Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection.

Integrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

NEU Screen Shows High Accuracy in Detecting Cognitive Impairment in Older Persons Living With HIV.

The NEUrocognitive (NEU) Screen is a practical tool proposed to screen for HIV-associated cognitive impairment in the clinical setting. This is a pencil-and-paper method that can be applied rapidly (≤10 minutes for administration) and has no copyright limitations. In this study, we aimed at investigating its diagnostic accuracy in an older population of persons living with HIV (PLWH), with cutoffs set at 30, 40, 50, and 60 years. Data were collected from a sample of 368 PLWH who underwent a comprehensive neuropsychological tests battery (gold standard). Results of statistical tests showed that accuracy of the NEU Screen increased with age of the participants. The highest degree of precision, with a sensitivity of 91% and specificity of 92%, was obtained for people ages 60 years or older (correct classification: 91%). These optimal results point to the great potential of the NEU Screen as a tool for detecting cognitive disorders in older PLWH.

Transdermal rivastigmine for HIV-associated cognitive impairment: A randomized pilot study.

OBJECTIVE: To assess the efficacy and safety of transdermal rivastigmine for the treatment of HIV-associated cognitive impairment. METHODS: We recruited HIV-infected patients with cognitive impairment on stable antiretroviral therapy in a randomized controlled pilot trial with a 48-week follow-up. An additional assessment was held at 12 weeks. Participants received transdermal rivastigmine (9.5 mg daily), lithium (400 mg twice daily, titrated progressively), or remained in a control group (no new medication). The primary efficacy endpoint was change in a global cognitive score (NPZ-7). Secondary endpoints included change in specific cognitive measures, domains, and functional parameters. Safety covered the frequency of adverse events and changes in laboratory results. RESULTS: Seventy-six subjects were screened, and 29 were finally enrolled. Better cognitive outcomes were observed in all groups, although there were no significant differences between the arms (mean NPZ-7 change [SD]): rivastigmine, 0.35 (0.14); lithium, 0.25 (0.40); control, 0.20 (0.44) (p = 0.78). The rivastigmine group showed the highest positive trend (mean NPZ-7 [SD], baseline vs week 48): rivastigmine, -0.47 (0.22) vs -0.11 (0.29), p = 0.06; lithium, -0.50 (0.40) vs -0.26 (0.21), p = 0.22; control, -0.52 (0.34) vs -0.32 (0.52), p = 0.44. The cognitive domains with the highest positive trends were information processing speed at week 12 and executive function at week 48 (rivastigmine vs control): information processing speed, 0.35 (0.64) vs -0.13 (0.25), p = 0.17, d = 0.96; and executive functioning, 0.73 (0.33) vs 0.03 (0.74), p = 0.09, d = 1.18. No relevant changes were observed regarding functional outcomes. A total of 12 (41%) individuals dropped out of the study: 2 (20%) were due to medication-related effects in the rivastigmine group and 4 (36%) in the lithium group. No severe adverse events were reported. CONCLUSIONS: The results from this small randomized trial indicate that transdermal rivastigmine did not provide significant cognitive benefits in people with HAND on stable antiretroviral therapy, even though positive trends were found in specific cognitive domains. Relevant tolerability issues were not observed.

Impact of different hypopnea definitions on obstructive sleep apnea severity and cardiovascular mortality risk in women and elderly individuals.

OBJECTIVE: To assess the impact of three hypopnea definitions on the severity classification of obstructive sleep apnea (OSA) and its association with cardiovascular mortality risk in women and elderly individuals. METHODS: We analyzed two Spanish clinical cohorts (1116 women and 939 elderly individuals) who were studied for suspicion of OSA between 1998 and 2007. A calibration model was used to apply different definitions of hypopnea to our two cohorts. Hypopnea was defined as a 30-90% reduction in oronasal flow for ≥10 s followed by (1) ≥4% fall in oxyhemoglobin saturation-AHI4%; (2) ≥3% fall in oxyhemoglobin saturation-AHI3%; or (3) ≥3% fall in oxyhemoglobin saturation or an event-related arousal-AHI3%a. RESULTS: In both cohorts, the prevalence of an AHI ≥30 events/h increased by 14% with AHI3%a, compared to AHI4% criteria. The percentage of women with an AHI <5 events/h decreased from 13.9% with AHI4% to 1.1% with the AHI3%a definition. In fully adjusted multivariable analyses, AHI ≥30 events/h was associated with increased cardiovascular mortality risk in women, regardless of the hypopnea definition, and in elderly individuals diagnosed using the AHI4% and AHI3% but not the AHI3%a definition. CONCLUSIONS: Our findings suggest that hypopnea definitions substantially influence OSA prevalence and severity classification, and also affect the association with cardiovascular outcomes. With the currently recommended criterion (AHI3%a), a threshold of 30 events/h is appropriate to identify women, but not elderly individuals with increased risk of cardiovascular death.

