Dysregulation of Plasma Growth Factors and Chemokines in Cocaine Use Disorder: Implications for Dual Diagnosis with Schizophrenia and Antisocial Personality Disorder in an Exploratory Study.

INTRODUCTION: Dual diagnosis in individuals with cocaine use disorders (CUDs) presents a mental health challenge marked by an increased susceptibility to disabling morbidities and premature mortality. Despite extensive research on depression and anxiety, other prevalent comorbidities, such as psychotic and personality disorders, have received less attention. This study explores inflammation-related mediators as potential biomarkers for CUD and dual diagnosis with schizophrenia (SCZ) or antisocial personality disorder (APD). METHODS: This exploratory study included 95 participants, comprising 40 healthy subjects and 55 abstinent patients with CUD. Lifetime CUD was diagnosed either as single diagnosis (CUD group, N = 25) or as a dual diagnosis (DD group. N = 30) with SCZ (CUD+SCZ subgroup) or APD (CUD+APD subgroup). Participants were clinically assessed, and the plasma concentrations of growth factors (i.e., G-CSF, BDNF, and VEGF-A) and chemokines (i.e., CCL11/eotaxin-1, CCL2/MCP-1, and CXCL12/SDF-1) were determined and log(10)-transformed for analysis. RESULTS: Growth factors and chemokines were dysregulated by CUD and psychiatric diagnoses. Specifically, patients in the CUD group exhibited significantly lower concentrations of G-CSF and CCL11/eotaxin-1 than the control group. In contrast, the DD group showed significantly higher concentrations of all analytes than both the CUD and control groups. Additionally, no differences in these analytes were observed between the CUD+SCZ and CUD+APD subgroups within the DD group. Regarding cocaine-related variables, significant associations were identified in the CUD group: an inverse correlation between the age at first cocaine use and the concentrations of BDNF and CCL2/MCP-1; and a positive correlation between the duration of the cocaine abstinence and the concentrations of BDNF and CCL11/eotaxin-1. Lastly, a logistic regression model incorporating all these analytes demonstrated high discriminatory power in distinguishing patients with CUD alone from those with dual diagnosis. CONCLUSIONS: Individuals with dual diagnosis of CUD exhibit elevated concentrations of growth factors and chemokines, distinguishing them from those with CUD alone. It is unclear whether the differences in these inflammatory mediators are specific to the presence of SCZ and APD. The study highlights potential biomarkers and associations, providing valuable insights into the intricate interplay of CUD and psychiatric disorders to enhance clinical diagnosis and therapeutics.

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.

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.

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.

Metabolic syndrome among individuals with heroin use disorders on methadone therapy: Prevalence, characteristics, and related factors.

BACKGROUND: Observational studies have reported a high prevalence of obesity and diabetes in subjects on methadone therapy; there are, however, limited data about metabolic syndrome. The aim of the study was to evaluate the prevalence of metabolic syndrome and related factors in individuals with heroin use disorder on methadone therapy. METHODS: A cross-sectional study in individuals with heroin use disorder on methadone therapy at a drug abuse outpatient center. Medical examinations and laboratory analyses after a 12-hour overnight fast were recorded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. RESULTS: One hundred and twenty-two subjects were included, with a mean age of 46.1 ± 9 years, a median body mass index (BMI) of 25.3 kg/m2 (interquartile range [IQR]: 21.2-28), and 77.9% were men. Median exposure to methadone therapy was 13 years (IQR: 5-20). Overweight and obesity were present in 29.5% and 17.2% of the participants, respectively. Metabolic syndrome components were low high-density lipoprotein (HDL) cholesterol (51.6%), hypertriglyceridemia (36.8%), high blood pressure (36.8%), abdominal obesity (27.0%), and raised blood glucose levels (18.0%). Abdominal obesity was more prevalent in women (52% vs. 20%, P = >0.01) and high blood pressure more prevalent in men (41.1% vs. 22.2%, P = .07). Prevalence of metabolic syndrome was 29.5% (95% confidence interval [CI]: 16.6-31.8). In the multivariate logistic regression analysis, BMI (per 1 kg/m2 increase odds ratio [OR]: 1.49, 95% CI: 1.27-1.76) and exposure time to methadone therapy (per 5 years of treatment increase OR: 1.38, 95% CI: 1.28-1.48) were associated with metabolic syndrome. CONCLUSIONS: Overweight and metabolic syndrome are prevalent findings in individuals with heroin use disorder on methadone therapy. Of specific concern is the association of methadone exposure with metabolic syndrome. Preventive measures and clinical routine screening should be recommended to prevent metabolic syndrome in subjects on methadone therapy.

