Treatment variability and its relationships to outcomes among patients with Wernicke's encephalopathy: A multicenter retrospective study.

BACKGROUND: Despite guidelines and recommendations, Wernicke's encephalopathy (WE) treatment lacks evidence, leading to clinical practice variability. AIMS: Given the overall lack of information on thiamine use for WE treatment, we analyzed data from a large, well-characterized multicenter sample of patients with WE, examining thiamine dosages; factors associated with the use of different doses, frequencies, and routes; and the influence of differences in thiamine treatment on the outcome. METHODS: This retrospective study was conducted with data from 443 patients from 21 centers obtained from a nationwide registry of the Spanish Society of Internal Medicine (from 2000 to 2012). Discharge codes and Caine criteria were applied for WE diagnosis, and treatment-related (thiamine dosage, frequency, and route of administration) demographic, clinical, and outcome variables were analyzed. RESULTS: We found marked variability in WE treatment and a low rate of high-dose intravenous thiamine administration. Seventy-eight patients out of 373 (20.9%) received > 300mg/day of thiamine as initial dose. Patients fulfilling the Caine criteria or presenting with the classic WE triad more frequently received parenteral treatment. Delayed diagnosis (after 24h hospitalization), the fulfillment of more than two Caine criteria at diagnosis, mental status alterations, and folic acid deficiency were associated significantly with the lack of complete recovery. Malnutrition, reduced consciousness, folic acid deficiency, and the lack of timely thiamine treatment were risk factors for mortality. CONCLUSIONS: Our results clearly show extreme variability in thiamine dosages and routes used in the management of WE. Measures should be implemented to ensure adherence to current guidelines and to correct potential nutritional deficits in patients with alcohol use disorders or other risk factors for WE.

Cytotoxic NK cells phenotype and activated lymphocytes are the main characteristics of patients with alcohol-associated liver disease.

T cells, natural killer (NK) and NKT cells have opposing actions in the development of alcohol-associated liver fibrosis. We aimed to evaluate the phenotype of NK cells, NKT cells and activated T cells in patients with alcohol use disorder (AUD) according to the presence of advanced liver fibrosis (ALF). Totally, 79 patients (51-years, 71% males) were admitted to treatment of AUD. ALF was defined as FIB4-score > 2.67. Immunophenotyping of NK cells (CD3-CD56+CD16+, CD3-CD56+CD16-, CD3-CD56-CD16+), NKT-like (CD3+CD56+), and the activation status of CD4+, CD8+ and regulatory T cells (Tregs) were evaluated according to the HLA-DR expression. Patients had an AUD duration of 18 ± 11 years with a daily alcohol consumption of 155 ± 77 gr/day prior to hospital admission. The values of absolute cells were 2 ± 0.9 cells/L for total lymphocytes, 1054 ± 501 cells/µL for CD4+, 540 ± 335 cells/µL for CD8+, 49.3 ± 24.8 cells/µL for Tregs, 150.3 ± 97.5 cells/µL for NK cells and 69.8 ± 78.3 cells/µL for NKT-like. The percentage of total NK cells (11.3 ± 5.5% vs. 7 ± 4.3%, p < 0.01), CD3-CD56+CD16+ regarding total lymphocytes (9.7 ± 5.1% vs. 5.8 ± 3.9%, p < 0.01), activated CD4+ cells (5.2 ± 3.2% vs. 3.9 ± 3%, p = 0.04) and activated CD8+ cells (15.7 ± 9.1% vs. 12.2 ± 9%, p = 0.05) were significantly higher in patients with ALF. The percentage of CD3-CD56+CD16- regarding NK cells (5.1 ± 3.4% vs. 7.6 ± 6.2%, p = 0.03) was significantly lower in patients with ALF. Activated Tregs (39.9 ± 11.5 vs. 32.4 ± 9.2, p = 0.06) showed a tendency to be higher in patients with ALF. The proportion of activated CD4+ cells (r = 0.40, p < 0.01) and activated CD8+ cells (r = 0.51, p < 0.01) was correlated with the proportion of NKT-like in patients without ALF. Patients with ALF presented an increased NK cytotoxic phenotype and activated T cells concomitant with a decreased NK cytokine-secreting phenotype.