Classification models for neurocognitive impairment in HIV infection based on demographic and clinical variables.

OBJECTIVE: We used demographic and clinical data to design practical classification models for prediction of neurocognitive impairment (NCI) in people with HIV infection. METHODS: The study population comprised 331 HIV-infected patients with available demographic, clinical, and neurocognitive data collected using a comprehensive battery of neuropsychological tests. Classification and regression trees (CART) were developed to obtain detailed and reliable models to predict NCI. Following a practical clinical approach, NCI was considered the main variable for study outcomes, and analyses were performed separately in treatment-naïve and treatment-experienced patients. RESULTS: The study sample comprised 52 treatment-naïve and 279 experienced patients. In the first group, the variables identified as better predictors of NCI were CD4 cell count and age (correct classification [CC]: 79.6%, 3 final nodes). In treatment-experienced patients, the variables most closely related to NCI were years of education, nadir CD4 cell count, central nervous system penetration-effectiveness score, age, employment status, and confounding comorbidities (CC: 82.1%, 7 final nodes). In patients with an undetectable viral load and no comorbidities, we obtained a fairly accurate model in which the main variables were nadir CD4 cell count, current CD4 cell count, time on current treatment, and past highest viral load (CC: 88%, 6 final nodes). CONCLUSION: Practical classification models to predict NCI in HIV infection can be obtained using demographic and clinical variables. An approach based on CART analyses may facilitate screening for HIV-associated neurocognitive disorders and complement clinical information about risk and protective factors for NCI in HIV-infected patients.

Quejas cognitivas en personas con infección por el virus de la inmunodeficiencia humana en España: prevalencia y variables relacionadas / Cognitive complaints in people with human immunodeficiency virus in Spain: prevalence and related variables

Fundamento y objetivo: La existencia de quejas cognitivas en personas con VIH ha sido poco estudiada en España. El objetivo de este estudio fue conocer la prevalencia de quejas cognitivas en personas con VIH, así como sus posibles relaciones con variables demográficas, clínicas y psicológicas, en la época de los tratamientos antirretrovirales combinados. Pacientes y método: Estudio multicéntrico observacional desarrollado en 4 hospitales y 10 ONGs en el que participaron 791 personas con VIH en España. Para la recogida de datos se utilizó un cuestionario autorreferido que evaluó variables demográficas y clínicas, e incluyó también la evaluación de quejas cognitivas, el estado emocional y la calidad de vida. El análisis de datos incluyó pruebas estadísticas descriptivas e inferenciales. Resultados: Casi la mitad de la muestra (49,8%) manifestó quejas cognitivas, un 72,1% hallando relación con interferencia en la vida diaria. La memoria y la concentración fueron las áreas más percibidas como alteradas. La presencia de queja cognitiva se relacionó significativamente con un mayor tiempo de infección, un menor número de CD4, carga viral indetectable y peor calidad de vida. Un análisis discriminante mostró que la depresión, la ansiedad, una mayor edad, estar sin pareja y un bajo nivel de estudios fueron las variables que permitieron clasificar mejor a las personas con VIH y queja cognitiva. Conclusiones: Las quejas cognitivas son frecuentes en personas con VIH en la época de los tratamientos antirretrovirales combinados. Este hecho está relacionado con una peor salud psicológica y calidad de vida, así como con un peor estado inmunológico y virológico (AU)

Background and objective Cognitive complaints have been scarcely studied in people with HIV in Spain. The aim of this research was to know the prevalence of cognitive complaints in HIV-infected people, as well as its potential relationships with demographic, clinical and psychological variables, in the era of combination antiretroviral therapies. Patients and method Observational multicenter study developed in 4 hospitals and 10 NGOs, in which 791 people with HIV in Spain participated. A self-reported questionnaire was used to evaluate demographic and clinical variables, and an assessment of cognitive complaints, emotional status and quality of life variables was also included. Descriptive and inferential tests were used for statistical analyses. Results Almost half of the sample (49.8%) referred cognitive complaints, in 72.1% of them an association with interference on daily living activities was found. Memory and attention were the areas most prevalently perceived as affected. The existence of cognitive complaints correlated with a longer HIV infection, lower CD4+ cell count, undetectable viral load and worse quality of life. A discriminant analysis determined that depression, anxiety, older age, living with no partner and low education level allowed to classify optimally HIV-infected people with cognitive complaints. Conclusions Self-reported cognitive complaints are frequent in people infected with HIV in the current era of combination antiretroviral therapies. This fact is related to emotional disturbances and poor quality of life, but also to impaired immunological and virological status (AU)

[Cognitive complaints in people with human immunodeficiency virus in Spain: prevalence and related variables]. / Quejas cognitivas en personas con infección por el virus de la inmunodeficiencia humana en España: prevalencia y variables relacionadas.

