Prevalence and management of delirium in community dwelling older people with dementia referred to a memory clinic.

OBJECTIVE: Our aim was to measure the prevalence of delirium, its clinical features, and outcomes in older patients referred to a memory clinic. METHODS: A retrospective cohort study of 109 older outpatients with delirium referred to a memory clinic with a home care service. Delirium was diagnosed using the confusion assessment method and dementia with the DSM-5 criteria. We collected information on cognitive and functional status, mortality, institutionalization, and hospitalization during 6 months following the delirium episode. RESULTS: Delirium prevalence was 3.6%, mostly of hyperactive type. Delirium worsened functional (ADL 2.95 ± 1.95 vs. 2.16 ± 1.84) and cognitive (MMSE 13.88 ± 8.96 vs.11.0 ± 9.49) status after 6 months compared to the baseline. The mortality rate was 29.4%, and 28.3% were admitted to a long-term facility after the episode of delirium. Of these patients, more than half were hospitalized during the follow-up. Of the 109 patients with delirium, 85 were managed at home and 24 were hospitalized. Patients who were hospitalized had more severe behavioral symptoms during the delirium episode. There was no difference in mortality and institutionalization according to the home or hospital management. CONCLUSIONS: This retrospective cohort study adds novel information to the existing literature of an understudied setting and population. The study supports the need to further investigate the feasibility and efficacy of the hospital at home models for the prevention and management of delirium in a high-risk population.

96 Week follow-up of HIV-infected patients in rescue with raltegravir plus optimized backbone regimens: a multicentre Italian experience.

BACKGROUND: Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. METHODS: Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. RESULTS: Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm(3); 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA <50 copies/mL). When analyzing the immuno-virologic outcome according to the number of drugs used in the regimen, 2 (n = 45), 3 (n = 111), 4 (n = 124), or >4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm(3), respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. CONCLUSIONS: In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

KIR-HLA genotypes in HIV-infected patients lacking immunological recovery despite effective antiretroviral therapy.

BACKGROUND: In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART. METHODS: KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: 'immunological non responders' (INR, N = 50, CD4(+) T-cell count <200/mm(3)) and full responders (FR, N = 104, CD4(+) T-cell count >350/mm(3)). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics. RESULTS: The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1(+)/KIR2DL3(+), even at multivariable analysis, when adjusted for nadir CD4(+) T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13-0.88), P = 0.03. CONCLUSIONS: Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy.

Abacavir and lamivudine for the treatment of human immunodeficiency virus.

INTRODUCTION: The introduction of combination antiretroviral therapy (cART) in 1996 dramatically changed the survival and the quality of life of people living with human immunodeficiency virus (HIV). Viral replication can be controlled by using a combination of more than 30 licensed drugs. Despite the fact that many advances have been made in the last 20 years of experience with antiretrovirals, certain needs remain to be addressed, such as the presence of chronic inflammation, the long-term side effects of newly introduced drugs and eradication. Abacavir (ABC) and lamivudine (3TC) are licensed in a fixed-dose combination to be administered once daily with other antiretroviral agents for the treatment of HIV. AREAS COVERED: This article provides an extensive review of the evidence on the combination of ABC 600 mg and 3TC 300 mg. Specifically, it discusses the chemistry-- including the phrarmacodynamics, resistance to treatment, pharmacokinetics and metabolism--and formulations available. It also looks at clinical efficacy, including safety and tolerability. EXPERT OPINION: In the last few years, new data regarding human leukocyte antigen (HLA) B*5701 testing to prevent the hypersensitivity reaction due to ABC have been presented, providing a landmark in the management of adverse events in HIV, and later a previously unexpected correlation of the recent exposure to ABC with an increased risk of cardiovascular disease. This review presents the current situation with regard to the long-term efficacy and safety data on the ABC/3TC combination.

Secondary hyperparathyroidism in HIV patients: is there any responsibility of highly active antiretroviral therapy?

Secondary hyperparathyroidism may develop in the presence of hypovitaminosis D in order to maintain calcium homeostasis. We conducted a cross-sectional analysis in a cohort of 371 patients, identifying secondary hyperparathyroidism in 65 patients. This high prevalence (17.5%) was in part justified by the high prevalence of hypovitaminosis D (77.4%) in the whole sample, but we also identified an independent association with the use of tenofovir.

Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study.

BACKGROUND: Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. METHODS: In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. RESULTS: A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir-emtricitabine group, -3.6%; P < .001) and lumbar spine (abacavir-lamivudine group, -1.6%; tenofovir-emtricitabine group, -2.4%; P = .036). BMD loss of >or=6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >or=6% in the hip; 15% vs 5% had a loss of >or=6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P < .001). CONCLUSIONS: This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Anti-inflammatory effect of maraviroc in an HIV-infected patient with concomitant myositis: a case report.

We report the surprising yet sought impact that an antiretroviral (ARV) regimen containing maraviroc had on an HIV-infected and heavily highly active antiretroviral therapy (HAART)-experienced patient with chronic polymyositis. The patient had elevated creatine kinase (CK) levels in serum for 6 years, reaching peaks over 900 U/L and showing only partial response to high-dose steroids, not responding to HAART withdrawal. The disease started while on second-line HAART and gradually impaired his muscular function, leading to the absolute loss of the ability to stand on his legs. Atherosclerosis and hypertension contributed to the development of myocardial infarction. The association of unboosted atazanavir (ATV) plus maraviroc was designed hoping in a protective role on the cardiovascular system and in an anti-inflammatory effect that some authors have hypothesized. After only 3 months the patient's CK levels had normalized and with the help of rehabilitation he recovered the ability to walk, which he still maintains at the one year of observation.

