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Papers by manuel crespo

Journal of Antimicrobial Chemotherapy, 2021

Background Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular... more Background Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known. Methods Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient’s characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multi...

AIDS Research and Therapy, 2020

Background The aim of this study was to investigate the effectiveness and tolerability of the com... more Background The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014–2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL)

Journal of Clinical Medicine, 2020

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual ... more HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients ≥ 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA < 50 copies/mL for ≥6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver® Care and OWLiver® tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4+ count 740 cells/mm3, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reduct...

Cells, 2018

Background: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the le... more Background: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4+ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. Methods: We performed a cross-sectional study on 238 HIV/HCV-coinfected patients (119 had <12.5 kPa, 73 had 12.5–25 kPa, and 46 had >25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4+ Tregs (p < 0.001), memory Tregs (p ≤ 0.001), and plasma cytokine levels [IFN-γ (p ≤ 0.05) and IL-10 (p ≤ 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced ...

Mucosal immunology, Jan 31, 2018

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but ... more Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in...

mBio, Jul 11, 2017

Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" ... more Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" in HIV-infected individuals. However, important technical limitations have precluded the characterization of this specific viral reservoir during both treated and untreated HIV-1 infections. Here, we used a novel single-cell RNA fluorescence in situ hybridization-flow cytometry (FISH-flow) assay that requires only 15 million unfractionated peripheral blood mononuclear cells (PBMCs) to characterize the specific cell subpopulations that transcribe HIV RNA in different subsets of CD4(+) T cells. In samples from treated and untreated HIV-infected patients, effector memory CD4(+) T cells were the main cell population supporting HIV RNA transcription. The number of cells expressing HIV correlated with the plasma viral load, intracellular HIV RNA, and proviral DNA quantified by conventional methods and inversely correlated with the CD4(+) T cell count and the CD4/CD8 ratio. We also found that a...

Hepatology (Baltimore, Md.), Aug 21, 2017

We assessed non-liver-related non-AIDS-related (NLR-NAR) events and mortality in a cohort of HIV/... more We assessed non-liver-related non-AIDS-related (NLR-NAR) events and mortality in a cohort of HIV/HCV-coinfected patients treated with interferon and ribavirin between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and non-responders. Fine and Gray regression analysis was conducted to determine the adjusted sub-hazard rate (sHR) of NLR deaths and NLR-NAR events considering death as the competing risk. The NLR-NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR-NAR cancer, bone events, and non-AIDS-related infections. The variables for adjustment were age, sex, prior AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, liver fibrosis, HCV genotype, and exposure to specific anti-HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median five-yea...

Enfermedades infecciosas y microbiologia clinica, Jan 23, 2016

GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and ... more GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for the year 2016. The objective of this study is to evaluate the costs and the efficacy of initiating treatment with these regimens. Economic assessment of costs and efficiency (cost/efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48 in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the cost...

Journal of Infectious Diseases, 2015

Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immuno... more Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immunodeficiency virus type 1 (HIV) DNA level. However, the short-term impact of IFN alfa on persistent HIV and its effects on immune activation after antiretroviral therapy remain unknown. Our study showed that the cell-associated HIV RNA level and CD4 + T-cell activation decreased in the IFN group (n = 10). No changes were detected in levels of residual plasma viremia, replicationcompetent reservoirs, proviral DNA, or 2-long-terminal repeat circles, although APOBEC3G, TRIM5α, BST2, and TRIM22 were upregulated in the IFN group. These data suggest that short-term treatment with IFN alfa combined with RBV decreases HIV expression, in part through inhibition of HIV transcription by TRIM22 and decrease in T-cell activation.

The Lancet Infectious Diseases, 2015

Background Our objective was to assess therapeutic non-inferiority of dual treatment with lopinav... more Background Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. Methods In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratifi ed by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The noninferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Findings Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86•6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87•8%) of 123 in the dual-treatment group (diff erence-1•2% [95% CI-9•6 to 7•3]; p=0•92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and fi ve (4%) in the dual-treatment group (p=0•515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0•223). Interpretation Dual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic effi cacy and is similarly tolerated to triple treatment.