Prevalence of non-alcoholic fatty liver disease in a multicentre cohort of people living with HIV in Spain.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most important liver comorbidities in people living with HIV (PLWH). Factors that could lead to a higher prevalence of NAFLD or ease the onset of fibrosis are unclear. METHODS: Cohort study of the Spanish HIV Research Network, which comprehends 46 hospitals and more than 15,000 PLWH. Primary objectives were to assess NAFLD prevalence and liver fibrosis according to hepatic steatosis index (HSI) and NAFLD fibrosis score, respectively. Factors associated with both were analysed. RESULTS: A total of 4798 PLWH were included of whom 1461 (30.5%) showed an HSI>36; these patients had higher risk for significant fibrosis (OR 1.91; 95%CI 1.11-3.28). Factors associated with NAFLD were body mass index (OR 2.05; 95%CI 1.94-2.16) and diabetes (OR 4.68; 95%CI 2.17-10.08), while exposure to integrase strand transfer inhibitors showed a lower risk (OR 0.78; 95%CI 0.62-0.97). In patients with HSI>36, being female (OR 7.33; 95%CI 1.34-40), age (OR 1.22; 95%CI 1.11-1.34), body mass index (OR 1.35; 95%CI 1.18-1.54) and exposure to thymidine analogues (OR 75.4, 95%CI 6.9-823.5) were associated with a higher risk of significant fibrosis. However, exposure to non-nucleoside reverse transcriptase inhibitors (OR 0.12, 95%CI 0.02-0.89) and time of exposure to protease inhibitors (OR 0.97, 95%CI 0.95-1) showed a lower risk. CONCLUSION: NAFLD prevalence was high in our cohort. Patients exposed to INSTI showed a lower risk of NAFLD. In patients with hepatic steatosis, exposure to thymidine analogues had 75-fold more risk of significant fibrosis while exposure to NNRTIs reduced this risk.

Plasma Amino Acid Concentrations in Patients with Alcohol and/or Cocaine Use Disorders and Their Association with Psychiatric Comorbidity and Sex.

(1) Background: Co-occurrence of mental and substance use disorders (SUD) is prevalent, but complicates their clinical courses, and specific biomarkers are required. Amino acids are altered in primary mental disorders; however, little is known about SUD and psychiatric comorbidity. Because most psychiatric disorders and biomarkers show sex differences, we investigated amino acids in men and women with alcohol and/or cocaine use disorders (AUD and/or CUD) and psychiatric comorbidity. (2) Methods: A cross-sectional study was conducted in 295 participants, who were divided into four groups (AUD, n = 60; CUD, n = 41; AUD + CUD, n = 64; and control, n = 130). Participants were clinically assessed, and plasma amino acid concentrations were analyzed in relation to sex, diagnosis of SUD and psychiatric comorbidity (3) Results: In the total sample, there were sex differences, and women showed lower Iso, Leu, Gln and Glu than men. While patients with CUD and AUD + CUD had higher Glu, Gly, Orn and Ser than controls, patients with AUD showed no differences. In SUD, patients with psychiatric comorbidity had lower Orn and higher Ala than non-comorbid patients in the AUD group. (4) Conclusions: There was a dysregulation of plasma amino acids in abstinent patients with SUD. However, our results suggest the importance of considering the clinical characteristics and sex in the validity of amino acids as potential biomarkers for SUD.

New Synthetic Opioids Use among Patients in Treatment for an Opioid Use Disorder in Barcelona.

INTRODUCTION: New synthetic opioids (NSO), a class of new psychoactive substances (NPS), have recently emerged and pose an upcoming global public health challenge. The effects produced by NSO are similar to those from morphine, but they present greater pharmacological potency and abuse potential. Due to the increasing number of fatal overdoses and seizures in which NSO have been detected as heroin substitutes or adulterants, individuals with Opioid Use Disorder (OUD) represent a vulnerable population. The aim of our study was to describe and characterize from a gender perspective a Spanish cohort of potential conscious or unconscious NSO users. METHODS: A cross-sectional study was conducted in a cohort of OUD participants under treatment in addiction care services in Barcelona and Badalona, Spain. Clinical evaluation was performed through an ad hoc survey, a scale to evaluate reasons to use an opioid without prescription (range 0-4) and the Wellbeing Index (WHO-5) (range 0-100). Objective consumption of NSO was assessed by urinalysis carried out by two validated methods: high-sensitivity gas chromatography-mass spectrometry (MS) and ultra-high-performance liquid chromatography-high-resolution MS. RESULTS: A total of 154 participants with OUD were enrolled. They were mainly men (72.7%), mean age 47.8 years. Methadone was the predominant medication for opioid agonist treatment (mean dose 61.25 mg/day). A total of 32 (20.8%) participants reported having consumed some opioid to become "high" in the previous 3 months. The principal reasons for consuming illicit opioids were Replacing other drugs (mean 2.03) and Availability (mean 1.62), although Low price, was more highly valued by men (p = 0.045) and Shorter effect duration, most highly rated by women (p = <0.001). In the WHO-5, the mean score was 55 (SD = 30.1) without differences by gender. Fentanyl and derivatives or/and metabolites were detected in 7 (6.1%) participants, but illicit/non-prescribed NSOs were found in 5 out of 114 patients (4.4%), and other non-fentanyl opioids in 36 participants (26 men and 10 women). CONCLUSION: A non-negligible consumption of NSO-fentanyl's (positive detection in 6.1% of biological samples) was detected. The reasons for using these substances and also the well-being differed between the genders. There is therefore both voluntary and involuntary NSO consumption in our country which highlights the importance of approaching this potential public health problem.

