Lipodistròfia en pacients infectats pel vih tractats amb fàrmacs antiretrovirals: determinants genètics i moleculars.

La lipodistròfia és un canvi en la distribució del greix corporal. És un efecte advers freqüent en pacients amb infecció pel VIH i s’ha relacionat amb els fàrmacs antiretrovirals, el propi VIH i una susceptibilitat genètica. Aquesta tesis analitza l’efecte de 3 molècules i els seus determinants genètics en l’etiopatogènia de la lipodistròfia associada al VIH en un estudi de casos i controls. Es determina l’expressió d’aquestes molècules en el teixit adipós de pacients VIH amb i sense lipodistròfia i controls no VIH. La interleukina-6 està hiperexpressada en el teixit adipós de pacients VIH, la seva variant genètica -174 G>C no s’ha relacionat amb la lipodistròfia. L’expressió de Peroxisome proliferator-activated receptor gamma (PPAR-γ) està disminuïda en pacients amb lipodistròfia, però no s’ha trobat una associació amb el polimorfisme Pro12Ala. La lipina está hiperexpressada en el teixit adipos de pacients VIH i existeix una associació amb la sensibilitat a la insulina.La lipodistrofia es un cambio en la distribución de la grasa corporal. Es un efecto adverso frecuente en pacientes con infección por VIH relacionado con los fármacos antiretrovirales, el propio VIH y una susceptibilidad genética. Esta tesis analiza el efecto de 3 moléculas y sus determinantes genéticos en la etiopatogenia de la lipodistrofia asociada al VIH en un estudio de casos y controles. Se determina la expresión de estas moléculas en tejido adiposo de pacientes VIH con y sin lipodistrofia y controles no VIH. La interleukina-6 está hiperexpresada en el tejido adiposo de pacientes VIH, su variante genética -174 G>C no se ha relacionado con lipodistrofia. La expresión de Peroxisome proliferator-activated receptor gamma (PPAR-γ) está disminuida en pacientes con lipodistrofia, pero no se encontró una asociación con el polimorfismo Pro12Ala. La lipina está hiperexpresada en el tejido adiposo de pacientes VIH y existe una asociación con la sensibilidad a la insulina.Lipodystrophy is a body fat redistribution condition. It is a common long term adverse effect in HIV-infected patients associated with antiretroviral drugs, HIV itself and genetic susceptibility. This doctoral thesis analyzes the effect of 3 molecules and their genetic variants in the pathogenesis of HIV-associated lipodystrophy in a case-control study. Expression (messanger RNA; mRNA) of these molecules in abdominal adipose tissue of HIV participants with and without lipodystrophy and in healthy controls was determined. Interleukin-6 mRNA was higher in adipose tissue of HIV-infected patients compared with healthy controls; its genetic variant -174 G>C was not associated with lipodystrophy. Peroxisome proliferator-activated receptor gamma (PPAR-γ) mRNA was decreased in patients with lipodystrophy, but no association between lipodystrophy and Pro12Ala polymorphism was found. Lipin was hiperexpressed in adipose tissue of HIV-infected patients; there was a positve association with insulin sensitivity and negative association with proinflammatory cytokines

Anesthesia for Advanced Endoscopic Procedures

The gastrointestinal endoscopy paradigm is rapidly changing, and technological advancements are largely responsible. In tandem, anesthesia providers are adapting to the changing needs and demands. The challenges are unique. Complications arising from the procedures are both routine, such as aspiration and hypoxia, and procedure specific, such as bleeding, pneumothorax, pneumopericardium, and pneumoperitoneum. It is crucial for the anesthesia provider to have a good understanding of the techniques employed by the endoscopist. A higher index of suspicion is also essential to diagnose and appropriately manage many of the complications. In this review, an effort is made to discuss both procedural aspects and anesthesia challenges. We hope that both endoscopists and anesthesia providers will benefit from this review

Do All Integrase Strand Transfer Inhibitors Have the Same Lipid Profile? Review of Randomised Controlled Trials in Naïve and Switch Scenarios in HIV-Infected Patients