Journal of AIDS & Clinical Research, 2010

Objective: To determine the influence of nevirapine (NVP) and lopinavir/ritonavir (LPV/r) on the ... more Objective: To determine the influence of nevirapine (NVP) and lopinavir/ritonavir (LPV/r) on the efficacy of pegylated interferon (peg-IFN) plus ribavirin (RBV) among HIV/HCV-coinfected patients. Methods: All HIV/HCV-coinfected patients who received peg-IFN plus RBV while under a three-drug antiretroviral regimen including tenofovir (TDF) plus lamivudine (3TC) or emtricitabine (FTC) along with NVP or along with LPV/r at twenty hospitals in Spain were included in this retrospective study. Sustained virological response (SVR) rates in both groups were compared. Results: A total of 165 patients were included in the study, 71 (43%) receiving NVP and 94 (57%) LPV/r. Significantly more patients on LPV/r had a baseline HCV-RNA load ≥600000 IU/mL (44% vs. 73%, p=0.001). Forty (56%) individuals included in the NVP group and 35 (37%) in the LPV/r group showed SVR (p=0.015). In the NVP group, 19 (43%) patients carrying genotype 1-4 and 21 (78%) subjects with genotype 2-3 achieved SVR. In the LPV/r group, the corresponding figures were 25% (p=0.04) and 59% (p=0.1). In the subpopulation of individuals with baseline HCV viral load ≥600,000 IU/mL, 18 (58%) of those taking NVP vs. 21 (31%) who were given LPV/r reached SVR (p=0.01). HCV genotype 2-3, adherence to HCV therapy >80% and use of NVP during peg-IFN plus RBV were independently associated with SVR in the multivariate analysis. Conclusions: HIV/HCV-coinfected patients who receive NVP respond better to peg-IFN plus RBV than those individuals receiving LPV/r. Lower HCV viral load due to NVP treatment may account for the former differences.

Journal of the International AIDS Society, 2014

Journal of Infection, 2012

To assess the frequency of severe liver toxicity in HIV/hepatitis C (HCV)-coinfected patients wit... more To assess the frequency of severe liver toxicity in HIV/hepatitis C (HCV)-coinfected patients with advanced liver fibrosis receiving efavirenz (EFV)-based antiretroviral combinations. One hundred and eighty-nine previously antiretroviral naïve, HIV/HCV-coinfected patients, who started a regimen including two nucleoside analogues plus EFV, and in whom the presence or absence of advanced liver fibrosis could be established, were retrospectively analyzed. Liver fibrosis was evaluated according to a stepwise algorithm including liver biopsy, transient elastography and FIB-4 index. Fifty-six patients had advanced fibrosis - 25 with cirrhosis - and 133 did not. Three (5.4%) subjects with and 9 (6.8%) (p=0.717) without advanced fibrosis developed grade 3-4 transaminase elevation (TE). Grade 4 total bilirubin elevation was seen in 5 (8.9%) patients with advanced fibrosis and in 1 (0.8%) without it (p=0.003). Liver events led to EFV discontinuation in 10 (5.3%) patients, 6 (10.7%) with and 4 (3%) without advanced fibrosis (p=0.031). The hepatic tolerability of EFV was good in HIV/HCV-coinfected patients with advanced liver fibrosis. The frequency of grade 3-4 TE was similar to that observed in patients without advanced fibrosis, there was no death attributable to liver failure caused by drug toxicity and the rate of EFV discontinuations due to liver events was low.

Journal of Antimicrobial Chemotherapy, 2008

Background: Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment... more Background: Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment for HCV infection in HIV co-infected patients. However, data available on the efficacy of this therapy in co-infected patients who failed a former interferon-based regimen are limited. Methods: We analysed the efficacy and safety of the Peg-IFN alfa-2a or alfa-2b plus ribavirin combination in a multicentre observational cohort study including 54 HCV/HIV co-infected patients who had failed to respond to or relapsed on interferon-based treatment. The primary efficacy endpoint was the proportion of patients who achieved a sustained virological response (SVR), defined as HCV RNA <50 IU/mL 24 weeks after completion of therapy. Results: By intention-to-treat analysis, 30% of the patients achieved an SVR. Viral eradication by genotype was 18.9% (7/37) genotype 1; 57.1% (8/14) genotype 3 and 33.3% (1/3) genotype 4. The only independent predictor of SVR was genotype 3 (odds ratio: 5.3; 95% confidence interval: 1.4-19.8). Fourteen (38%) patients with genotype 1 had undetectable viral load at week 48 of treatment. Nevertheless, 50% of them relapsed during the follow-up period. Severe adverse events or progression of HIV infection did not occur during the study; however, 39% of the patients required Peg-IFN dose reduction because of intolerance or haematological toxicity. Conclusions: Combined Peg-IFN and ribavirin achieved a substantial rate of SVR in HCV/HIV co-infected patients who failed a prior standard interferon-based regimen. The decision to retreat any co-infected patient should be individual-based. More aggressive strategies may be necessary to avoid the high relapse rate observed among patients with genotype 1.

