Mar Masiá

Prediction of Neuropsychiatric Adverse Events Associated with Long-Term Efavirenz Therapy, Using Plasma Drug Level Monitoring

BACKGROUND Data on long-term central nervous system (CNS) toxicity associated with efavirenz therapy are scarce, and risk factors remain largely unknown. We aimed to determine whether monitoring the plasma concentration of efavirenz could predict neuropsychiatric adverse events associated with long-term therapy with efavirenz. METHODS We performed a longitudinal study involving 17 consecutive human immunodeficiency virus (HIV)-infected subjects with virological suppression after at least 6 months of antiretroviral therapy with an efavirenz-containing regimen. Efavirenz plasma concentrations were measured at study entry and at different time points through an 18-month study period. RESULTS Median duration of efavirenz therapy before study entry was 18 months (range, 6-27 months). Ten (58.8%) of the patients experienced CNS-related adverse effects, ranging from insomnia and abnormal dreams to depression with suicidal ideation. In 4 (23.5%) of the cases, CNS toxicity led to efavirenz discontinuation. Mean (+/- standard deviation) plasma levels were higher for patients experiencing neuropsychiatric symptoms (5.10 +/- 2.15 microg/mL vs. 2.79 +/- 1.31 microg/mL; P = .024). A plasma level of 2.74 microg/mL had a sensitivity of 90.9% and specificity of 72% to predict CNS toxicity (area under the curve, 0.839; 95% confidence interval, 0.73-0.95; P < .0001). Patients having efavirenz plasma concentrations > 2.74 microg/mL at any time point of the study were 5.68 times more likely to experiencing CNS toxicity than were other patients (95% confidence interval, 1.97-16.37). CONCLUSIONS In patients with HIV infection receiving long-term therapy with efavirenz-containing antiretroviral regimens, CNS toxicity is related to efavirenz plasma levels. Patients achieving higher plasma levels are at increased risk of experiencing neuropsychiatric adverse events.

Epidemiology of community-acquired pneumonia in adult patients at the dawn of the 21st century: a prospective study on the Mediterranean coast of Spain

ABSTRACT This study presents data from a prospective study of adult patients with community-acquired pneumonia (CAP). Of 493 patients included in the study, 223 (45.2%) were aged ≥ 65 years, and 265 (53.7%) had one or more underlying diseases, mostly chronic obstructive pulmonary disease, diabetes mellitus or dementia. In total, 281 microorganisms were identified in 250 (50.7%) patients, with two or more pathogens detected in 28 (5.7%) cases. Microbial diagnosis varied according to age, severity, co-morbidity and site-of-care, but there was much overlap among groups. Streptococcus pneumoniae was the single most prevalent organism in outpatients, patients admitted to hospital, and patients who died, either as a single pathogen or combined with another organism. Infections caused by ‘atypical’ pathogens were seen across all groups, including the elderly and patients with co-morbidities. Mortality varied according to the pneumonia severity index (PSI) of the pneumonia patient outcomes research team. Shock (OR 34.48), an age of > 65 years (OR 25) and altered mental status (OR 9.92) were factors associated independently with 30-day mortality. Key findings from this study were the advanced age of the population with CAP, and the high prevalence of dementia as an underlying disease. The study also revealed that microbiological diagnosis of CAP remains problematic. Although certain epidemiological features may help to predict the microbial aetiology, the overlap among groups reduces the usefulness of this information in guiding therapeutic decisions. Greater effort should be made to improve identification methods for microbial pathogens causing CAP.

Lopinavir plasma concentrations and changes in lipid levels during salvage therapy with lopinavir/ritonavir-containing regimens

