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Biomedical subjects

Francisco Blanco

Publications and source records attributed to Francisco Blanco.

At least 19 recordsLinked to original sources
PubMed2006

Successful rescue therapy with darunabir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors.

Darunabir, formerly TMC114, is a new protease inhibitor (PI) under clinical development designed to be active against HIV strains resistant to currently available PI. The virological and immunological response to ritonavir-boosted darunabir was assessed in four heavily antiretroviral-experienced patients who had failed enfuvirtide and two or more previous ritonavir-boosted PI regimens, including tipranavir in one instance. All four patients reached undetectable plasma HIV-RNA levels within 8 weeks of therapy and experienced significant CD4 cell count gains.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Rate of virologic failure and selection of drug resistance mutations using different triple nucleos(t)ide analogue combinations in HIV-infected patients.

Virologic failure seems to occur more frequently in HIV-infected patients treated with triple nucleoside analogue (NA) combinations than with regimens including nonnucleoside reverse transcriptase inhibitors or protease inhibitors. However, the rate of failure and resistance profiles may differ with distinct triple NA combinations. A retrospective review of all HIV-infected individuals who received triple NA combinations at our institution was conducted. Virologic failure was defined as lack of achievement of plasma HIV-RNA<50 copies/ml at week 16 following initiation of antiretroviral therapy or as viral rebound in subjects with prior undetectable viremia. Genotypic analyses were performed at the time of first virological failure. Of the 261 patients identified, 13 were drug naive, 126 had underwent simplification, and 122 were antiretroviral-experienced patients with detectable viral load. Virologic failure was recorded in 95 (36.4%) after an average follow-up of 19 months. Rates were 0.67 in drug-naive, 0.55 in simplification, and 2.38 in rescue interventions for 100 persons-month follow-up. Factors associated with virologic failure in the multivariate Cox regression analysis were rescue vs naive or simplification strategies (OR 2.6; 95% CI 1.6-4.2) and using tenofovir as part of the combination (OR 2.04; 95% CI 1.3-3.2). In contrast, the use of AZT prevented virologic failure (OR 0.52; 95% CI 0.3-0.8). M184V was the most frequent resistance mutation (75.4%), followed by T215Y (52.5%) and K65R (14.8%). Of note, K65R did not develop in patients taking AZT nor in those with prior thymidine-associated mutations (TAMs). Conversely, subjects who developed K65R did not accumulate TAMs. Virologic failure is relatively frequent in patients treated only with triple NA regimens, particularly in the setting of rescue therapy. The use of TDF might be associated with a higher risk of virologic failure and, conversely, AZT might be protective. The presence of TAMs precluded the selection of K65R in patients treated with TDF. Resistance pathways for TDF and thymidine analogues seem to be divergent and could be the basis to explore a synergism between these drugs.

Adenine↗
PubMed2006

Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir.

The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination.

Adenine↗
PubMed2006

Association of clinic and ambulatory blood pressure with vascular damage in the elderly: the EPICARDIAN study.

OBJECTIVES: In middle-aged adults, vascular damage correlates better with ambulatory than with clinic blood pressure. This study aimed to determine whether vascular damage evaluated by carotid ultrasonography in the elderly is also more closely related to ambulatory than to clinic blood pressure, and which blood pressure variables are better associated with vascular damage. METHODS: Cross-sectional study of 292 randomly selected >65 years old participants who underwent 24-h noninvasive ambulatory blood pressure monitoring. Blood pressure variables analyzed were (a) clinic blood pressure: systolic and diastolic blood pressure, pulse pressure; (b) ambulatory blood pressure monitoring: mean values of systolic and diastolic blood pressure, systolic and diastolic blood pressure load, pulse pressure, as well as variability, evaluated within 24 h, diurnal and nocturnal periods; and day-night blood pressure difference. A clinical history, physical examination, carotid ultrasonography and laboratory tests were performed. To estimate the relationship between blood pressure and vascular damage, univariate and multivariate analyses were performed. RESULTS: Mean age: 73+/-6 years, 45% men, 76.7% hypertensive patients. In the simple regression analysis, the best significant correlations (P<0.05) were common carotid intima-media thickness with 24-h and nocturnal pulse pressure (r=0.32), and common carotid diameter with 24-h systolic blood pressure load (r=0.47). In the multivariate analysis, the significant associations (P<0.05) were (a) linear regression: nocturnal pulse pressure with common carotid intima-media thickness, and diurnal pulse pressure as well as 24-h systolic blood pressure load with common carotid diameter; (b) logistic regression, adjusted odds ratio: nocturnal pulse pressure and nocturnal diastolic blood pressure load with the presence of carotid atherosclerotic plaques 1.03 and 0.98, respectively. CONCLUSIONS: In the elderly, ambulatory blood pressure monitoring is better associated with carotid damage than clinic blood pressure. Systolic blood pressure variables are the best associated, blood pressure load and pulse pressure being better associated with carotid damage than the mean levels of ambulatory blood pressure.