Journal of Antimicrobial Chemotherapy, 2014

Ritonavir-boosted protease inhibitor monotherapy (PIMT) is a maintenance strategy that prevents n... more Ritonavir-boosted protease inhibitor monotherapy (PIMT) is a maintenance strategy that prevents nucleoside reverse transcriptase inhibitor toxicity and reduces costs. Some trials compare PIMT with combined antiretroviral therapy, but restricted selection criteria and low sample size hamper data extrapolation to routine practice. Here, we analyse the effectiveness and safety of PIMT in clinical practice. Methods: This was a retrospective, observational, multicentre study. Adult HIV-1 patients receiving PIMT with darunavir or lopinavir were included. A Cox regression model identified independent predictors for virological failure (VF). Results: A total of 664 patients (435 on darunavir/ritonavir and 229 on lopinavir/ritonavir) [74% male, median age of 54 years, one-third with previous protease inhibitor VF, CD4 nadir 189 cells/mm 3 and 42% coinfected with hepatitis C virus (HCV)] were analysed. After a median follow-up of 16 months, 78% of patients (95% CI 74%-81%) remained free from therapeutic failure (TF) (change between ritonavir-boosted PIs not considered failure). At 12 months, by intention-to-treat analysis (change between ritonavir-boosted PIs equals failure), 83% of patients were free from TF (87% darunavir/ritonavir versus 77% lopinavir/ritonavir, P¼0.001). Regarding VF, 88% of patients maintained viral suppression at 12 months (93% darunavir/ritonavir versus 88% lopinavir/ritonavir, P¼not significant). CD4 nadir ,200 cells/mm 3 [hazard ratio (HR) 1.58, 95% CI 1.01-2.49] and undetectable viral load prior to PIMT ,24 months (HR 1.86, 95% CI 1.20-2.91) were independent predictors for VF. Prior protease inhibitor failure, HCV coinfection and the protease inhibitor/ritonavir used were not associated with PIMT outcome. A total of 158 patients stopped PIMT, 6% due to adverse events. Two patients developed encephalitis. Conclusions: PIMTeffectiveness was consistent with data from clinical trials. Viral suppression duration prior to PIMT and CD4 cell count nadir were independent predictors for PIMT outcome.

Journal of Antimicrobial Chemotherapy, 2008

Background: Preliminary data suggest that a once-daily combination of lamivudine, didanosine and ... more Background: Preliminary data suggest that a once-daily combination of lamivudine, didanosine and efavirenz is an effective alternative regimen for antiretroviral-naive HIV-1-infected patients. However, data from randomized trials comparing this combination versus standard first-line regimens are not available yet. In an observational study, we analyse the efficacy and tolerability of didanosine plus lamivudine and efavirenz versus zidovudine plus lamivudine and efavirenz in a cohort of therapy naive patients. Methods: We performed an observational study on prospectively collected data from patients participating in a multicentre Spanish treatment-naive cohort (VACH cohort). Efficacy was assessed comparing time to therapeutic failure and CD4 cell recovery. Safety was analysed comparing the proportion of patients who discontinued therapy for toxicity or any other reason. Results: Overall, 219 patients treated with once-daily didanosine/lamivudine/efavirenz and 409 patients receiving twice-daily zidovudine/lamivudine (Combivir w) plus efavirenz were evaluated. By intent-to treat analysis (non-completers and therapeutic change 5 failure), time to treatment failure was similar in both groups of treatment: 40.0 months (95% CI 23.3-56.8 months) among patients on didanosine/ lamivudine/efavirenz and 33.3 months (95% CI 25.6-41.1 months) in patients treated with zidovudine/ lamivudine/efavirenz (P 5 0.253). The risk of failure due to treatment change was almost double among patients treated with zidovudine/lamivudine/efavirenz compared with those who received didanosine/ lamivudine/efavirenz.

