SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV.

BACKGROUND: Neuropsychiatric symptoms (NPs) have been reported with dolutegravir use. We hypothesized that increasing dolutegravir trough concentrations (Ctrough) and/or polymorphism in the SLC22A2 gene, encoding the organic cation transporter-2 (OCT2), which is involved in monoamine clearance in the CNS and is inhibited by dolutegravir, might be associated with NPs. METHODS: A cross-sectional cohort of HIV-positive patients treated with a dolutegravir-containing regimen underwent determination of allelic discrimination for SLC22A2 808 C → A polymorphism and dolutegravir Ctrough. The Symptom Checklist-90-R [investigating 10 psychiatric dimensions and reporting a general severity index (GSI)], a self-reported questionnaire and the Mini-International Neuropsychiatric Interview were offered to investigate current NPs. The effects of dolutegravir Ctrough and the SLC22A2 gene variant on NPs were explored by multivariable logistic regression. RESULTS: A cohort of 203 patients was analysed: 71.4% were male, with median age 51 years and 11 years of ART exposure. Median time on dolutegravir was 18 months. Dolutegravir was associated with different antiretroviral combinations (mainly lamivudine, 38.9%, and abacavir/lamivudine, 35.5%). SLC22A2 CA genotype was independently associated with an abnormal GSI [adjusted OR (aOR) 2.43; P = 0.072], anxiety (aOR 2.61; P = 0.044), hostility (aOR 3.76; P = 0.012) and with moderate to severe headache (aOR 5.55; P = 0.037), and dolutegravir Ctrough was associated with hostility (fourth versus first quartile aOR 6.70; P = 0.007) and psychoticism (fourth versus first quartile aOR 19.01; P = 0.008). Other NPs were not associated with SLC22A2 polymorphism or dolutegravir Ctrough. CONCLUSIONS: A variant of the OCT2-encoding gene, in addition to or in synergy with higher dolutegravir Ctrough, is associated with a set of NPs observed during dolutegravir therapy.

Efficacy and safety of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression: 144 week follow-up of the AtLaS pilot study.

OBJECTIVES: AtLaS was a single-arm pilot study that demonstrated promising efficacy and safety of treatment simplification to a dual regimen with atazanavir/ritonavir + lamivudine in virologically suppressed HIV-positive patients. Here, we report data from the 144 week follow-up. METHODS: At baseline, patients treated with a three-drug atazanavir/ritonavir-based regimen were switched to 300/100 mg of atazanavir/ritonavir plus 300 mg of lamivudine once daily. Major clinical events, laboratory parameters, neurocognitive performance, bone composition and body fat distribution were monitored. Treatment failure was defined as a discontinuation/switch of the regimen or virological failure (HIV-RNA >50 copies/mL in two consecutive determinations or a single level above 1000 copies/mL). RESULTS: After 144 weeks, 9/40 (22.5%) treatment failures occurred, including two virological failures (Weeks 48 and 53, without resistance). A significant increase in the CD4 count was observed at Week 96 (+124 cells/mm(3); P = 0.002) and Week 144 (+94 cells/mm(3); P = 0.008). After 144 weeks, a significant increase in total cholesterol (+25 mg/dL; P = 0.001), HDL cholesterol (+6 mg/dL; P = 0.024) and LDL cholesterol (+12 mg/dL; P = 0.008) was observed, without any change in triglyceride levels, total cholesterol/HDL ratio or LDL/HDL ratio. A significant increase in the estimated glomerular filtration rate (+25 mL/min/1.73 m(2); P < 0.001) and lumbar spine T-score and Z-score (+0.2, P = 0.011; and +0.35, P = 0.001, respectively) and a decrease in trunk fat (-1.898 g; P = 0.005) were also observed. Neurocognitive function did not decline over time. Concerning safety, 10 moderate to severe adverse events were recorded in eight patients; overall seven cases of renal colic (possibly treatment related) were observed, leading to a discontinuation of treatment in two patients. CONCLUSIONS: Data from the 144 week follow-up suggested good long-term efficacy of the simplification strategy that was investigated, with rare virological failure and a potential for improvement of the CD4 count, renal function and bone mineral density. This strategy warrants further investigation in a randomized trial.

Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients.