Prevalence and associations of metabolic syndrome in patients with alcohol use disorder.

Excessive alcohol consumption has been associated with different components of the metabolic syndrome (MetS) such as arterial hypertension, dyslipidemia, type 2 diabetes or obesity. We aimed to analyze the prevalence and associations of MetS in patients with Alcohol Use Disorder (AUD). Cross-sectional study in heavy drinkers admitted for the treatment of AUD between 2013 and 2017. Medical comorbidity, anthropometric data, alcohol use and biological parameters were obtained. MetS was established according to the harmonized definition. A total of 728 patients (22% women) were included; median age was 47 years (IQR: 40-53.5), median alcohol consumption was 160 g/day (IQR: 115-240) and prevalence of MetS was 13.9%. The multivariate analysis showed a significant dose-response effect of estimated glomerular filtration (eGFR) and MetS: relative to patients with eGFR > 90 mL/min, those with eGFR (60-90 mL/min) and those with eGFR < 60 mL/min were 1.93 times (95% CI 1.18-3.15) and 5.61 times (95% CI 1.66-19.0) more likely to have MetS, respectively. MetS was significantly associated with hyperuricemia (OR 2.28, 95% CI 1.36-3.82) and elevated serum GGT (OR 3.67, 95% CI 1.80-7.46). Furthermore, for every increase of 1 year in age, the probability of MetS increased significantly (OR 1.03, 95% CI 1.01-1.05). MetS in heavy drinkers is independently associated with reduced kidney function and metabolic risk factors including hyperuricemia and elevated serum GGT.

Increased Natural Killer Cells Are Associated with Alcohol Liver Fibrosis and with T Cell and Cytotoxic Subpopulations Change.

Natural killer (NK) cells play a therapeutic role in liver fibrosis (LF). We aimed to analyze NK cells in heavy drinkers without cirrhosis or decompensated liver disease and establish correlations with other related subpopulations. Data on sociodemographic characteristics, alcohol consumption, laboratory parameters, and immunophenotyping of NK (CD16+/CD56+), T (CD3+), B (CD19+), NKT (CD16+/CD56+/CD3+), and cytotoxic (CD3-CD8+) cells were collected. Fibrosis-4 (FIB-4) scores were used to compare patients without (FIB-4 < 1.45) and with (FIB-4 > 3.25) advanced LF (ALF). We included 136 patients (76% male) with a mean age of 49 years who had a 15-year alcohol use disorder (AUD) and alcohol consumption of 164 g/day. Patients with ALF (n = 25) presented significantly lower absolute total lymphocyte, T cell, B cell, and NKT cell numbers than patients without LF (n = 50; p < 0.01). However, the NK cells count was similar (208 ± 109 cells/µL vs. 170 ± 105 cells/µL) in both groups. The T cells percentage was lower (80.3 ± 5.6% vs. 77 ± 7%; p = 0.03) and the NK cells percentage was higher (9.7 ± 5% vs. 13 ± 6%; p = 0.02) in patients with ALF than in those without LF. The percentages of NK cells and T cells were inversely correlated in patients without (r = -0.65, p < 0.01) and with ALF (r = -0.64; p < 0.01). Additionally, the NK cells and CD3-CD8+ cell percentages were positively correlated in patients without (r = 0.87, p < 0.01) and with (r = 0.92; p < 0.01) ALF. Conclusions: Heavy drinkers without decompensated liver disease showed an increase in NK cells related to T cells lymphopenia and an increase in cytotoxic populations. The interaction of NK cells with other subpopulations may modify alcohol-related liver disease progression.