Patients with alcohol use disorder: initial results from a prospective multicenter registry in the Spanish Network on Addiction Disorders. CohRTA Study. / Pacientes con trastorno por uso de alcohol: resultados iniciales de un registro multicéntrico en la Red de Trastornos Adictivos-RTA. Estudio CohRTA.

The Alcohol Program of the Spanish Network on Addictive Disorders-RTA requires a longitudinal study to address different research questions related to alcoholism. The cohort study (CohRTA) focuses on patients seeking treatment for alcohol use disorder, as a multicentre, collaborative research project aimed to improve secondary prevention and early diagnosis of pathological processes associated with the disorder. Methods: multicentre cohort study in adults (>18 years) seeking their first treatment of the disorder. Patients sign an informed consent and data is collected in an online platform specifically designed for the study; patients are also requested to provide biological samples that are stored in a biobank. Baseline and prospective, socio-demographic, epidemiological, clinical and treatment data are collected. Currently there are 10 participating centres that expect to recruit more than 1,000 patients. Results: As of December 2015, 344 patients (77% men) were included. Median age at admission was 50 years (IQR: 43-55 years). Median age at the start of alcohol consumption was 15 years (IQR: 14-18 years) and 61% of cases reported antecedents of alcohol use disorder in the family. During the 30 days prior to admission, alcohol consumption amounted to 12.5 SDU/day (IQR: 7.1-20 SDU/day), 72% of the patients were tobacco smokers and 30% currently used cocaine. Organising an open cohort of patients with alcohol use disorder may be crucial to better understand the clinical consequences of alcoholism in Spain. This cohort may potentiate quantitative and qualitative research within the Spanish Network on Addictive Disorders-RTA/RETICS. Having a well-established, representative cohort of patients will increase translational research on consequences of alcoholism in our country.

El Programa Alcohol de la Red de Trastornos Adictivos (RTA) requiere de un estudio clínico longitudinal para dar respuesta a preguntas de investigación en el trastorno por uso de alcohol. El proyecto CohRTA es un estudio multicéntrico de investigación cooperativa que se pone en marcha para mejorar la prevención secundaria y el diagnóstico precoz de los procesos patológicos asociados al trastorno por uso de alcohol. Método: estudio observacional en cohorte multicéntrica de pacientes mayores de 18 años que solicitan tratamiento del trastorno por primera vez y autorizan su participación. La información clínica se recoge en una plataforma online diseñada para el estudio y puede ir acompañada de una muestra biológica que se deposita en un biobanco. Se recogen datos basales y prospectivos, sociodemográficos, epidemiológicos, clínicos y de tratamiento. A diciembre de 2015 son 10 los centros proveedores de pacientes y se espera reclutar más de 1.000 pacientes en los próximos años. Resultados: se dispone de 344 pacientes (77% hombres) que cumplen los criterios de inclusión en el estudio y con una edad de 50 años (RIQ: 43-55 años). La edad de inicio de consumo de alcohol fue de 15 años (RIQ: 14-18 años) y un 61% tenían antecedente familiar de trastorno por uso de alcohol. Durante los 30 días previos al inicio del tratamiento los pacientes bebían 12.5 UBE/día (RIQ: 7.1-20 UBE/día), el 72% fumaba tabaco y el 30% consumía cocaína. Conclusiones: Disponer de una cohorte abierta y multicéntrica de pacientes con trastorno por uso de alcohol será útil para analizar las consecuencias del abuso de alcohol, potenciar la investigación traslacional y añadir valor a la investigación clínica y básica del Programa Alcohol dentro de RTA/RETICS. Con una cohorte bien establecida y representativa se espera aumentar la cantidad y calidad científica en relación a las complicaciones del trastorno por uso de alcohol y sus consecuencias clínicas y sociales en España.

Long-Term Mortality of Patients with an Alcohol-Related Wernicke-Korsakoff Syndrome.

AIMS: To characterize a series of contemporary patients with alcohol-related Wernicke's encephalopathy (WE) or Korsakoff's syndrome (KS) and to update the current prognosis of disease. METHODS: Retrospective and prospective study of patients diagnosed with an alcohol-related WE or KS between 2002 and 2011 in a tertiary hospital. Socio-demographic, alcohol use characteristics, signs and symptoms, co-morbidity and blood parameters were obtained at admission. Patients were followed up until 2013 and causes of death were ascertained through the review of charts. RESULTS: Sixty-one patients were included (51 with WE and 10 with KS). Among patients with WE, 78% were men and age at diagnosis was 57 years (interquartile range (IQR): 49-66). Twenty-three percent fulfilled the classic WE triad. Regarding Caine's criteria for WE, 70.6% presented with at least two out of four signs or symptoms. Median follow-up of patients with WE syndrome was 5.3 years (IQR: 2.6-8.8), the cumulated mortality was 45% and death rate of 7.4 × 100 person-years (95% confidence interval (CI): 4.8-10.9). Overall, 50% of patients would be expected to die within 8 years of WE episode and main causes of death included serious bacterial infections (44.5%) and cancer (33.3%). CONCLUSIONS: Survival of patients with an alcohol-related Wernicke-Korsakoff syndrome is poor; pursuing treatment of alcohol use disorder and early diagnosis of thiamine deficiency is a priority for improving clinical outcomes.

