Publications by authors named "Antonio Poyato"

10 Publications

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High efficacy of resistance-guided retreatment of HCV patients failing NS5A inhibitors in the real world.

J Hepatol 2019 11 4;71(5):876-888. Epub 2019 Jul 4.

Clinical Microbiology Unit, University Hospital San Cecilio, Instituto de Investigacion Biosanitaria Ibs.Granada, Granada, Spain. Electronic address:

Background & Aims: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available.

Methods: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded.

Results: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin.

Conclusions: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited.

Lay Summary: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.
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http://dx.doi.org/10.1016/j.jhep.2019.06.022DOI Listing
November 2019

mTOR Expression in Liver Transplant Candidates with Hepatocellular Carcinoma: Impact on Histological Features and Tumour Recurrence.

Int J Mol Sci 2019 Jan 15;20(2). Epub 2019 Jan 15.

Department of Hepatology and Liver Transplantation, CIBERehd, Reina Sofía University Hospital, 14004 Córdoba, Spain.

(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including a cohort of HCC patients who underwent LT (2012⁻2015). MTOR pathway expression was evaluated in the explanted liver by using the "PathScan Intracellular Signalling Array Kit" (Cell Signalling). Kaplan-Meier and Cox regression analyses were performed to evaluate post-LT HCC recurrence. (3) Results: Forty-nine patients were included (average age 56.4 ± 6, 14.3% females). Phospho-mTOR (Ser2448) was over-expressed in peritumoral tissue as compared with tumoral tissue (ΔSignal 22.2%; < 0.001). The mTOR activators were also increased in peritumoral tissue (phospho-Akt (Thr308) ΔSignal 18.2%, = 0.004; phospho-AMPKa (Thr172) ΔSignal 56.3%, < 0.001), as they were the downstream effectors responsible for cell growth/survival (phospho-p70S6K (Thr389) ΔSignal 33.3%, < 0.001 and phospho-S6RP (Ser235/236) ΔSignal 54.6%, < 0.001). MTOR expression was increased in patients with multinodular HCC (tumoral = 0.01; peritumoral = 0.001). Increased phospho-mTOR in tumoral tissue was associated with higher HCC recurrence rates after LT (23.8% vs. 5.9% at 24 months, = 0.04). (4) Conclusion: mTOR pathway is over-expressed in patients with multinodular HCC and is it associated with increased post-LT tumour recurrence rates.
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http://dx.doi.org/10.3390/ijms20020336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359509PMC
January 2019

Analysis of spontaneous resolution of cytomegalovirus replication after transplantation in CMV-seropositive patients with pretransplant CD8+IFNG+ response.

Antiviral Res 2018 07 18;155:97-105. Epub 2018 May 18.

Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain(1).

This prospective study evaluates whether CMV-seropositive (R+) transplant patients with pretransplant CD8+IFNG+ T-cell response to cytomegalovirus (CMV) (CD8+IFNG+ response) can spontaneously clear the CMV viral load without requiring treatment. A total of 104 transplant patients (kidney/liver) with pretransplant CD8+IFNG+ response were evaluable. This response was determined using QuantiFERON-CMV assay. The incidence of CMV replication and disease was 45.2% (47/104) and 6.7% (7/104), respectively. Of the total patients, 77.9% (81/104) did not require antiviral treatment, either because they did not have CMV replication (n = 57) or because they had asymptomatic CMV replication that could be spontaneously cleared (n = 24). Both situations are likely related to the presence of CD8+IFNG+ response to CMV, which has a key role in controlling CMV infection. However, 22.1% of the patients (23/104) received antiviral treatment, although only 7 of them did so because they had symptomatic CMV replication. These patients developed symptoms in spite of having pretransplant CD8+IFNG+ response, thus suggesting that other immunological parameters might be involved, such as a dysfunctional CD4 response or that they might have become QFNon-reactive due to the immunosuppression. In conclusion, around 80% of R+ patients with pretransplant CD8+IFNG+ response to CMV did not require antiviral treatment, although this percentage might be underestimated. Nevertheless, other strategies such as performing an additional CD8+IFNG+ response determination at posttransplant time might provide more reliable information regarding the patients who will be able to spontaneously clear the viremia.
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http://dx.doi.org/10.1016/j.antiviral.2018.05.006DOI Listing
July 2018

Impact of Early Initiated Everolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Transplantation 2018 12;102(12):2056-2064

Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.