In this study, we aim to explore the effects on lipids of integrase strand transfer inhibitors (INSTIs) in naïve and switch randomised controlled trials, and compare them with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). We reviewed phase 3/4 randomised clinical trials in the Cochrane and PubMed databases that compare an INSTI with a boosted PI, an NNRTI, or another INSTI plus one or two nucleoside/nucleotide reverse transcriptase inhibitors (NtRTIs) in naïve patients and switching strategies in HIV-infected patients. We reported the baseline plasma concentration of total cholesterol (TC), low and high-density lipoprotein cholesterol (LDL-c, HDL-c), triglycerides (TG), and the TC/HDL-c ratio, as well as the change at weeks 48 and 96, when available. In naïve HIV-infected patients, raltegravir (RAL) and dolutegravir (DTG) have a more favourable lipid profile compared with NNRTI and boosted PI. Elvitegravir (EVG/c) has a superior lipid profile compared with efavirenz and is similar to that observed with ritonavir-boosted atazanavir except in TG, which increases less with EVG/c. In naïve patients, RAL, DTG, and bictegravir (BIC) produce a similar, slight increase in lipids. In switching trials, the regimen change based on a boosted PI or efavirenz to RAL, DTG, or BIC is associated with clinically significant decreases in lipids that are minor when the change is executed on EVG/c. No changes were observed in lipids by switching trials between INSTIs. In summary, RAL, DTG, and BIC have superior lipid profiles compared with boosted-PI, efavirenz, and EVG/c, in studies conducted in naïve participants, and they are associated with a clinically significant decrease in lipoproteins by switching studies

CSF LPV concentrations and viral load in viral suppressed patients on LPV/r monotherapy given once daily

Introduction: Plasma trough concentrations of lopinavir (LPV) given as LPV/r 800/200 mg once daily (OD) are reduced in comparison with 400/100 mg twice daily (BID). While OD dosage of LPV/r is sufficient to achieve viral suppression in plasma, data about drug penetration and viral suppression in central nervous system (CNS) is needed, mainly if LPVr is used as maintenance monotherapy strategy in selected patients. The objective of this study was to evaluate CSF HIV‐1 RNA and CSF LPV concentrations in patients receiving LPV/r monotherapy OD (LPVrMOD). Material and Methods: This is a cross‐sectional sub‐study within a prospective, open‐label pilot simplification study to evaluate the efficacy and safety of LPV/rMOD in virologically suppressed patients previously receiving a BID LPV/r monotherapy regimen (LPV/rMBID), the “Kmon study” (NCT01581853). To assess LPV concentrations and HIV‐1 RNA in CSF, a lumbar puncture (LP) was performed in a subgroup of patients after at least one month of LPVrMOD treatment. Plasma‐paired samples of all patients were also obtained. HIV‐1 RNA was determined by real‐time PCR (limit of detection 40 copies/mL). Liquid chromatography‐tandem mass spectrometry (Tandem labs, NJ) was used to determine CSF and blood plasma LPV concentrations. Results: Nine patients were included. Median (range) age was 48 (34–56) years, median CD4 cell count 672 (252–1,408) cells/mL, median nadir CD4 count 125 (35–537) cells/mL and 40% of subjects were HCV‐positive. Before starting LPV/rMOD median time on a LPV/r‐containing regimen and on LPV/rMBID were 9 (4–11) years and 15 (7–24) months respectively, median time with undetectable HIV viral load was 5 (3–12) years and 2 patients had a previous documented blip. LP was performed a median of 24 (8–36) weeks after starting LPV/rMOD and 24 (11–28) hours after the last LPV/rMOD dose CSF and plasma HIV RNA was 40 copies/mL in all patients. Median LPV CSF concentration was 9.78 (1.93–78.3) ng/mL, median LPV plasma concentration 1,103 (377–16,700) ng/mL and median LPV CSF/plasma ratio 0.3% (0.1–1.2). Conclusions: No CSF viral escape was detected and LPV concentrations were above the IC50 for wtHIV‐1 (1.9 ng/mL). However, as concentrations were close to IC50 in some patients, a careful clinical follow up of patients receiving this regimen would be advisable. Larger longitudinal studies will be helpful for a better understanding of the CNS antiviral activity of LPVr monotherapy

Long-term fat redistribution in ARV-naïve HIV+ patients initiating a non-thymidine containing regimen in clinical practice

Lipodystrophy is still a matter of concern in HIV patients receiving ART. However, long-term fat change in patients taking non-thymidine regimens is not well known

Effectiveness of first-line antiretroviral therapy based on NNRTIs vs ritonavir-boosted PIs in HIV-1 infected patients with high plasma viral load