OBJECTIVES: The aim of the study was to investigate the relationship between metabolic comorbidities, cardiovascular risk factors or common carotid intima-media thickness (cIMT) and cognitive performance in HIV-infected patients. METHODS: Asymptomatic HIV-infected subjects were consecutively enrolled during routine out-patient visits at two clinical centres. All patients underwent an extensive neuropsychological battery and assessment of metabolic comorbidities and cardiovascular risk factors. Moreover, cIMT was assessed by ultrasonography. Cognitive performance was evaluated by calculating a global cognitive impairment (GCI) score obtained by summing scores assigned to each test (0 if normal and 1 if pathological). RESULTS: A total of 245 patients (median age 46 years; 84.1% with HIV RNA < 50 copies/mL; median CD4 count 527 cells/µL) were enrolled in the study. Cardiovascular risk factors were highly prevalent in our population: the most frequent were dyslipidaemia (61.2%), cigarette smoking (54.3%) and hypertension (15.1%). cIMT was abnormal (≥ 0.9mm) in 31.8% of patients. Overall, the median GCI score was 2 [interquartile range (IQR) 1-4]; it was higher in patients with diabetes (P = 0.004), hypertension (P = 0.030) or cIMT ≥ 0.9 mm (P < 0.001). In multivariate analysis, it was confirmed that diabetes (P = 0.007) and cIMT ≥ 0.9 mm (P = 0.044) had an independent association with lower cognitive performance. In an analysis of patients on combination antiretroviral therapy (cART), abacavir use was independently associated with a better cognitive performance (P = 0.011), while no association was observed for other drugs or neuroeffectiveness score. CONCLUSIONS: Diabetes, cardiovascular risk factors and cIMT showed a strong association with lower cognitive performance, suggesting that metabolic comorbidities could play a relevant role in the pathogenesis of HIV-associated neurocognitive disorders in the recent cART era.

Comparison of cognitive performance in HIV or HCV mono-infected and HIV-HCV co-infected patients.

PURPOSE: Our aim was to explore the interplay between human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in the expression of cognitive disorders. METHODS: We performed a multi-centre cross-sectional study, enrolling three groups of asymptomatic outpatients matched for age and education: (1) HIV mono-infected; (2) HCV mono-infected; (3) HIV-HCV co-infected. All subjects were subjected to the Zung depression scale and a comprehensive neuropsychological battery. RESULTS: A total of 50 patients for each group were enrolled. Patients in the three groups did not significantly differ in the main common demographic and clinical characteristics, except for a lower proportion of past injecting drug use (IDU) in group 1 (4 %) in comparison to groups 2 (38 %, p < 0.001) and 3 (78 %, p < 0.001), a longer duration of HIV infection in group 3 in comparison to group 1 (p < 0.001) and a longer duration of HCV infection in group 3 in comparison to group 2 (p = 0.028). Overall, 39.3 % of patients showed minor cognitive impairment, with a higher proportion in group 3 (54 %) when compared to groups 1 (28 %, p = 0.015) or 2 (36 %, p = 0.108). Patients in group 3 [odds ratio (OR) 3.35, p = 0.038 when compared to group 1] and those with higher depression scores (OR 1.05, p = 0.017) showed an increased risk of cognitive impairment after adjusting for education and past injection drug use. In particular, group 3 showed worse performance in psychomotor speed tasks when compared to group 1 (p = 0.033). CONCLUSIONS: A worse cognitive performance in HIV-HCV co-infected patients was observed, suggesting an additive role of the two viruses in the pathogenesis of cognitive disorders.

Health-related quality of life (HRQoL) from HIV patients' perspective: comparison of patient-reported outcome (PRO) measures among people living with hiv (PLWH) and other chronic clinical conditions.