Aged↗
PubMed2005

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.

Adenine↗
PubMed2004

Changes in mitochondrial DNA copy number in blood cells from HIV-infected patients undergoing antiretroviral therapy.

Mitochondrial DNA (mtDNA) copy number was measured in peripheral blood mononuclear cells (PBMCs) from 69 individuals using a real-time NASBA quantitative assay. Patients with HIV infection harbored significantly lower mtDNA copy number in PBMC than HIV-negative controls. Besides, subjects on stavudine-containing regimens showed significantly lower median mtDNA amounts than HIV-positive patients receiving other antiretroviral drugs, and this was associated with higher lactate levels. Thus, either HIV infection itself or treatment with stavudine-containing regimens might induce mtDNA depletion and related metabolic disturbances as hyperlactatemia.

Anti-HIV Agents↗
PubMed2004

Short communication: benefits in the lipid profile after substitution of abacavir for Stavudine: a 48-week prospective study.

Stavudine (d4T) has been associated with lipoatrophy and hyperlactatemia. In recent studies, d4T has also been related to both hypercholesterolemia and hypertriglyceridemia. Replacing d4T with another nucleoside analogue such as abacavir (ABC) may reduce lactate levels and improve lipoatrophy in the long term. However, the impact of this strategy on the lipid profile is still unclear. In a prospective and randomized study, fasting lipids were examined over 48 weeks in 112 subjects on d4T regimens, 49 of whom replaced d4T with ABC. The substitution of ABC for d4T was found to be safe and provided a reduction in both LDL cholesterol and the total cholesterol (TC)/HDLc ratio, which might impact favorably on cardiovascular risk.

Adult↗
PubMed2003

[Mitochondrial damage by antiretrovirals: diagnosis and monitoring].

Combination of antiretroviral drugs has dramatically improved the prognosis of individuals with HIV infection. However, their long-term benefit is limited by two main factors: the selection of drug-resistant strains and side effects. A large part of the toxicity of antiretroviral drugs has been associated with mitochondrial damage. Nucleoside analogue reverse transcriptase inhibitors (NRTI), which lack the hydroxyl group needed for further DNA chain elongation, block HIV reverse transcriptase. These nucleosides can be mistaken as natural substrates by the polymerase gamma, the enzyme responsible for the replication of mitochondrial DNA (mtDNA). Depletion or damage of mtDNA may affect the aerobic metabolism of carbohydrates and lipids, resulting in the accumulation of pyruvate/lactate and fatty acids, and ultimately in lactic acidosis and lipoatrophy, respectively. However, the relationship between hyperlactatemia and/or lipoatrophy and mtDNA depletion due to NRTIs has not been demonstrated conclusively. The design of methods to measure mtDNA may help to recognize the mitochondrial toxicity of antiretroviral therapy.

Acidosis, Lactic↗
PubMed2003

Gynecomastia in HIV-infected patients receiving antiretroviral therapy.

Thirty-four HIV-positive men with gynecomastia were seen in an HIV outclinic during a 20-month period (incidence of 2.4 cases/100 patients receiving HAART per year). It developed mainly in subjects having good immunologic and virologic status, after an average of 3 years of HAART. No hormone abnormalities were found, or association with specific drugs. Although initially unilateral, more than half of cases progressed to bilateral gynecomastia. Spontaneous resolution occurred in most subjects with 12 months without modifying therapy.

Adult↗
PubMed2003

Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir.

