Browsing by Author "Figueroa, MI"

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    Dual therapy (ritonavir boosted atazanavir+raltegravir) versus standard triple therapy (ritonavir boosted atazanavir+tenofovir/emtricitabine) in patients failing first line therapy: 48 week results from a randomized pilot study
    (2018-08) Sued, Omar; Figueroa, MI; Cesar, Carina; Patterson, Patricia; Yamamoto, C; Fink, N; Gun, Ana; Cahn, Pedro
    Background: Dual therapy has emerged as a novel concept in treatment optimization in naive and supressed HIV patients. This study aimed at exploring virological response, safety and inflammation markers of a nucleoside-sparing dual regimen consisting of ATV/r + RAL (DT) vs standard therapy of ATV/r + TDF/FTC (TT) among patients failing first NNRTI-containing treatment. Methods & Materials: Randomized open label pilot study. Primary outcome measures were proportion of subjects with plasma HIV-1 RNA below the limit of detection (<50 copies/uL) and proportion of subjects discontinuing due to adverse events (AEs) during the first 48 weeks. ClinicalTrials.gov Identifier: NCT01829802. Results: Out of 57 patients screened, 34 were randomized to receive: DT (n: 18) or TT (n: 16). At baseline 80% males, 50% MSM, median age 38 years, CDC stage C:35%, Median pVL: 3.9 Log10, CD4: 289 cells/uL. At week 48, data from 32 participants (2 did not reach week 48 yet) showed virological response in 69% (n: 11/16) of participants receiving DT and 88% (n: 14/16) receiving TT by FDA snapshot analysis (p = NS) and 73% (DT) and 93% (TT) by per-protocol analysis (p = NS). CD4 cell count median change from baseline to week 48 was +119 and + 52 cell/uL in DT and TT, respectively. No deaths were recorded. Three SAEs occurred in 2 participants (pneumonia and stroke and, Belĺs paralysis), none related to study drugs. Eight Grade 2, probably drug-related AEs were observed: 1 in DT (gastrointestinal) and 7 in TT (5 gastrointestinal, 1 renal stone and 1 rash). Hyperbilirubinemia Grade 2/3 was seen in 77% in DT and 94% in TT, none requiring stopping ART. Two participants were discontinued due to loss of follow-up, one in each arm. Five participants had virological failure at W48, 4 in DT and 1 in TT, all with low pVL (52-589 copies/uL). One participant developed integrase resistance mutation and suppressed later on TT. Conclusion: ATV/r+RAL as second-line therapy showed a trend to more frequent virological failure, compared to TT, although the study was unpowered to prove this difference. No major differences were seen in tolerance or toxicity.
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    Functionality of CD8+ T-cells in subjects under cART: implications on cure strategies
    (2018-08) Salido, J; Ruiz, Maria; Trifone, C; Figueroa, MI; Caruso, MP; Gherardi, MM; Sued, Omar; Horacio, S; Natalia, L; Ghiglione, Y; Turk, Gabriela
    Background: Reaching HIV cure will largely depend on the capacity of HIV-specific memory CD8+ T-cells (CD8TC) to eliminate the viral reservoir. However, CD8TC response is limited in subjects on cART. Here, we aimed to investigate the phenotype and function of in vitro expanded CD8TCs in HIV+ subjects and the impact of ART initiation timing on these parameters. Methods & Materials: PBMCs from 28 HIV+ subjects on cART for 1 year were obtained. Twelve initiated treatment during chronic infection (Delayed Treatment, DT) and 16 within four months post-infection (Early Treatment, ET). PBMCs were stimulated with peptides spanning Nef and Gag plus IL-2 during 14 days. ELISPOT (pre and post-expansion) and Flow Cytometry (FC, post-expansion) were performed to assess expanded CD8TC function (CD107a/b, IFN-g, IL-2, MIP-1b and TNF-a) and phenotype (CD45RO, CCR7, CD95 and PD1). Data was analyzed using non-parametric statistics. Results: Magnitude of ELISPOT responses increased after expansion by 103 times (p < 0.002), in both groups, being this effect more pronounced in CD8TCs, compared to CD4TCs (p < 0.0001), as confirmed by FC. Cells showed higher avidity after stimulation (evidenced by greater spot sizes, p < 0.002). DT subjects displayed a broader response to HIV than ET, after expansion. ET group had a significantly higher proportion of monofunctional degranulating CD8TCs (CD107a/b+), when challenged against Gag peptides (p = 0.037) compared to DT. Contrary, DT group showed higher polyfunctionality (p = 0.009). In both groups, CD4TC responses were of lesser magnitude compared to CD8TCs and predominantly monofunctional. Bulk and HIV-specific CD8TC phenotype varied significantly between groups: ET subjects showed a preservation of stem and central memory cells while DT showed a fully-differentiated profile (p < 0.005). When analyzing memory distribution within PD1+CD8+ cells, terminal effector were the most frequent subpopulation in DT and effector memory cells in ET individuals; evidencing a differential cell exhaustion profile in both groups. Conclusion: We demonstrated that HIV-specific CD8TCs could be selectively stimulated and expanded in subjects under ART. We also showed that ART initiation timing has an impact on phenotype and function of CD8TCs, reflecting consequences of longer antigen persistence on immune function. Overall, results presented in this work have important implications for the development of cure strategies aim at boosting CD8TC responses.