Objective: To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in lipid levels. Design: A prospective, nonrandomized study. Subjects: HIV‐infected subjects with virologic failure on protease inhibitorcontaining regimens. Twenty‐two consecutive patients were enrolled, 19 completed 24 weeks of treatment, and 16 completed the full 48‐week study period. Intervention: Patients were treated with LPV/ritonavir (LPV/r) in combination with other antiretroviral agents. Subjects were evaluated at baseline and weeks 4, 8, 12, 24, 36, and 48. LPV trough plasma concentrations and lipid levels were measured. Results: LPV trough concentrations were higher in patients experiencing grade 3 or higher lipid elevations (mean [SD]: 9.71 &mgr;g/mL (5.62) vs. 6.09 &mgr;g/mL (3.83); P = 0.002) and in those developing grade 2 or higher hypercholesterolemia (mean [SD]; 8.48 &mgr;g/mL (4.64] vs. 5.71 &mgr;g/mL [3.94]; P = 0.003). All patients developing grade 2 or higher cholesterol elevation had an LPV trough concentration at week 4 greater than 8 &mgr;g/mL. Significant positive correlations were found between LPV trough concentrations and changes in triglyceride and cholesterol levels. Conclusions: In patients receiving salvage therapy with LPV/r, there is an association between LPV plasma concentrations and lipid changes. Patients achieving higher LPV trough concentrations may be at greater risk of experiencing dyslipidemia. Further investigations are warranted to support a direct cause and effect relationship.

Patients' characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy.

To describe characteristics and prognosis of patients with suboptimal immunological response to combined antiretroviral therapy (CART). Using data from a multicenter cohort study, we selected patients who initiated CART and showed suboptimal CD4-T cell response (defined as <50 cells/L increase) after 1 year of therapy, despite sustained virological suppression. Characteristics of those patients were compared with subjects who showed optimal immunological response. Of 650 patients with virological suppression, 108 (16.6%) showed suboptimal CD4-T cell response. Independent predictors of suboptimal response were previous injection drug use (OR, 1.85; 95% CI, 1.12-2.98) and age at CART initiation (OR, 1.04 per year increase; 95%CI, 1.01-1.06). Hepatitis C virus coinfection was not associated with impaired immunological response. As compared with patients with optimal immunological response, those with suboptimal response had a higher mortality rate (3.22 versus 0.71 per 100 person-years; p=.001), but a similar rate of new AIDS-defining events. In patients with sustained virological suppression with CART, previous injection drug use, but not hepatitis C virus coinfection, and older age at initiation of therapy were associated with suboptimal CD4 T-cell responses. Patients with suboptimal response had a higher mortality over time, mainly due to diseases other than AIDS-defining events.

High-Density Lipoprotein Cholesterol in HIV-Infected Patients: Evidence for an Association with HIV-1 Viral Load, Antiretroviral Therapy Status, and Regimen Composition

Low high-density lipoprotein-cholesterol (HDL-C) levels have been associated with cardiovascular risk in non-HIV populations. Limited information exists on the prevalence of low HDL-C in HIV- infected patients and related factors remain largely unknown. The aims of this study were to estimate the prevalence and characteristics of low HDL-C levels in HIV-infected patients. A cross-sectional study was performed in consecutive HIV-infected patients cared for in an outpatient HIV clinic on the Mediterranean coast of Spain during a 2-month period (September 15, 2003 to November 15, 2003). HDL-C levels below 40 mg/dL were considered low. We analyzed data from 219 patients, 167 of whom were on antiretroviral therapy. The majority (45.20 %) were on non-nucleoside reverse transcriptase inhibitors (NNRTI); 22.83 % were on treatment with protease inhibitors. The prevalence of low HDL-C levels was 44.74 % (98 of 219 patients). In multivariate analysis, hypertriglyceridemia (triglycerides >150 mg/dL; odds ratio [OR], 5.65; 95% confidence interval [CI], 2.85-11.23; p = 0.0001), HIV-1 RNA viral load greater than 50 copies per milliliter (OR, 3.15; 95% CI, 1.63-6.109; p = 0.001) and antiretroviral therapy with regimens other than NNRTIs-based regimens (OR, 2.17; 95% CI, 1.12-4.16; p = 0.021) were associated with low HDL-C levels. These data indicate that prevalence of low HDL-C among HIV-infected patients from this cohort was very high. Low HDL-C was related to triglyceride levels, HIV-1 RNA viral load and antiretroviral therapy composition. Undetectable viral load and treatment with NNRTIs are protective factors, whereas hypertriglyceridemia is directly associated with low HDL-C levels.