BACKGROUND: People living with HIV (PLWH) are generally known to suffer from a lower quality of life compared to the one of general population, but still very few is known about the self-perception of quality of life when comparing HIV to non-communicable diseases. We performed a comprehensive assessment of patient's reported outcomes measures (PROMs) among PLWH and patients affected by other chronic conditions (OC) such as diabetes mellitus type 1, rheumatoid arthritis, breast cancer in hormonal therapy, in order to investigate differences in PROMs outcomes between PLWH and other pathologies. METHODS: A cross-sectional observational study was performed by using questionnaires investigating health-related quality of life (Medical Outcomes Study Short Form 36-item Health Survey), work productivity (WPI), and global health status (EQ-5D-3L). They were administered to patients affected by chronic diseases consecutively observed at a single University Hospital during a 10 months period, with comparable disease related aspects. Logistic regression analysis was used to analyze the association between disease group (HIV vs OC) and PROMs. RESULTS: 230 patients were enrolled (89 PLWH, 143 OC). Mean age: 49 years (SD 10), mean time of disease 12 years (10), 96% were Caucasian, 35% assumed polypharmacy, 42% of male were PLWH versus 16% OC (p < 0.001), 19% PLWH versus 6% OC had clinical complications (p < 0.001). HIV infection was independently associated to a better health-related quality of life in several domains compared with the other conditions, except in mental health, whereas a worst health-related quality of life in most domains was reported by older patients and those experiencing polypharmacy. CONCLUSIONS: In this cohort of patients with chronic conditions followed within the same health setting, PLWH showed better self-reported health outcomes compared to other chronic conditions with comparable characteristics of chronicity. The potential detrimental role of older age and polypharmacy in most outcomes suggests the need of longitudinal assessment of PROMs in clinical practice.

Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients.

BACKGROUND: Despite the availability of potent antiretroviral regimens (combination antiretroviral therapy [cART]), HIV-associated neurocognitive disorders (HAND) are increasingly recognized. Our aim was to investigate the prevalence and treatment-related correlates of HAND, exploring the potential neurotoxicity of antiretrovirals on cognitive functions. METHODS: We performed a cross-sectional single cohort study by consecutively enrolling asymptomatic HIV+ subjects during routine outpatient visits. Each patient was submitted to a comprehensive neuropsychological battery and was considered cognitively impaired on the basis of results obtained in matched healthy HIV-negative subjects. CNS penetration effectiveness (CPE) rank was calculated for cART regimens according to 2010 CHARTER criteria. Factors associated with cognitive impairment were investigated by linear or logistic regression analysis. RESULTS: A total of 146 patients were enrolled. Of these, 129 (88.4%) were on cART and 59.6% of them were on current regimen from ≥1 year. Sixty-nine patients (47%) were classified as cognitively impaired (35.6% asymptomatic and 11.6% mild neurocognitive impairment). In the multivariate analysis, efavirenz use (odds ratio [OR] = 4.00; p = 0.008) and non-Italian nationality (OR = 3.46; p = 0.035) were associated with increased risk of cognitive impairment, whereas higher education was associated with a lower risk (OR = 0.85; p = 0.002). Furthermore, efavirenz use and age ≥65 years independently predicted worse performance on the double barrage and the Stroop test (time). No association between CPE rank and cognitive impairment was observed. CONCLUSIONS: A high prevalence of HAND was observed in apparently asymptomatic HIV+ individuals. HAND was associated with efavirenz use, suggesting the potential neurotoxicity of this drug. Routine neuropsychological examinations could help clinicians make correct diagnoses and manage mild, but clinically relevant, forms of HAND.

Sibship size, birth order, and atopy in 11,371 Italian young men.

BACKGROUND: Having a low number of siblings and a low birth order has been reported to be a relevant risk factor for development of atopic diseases and skin sensitization to common inhalants. Although the inverse association of atopy with sibship size has been confirmed repeatedly, the association with birth order has provided conflicting results. This possibly is due to the relatively small size of the population sample examined. OBJECTIVE: The objective of this study was to investigate the relation between sibship size, birth order, and atopy in a very large population sample, highly homogeneous for age and sex. METHODS: This was a retrospective survey of 11,371 Italian young men, 18 to 24 years old, all candidates for enrollment in the Italian Air Force. Demographic data had been collected by a standard questionnaire. Specific IgE for locally relevant airborne allergens had been tested by a multi-RAST assay (CAP-Phadiatop). RESULTS: The prevalence of atopy (defined as a high level of specific IgE against inhalants [cut-point >1.2 log RU]) was inversely related to the total number of siblings (25% in those with no siblings and 9% in those with five or more siblings), with a mean of a 3% decrease in prevalence for each added sibling. This relation persisted after adjustment for relevant variables such as father's education and rural and southern residence. An independent association between birth order and atopy was also observed because the decrease in atopy prevalence with increasing numbers of older siblings was significantly steeper than that found with the number of younger siblings (chi2 = 179, df = 1, p < 0.0001). CONCLUSIONS: In a very large and homogeneous population sample of a Mediterranean country, not only sibship size but also birth order was significantly associated with atopy. This observation further highlights the role of family structure in the development of atopy and supports the hypothesis that cross-infections acquired early in infancy or in later childhood might prevent development of atopy later in life.