Expert Opinion on Pharmacotherapy, 2003

The incidence of nucleoside analogue-related lactic acidosis has been estimated in 0.57 - 8.5 cas... more The incidence of nucleoside analogue-related lactic acidosis has been estimated in 0.57 - 8.5 cases/1000 person years of antiretroviral therapy. The onset of lactic acidosis is usually insidious and patients complain of nausea, vomiting, abdominal pain, fatigue and weight loss. When lactate levels are high enough, a catastropic clinical situation develops, resulting in multiorgan failure. The mortality rate of patients with lactic acidosis related to nucleoside therapy is very high, 33 - 60%. Although all nucleoside analogues have been implicated in lactic acidosis, most cases are associated with stavudine. At present, there are no controlled trials to evaluate the treatment of nucleoside-induced lactic acidosis. Therapy is based on supportive measures and discontinuation of all antiretroviral drugs. Administration of essential vitamin coenzymes, electron acceptors and L-carnitine may be useful in some cases.

Antiviral Therapy, 2011

Background HCV is a major cause of morbidity and mortality in HIV-coinfected patients. Several ob... more Background HCV is a major cause of morbidity and mortality in HIV-coinfected patients. Several observational studies have suggested that HCV response to pegylated interferon and ribavirin is lower in HIV-coinfected patients treated with abacavir. It has been postulated that abacavir could compete with ribavirin to be phosphorylated, leading to a reduction in the active form of the drug (triphosphorylated ribavirin). Here, we studied the effect of abacavir, tenofovir or lamivudine addition on the suppressive activity of ribavirin in an HCV RNA replicon system. Methods We used the human hepatoma HuH-7 cell clone 9B containing the HCV genotype 1b replicon I389/ NS3-3’. Cells were treated for 24 h with ribavirin (0, 10 and 50 μM) plus abacavir, tenofovir or lamivudine at doses of 0, 10 and 50 μM and HCV RNA production was quantified by real-time PCR in triplicate assays. Results were expressed as mean ±sd of the HCV RNA produced per cell (log10 IU/cell). Means were compared using the St...

Antimicrobial Agents and Chemotherapy, 2004

Management of treatment-experienced human immunodeficiency virus patients has become complex, and... more Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC0-12), 85.1 μg/ml · h; maximum concentration of drug in serum (C max), 10.0 μg/ml; trough concentration of drug in serum (C trough), 7.3 μg/ml; and minimum concentration of drug in serum (C min), 5.5 μg/ml. Lopinavir concentrations were ...

AIDS, 2006

Objective: To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) an... more Objective: To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) and atazanavir (ATV) as a double-boosted protease inhibitor regimen in HIVinfected adults. Methods: Sixteen patients who started LPV/RTV (400/100 mg b.i.d.) and ATV (300 mg q.d.) were enrolled in the study group (arm A). LPV pharmacokinetics were compared to those of two historical groups: arm B, 15 patients who received LPV/RTV (400/100 mg b.i.d.); and arm C, 25 patients who received LPV/RTV/saquinavir (SQV) (400/100/ 1000 mg b.i.d.). ATV pharmacokinetics were compared to those of 15 consecutive patients who received ATV and RTV (300/100 mg q.d.) (arm D). Drug concentrations were measured by HPLC. Results: LPV concentrations were significantly higher in arm A than in arms B and C. Median (interquartile range) LPV area under the curve (AUC) 0-12 values were 115.7 (99.8-136.5), 85.2 (68.3-109.2) and 85.1 (60.6-110.1) mg/h/ml, respectively. C max values were 12.

Journal of Antimicrobial Chemotherapy, 2021

Background Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular... more Background Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known. Methods Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient’s characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multi...

AIDS Research and Therapy, 2020

Background The aim of this study was to investigate the effectiveness and tolerability of the com... more Background The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014–2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL)

Journal of Clinical Medicine, 2020

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual ... more HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients ≥ 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA < 50 copies/mL for ≥6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver® Care and OWLiver® tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4+ count 740 cells/mm3, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reduct...

