Browsing by Author "Cahn, Pablo"

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    Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents
    (2009-09-24) Blanche, Stéphane; Bologna, Rosa; Cahn, Pablo; Rugina, Sorin; Flynn, Patricia; Fortuny, Claudia; Vis, Peter; Sekar, Vanitha; van Baelen, Ben; Dierynck, Inge; Spinosa-Guzman, Sabrina
    Objective: To assess pharmacokinetics, safety and efficacy of darunavir/ritonavir (DRV/r) and optimized background regimen in treatment-experienced patients (6–17 years). Design: Forty-eight-week, open-label, two-part, phase II study. Methods: In part I, 44 patients were randomized (1: 1 ratio) to receive a body weight-adjusted, adult-equivalent dose (group A) or a 20–33% higher DRV/r twice daily (b.i.d.) dose (group B). Pharmacokinetics, safety and efficacy were assessed following 2-week dosing (part I), which determined dosing for part II (evaluated 48-week safety and efficacy). Results: In part I, both groups met the protocol-specified criteria for pharmacokinetics and showed favorable tolerability and efficacy. The following body-weight doses were selected: DRV/r 375/50 mg b.i.d. (20–<30 kg), 450/60 mg b.i.d. (30–<40 kg) and 600/100 mg b.i.d. (≥40 kg); these gave an AUC24h, C0h and Cmax of 102, 114 and 112%, respectively, versus the corresponding mean adult pharmacokinetic parameter. In part II, 80 patients received DRV/r (median age: 14 years, mean baseline HIV-1 RNA: 4.64 log10copies/ml). One patient (1%) discontinued (treatment-unrelated grade 3 anxiety). An abnormal mean baseline triglyceride level was normalized at 48 weeks (P < 0.01). At week 48, 65% had at least 1.0 log10HIV-1 RNA reduction; 59 and 48% achieved HIV-1 RNA less than 400 and less than 50 copies/ml, respectively (time-to-loss-of-virologic response). Mean age-adjusted weight z-score increased by 0.2 (P = 0.003). Conclusion: In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population. Introduction
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    Pre-cART Immune Parameters in People Living With HIV Might Help Predict CD8+ T-Cell Characteristics, Inflammation Levels, and Reservoir Composition After Effective cART
    (2021-10-01) Salido, Jimena; Czernikier, Alejandro; Trifone, César; Polo, María Laura; Figueroa, María Inés; Urioste, Alejandra; Cahn, Pablo; Sued, Omar; Solomon, Horacio; Laufer, Natalia; Ghiglione, Yanina; Turk, Gabriela
    Background: Combined antiretroviral treatment (cART) for HIV infection is highly effective in controlling viral replication. However, it cannot achieve a sterilizing cure. Several strategies have been proposed to achieve a functional cure, some of them based on immune-mediated clearing of persistently infected cells. Here, we aimed at identifying factors related to CD8TC and CD4TC quality before cART initiation that associate with the persistence of CD8TC antiviral response after cART, inflammation levels, and the size of the viral reservoir. Methods: Samples from 25 persons living with HIV were obtained before and after (15 months) cART initiation. Phenotype and functionality of bulk and HIV-specific T cells were assayed by flow cytometry ex vivo or after expansion in pre-cART or post-cART samples, respectively. Cell-Associated (CA) HIV DNA (total and integrated) and RNA (unspliced [US] and multiple spliced [MS]) were quantitated by real-time PCR on post-cART samples. Post-cART plasma levels of CXCL10 (IP-10), soluble CD14 (sCD14) and soluble CD163 (sCD163) were measured by ELISA. Results: Pre-cART phenotype of CD8TCs and magnitude and phenotype of HIV-specific response correlated with the phenotype and functionality of CD8TCs post-cART. Moreover, the phenotype of the CD8TCs pre-cART correlated with markers of HIV persistence and inflammation post-cART. Finally, exhaustion and differentiation of CD4TCs pre-cART were associated with the composition of the HIV reservoir post-cART and the level of inflammation. Conclusions: Overall, this work provides data to help understand and identify parameters that could be used as markers in the development of immune-based functional HIV cure strategies.