIV-1 load reduction ⩾1 log10 less than the baseline value without a treatment change at week 24. Results. A total of 863 patients were randomized and treated. At baseline, the mean HIV-1 load was 4.73 log10 copies/mL, and the mean CD4+ cell count was 218 cells/mm3. The preplanned 24-week efficacy analyses of 539 patients demonstrated treatment response rates of 41% in the TPV/r arm and 14.9% in the CPI/r arm (intent-to-treat analysis; P < .0001). The mean CD4+ cell count increased by 51 cells/mm3 in the TPV/r arm and by 18 cells/mm3 in the CPI/r arm. The most common adverse events were mild-to-moderate diarrhea, nausea, and headache. Grade 3 or greater elevations in serum transaminase, cholesterol, and triglyceride levels were more frequent in the TPV/r arm. Conclusions. TPV/r had superior antiviral activity and increased immunologic benefits, compared with CPI/r, at week 24 among treatment-experienced patients infected with multidrug-resistant HIV-1.