Cells, 2018

Background: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the le... more Background: Advanced cirrhosis is related to alterations in immunity. We aimed to evaluate the levels of peripheral CD4+ T cells (Tregs) and plasma cytokine in patients coinfected with human immunodeficiency virus and hepatitis C virus (HIV/HCV) according to liver fibrosis stages [evaluated as liver stiffness measure (LSM)] and their linear relationship. Methods: We performed a cross-sectional study on 238 HIV/HCV-coinfected patients (119 had <12.5 kPa, 73 had 12.5–25 kPa, and 46 had >25 kPa). Peripheral T-cell subsets were phenotyped by flow cytometry, plasma biomarkers were assessed by multiplex immunoassays, and LSM was assessed by transient elastography. Results: We found HIV/HCV-coinfected patients had higher values of CD4+ Tregs (p < 0.001), memory Tregs (p ≤ 0.001), and plasma cytokine levels [IFN-γ (p ≤ 0.05) and IL-10 (p ≤ 0.01)] compared with healthy donors and HIV-monoinfected patients. In the multivariate analysis, higher LSM values were associated with reduced ...

Mucosal immunology, Jan 31, 2018

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but ... more Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in...

mBio, Jul 11, 2017

Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" ... more Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" in HIV-infected individuals. However, important technical limitations have precluded the characterization of this specific viral reservoir during both treated and untreated HIV-1 infections. Here, we used a novel single-cell RNA fluorescence in situ hybridization-flow cytometry (FISH-flow) assay that requires only 15 million unfractionated peripheral blood mononuclear cells (PBMCs) to characterize the specific cell subpopulations that transcribe HIV RNA in different subsets of CD4(+) T cells. In samples from treated and untreated HIV-infected patients, effector memory CD4(+) T cells were the main cell population supporting HIV RNA transcription. The number of cells expressing HIV correlated with the plasma viral load, intracellular HIV RNA, and proviral DNA quantified by conventional methods and inversely correlated with the CD4(+) T cell count and the CD4/CD8 ratio. We also found that a...

Hepatology (Baltimore, Md.), Aug 21, 2017

We assessed non-liver-related non-AIDS-related (NLR-NAR) events and mortality in a cohort of HIV/... more We assessed non-liver-related non-AIDS-related (NLR-NAR) events and mortality in a cohort of HIV/HCV-coinfected patients treated with interferon and ribavirin between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and non-responders. Fine and Gray regression analysis was conducted to determine the adjusted sub-hazard rate (sHR) of NLR deaths and NLR-NAR events considering death as the competing risk. The NLR-NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR-NAR cancer, bone events, and non-AIDS-related infections. The variables for adjustment were age, sex, prior AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, liver fibrosis, HCV genotype, and exposure to specific anti-HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median five-yea...

Enfermedades infecciosas y microbiologia clinica, Jan 23, 2016

GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and ... more GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for the year 2016. The objective of this study is to evaluate the costs and the efficacy of initiating treatment with these regimens. Economic assessment of costs and efficiency (cost/efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48 in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the cost...

Journal of Infectious Diseases, 2015

Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immuno... more Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immunodeficiency virus type 1 (HIV) DNA level. However, the short-term impact of IFN alfa on persistent HIV and its effects on immune activation after antiretroviral therapy remain unknown. Our study showed that the cell-associated HIV RNA level and CD4 + T-cell activation decreased in the IFN group (n = 10). No changes were detected in levels of residual plasma viremia, replicationcompetent reservoirs, proviral DNA, or 2-long-terminal repeat circles, although APOBEC3G, TRIM5α, BST2, and TRIM22 were upregulated in the IFN group. These data suggest that short-term treatment with IFN alfa combined with RBV decreases HIV expression, in part through inhibition of HIV transcription by TRIM22 and decrease in T-cell activation.

The Lancet Infectious Diseases, 2015

Background Our objective was to assess therapeutic non-inferiority of dual treatment with lopinav... more Background Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. Methods In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratifi ed by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The noninferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Findings Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86•6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87•8%) of 123 in the dual-treatment group (diff erence-1•2% [95% CI-9•6 to 7•3]; p=0•92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and fi ve (4%) in the dual-treatment group (p=0•515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0•223). Interpretation Dual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic effi cacy and is similarly tolerated to triple treatment.