Alcoholic Liver Disease Among Patients with Wernicke Encephalopathy: A Multicenter Observational Study.

BACKGROUND: data regarding the association between Wernicke encephalopathy (WE) and alcoholic liver disease (ALD) are scarce in spite of alcohol consumption being the main risk factor for WE. AIMS: to describe the frequency of ALD in a cohort of patients diagnosed with WE and alcohol use disorders (AUDs) and to compare the characteristics of WE patients with and without ALD. METHODS: we conducted an observational study in 21 centers through a nationwide registry of the Spanish Society of Internal Medicine. WE Caine criteria were applied and demographic, clinical, and outcome variables were analyzed. RESULTS: 434 patients were included in the study, of which 372 were men (85.7%), and the mean age was 55 ± 11.8 years. ALD was present in 162 (37.3%) patients and we found a higher percentage of cases with tremor, flapping and hallucinations in the ALD group. A total of 22 patients (5.0%) died during admission (7.4% with ALD vs 3.7% without ALD; P = 0.087). Among the ALD patients, a relationship between mortality and the presence of anemia (Odds ratio [OR]=4.6 Confidence interval [CI]95% 1.1-18.8; P = 0.034), low level of consciousness (OR=4.9 CI95% 1.1-21.2; P = 0.031) and previous diagnosis of cancer (OR=10.3 CI95% 1.8-59.5; P = 0.009) was detected. Complete recovery was achieved by 27 patients with ALD (17.8%) and 71 (27.8%) without ALD (P = 0.030). CONCLUSION: the association of WE and ALD in patients with AUDs is frequent and potentially linked to differences in clinical presentation and to poorer prognosis, as compared to alcoholic patients with WE without ALD.

Plasma concentrations of granulocyte colony-stimulating factor (G-CSF) in patients with substance use disorders and comorbid major depressive disorder.

Granulocyte colony-stimulating factor (G-CSF) has raised much interest because of its role in cocaine addiction in preclinical models. We explored the plasma concentrations of G-CSF in patients diagnosed with substance use disorder (SUD) and highly comorbid psychiatric disorders. In particular, we investigated the association between G-CSF concentrations and comorbid major depressive disorder (MDD) in patients with cocaine and alcohol use disorders (CUD and AUD, respectively). Additionally, patients with MDD but not SUD were included in the study. Three hundred and eleven participants were enrolled in this exploratory study: 136 control subjects, 125 patients with SUD (SUD group) from outpatient treatment programs for cocaine (N = 60, cocaine subgroup) and alcohol (N = 65, alcohol subgroup), and 50 patients with MDD but not SUD (MDD group) from primary-care settings. Participants were assessed based on DSM-IV-TR criteria, and a blood sample was collected to examine the plasma concentrations of G-CSF. G-CSF concentrations were negatively correlated with age in the entire sample (r = - 0.233, p < 0.001) but not in the patients with MDD. G-CSF concentrations were lower in patients with SUD than in controls (p < 0.05), specifically in the cocaine subgroup (p < 0.05). Patients with SUD and comorbid MDD had lower G-CSF concentrations than patients with SUD but not comorbid MDD or controls (p < 0.05). In contrast, patients with MDD but not SUD showed no differences compared with their controls. The negative association between G-CSF concentrations and age in the sample was not observed in patients with MDD. G-CSF concentrations were decreased in patients with SUD and comorbid MDD but not in patients with MDD. Therefore, G-CSF may be useful to improve the stratification of patients with dual diagnosis seeking treatment. Further investigation is needed to explore the impact of sex and type of drug on the expression of G-CSF.

Association of Opioid Agonist Treatment With All-Cause Mortality and Specific Causes of Death Among People With Opioid Dependence: A Systematic Review and Meta-analysis.