Lopinavir (LPV)/ritonavir (RTV) used in combination, is a potent antiretroviral drug. However, its benefit is limited by its inherent effect on lipid metabolism, causing dislypemia in a large proportion of treated patients. Fasting triglyceride (TG) and cholesterol levels were assessed in 126 HIV-infected patients who initiated salvage therapy based on LPV/RTV. Both TG and cholesterol significantly increased from baseline to month 3. A positive correlation was found between the percentage increase in TG and LPV trough levels (r = 0.32; p = 0.003). Moreover, patients with TG elevations above the median (27%) showed higher LPV Ctrough levels than those with lower TG elevations (7.1 vs. 4.7 microg/ml, p = 0.004). In contrast, no correlation was found between LPV Ctrough and increases in cholesterol levels. Cholesterol elevations were positively correlated with RTV Ctrough concentrations (r = 0.32; p = 0.003).

Adult↗
PubMed2002

Effect of dietary intervention on highly active antiretroviral therapy-related dyslipemia.

Changes in cholesterol and triglyceride levels after prescribing a lipid-lowering diet were assessed in 230 HIV-infected patients with dyslipemia associated with antiretroviral therapy. Lipid levels decreased significantly in subjects having good diet compliance. The reduction in triglyceride levels was greater than in cholesterol levels. Patients on protease inhibitor-containing regimens experienced a slightly greater decline in lipid levels compared with the rest.

Adult↗
PubMedDate not supplied

Immune-neuroendocrine interactions and autoimmune diseases.

The relationship between immune-neuroendocrine system is firmly established. The messengers of this connection are hormones, neuropeptides, neurotransmitters and cytokines. The immune-neuroendocrine system have the capacity to synthesize and release these molecules, which, in turn, can stimulate or suppress the activity of immune or neuroendocrine cells by binding to receptors. In fact, hormones, neuropeptides and neurotransmitters participate in innate and adaptive immune response. Autoimmune rheumatic diseases (ARD) are characterized by aberrant production of pro-inflammatory cytokines, which are a potent activator of the HPA axis. In consequence, high levels of pro-inflammatory hormones such as estrogens and prolactin, and low levels of glucocorticoids, an anti-inflammatory hormone, have been described in the active phase of ARD. In addition, high levels of pro-inflammatory hormones and cytokines have also been frequently detected in organ involvement of patients with ARD, suggesting an abnormal local neuroendocrine immune interaction. There is evidence that hormonal changes may appear before the symptomatic phase of the disease. Therefore, it is possible that a pro-inflammatory hormone favors the rupture of tolerance, which is a key feature of autoimmune diseases. The interactions between the immune-neuroendocrine system have a major impact on our understanding of the pathogenic mechanisms, diagnosis and therapy of ARD.

Animals↗
PubMedDate not supplied

SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals.

PURPOSE: A randomized, open-label, pilot study was undertaken to explore the antiviral activity and tolerability of two nonnucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine (NVP) and efavirenz (EFV). METHOD: HIV-infected antiretroviral-naive adults with CD4 counts >100 cells/mm(3) and detectable plasma HIV RNA below 100,000 copies/mL were randomized to receive didanosine (ddI) and stavudine (d4T) plus either NVP or EFV. Assessments were made every 12 weeks. Primary endpoints were the proportion of patients reaching plasma HIV RNA <50 copies/mL and/or developing NNRTI-related toxicities leading to drug discontinuation. Baseline characteristics were comparable for participants in the EFV (n = 31) and NVP arms (n = 36). RESULTS: At 48 weeks, 23/31 (74%) patients in the EFV group and 23/36 (64%) in the NVP group had <50 HIV RNA copies/mL (intention-to-treat analysis). Adverse events led to NNRTI discontinuation in 4 and 3 patients in the EFV and NVP arms, respectively. There were no statistically significant differences between groups regarding any primary endpoint. NVP and EFV along with two NRTIs may be equally well tolerated and effective at achieving <50 HIV RNA copies/mL in naive patients with CD4 counts >100 cells/mm(3) and HIV RNA <10(5) copies/mL. CONCLUSION: A much larger study is needed to demonstrate any significant differences between NVP and EFV, if they exist at all.

Adult↗