BACKGROUND AND OBJECTIVE: Cognitive complaints have been scarcely studied in people with HIV in Spain. The aim of this research was to know the prevalence of cognitive complaints in HIV-infected people, as well as its potential relationships with demographic, clinical and psychological variables, in the era of combination antiretroviral therapies. PATIENTS AND METHOD: Observational multicenter study developed in 4 hospitals and 10 NGOs, in which 791 people with HIV in Spain participated. A self-reported questionnaire was used to evaluate demographic and clinical variables, and an assessment of cognitive complaints, emotional status and quality of life variables was also included. Descriptive and inferential tests were used for statistical analyses. RESULTS: Almost half of the sample (49.8%) referred cognitive complaints, in 72.1% of them an association with interference on daily living activities was found. Memory and attention were the areas most prevalently perceived as affected. The existence of cognitive complaints correlated with a longer HIV infection, lower CD4+ cell count, undetectable viral load and worse quality of life. A discriminant analysis determined that depression, anxiety, older age, living with no partner and low education level allowed to classify optimally HIV-infected people with cognitive complaints. CONCLUSIONS: Self-reported cognitive complaints are frequent in people infected with HIV in the current era of combination antiretroviral therapies. This fact is related to emotional disturbances and poor quality of life, but also to impaired immunological and virological status.

A brief and feasible paper-based method to screen for neurocognitive impairment in HIV-infected patients: the NEU screen.

OBJECTIVE: Practical screening methods are necessary to detect neurocognitive impairment (NCI) in HIV-infected patients. We aimed to find a brief and feasible paper-based tool to facilitate the diagnosis of an HIV-associated neurocognitive disorder. METHODS: A total of 106 HIV-infected outpatients with variable clinical characteristics were recruited in a multicenter investigation. NCI was diagnosed using a standardized neuropsychological tests battery (7 areas, 21 measures, ∼2 hours). Multiple score combinations were compared to find a paper-based method that took ≤10 minutes to apply. The presence of NCI was considered the gold standard for comparisons, and the sensitivity and specificity were calculated. RESULTS: Subjects were mostly middle-aged (median, 44 years) men (87%) on antiretroviral treatment. NCI was detected in 51 individuals (48%) and was associated with lower nadir CD4 count (P < 0.001), receiving antiretroviral therapy (P = 0.004), fewer years of education (P = 0.009), and presence of comorbidities (P < 0.001). The score combination that showed the highest sensitivity (74.5%) and specificity (81.8%) detecting NCI included 3 measures of attention/working memory, executive functioning, and verbal fluency (part A of Trail Making Test, part B of Trail Making Test, and Controlled Oral Word Association Test scores). A broader paper-based selection of measures covering 7 areas indicated a sensitivity of 100% and a specificity of 96.3% (7 measures, ∼35 minutes). CONCLUSIONS: The combination of the 3 measures presented in this study seems to be a rapid and feasible screening mean for NCI in HIV-infected patients. This approach, combined with screening for potential comorbidities and daily functioning interference, could help in the initial stages of a HIV-associated neurocognitive disorder diagnosis and in settings with limited access to neuropsychological resources.

Otitis externa maligna. Nuestra experiencia / Malignant otitis externa. Our experience

La otitis externa maligna es una infección severa cuyo diagnóstico y tratamiento continua suponiendo un reto para el clínico. El objeto de este estudio es demostrar la importancia de un análisis clínico detallado y aportar una puesta al día de las herramientas diagnósticas y terapéuticas actualmente disponibles (AU)

Malignant otitis externa is a devastating disease that poses a diagnostic and therapeutic challenge. The objective of our study was to demonstrate the importance of detailed clinical analysis and to provide an update on the current diagnostic and therapeutic tools available (AU)

Interruptions of antiretroviral therapy in human immunodeficiency virus infection: are they detrimental to neurocognitive functioning?