Importance: Mortality among people with opioid dependence is higher than that of the general population. Opioid agonist treatment (OAT) is an effective treatment for opioid dependence; however, there has not yet been a systematic review on the relationship between OAT and specific causes of mortality. Objective: To estimate the association of time receiving OAT with mortality. Data Sources: The Embase, MEDLINE, and PsycINFO databases were searched through February 18, 2020, including clinical trial registries and previous Cochrane reviews. Study Selection: All observational studies that collected data on all-cause or cause-specific mortality among people with opioid dependence while receiving and not receiving OAT were included. Randomized clinical trials (RCTs) were also included. Data Extraction and Synthesis: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data on study, participant, and treatment characteristics were extracted; person-years, all-cause mortality, and cause-specific mortality were calculated. Crude mortality rates and rate ratios (RRs) were pooled using random-effects meta-analyses. Main Outcomes and Measures: Overall all-cause and cause-specific mortality both by setting and by participant characteristics. Methadone and buprenorphine OAT were evaluated specifically. Results: Fifteen RCTs including 3852 participants and 36 primary cohort studies including 749 634 participants were analyzed. Among the cohort studies, the rate of all-cause mortality during OAT was more than half of the rate seen during time out of OAT (RR, 0.47; 95% CI, 0.42-0.53). This association was consistent regardless of patient sex, age, geographic location, HIV status, and hepatitis C virus status and whether drugs were taken through injection. Associations were not different for methadone (RR, 0.47; 95% CI, 0.41-0.54) vs buprenorphine (RR, 0.34; 95% CI, 0.26-0.45). There was lower risk of suicide (RR, 0.48; 95% CI, 0.37-0.61), cancer (RR, 0.72; 95% CI, 0.52-0.98), drug-related (RR, 0.41; 95% CI, 0.33-0.52), alcohol-related (RR, 0.59; 95% CI, 0.49-0.72), and cardiovascular-related (RR, 0.69; 95% CI, 0.60-0.79) mortality during OAT. In the first 4 weeks of methadone treatment, rates of all-cause mortality and drug-related poisoning were almost double the rates during the remainder of OAT (RR, 2.01; 95% CI, 1.55-5.09) but not for buprenorphine (RR, 0.58; 95% CI, 0.18-1.85). All-cause mortality was 6 times higher in the 4 weeks after OAT cessation (RR, 6.01; 95% CI, 4.32-8.36), remaining double the rate for the remainder of time not receiving OAT (RR, 1.81; 95% CI, 1.50-2.18). Opioid agonist treatment was associated with a lower risk of mortality during incarceration (RR, 0.06; 95% CI, 0.01-0.46) and after release from incarceration (RR, 0.09; 95% CI, 0.02-0.56). Conclusions and Relevance: This systematic review and meta-analysis found that OAT was associated with lower rates of mortality. However, access to OAT remains limited, and coverage of OAT remains low. Work to improve access globally may have important population-level benefits.

Sex-specific Associations of Alcohol Withdrawal in Patients Admitted for the Treatment of Alcohol Use Disorder.

OBJECTIVES: There are sex differences in the pattern of alcohol consumption and in the complications of alcohol use disorder (AUD). We aimed to identify sex-specific differences in the factors associated with alcohol withdrawal syndrome (AWS) among patients that requested a first treatment for AUD. METHODS: We enrolled 313 patients (75% men) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis that started treatment between 2014 and 2016. We collected socio-demographics, the type and amount of alcohol and other substances consumed, and clinical and laboratory parameters. According to Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD criteria, AWS occurred when patients experienced 2 or more clinical signs/symptoms and/or consumed alcohol to relieve symptoms. Logistic regression models were used to determine factors associated with AWS according to sex. RESULTS: The median age of participants was 50 years (interquartile range [IQR]: 43-54 years). The median age of starting alcohol consumption was 16 years (IQR: 14-18 years). Notably, 69% of participants smoked tobacco, and 61% had a family history of AUD; 18% currently used cannabis, and 7.7% used cocaine. Overall, 73% of patients exhibited AWS criteria, and men (76.5%) were more likely than women (64.6%) to report AWS (P = 0.038). In the adjusted analysis, factors associated with AWS were the age at starting alcohol consumption (odds ratio [OR] for every 5 years = 1.89, 95% confidence interval [CI]: 1.69-2.08), and cannabis use (OR = 2.8, 95% CI: 1.04-7.7) in men, and a family history of AUD in women (OR = 2.85 95% CI: 1.07-7.54). CONCLUSIONS: factors associated with AWS differ by sex which may have clinical implications for proactive management of AWS during treatment for AUD.

Association of hyperuricemia and gamma glutamyl transferase as a marker of metabolic risk in alcohol use disorder.