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    Phenotype and functionality of CD8+ T cells before and after cART are related to the viral reservoir size in people living with HIV-1
    (2019) Czernikier, A; Salido, J; Trifone, C; Figueroa, MI; Salomon, Horacio; Cahn, Pedro; Sued, Omar; Laufer, N; Ghiglione, Y; Trifone, C
    Background: the persistence of latently infected t-cells remains the major obstacle to cure HIV. special emphasis has been placed to identify the characteristics of cD8+ t-cells (cD8tcs) associated with viral control. We aimed to determine the relationship between the quality of the immune response before and after antiretroviral treatment (cart) and HIV persistence on cart. Methods: 18 subjects were enrolled during acute/early HIV infection (median 2 month post-infection). blood samples were obtained at enrollment (baseline sample, pre-cart) and after 18 months post-art (on-cart). Phenotypic (cD45ro, ccr7, cD95, PD-1) and functional (cD107, cytokines) markers were studied on bulk and HIV-specific cD8tcs by flow cytometry, in both samples. cell- associated HIV DNa forms (total and integrated) were quantitated by real-time Pcr in samples on-cart. Data was analyzed using non-parametric statistics. Results: spearman’s correlations showed that higher HIV-integrated DNa levels on samples on-cart were related to lower expression of baseline cD107+ cD8tcs and lower proportion of HIV-specific terminal effector (te) cD8tcs (p=0,003 and p=0,049). Moreover, total HIV DNa levels post-cart directly correlated with baseline HIV-specific PD-1+cD8tcs. HIV-integrated DNa levels positively correlated with the percent- age of PD-1+cD8tcs (p< 0,0001), and inversely with the per- centage of bi- and trifunctional cD8tcs (p=0,024 and p=0,048) at on-cart samples. Moreover, direct correlations between the percentage of effector memory cD8tcs at: bulk, HIV-specific, and PD-1+ compartments and the levels of HIV-integrated DNa were observed (p= 0,005, p=0,0003 and p=0,004). similarly, HIV-integrated DNa inversely correlated with the proportion of cD8tc te in the same three compartments (p=0,016, p=0,0003 and p=0,007). Finally, negative correlations between HIV- integrated DNa levels and the percentage of naïve and stem cell memory cD8tcs (r=-0,561, p=0,002; r=-0,398, p=0,044) were found. Conclusions: Different immune parameters evaluated pre- and post-cart were related to HIV persistence. overall, results suggest that an exhausted and dysfunctional HIV-specific immune response, both before and after treatment initiation, was related to a higher reservoir size at 18 months post-cart. this should be considered when designing functional cure approaches. also, the potential use of these parameters as markers of reservoir size and/or remission should be studied.
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    The effect of protease inhibitor-based dual antiretroviral regimens on CD4/CD8 ratio during the first year of therapy in ART-naïve patients with HIV-infection
    (2020-12-17) Figueroa, MI; Camiro-Zuñiga, A; Belaunzaran-Zamudio, PF; Sierra Madero, J; Andrade Villanueva, J; Arribas, JR; Lama, JR; Cecchini, DM; Lopardo, G; Crabtree-Ramírez, B; Gun, Ana; Patterson, Patricia; VI, Fink; Sued, Omar; Cahn, Pedro
    Objectives To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. Methods We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio > 1 at 48 weeks after ART initiation in both treatment arms using the Mann–Whitney U-test and the χ2 test. We performed subgroup analysis for patients > 50 years old, with baseline CD4 counts ≤ 200 cells/μL, viral load > 100 000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. Results We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P = 0.729) or in the proportion of patients with CD4/CD8 ratio > 1 (17.9% vs. 19.3%, P = 0.678) 48 weeks after ART initiation. Subgroup analysis showed no further differences. Conclusion The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.