Purpose of the study: Few clinical trials have compared non-nucleoside reverse transcriptase inhibitors (NNRTI) and ritonavir-boosted protease inhibitors (PI/r) as initial combined antiretroviral therapy (cART) for HIV-1-infected patients with high plasma viral load (pVL), and non-conclusive results have been reported. We compared the effectiveness between NNRTI and PI/r as first-line cART for HIV-1-infected patients with high pVL. Methods: Observational retrospective study of 664 consecutive treatment-naïve HIV-1-infected patients with pVL (HIV-1 RNA) >100,000 copies/mL who initiated NNRTI or PI/r-based cART between 2000–2010 in three University hospitals. Only currently preferred or alternative regimens in clinical guidelines were included. Primary endpoint: percentage of therapeutic failures at week 48. Virologic failure was defined as: a) lack of virologic response (<1 log RNA HIV-1 decrease in first 3 months); b) RNA HIV-1 >50 c/mL at week 48; c) confirmed rebound >50 c/ml after a previous value <50 c/mL. Intent-to-treat (ITT noncompleter=failure) and on-treatment (OT) analyses were performed. Results: 62% of patients initiated NNRTI-regimens (83% efavirenz) and 38% PI/r-regimens (62% lopinavir/). Baseline characteristics: male 83%; median age 39 yrs; median CD4 count: 212/µL (NNRTI 232 vs PI/r 177, p=0.028); pVL 5.83 log10 c/mL (NNRTI 5.43 vs PI/r 5.55, p=0.007); AIDS 24% (NNRTI 21% vs PI/r 29%, p=0.015). NRTI backbones were tenofovir plus 3TC or FTC in 72%. The percentage of therapeutic failure was higher in the PI/r group (ITT NC=F 26% vs 18%, p=0.012) with no differences in virologic failures (PI/r 5%, NNRTI 6%, p=0.688). The rate of treatment changes due to toxicity and/or voluntary discontinuations was higher in the PI/r group (15% vs 8%, p=0.008). A multivariate analysis adjusted for age, gender, CD4 count, VL and AIDS showed NNRTI vs PI/r as the only variable associated with treatment response (OR 0.61, 95% CI 0.41–0.88). Median pVL and rate of resistance at virologic failure were higher in patients receiving NNRTI (3.97 vs 2.49 log copies/mL, p<0.001 and 62% vs 12%, p=0.004, respectively). Conclusions: Initial NNRTI-regimens showed higher effectiveness compared with PI/r-regimens in HIV-1-infected patients with high pVL, although virologic failure rates were low and comparable. Resistance emergence was more frequent and pVL higher in patients failing NNRTI. However, more patients initiating PI/r-based regimens changed or discontinued therapy

Randomized, crossover, double-blind, placebo-controlled trial to assess the lipid lowering effect of co-formulated TDF/FTC

Abstract INTRODUCTION: Previous studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1-3] It is unknown, however, if TDF has an intrinsic lipid-lowering effect or such findings are due to the addition or removal of other offending agents or other reasons. MATERIALS AND METHODS: RESULTS: 46 subjects with a median age of 43 (40-48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL-cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL-cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL-cholesterol (p<0.001) and HDL-cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total-cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL-cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure. CONCLUSION: Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF

Predictors of Limb Fat Gain in HIV Positive Patients Following a Change to Tenofovir-Emtricitabine or Abacavir-Lamivudine

Background Antiretroviral treatment (cART) in HIV causes lipoatrophy. We examined predictors of anthropometric outcomes over 96 weeks in HIV-infected, lipoatrophic adults receiving stable cART randomised to tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine (ABC-3TC) fixed dose combinations. Methodology/Principal Findings The STEAL study was a prospective trial of virologically suppressed participants randomised to either TDF-FTC (n = 178) or ABC-3TC (n = 179). Anthropometric assessment was conducted at baseline, weeks 48 and 96. The analysis population included those with baseline and week 96 data remaining on randomised therapy. Distribution of limb fat change was divided into four categories (≤0%, \u3e0-10%, \u3e10-20%, \u3e20%). Baseline characteristics [demographics, medical history, metabolic and cardiovascular biomarkers] were assessed as potential predictors of change in percent subcutaneous limb fat using linear regression. 303 participants (85% of STEAL population) were included. Baseline characteristics were: mean (±SD) age 45 (±8) years; thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) duration 4 (±3) years; limb fat 5.4 (±3.0)kg; body mass index 24.7 (±3.5) kg/m2. Mean (SD) limb fat gain to week 48 and 96 was 7.6% (±22.4) and 13.2% (±27.3), respectively, with no significant difference between groups. 51.5% of all participants had \u3e10% gain in limb fat. Predictors of greater limb fat gain at week 96 were baseline tNRTI (10.3, p = 0.001), glucose \u3e6 mmol/L (16.1, p = 0.04), higher interleukin 6 (IL-6) (2.8, p = 0.004) and lower baseline limb fat (3.8-6.4 kg - 11.2; \u3e6.4 kg - 15.7, p trend\u3c0.001). Conclusions/Significance Modest peripheral fat gain occurred with both TDF-FTC and ABC-3TC. Baseline factors associated with more severe lipodystrophy (lipoatrophy, baseline tNRTI, raised IL6, and glucose) predicted greater limb fat recovery at 96 weeks