Excessive alcohol consumption leads to overproduction of urates and renal function plays a critical role in serum uric acid levels. We aimed to assess associations of hyperuricemia in patients with alcohol use disorder (AUD) and comparable Glomerular Filtration Rate (GFR). A total of 686 patients undergoing treatment for AUD between 2013 and 2017 were eligible (77% men); age at admission was 47 years [interquartile range (IQR), 40-53 years], age of onset of alcohol consumption was 16 years [IQR, 16-18 years] and the amount of alcohol consumed was 160 g/day [IQR, 120-240 g/day]. Body Mass Index was 24.7 kg/m2 [IQR, 21.9-28.4 kg/m2], eGFR was 105 mL/min/1.73 m2 [IQR, 95.7-113.0 mL], 9.7% had metabolic syndrome and 23% had advanced liver fibrosis (FIB-4 > 3.25). Prevalence of hyperuricemia was 12.5%. The eGFR-adjusted multivariate analysis showed that relative to patients with GGT ≤ 50, those with GGT between 51 and 300 U/L and those with GGT > 300 U/L were 4.31 (95% CI 1.62-11.46) and 10.3 (95% CI 3.50-29.90) times more likely to have hyperuricemia, respectively. Our data shows that hyperuricemia in the context of AUD is strongly associated with serum GGT levels and suggest an increased cardio-metabolic risk in this population.

Loss of naive T lymphocytes is associated with advanced liver fibrosis in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with changes in cellular immunity. The objective of the present study was to analyze the contribution of AUD to the differentiation of T cells and associations with advanced liver fibrosis (ALF). METHODS: This cross-sectional study included patients admitted for treatment of AUD between 2013 and 2016. T cell immune-phenotyping defined four profiles of cellular differentiation according to the expression of CCR7 and CD45RA: naive T cells, central memory (TCM) cells, effector memory (TEM) cells, and terminal effector (TEMRA) cells. CD4+ memory cells were subdivided into Th1, Th2, and Th17 according to the expression of CXCR3 and CCR6. The stages of cellular differentiation were compared to healthy controls. ALF was defined as FIB-4 > 3.25. RESULTS: Seventy-nine patients (81% men) with a median age of 50 years (IQR: 45-56 years) and median ethanol consumption of 150 g/day (IQR: 100-200 g/day) were included in the study. Compared to healthy controls, patients with AUD had fewer CD4+ naive cells (p < 0.001), more TCM and TEM cells (p = 0.003 and p = 0.050, respectively), and larger Th2 populations (p = 0.03). Among CD8+ cells, the percentage of TCM, TEM, and TEMRA were higher in patients with AUD than in the healthy controls (p < 0.05). Patients with ALF had fewer CD4+ and CD8+ naive cells (p < 0.05) and more CD4+ memory cells than patients without ALF. CONCLUSIONS: Altered lymphocyte differentiation in AUD patients suggests immunosenescence. An increase in memory cells and decrease in naive cells is associated with ALF.

MDMA interactions with pharmaceuticals and drugs of abuse.

Introduction: MDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, has become one of the most widely used recreational psychostimulant drugs in the world. Among recreational ecstasy/MDMA users, polydrug use is a phenomenon whose common purpose is to experience the synergistic effect of the combined drugs, moderate MDMA effects, prevent potential toxicity, enhance a high or come down from a high from other drugs, or simply to treat existing medical conditions. Thus, MDMA-drug interactions (MDMA-DIs) lead to a higher risk of acute and life-threatening MDMA toxicity.Areas covered: This article provides an overview of the MDMA-DIs with pharmaceuticals and drugs of abuse. In addition, available evidence is summarized along with clinical recommendations. Finally, the increasing importance of MDMA-DIs is highlighted.Expert opinion: There is a reduced number of published MDMA-DIs studies and scarce clinically significant MDMA-DIs documented in the literature. Experimental evidence points out the relevance of MDMA-DI's when MDMA is co-administered with pharmaceuticals that are metabolized by the CYP2D6 due to MDMA inhibitory action and in the case of repeated MDMA administration (MDMA-MDMAIs).

DSM-5 in patients seeking their first treatment for alcohol use disorder. Sex differences in the multicenter CohRTA study. / DSM-5 en pacientes que solicitan el primer tratamiento del trastorno por uso de alcohol. Diferencias de sexo en el estudio multicéntrico CohRTA.