Journal of AIDS & Clinical Research, 2010

Objective: To determine the influence of nevirapine (NVP) and lopinavir/ritonavir (LPV/r) on the ... more Objective: To determine the influence of nevirapine (NVP) and lopinavir/ritonavir (LPV/r) on the efficacy of pegylated interferon (peg-IFN) plus ribavirin (RBV) among HIV/HCV-coinfected patients. Methods: All HIV/HCV-coinfected patients who received peg-IFN plus RBV while under a three-drug antiretroviral regimen including tenofovir (TDF) plus lamivudine (3TC) or emtricitabine (FTC) along with NVP or along with LPV/r at twenty hospitals in Spain were included in this retrospective study. Sustained virological response (SVR) rates in both groups were compared. Results: A total of 165 patients were included in the study, 71 (43%) receiving NVP and 94 (57%) LPV/r. Significantly more patients on LPV/r had a baseline HCV-RNA load ≥600000 IU/mL (44% vs. 73%, p=0.001). Forty (56%) individuals included in the NVP group and 35 (37%) in the LPV/r group showed SVR (p=0.015). In the NVP group, 19 (43%) patients carrying genotype 1-4 and 21 (78%) subjects with genotype 2-3 achieved SVR. In the LPV/r group, the corresponding figures were 25% (p=0.04) and 59% (p=0.1). In the subpopulation of individuals with baseline HCV viral load ≥600,000 IU/mL, 18 (58%) of those taking NVP vs. 21 (31%) who were given LPV/r reached SVR (p=0.01). HCV genotype 2-3, adherence to HCV therapy >80% and use of NVP during peg-IFN plus RBV were independently associated with SVR in the multivariate analysis. Conclusions: HIV/HCV-coinfected patients who receive NVP respond better to peg-IFN plus RBV than those individuals receiving LPV/r. Lower HCV viral load due to NVP treatment may account for the former differences.

Journal of the International AIDS Society, 2014

Journal of Infection, 2012

To assess the frequency of severe liver toxicity in HIV/hepatitis C (HCV)-coinfected patients wit... more To assess the frequency of severe liver toxicity in HIV/hepatitis C (HCV)-coinfected patients with advanced liver fibrosis receiving efavirenz (EFV)-based antiretroviral combinations. One hundred and eighty-nine previously antiretroviral naïve, HIV/HCV-coinfected patients, who started a regimen including two nucleoside analogues plus EFV, and in whom the presence or absence of advanced liver fibrosis could be established, were retrospectively analyzed. Liver fibrosis was evaluated according to a stepwise algorithm including liver biopsy, transient elastography and FIB-4 index. Fifty-six patients had advanced fibrosis - 25 with cirrhosis - and 133 did not. Three (5.4%) subjects with and 9 (6.8%) (p=0.717) without advanced fibrosis developed grade 3-4 transaminase elevation (TE). Grade 4 total bilirubin elevation was seen in 5 (8.9%) patients with advanced fibrosis and in 1 (0.8%) without it (p=0.003). Liver events led to EFV discontinuation in 10 (5.3%) patients, 6 (10.7%) with and 4 (3%) without advanced fibrosis (p=0.031). The hepatic tolerability of EFV was good in HIV/HCV-coinfected patients with advanced liver fibrosis. The frequency of grade 3-4 TE was similar to that observed in patients without advanced fibrosis, there was no death attributable to liver failure caused by drug toxicity and the rate of EFV discontinuations due to liver events was low.