Background: Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation.

Methods: This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders.

Results: Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation.

Conclusion: Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.
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http://dx.doi.org/10.1097/TP.0000000000002270DOI Listing
December 2018

Incidental hepatocellular carcinoma after liver transplantation: Prevalence, histopathological features and prognostic impact.

PLoS One 2017 12;12(4):e0175010. Epub 2017 Apr 12.

Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Córdoba, Spain.

Background: Incidental hepatocellular carcinoma (iHCC) is a histological finding after liver transplantation (LT) which relevance has been scarcely studied.

Aims: to describe the histopathological features of iHCC and to determine its prognostic impact in terms of tumor recurrence and overall survival.

Methods: Observational study including 451 consecutive adult LT patients (2000-2013). Patients aged<18, retransplanted or with early postoperative death were excluded. Median follow-up after LT was 58 months. Multiple Cox's regression was used to assess the prognostic impact of iHCC on tumor recurrence and mortality while controlling for potential confounders.

Results: 141 patients had known HCC before LT (31.3%). Among the remaining 310 patients, the prevalence of iHCC was 8.7% (n = 27). In the explanted liver, 36.2% of patients with known HCC and 25.9% of patients with iHCC trespassed Milan criteria (p = 0.30). Patients with known and iHCC had similar rates of multinodular disease (50.4% vs 55.6%; p = 0.62), macrovascular invasion (6.5% vs 3.7%; p = 0.58), microvascular invasion (12.9% vs 14.8%; p = 0.76) and moderate-poor tumor differentiation (53.9% vs 70.4%; p = 0.09). In the multivariate analysis, iHCC and known HCC had identical recurrence-free survival after controlling for histological features (RR = 1.06, 95%CI 0.36-3.14; p = 0.90). Cumulative 5-year overall survival rates were similar between patients with known and iHCC (65% vs 52.8% respectively; log rank p = 0.44), but significantly inferior as compared with patients without HCC (77.8%) (p = 0.002 and p = 0.007 respectively). Indeed, in the overall cohort, iHCC was an independent predictor of mortality (RR = 3.02; 95%CI 1.62-5.65; p = 0.001).

Conclusion: The risk of tumor recurrence after LT is similar in patients with iHCC and known HCC. A close imaging surveillance is strongly recommended for patients awaiting LT in order to detect HCC prior to LT, thus allowing for an adequate selection of candidates, prioritization and indication of bridging therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175010PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389640PMC
April 2017

Everolimus is safe within the first month after liver transplantation.

Transpl Immunol 2015 Oct 24;33(2):146-51. Epub 2015 Sep 24.

Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC. CIBERehd, Córdoba, Spain. Electronic address:

Background & Aims: Sirolimus should not be started within the first month after liver transplantation (LT) because of an increased risk of adverse outcomes. The evidence regarding everolimus is lacking but the manufacturer transposed the same warning. We aimed to evaluate the safety of everolimus started within the first month after LT.

Methods: A consecutive cohort 187 LT patients (2009-2013) with a tacrolimus-based immunosuppression was evaluated. Patients starting everolimus within the first month after LT (n = 33; 17.6%) were compared with those starting everolimus thereafter (n = 25; 13.4%) or not receiving everolimus (n = 129; 69%). The median follow-up after LT was 21 months (IQR 7-36). Prospective outcomes were evaluated by using Kaplan-Meier curves and Cox's regression.

Results: The incidence of hepatic artery thrombosis was not significantly different in patients early treated with everolimus when compared with the remaining cohort (0% vs 9.1%; p = 0.12). Other vascular complications occurred in 9.1% of patients with early everolimus vs 7.3% in the remaining cohort (p = 0.72). No wound healing complications were detected with early everolimus. There were similar rates of incisional hernia (p = 0.31), infections (p = 0.15), renal impairment (p = 0.37), and histologically-proven acute rejection (p = 0.24) between groups. The rates of hyperlipidemia were increased with early everolimus (29.9% vs 16.5% at 3 years; p = 0.018). Graft loss and mortality rates were similar between groups (p = 0.34 and p = 0.94 respectively), after adjusting for possible confounding factors.

Conclusions: Everolimus combined with reduced tacrolimus proved to be safe within the first month after LT. Future trials may be allowed to implement everolimus early after LT.
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http://dx.doi.org/10.1016/j.trim.2015.09.002DOI Listing
October 2015

Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study.