Boosted lopinavir- versus boosted atazanavir-containing regimens and immunologic, virologic, and clinical outcomes: a prospective study of HIV-infected individuals in high-income countries.

BACKGROUND: Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience. METHODS: We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004-2013. Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the 'intention-to-treat' effect for atazanavir vs lopinavir regimens on each of the outcomes. RESULTS: A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53-.91) for death, 0.67 (95% CI, .55-.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84-.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, -.13 to 16.43) cells/µL higher in the atazanavir group. Estimates differed by NRTI backbone. CONCLUSIONS: Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens.

Hepatitis C associated to substance abuse: ever closer to a treatment without Interferon.

With 3-4 million of new infections occurring annually, hepatitis C virus (HCV) infection is a global Public Health problem. In fact, hepatitis C virus infection is one of the leading causes of liver disease in the world; in Western countries, two thirds of the new HCV infections are associated with injection drug use. The treatment of hepatitis C will change in the coming years with the irruption of new anti-HCV drugs, the so called Direct Antiviral Agents (DAA) that attack key proteins of the HCV life cycle. The new antiviral drugs are effective, safer and better tolerated. The 2014 WHO HCV treatment guidelines include some of them. The new DAA are used in combination and it is expected that Interferon will be not necessary in future treatment regimens against HCV infection. The irruption of new and potent antivirals mandate the review of the current standards of care in the HCV infected population. More inclusive and proactive treatment policies will be necessary in those individuals with substance use disorders.

La infección por el virus de la hepatitis C (VHC) es un problema de Salud Pública de primera magnitud; cada año ocurren entre 3 y 4 millones de nuevas infecciones y de hecho, la hepatitis crónica C es una de las principales causas de enfermedad hepática en el mundo. Usar drogas por vía parenteral está en el origen de dos de cada tres nuevas infecciones por VHC en el mundo occidental.El tratamiento de la hepatitis C va a cambiar en los próximos años. El cambio es debido a la aparición de los llamados Antivirales de Acción Directa (AAD), unos fármacos que actúan contra proteínas clave del ciclo vital del VHC y que serán más eficaces, mejor tolerados y se administrarán durante menos tiempo. En este sentido, la nueva guía de tratamiento de la OMS en 2014 ya incluye alguno de ellos en sus recomendaciones; los nuevos fármacos se utilizarán en combinación y probablemente se podrá prescindir del Interferón.Con la aparición de más y mejores antivirales contra el VHC es probable que debamos revisar el modelo asistencial vigente y orientarlo hacia uno más ágil e integrador, que trate al mayor número posible de pacientes, incluyendo a aquellos con abuso de sustancias.

Effect of HCV infection on cause-specific mortality after HIV seroconversion, before and after 1997.

BACKGROUND & AIMS: Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the duration of HIV infection. METHODS: We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural. RESULTS: Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease. CONCLUSIONS: Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression.

Sex-specific disease outcomes of HIV-positive and HIV-negative drug users admitted to an opioid substitution therapy program in Spain: a cohort study.

BACKGROUND: Opioid substitution therapy has improved the survival of heroin users with and without HIV infection. We aimed to analyze sex differences in mortality rates and predictors of death among those admitted to a methadone treatment program (MTP). METHODS: Longitudinal study of patients enrolled in a MTP from 1992 to 2010. Socio-demographic and drug use characteristics, and markers of viral infections were assessed at entry. Vital status was ascertained by clinical charts and the mortality register. Four calendar periods were defined according to the introduction of preventive and treatment interventions in Spain. Predictors of death were analyzed by Cox regression models. RESULTS: 1,678 patients (82.8% men) were included; age at first heroin use was 18.6 years (IQR: 16-23 years), and age at first entry into a MTP was 30.7 years (IQR: 26-36 years). A total of 441 (26.3%) deaths occurred during 15,124 person-years (p-y) of follow-up (median: 9.2 years, IQR: 4-13 years). HIV infection was the main predictor of death in men (HR = 3.5, 95% CI: 2.1-5.7) and women (HR = 3.2, 95% CI: 1.2-8.7 ) and main cause of death was HIV/AIDS. Overall mortality rate was 2.9 per 100 p-y (95% CI: 2.7-3.2 per 100 p-y) and death rates decreased over time: 7.4 per 100 p-y (95% CI: 6.3-8.8 per 100 p-y) for the 1992-1996 period to 1.9 per 100 p-y (95% CI: 1.6-2.4 per 100 p-y) for the 2007-2010 period. In women, a slightly increase in mortality was observed in recent periods specifically among HIV-positive women (3.7 per 100 p-y in period 2002-2006 and 4.5 per 100 p-y in 2007-2010). CONCLUSIONS: Significant reductions in mortality of patients in MTP are observed after nineteen years of observation. However, HIV infection shows a great impact on survival, particularly among HIV-infected women.