Journal of Antimicrobial Chemotherapy, 2008

Background: Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment... more Background: Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment for HCV infection in HIV co-infected patients. However, data available on the efficacy of this therapy in co-infected patients who failed a former interferon-based regimen are limited. Methods: We analysed the efficacy and safety of the Peg-IFN alfa-2a or alfa-2b plus ribavirin combination in a multicentre observational cohort study including 54 HCV/HIV co-infected patients who had failed to respond to or relapsed on interferon-based treatment. The primary efficacy endpoint was the proportion of patients who achieved a sustained virological response (SVR), defined as HCV RNA <50 IU/mL 24 weeks after completion of therapy. Results: By intention-to-treat analysis, 30% of the patients achieved an SVR. Viral eradication by genotype was 18.9% (7/37) genotype 1; 57.1% (8/14) genotype 3 and 33.3% (1/3) genotype 4. The only independent predictor of SVR was genotype 3 (odds ratio: 5.3; 95% confidence interval: 1.4-19.8). Fourteen (38%) patients with genotype 1 had undetectable viral load at week 48 of treatment. Nevertheless, 50% of them relapsed during the follow-up period. Severe adverse events or progression of HIV infection did not occur during the study; however, 39% of the patients required Peg-IFN dose reduction because of intolerance or haematological toxicity. Conclusions: Combined Peg-IFN and ribavirin achieved a substantial rate of SVR in HCV/HIV co-infected patients who failed a prior standard interferon-based regimen. The decision to retreat any co-infected patient should be individual-based. More aggressive strategies may be necessary to avoid the high relapse rate observed among patients with genotype 1.

Journal of Antimicrobial Chemotherapy, 2014

Ritonavir-boosted protease inhibitor monotherapy (PIMT) is a maintenance strategy that prevents n... more Ritonavir-boosted protease inhibitor monotherapy (PIMT) is a maintenance strategy that prevents nucleoside reverse transcriptase inhibitor toxicity and reduces costs. Some trials compare PIMT with combined antiretroviral therapy, but restricted selection criteria and low sample size hamper data extrapolation to routine practice. Here, we analyse the effectiveness and safety of PIMT in clinical practice. Methods: This was a retrospective, observational, multicentre study. Adult HIV-1 patients receiving PIMT with darunavir or lopinavir were included. A Cox regression model identified independent predictors for virological failure (VF). Results: A total of 664 patients (435 on darunavir/ritonavir and 229 on lopinavir/ritonavir) [74% male, median age of 54 years, one-third with previous protease inhibitor VF, CD4 nadir 189 cells/mm 3 and 42% coinfected with hepatitis C virus (HCV)] were analysed. After a median follow-up of 16 months, 78% of patients (95% CI 74%-81%) remained free from therapeutic failure (TF) (change between ritonavir-boosted PIs not considered failure). At 12 months, by intention-to-treat analysis (change between ritonavir-boosted PIs equals failure), 83% of patients were free from TF (87% darunavir/ritonavir versus 77% lopinavir/ritonavir, P¼0.001). Regarding VF, 88% of patients maintained viral suppression at 12 months (93% darunavir/ritonavir versus 88% lopinavir/ritonavir, P¼not significant). CD4 nadir ,200 cells/mm 3 [hazard ratio (HR) 1.58, 95% CI 1.01-2.49] and undetectable viral load prior to PIMT ,24 months (HR 1.86, 95% CI 1.20-2.91) were independent predictors for VF. Prior protease inhibitor failure, HCV coinfection and the protease inhibitor/ritonavir used were not associated with PIMT outcome. A total of 158 patients stopped PIMT, 6% due to adverse events. Two patients developed encephalitis. Conclusions: PIMTeffectiveness was consistent with data from clinical trials. Viral suppression duration prior to PIMT and CD4 cell count nadir were independent predictors for PIMT outcome.

Journal of Antimicrobial Chemotherapy, 2008

Background: Preliminary data suggest that a once-daily combination of lamivudine, didanosine and ... more Background: Preliminary data suggest that a once-daily combination of lamivudine, didanosine and efavirenz is an effective alternative regimen for antiretroviral-naive HIV-1-infected patients. However, data from randomized trials comparing this combination versus standard first-line regimens are not available yet. In an observational study, we analyse the efficacy and tolerability of didanosine plus lamivudine and efavirenz versus zidovudine plus lamivudine and efavirenz in a cohort of therapy naive patients. Methods: We performed an observational study on prospectively collected data from patients participating in a multicentre Spanish treatment-naive cohort (VACH cohort). Efficacy was assessed comparing time to therapeutic failure and CD4 cell recovery. Safety was analysed comparing the proportion of patients who discontinued therapy for toxicity or any other reason. Results: Overall, 219 patients treated with once-daily didanosine/lamivudine/efavirenz and 409 patients receiving twice-daily zidovudine/lamivudine (Combivir w) plus efavirenz were evaluated. By intent-to treat analysis (non-completers and therapeutic change 5 failure), time to treatment failure was similar in both groups of treatment: 40.0 months (95% CI 23.3-56.8 months) among patients on didanosine/ lamivudine/efavirenz and 33.3 months (95% CI 25.6-41.1 months) in patients treated with zidovudine/ lamivudine/efavirenz (P 5 0.253). The risk of failure due to treatment change was almost double among patients treated with zidovudine/lamivudine/efavirenz compared with those who received didanosine/ lamivudine/efavirenz.