Gastroenterol Hepatol 2014 Jan 17;37(1):1-8. Epub 2013 Dec 17.

Hospital Universitario Fundacion Alcorcon, Unit of Gastroenterology and Hepatology, Madrid, Spain.

Introduction: Less than half of patients with chronic hepatitis C genotype 3 (G3) and high viral load (HVL) without a rapid virological response (RVR) achieve a sustained virological response (SVR) when treated with peginterferon plus ribavirin (RBV).

Objectives: To assess the impact of high doses of RBV on SVR in patients with G3 and HVL.

Methods: Ninety-seven patients were randomized to receive peginterferon α-2a+RBV 800 mg/day (A; n=42) or peginterferon α-2a+RBV 1600 mg/day+epoetin β 400 IU/kg/week SC (B; n=55). Patients allocated to group B who achieved RVR continued on RBV (800mg/day) for a further 20 weeks (B1; n=42) while non-RVR patients received a higher dose of RBV (1600 mg/day)+epoetin β (B2; n=13).

Results: RVR was observed in 64.3% of patients in A and in 76.4% in B (p=0.259). Intention-to-treat (ITT) analysis showed SVR rates of 64.3% (A) and 61.8% (B), with a reduction of -2.5% (-21.8% to 16.9%) (p=0.835). The SVR rate was 61.9% in arm B1 and 61.5% in arm B2. No serious adverse events were reported, and the rate of moderate adverse events was < 5%.

Conclusions: G3 patients with high viral load without RVR did not obtain a benefit from a higher dose of RBV. Higher doses of RBV plus epoetin β were safe and well tolerated (Clin Trials Gov NCT00830609).
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http://dx.doi.org/10.1016/j.gastrohep.2013.10.005DOI Listing
January 2014

N-acetylcysteine, coenzyme Q10 and superoxide dismutase mimetic prevent mitochondrial cell dysfunction and cell death induced by d-galactosamine in primary culture of human hepatocytes.

Chem Biol Interact 2009 Sep 11;181(1):95-106. Epub 2009 Jun 11.

Liver Research Unit, Reina Sofía University Hospital, Córdoba, Spain.

D-Galactosamine (D-GalN) induces reactive oxygen species (ROS) generation and cell death in cultured hepatocytes. The aim of the study was to evaluate the cytoprotective properties of N-acetylcysteine (NAC), coenzyme Q(10) (Q(10)) and the superoxide dismutase (SOD) mimetic against the mitochondrial dysfunction and cell death in D-GalN-treated hepatocytes. Hepatocytes were isolated from liver resections. NAC (0.5 mM), Q(10) (30 microM) or MnTBAP (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (1mg/mL) were co-administered with D-GalN (40 mM) in hepatocytes. Cell death, oxidative stress, mitochondrial transmembrane potential (MTP), ATP, mitochondrial oxidized/reduced glutathione (GSH) and Q(10) ratios, electronic transport chain (ETC) activity, and nuclear- and mitochondria-encoded expression of complex I subunits were determined in hepatocytes. d-GalN induced a transient increase of mitochondrial hyperpolarization and oxidative stress, followed by an increase of oxidized/reduced GSH and Q(10) ratios, mitochondrial dysfunction and cell death in hepatocytes. The cytoprotective properties of NAC supplementation were related to a reduction of ROS generation and oxidized/reduced GSH and Q(10) ratios, and a recovery of mitochondrial complexes I+III and II+III activities and cellular ATP content. The co-administration of Q(10) or MnTBAP recovered oxidized/reduced GSH ratio, and reduced ROS generation, ETC dysfunction and cell death induced by D-GalN. The cytoprotective properties of studied antioxidants were related to an increase of the protein expression of nuclear- and mitochondrial-encoded subunits of complex I. In conclusion, the co-administration of NAC, Q(10) and MnTBAP enhanced the expression of complex I subunits, and reduced ROS production, oxidized/reduced GSH ratio, mitochondrial dysfunction and cell death induced by D-GalN in cultured hepatocytes.
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http://dx.doi.org/10.1016/j.cbi.2009.06.003DOI Listing
September 2009

Multiple lymphomatous polyposis of the GI tract: report of a case and review.

Gastrointest Endosc 2002 Oct;56(4):579-82

Department of Gastroenterology and Hepatology, Reina Sofia University Hospital, Córdoba, Spain.

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http://dx.doi.org/10.1016/s0016-5107(02)70453-7DOI Listing
October 2002