Risk of QTc prolongation in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy.

BACKGROUND: Concern regarding the QTc interval in human immunodeficiency virus (HIV)-infected patients has been growing in recent years, and cases of prolonged QTc interval and torsades de pointes have been described in HIV-infected patients on methadone therapy. This study aimed to determine the prevalence and factors associated with long QTc interval in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. METHODS: A cross-sectional study was conducted in opioid-dependent HIV-infected patients on methadone maintenance therapy at a drug abuse outpatient center. Patients with any cardiac disease, drug-positive urine test, electrolyte abnormalities, and changes in their antiretroviral therapy (ART) or methadone doses in the last 2 months were excluded. Heart rate and QT interval in lead II were measured using the Bazett formula. RESULTS: Ninety-one patients were included: 58 (63.7%) were men with a median age of 44.5 years and 68 of 91 (74.7%) were on ART. Median methadone dose was 70 mg/day (range 15-250 mg/day) and mean QTc interval was 438 ± 34 ms. Prolonged QTc interval (>450 ms) was documented in 33 of 91(36.3%) patients, and 3 of 91 (3.2%) had QTc >500 ms. On multiple linear regression analysis, methadone doses (P = .005), chronic hepatitis C-induced cirrhosis (P = .008), and being ART-naive (P = .036) were predictive of prolonged QTc. CONCLUSIONS: The prevalence of prolonged QTc interval in opioid-dependent HIV-infected patients on methadone maintenance therapy is high. Risk factors for prolongation of the QTc interval are chronic hepatitis C-induced cirrhosis, higher methadone doses, and being ART-naive. Thus, electrocardiographic monitoring is required to minimize cardiovascular morbidity and mortality in this specific HIV group.

Risk of tuberculosis following HIV seroconversion in high-income countries.

BACKGROUND: Few data exist on tuberculosis (TB) incidence according to time from HIV seroconversion in high-income countries and whether rates following initiation of a combination of antiretroviral treatments (cARTs) differ from those soon after seroconversion. METHODS: Data on individuals with well estimated dates of HIV seroconversion were used to analyse post-seroconversion TB rates, ending at the earliest of 1 January 1997, death or last clinic visit. TB rates were also estimated following cART initiation, ending at the earliest of death or last clinic visit. Poisson models were used to examine the effect of current and past level of immunosuppression on TB risk after cART initiation. RESULTS: Of 19 815 individuals at risk during 1982-1996, TB incidence increased from 5.89/1000 person-years (PY) (95% CI 3.77 to 8.76) in the first year after seroconversion to 10.56 (4.83 to 20.04, p=0.01) at 10 years. Among 11 178 TB-free individuals initiating cART, the TB rate in the first year after cART initiation was 4.23/1000 PY (3.07 to 5.71) and dropped thereafter, remaining constant from year 2 onwards averaging at 1.64/1000 PY (1.29 to 2.05). Current CD4 count was inversely associated with TB rates, while nadir CD4 count was not associated with TB rates after adjustment for current CD4 count, HIV-RNA at cART initiation. CONCLUSIONS: TB risk increases with duration of HIV infection in the absence of cART. Following cART initiation, TB incidence rates were lower than levels immediately following seroconversion. Implementation of current recommendations to prevent TB in early HIV infection could be beneficial.

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997-2010.

BACKGROUND: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIV-infected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. METHODS: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 person-years (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. RESULTS: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997-2003). CONCLUSION: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection.

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.

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.

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study.

BACKGROUND: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate. OBJECTIVE: To identify the optimal CD4 cell count at which cART should be initiated. DESIGN: Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L. SETTING: HIV clinics in Europe and the Veterans Health Administration system in the United States. PATIENTS: 20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis. MEASUREMENTS: Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death. RESULTS: Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. LIMITATIONS: CD4 cell count at cART initiation was not randomized. Residual confounding may exist. CONCLUSION: Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.

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.

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.