Because interruptions of antiretroviral treatment may entail clinical risks for human immunodeficiency virus (HIV)-infected individuals, we investigated their impact on neurocognitive functioning. Cross-sectional study was carried out, comparing HIV-infected persons who had interrupted antiretroviral therapy in the past (interruption group, IG) with persons who had never discontinued therapy (noninterruption group, NIG). Interruption was defined as the discontinuation of highly active antiretroviral therapy (HAART) for more than 15 days after previous treatment of at least 15 days. All the participants were on therapy. Demographic, clinical, and neurocognitive variables were assessed. The primary end point was the percentage of people with neurocognitive impairment. The score in different neurocognitive domains was a secondary end point. A total of 83 subjects participated in the study (IG: n = 27; NIG: n = 56). Demographic and clinical characteristics were balanced between the groups, except for years since HIV diagnosis (IG, 13.8; NIG, 10.2 [P = .003]). The percentage of people with neurocognitive impairment was significantly higher in the IG group (IG, 59.25%; NIG, 33.92% [P = 0.02]). As for scores in neurocognitive domains, individuals in the IG showed worse neurocognitive functioning, and significant differences in attention/working memory and information processing speed were found. The adjusted analysis supported the unadjusted analysis. In this study, a higher prevalence of neurocognitive impairment was detected in HIV-infected persons who had interrupted antiretroviral therapy in the past. Additionally, neurocognitive functioning was observed to be more impaired in the same individuals. Further studies should examine the potential negative effects of antiretroviral therapy interruptions on neurocognitive functioning.

[Malignant otitis externa. Our experience]. / Otitis externa maligna. Nuestra experiencia.

Malignant otitis externa is a devastating disease that poses a diagnostic and therapeutic challenge. The objective of our study was to demonstrate the importance of detailed clinical analysis and to provide an update on the current diagnostic and therapeutic tools available.

Neuropsychiatric symptoms associated with efavirenz: prevalence, correlates, and management. A neurobehavioral review.

The non-nucleoside analog reverse transcriptase inhibitor efavirenz is one of the most common components of HAART. Neuropsychiatric symptoms are frequently reported in patients taking efavirenz-based regimens. These symptoms are usually transient, although they can sometimes persist for up to two years after initiation of treatment. This review describes in detail the most common neuropsychiatric symptoms related to efavirenz, outlines relevant and recent findings on this agent, and suggests possible interventions based on neurobehavioral results. Different recommendations on the assessment of efavirenz-related adverse events are also provided.

Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients.

Though antiretroviral therapy attenuates neurocognitive disruption, impairment is still observed. We studied the nadir CD4 cell count as a predictor of neurocognitive changes. This cross-sectional study assessed 64 HIV-infected patients in two groups: G1 (n = 26, nadir CD4 < or =200 cells/ml) and G2 (n = 38, nadir CD4 >200 cells/ml). Percentages of patients showing neurocognitive impairment were compared according to different nadir CD4 cutoffs (200, 250, 300, and 350 cells/ml). From G2, we also took the subgroup of patients receiving treatment (G3) and compared this group with G1, in which all patients were being treated. Demographic and clinical variables were evaluated, as were differences in neurocognitive function. Neurocognitive impairment tended to be more prevalent in G1 [19 patients (73.1%)] than in G2 [20 (52.6%), p = 0.123]. When nadir CD4 cutoffs were compared, there was a trend toward more impaired subjects as the CD4 nadir decreased. Significantly different functioning was found in attention/working memory (digit span backward, p = 0.032) and executive functions (trail making test, part B, p = 0.020), with better performance in G2. Comparison between G1 and G3 confirmed those findings. We found differences in neurocognitive functioning in relation to nadir CD4 count in HIV-infected patients. Attention should be given to this value in the management of neurocognitive protection in HIV infection.

Assessing self-reported adherence to HIV therapy by questionnaire: the SERAD (Self-Reported Adherence) Study.

The relationship between adherence to highly active antiretroviral therapy (HAART) and RNA-HIV viral load outcomes has been extensively shown. Although there are different procedures for assessing treatment adherence, there is no ideal method. We present the SERAD (Self-Reported Adherence) questionnaire, a qualitative and quantitative self-reported instrument designed to provide an easier adherence measurement. We also compared the questionnaire to three other methods to evaluate adherence to HAART regimens in HIV-infected patients. Two prospective, observational, longitudinal studies were developed: a single-center pilot study followed by a multicenter study. A total of 530 HIV-infected outpatients was prospectively included, 66 in the pilot study and 464 in the multicenter study. Four methods were used to study adherence to HAART regimens: the SERAD questionnaire, pill count, electronic monitoring, and plasma drug monitoring. Pearson's correlations and Bland and Altman's method were developed. The SERAD questionnaire showed good feasibility and significant validity. Adequate levels of agreement between methods were observed, particularly when adherence was high. Differences increased as adherence fell. Moreover, the questionnaire was completed correctly, the interviewers did not report uncovered aspects, and the information was collected easily. Our results suggest that the SERAD questionnaire is a feasible and useful instrument for assessing adherence to HAART regimens in HIV-infected patients, and makes it possible to obtain reliable qualitative and quantitative information related to treatment adherence.