OBJECTIVE: We aimed to analyze sex differences in the DSM-5 criteria among patients admitted to  their first treatment of alcohol use disorder (AUD). METHODS: Assessment of AUD was carried out using DSM-5 diagnostic criteria in a multicenter study (CohRTA) within the Spanish Network on Addictive Disorders. Further, baseline questionnaires including socio-demographics, family history, lifetime alcohol consumption and other substance use, as well as clinical and laboratory parameters were obtained during admission. RESULTS: 313 patients (74.8%M) were eligible; mean age at first AUD treatment was 48.8 years (standard deviation (SD): 9.9 years). Age at onset of alcohol use was 15.9 years (SD: 3.3 years) and age at starting regular alcohol consumption was 25.6 years (SD: 9.6 years). Almost 69.3% of patients were tobacco smokers and 61% had family history of AUD. Regarding other substance use, 7.7% were current cocaine users and 18.2% were cannabis users. Women started regular alcohol consumption later than men (p<,001) and used benzodiazepines more frequently (p=.013). According to DSM-5, 89.5% of cases had severe AUD (≥6 criteria). In the adjusted analysis (logistic regression), men were more likely to neglect major rules (OR=1.92, 95%CI: 1.06-3.48) and to have hazardous alcohol use (OR=3.00, 95%CI: 1.65-5.46). DISCUSSION: DSM-5 detects sex differences in patients seeking their first AUD treatment. Social impairment and risky alcohol use are significantly more frequent in men.

Objetivo: Analizar las diferencias de sexo en los criterios diagnósticos del DSM-5 de los pacientes que solicitan un tratamiento para el trastorno por uso de alcohol (TUA) por primera vez. Métodos: Pacientes incluidos entre enero 2014 y marzo 2016 en el estudio multicéntrico CohRTA de la Red de Trastornos Adictivos. El diagnóstico del TUA se realizó mediante el DSM-5. Además, se recogieron datos sociodemográficos, sobre el consumo de alcohol y otras sustancias, variables clínicas y una analítica general. Resultados: se incluyeron 313 pacientes (74,8% hombres); la edad al inicio del primer tratamiento fue de 48,8 años (desviación estándar (DE): 9,9 años), la edad al inicio del consumo de alcohol de 15,9 años (DE: 3,3 años) y la de inicio del consumo regular de 25,6 años (DE: 9,6 años). Un 69,3% de los pacientes eran fumadores y un 61% tenían antecedentes familiares de TUA. Un 7,7% eran consumidores de cocaína y un 18,2% de cannabis. Las mujeres iniciaron el consumo regular de alcohol más tarde que los hombres (p<,001) y usaban benzodiacepinas con mayor frecuencia (p=,013). Según el DSM-5, el 89,5% de los pacientes presentaban un TUA grave (≥6 criterios). En el análisis ajustado (regresión logística), los hombres tenían mayor probabilidad de presentar el criterio diagnóstico relacionado con el incumplimiento de los deberes fundamentales en el trabajo o en el hogar (OR=1,92, IC95%: 1,06-3,48) y el criterio diagnóstico de consumir alcohol en situaciones de riesgo físico (OR=3,00, IC95%: 1,65-5,46). Discusión: El DSM-5 detecta diferencias de sexo en pacientes que solicitan el primer tratamiento del TUA. El deterioro social y el consumo de alcohol de riesgo son significativamente más frecuentes en hombres.

Reasons for noncompliance with the national guidelines for initial antiretroviral therapy of HIV-infected patients in Spain, 2010-2015 / Razones para no cumplir las recomendaciones de las guías de práctica clínica en el tratamiento antirretroviral inicial de pacientes con infección por VIH en España, 2010-2015

INTRODUCTION: Our aims were to investigate the adherence to national guidelines of initial antiretroviral therapy (ART) in the Spanish multicenter CoRIS cohort during the years 2010-2015, to identify the reasons for the prescription of nonrecommended treatments, and to explore the role of institutional constraints to guideline compliance. METHODS: ART regimens were classified as recommended, alternative or nonrecommended according to the guidelines. Physicians were asked the reasons for prescribing nonrecommended regimens. Factors associated with the prescription of non recommended regimens were assessed using multivariable logistic regression. RESULTS: During the study period, 586 (10.7%) of 5479 patients who started ART were given a regimen not recommended in the guidelines. The most frequent reasons for prescribing nonrecommended regimens were: enrolment in clinical trials (43.3%), comorbidities and/or interactions (10.2%), pregnancy (8.7%), and cost (7.7%). Among 37 participating centers, 16 (43%), treating 3561 patients, reported limitations related with the cost of ART, and 20 (54%), treating 1365 patients, reported restrictions for prescribing at least one recommended antiretroviral. In multivariable analysis, a higher risk of receiving nonrecommended regimens was associated with male gender, HIV acquisition by heterosexual transmission, low viral loads, initiation of treatment during the years 2011 to 2015, and initiation of treatment in a center with restricted access to at least one antiretroviral drug. CONCLUSIONS: Compliance to clinical guidelines was high. A high proportion of centres reported cost limitations for ART or restricted access to at least one recommended antiretroviral drug, with a significant impact on the choice of initial regimens