Expert Opinion on Pharmacotherapy, 2003

The incidence of nucleoside analogue-related lactic acidosis has been estimated in 0.57 - 8.5 cas... more The incidence of nucleoside analogue-related lactic acidosis has been estimated in 0.57 - 8.5 cases/1000 person years of antiretroviral therapy. The onset of lactic acidosis is usually insidious and patients complain of nausea, vomiting, abdominal pain, fatigue and weight loss. When lactate levels are high enough, a catastropic clinical situation develops, resulting in multiorgan failure. The mortality rate of patients with lactic acidosis related to nucleoside therapy is very high, 33 - 60%. Although all nucleoside analogues have been implicated in lactic acidosis, most cases are associated with stavudine. At present, there are no controlled trials to evaluate the treatment of nucleoside-induced lactic acidosis. Therapy is based on supportive measures and discontinuation of all antiretroviral drugs. Administration of essential vitamin coenzymes, electron acceptors and L-carnitine may be useful in some cases.

Antiviral Therapy, 2011

Background HCV is a major cause of morbidity and mortality in HIV-coinfected patients. Several ob... more Background HCV is a major cause of morbidity and mortality in HIV-coinfected patients. Several observational studies have suggested that HCV response to pegylated interferon and ribavirin is lower in HIV-coinfected patients treated with abacavir. It has been postulated that abacavir could compete with ribavirin to be phosphorylated, leading to a reduction in the active form of the drug (triphosphorylated ribavirin). Here, we studied the effect of abacavir, tenofovir or lamivudine addition on the suppressive activity of ribavirin in an HCV RNA replicon system. Methods We used the human hepatoma HuH-7 cell clone 9B containing the HCV genotype 1b replicon I389/ NS3-3’. Cells were treated for 24 h with ribavirin (0, 10 and 50 μM) plus abacavir, tenofovir or lamivudine at doses of 0, 10 and 50 μM and HCV RNA production was quantified by real-time PCR in triplicate assays. Results were expressed as mean ±sd of the HCV RNA produced per cell (log10 IU/cell). Means were compared using the St...

Antimicrobial Agents and Chemotherapy, 2004

Management of treatment-experienced human immunodeficiency virus patients has become complex, and... more Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC0-12), 85.1 μg/ml · h; maximum concentration of drug in serum (C max), 10.0 μg/ml; trough concentration of drug in serum (C trough), 7.3 μg/ml; and minimum concentration of drug in serum (C min), 5.5 μg/ml. Lopinavir concentrations were ...

AIDS, 2006

Objective: To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) an... more Objective: To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) and atazanavir (ATV) as a double-boosted protease inhibitor regimen in HIVinfected adults. Methods: Sixteen patients who started LPV/RTV (400/100 mg b.i.d.) and ATV (300 mg q.d.) were enrolled in the study group (arm A). LPV pharmacokinetics were compared to those of two historical groups: arm B, 15 patients who received LPV/RTV (400/100 mg b.i.d.); and arm C, 25 patients who received LPV/RTV/saquinavir (SQV) (400/100/ 1000 mg b.i.d.). ATV pharmacokinetics were compared to those of 15 consecutive patients who received ATV and RTV (300/100 mg q.d.) (arm D). Drug concentrations were measured by HPLC. Results: LPV concentrations were significantly higher in arm A than in arms B and C. Median (interquartile range) LPV area under the curve (AUC) 0-12 values were 115.7 (99.8-136.5), 85.2 (68.3-109.2) and 85.1 (60.6-110.1) mg/h/ml, respectively. C max values were 12.