Performance of a molecular viability assay for the diagnosis of Pneumocystis pneumonia in HIV-infected patients.

Pneumocystis pneumonia (PCP), caused by infection with Pneumocystis jirovecii, remains an important opportunistic infection in humans. A reverse transcriptase polymerase chain reaction assay has been shown to specifically detect viable P. jirovecii organisms. In the current study, we evaluated this assay on different types of respiratory samples. The assay had a diagnostic sensitivity of 100% and a specificity of 86% when applied to bronchoalveolar lavage samples. The assay's performance declined when applied to less invasive induced sputum and oropharyngeal wash (OPW) samples. The sensitivity, when applied to OPWs, was improved by examining multiple sequential OPW samples and was affected by clinical sampling parameters that could increase or decrease the number of potential organisms in the oropharynx. When used in conjunction with an optimized clinical sampling protocol, this assay may become a useful tool for detecting and monitoring P. jirovecii in minimally invasive clinical samples.

Limited sampling strategy for the estimation of systemic exposure to the protease inhibitor nelfinavir.

Therapeutic drug monitoring (TDM) of antiretroviral drugs has been proposed as a means of optimizing response to highly active antiretroviral therapy (HAART) in HIV infection because suboptimal exposure to these agents may lead to the development of resistant viral strains and subsequent therapeutic failure. The area under the curve (AUC), though considered to make the best estimate of total drug exposure, requires repeated blood sampling. The authors investigated the predictability of individual nelfinavir (NFV) concentrations at different time points for the AUC and tried to find the best sampling time for the abbreviated AUC to predict NFV total body exposure. A total of 99 NFV AUC0-12h values were measured in 99 patients receiving a 1250-mg oral dose twice a day. Venous blood samples were collected at baseline (predose, 0) and 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose. A stepwise forward-selection, multiple-regression technique was chosen to assess the relative importance of single and combination concentration time points to predict the AUC calculated from the entire pharmacokinetic profile. Data were split into a development set and a validation set. The development set contained 49 randomly selected HIV patients. Of these, 22 HIV patients were coinfected with HCV, 7 with and 15 without cirrhosis. One-point predictors provided the lowest prediction precision, but predictive performance improved after the first 2 hours postdose. Plasma concentrations at 0 and 4 hours after the oral dose were most predictive if 2 variables were used in the regression equation. The AUC could be estimated from data for these 2 samples by using the following equation: AUC0-12 = 3.0 + 2.7 (C0) + 6.4 (C4), r = 92. The predictive performance of 2-point predictors at 0 and 4 hours (C0 + C4) was validated by comparing their ability to predict the full AUC in a validation set representative of HIV/HCV patients (n = 28) and HIV/HCV patients, with (n = 8) and without (n = 14) cirrhosis. The results showed a mean bias ranging from +2.7% in HIV/HCV patients to -6.0% in HCV coinfection with cirrhosis. The authors conclude that this result is clinically significant. The limited sampling strategy (LSS) described could be used in clinical practice for the easy assessment of the total exposure to NFV in HIV/HCV patients, both with and without cirrhosis.

Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV-hepatitis C virus-coinfected subjects.

In order to evaluate the potential risk of nelfinavir (NFV) accumulation in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients with liver disease, we investigated the concentrations of NFV and M8, the active metabolite of NFV, in plasma HIV-positive (HIV+) patients coinfected with HCV. A total of 119 HIV+ subjects were included in our study: 67 HIV+ patients, 32 HIV+ and HCV-positive (HCV+) patients without cirrhosis, and 20 HIV+ and HCV+ patients with cirrhosis. Most of the enrolled patients (chronically treated) were taking NFV at the standard dosage of 1,250 mg twice a day. To assay plasma NFV and M8 concentrations, patients underwent serial plasma samplings during the dosing interval at steady state. Plasma NFV and M8 concentrations were measured simultaneously by a high-performance liquid chromatography method with UV detection. The HIV+ and HCV+ patients with and without cirrhosis had significantly lower NFV oral clearances than the HIV+ and HCV-negative individuals (28 and 58% lower, respectively; P < 0.05), which translated into higher areas under the concentration-time curves for cirrhotic and noncirrhotic patients. The NFV absorption rate was significantly lower in cirrhotic patients, resulting in a longer time to the maximum concentration in serum. The mean ratios of the M8 concentration/NFV concentration were significantly lower (P < 0.05) in HIV+ and HCV+ subjects with cirrhosis (0.06 +/- 0.074) than in the subjects in the other two groups. The mean ratios for M8 and NFV were not statistically different between HIV+ and HCV-negative patients (0.16 +/- 0.13) and HIV+ and HCV+ patients without cirrhosis (0.24 +/- 0.17), but the interpatient variability was high. Our results indicate that the pharmacokinetics of NFV and M8 are altered in HIV+ and HCV+ patients, especially those with liver cirrhosis. Therefore, there may be a role for therapeutic drug monitoring in individualizing the NFV dosage in HIV-HCV-coinfected patients.