INTRODUCCIÓN: Nuestros objetivos fueron investigar la adecuación del tratamiento antirretroviral (TAR) inicial a las guías nacionales en la cohorte multicéntrica española CoRIS durante los años 2010-2015, identificar las razones para la prescripción de pautas no recomendadas y estudiar la influencia de limitaciones institucionales en el cumplimiento de las guías. MÉTODOS: Se clasificaron las pautas de TAR en recomendadas, alternativas o no recomendadas según las guías de GeSIDA/Plan Nacional sobre el sida. Se preguntaron las razones para haber prescrito pautas no recomendadas a los médicos prescriptores. Se evaluaron los factores asociados a la prescripción de pautas no recomendadas mediante regresión logística multivariable. RESULTADOS: Durante el periodo de estudio 586 (10,7%) de 5.479 pacientes que iniciaron TAR recibieron una pauta no recomendada. Las razones más frecuentes para prescribir pautas no recomendadas fueron: participación en ensayo clínico (43,3%), comorbilidades y/o interacciones (10,2%), embarazo (8,7%) y coste (7,7%). Entre los 37 centros participantes 16 (43%), que incluían 3.561 pacientes, referían limitaciones en el coste del TAR y 20 (54%), que incluían 1.365 pacientes, referían restricciones para la prescripción de al menos un fármaco recomendado. En el análisis multivariable el riesgo de recibir una pauta no recomendada se asoció a ser varón, adquisición del VIH por vía heterosexual, carga viral baja, inicio del tratamiento durante los años 2011 a 2015 e inicio del tratamiento en un centro con acceso restringido al menos a un antirretroviral. CONCLUSIONES: El cumplimiento de las guías de TAR fue elevado. Una alta proporción de centros refirieron limitaciones de coste para el TAR o acceso restringido al menos a uno de los fármacos antirretrovirales recomendados; esto último influyó en la elección de pautas no recomendadas

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors.

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4<200 cells/µL and HIV-RNA>100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4<200 cells/µL and HIV-RNA>100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//µL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location.

Reasons for noncompliance with the national guidelines for initial antiretroviral therapy of HIV-infected patients in Spain, 2010-2015.

INTRODUCTION: Our aims were to investigate the adherence to national guidelines of initial antiretroviral therapy (ART) in the Spanish multicenter CoRIS cohort during the years 2010-2015, to identify the reasons for the prescription of nonrecommended treatments, and to explore the role of institutional constraints to guideline compliance. METHODS: ART regimens were classified as recommended, alternative or nonrecommended according to the guidelines. Physicians were asked the reasons for prescribing nonrecommended regimens. Factors associated with the prescription of non recommended regimens were assessed using multivariable logistic regression. RESULTS: During the study period, 586 (10.7%) of 5479 patients who started ART were given a regimen not recommended in the guidelines. The most frequent reasons for prescribing nonrecommended regimens were: enrolment in clinical trials (43.3%), comorbidities and/or interactions (10.2%), pregnancy (8.7%), and cost (7.7%). Among 37 participating centers, 16 (43%), treating 3561 patients, reported limitations related with the cost of ART, and 20 (54%), treating 1365 patients, reported restrictions for prescribing at least one recommended antiretroviral. In multivariable analysis, a higher risk of receiving nonrecommended regimens was associated with male gender, HIV acquisition by heterosexual transmission, low viral loads, initiation of treatment during the years 2011 to 2015, and initiation of treatment in a center with restricted access to at least one antiretroviral drug. CONCLUSIONS: Compliance to clinical guidelines was high. A high proportion of centres reported cost limitations for ART or restricted access to at least one recommended antiretroviral drug, with a significant impact on the choice of initial regimens.

Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals.

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the "no direct effect" assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/µl compared with 500 cells/µl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size.