Risk, predictors, and mortality associated with non-AIDS events in newly diagnosed HIV-infected patients: role of antiretroviral therapy

Objective:We aimed to characterize non-AIDS events (NAEs) occurring in newly diagnosed HIV-infected patients in a contemporary cohort. Methods:The Cohort of the AIDS Research Network (CoRIS) is a prospective, multicenter cohort of HIV-infected adults antiretroviral naive at entry, established in 2004. We evaluated the incidence of and the mortality due to NAEs and AIDS events through October 2010. Poisson regression was used to investigate factors associated with a higher incidence of NAEs. Results:Overall, 5185 patients (13.306 person-years of follow-up), median age (interquartile range) 36 (29–43) years, participated in the study. A total of 86.5% patients had been diagnosed in 2004 or later. The incidence rate of NAEs was 28.93 per 1000 person-years [95% confidence interval (CI) 26.15–32.07], and of AIDS-defining events 25.23 per 1000 person-years (95% CI 22.60–28.16). The most common NAEs were psychiatric, hepatic, malignant, renal, and cardiovascular related. After adjustment, age, higher HIV-viral load, and lower CD4 cell count at cohort entry were associated with the occurrence of NAEs, whereas likelihood significantly decreased with sexual transmission and higher educational level. Additionally, antiretroviral therapy was inversely associated with the development of some NAEs, specifically of psychiatric [incidence rate ratio (95% CI) 0.54 (0.30–0.96)] and renal-related [incidence rate ratio (95% CI) 0.31 (0.13–0.72)] events. One hundred and seventy-three (3.33%) patients died during the study period. NAEs contributed to 28.9% of all deaths, with an incidence rate (95% CI) of 3.75 (2.84–4.94) per 1000 person-years. Conclusion:In patients newly diagnosed with HIV infection, NAEs are a significant cause of morbidity and mortality. Our results suggest a protective effect of antiretroviral therapy in the occurrence of NAEs, in particular of psychiatric and renal-related events.

Tuberculosis en inmigrantes: diferencias clinicoepidemiológicas con la población autóctona (1999-2002)

Antecedentes La tuberculosis en inmigrantes es una enfermedad emergente en los paises industrializados. Metodo Se han comparado retrospectivamente las caracteristicas clinicoepidemiologicas de los casos de tuberculosis con confirmacion microbiologica en poblacion inmigrante y autoctona. Resultados De los 105 casos de tuberculosis, 22 (21%) fueron en inmigrantes. La incidencia en el ano 2002 fue de 64,3 casos/100.000 inmigrantes. La edad de los inmigrantes era de 28,5 anos, inferior a la de la poblacion autoctona (p Conclusiones La tuberculosis en la poblacion inmigrante es generalmente pulmonar, aparece en jovenes y supone un reto sanitario por la elevada perdida durante el seguimiento.

Clinical Outcome of HIV-Infected Patients with Sustained Virologic Response to Antiretroviral Therapy: Long-Term Follow-Up of a Multicenter Cohort

Background Limited information exists on long-term prognosis of patients with sustained virologic response to antiretroviral therapy. We aimed to assess predictors of unfavorable clinical outcome in patients who maintain viral suppression with HAART. Methods Using data collected from ten clinic-based cohorts in Spain, we selected all antiretroviral-naive adults who initiated HAART and maintained plasma HIV-1 RNA levels <500 copies/mL throughout follow-up. Factors associated with disease progression were determined by Cox proportional-hazards models. Results Of 2,613 patients who started HAART, 757 fulfilled the inclusion criteria. 61% of them initiated a protease inhibitor-based HAART regimen, 29.7% a nonnucleoside reverse-transcriptase inhibitor-based regimen, and 7.8% a triple-nucleoside regimen. During 2,556 person-years of follow-up, 22 (2.9%) patients died (mortality rate 0.86 per 100 person-years), and 40 (5.3%) died or developed a new AIDS-defining event. The most common causes of death were neoplasias and liver failure. Mortality was independently associated with a CD4-T cell response <50 cells/L after 12 months of HAART (adjusted hazard ratio [AHR], 4.26 [95% confidence interval {CI}, 1.68–10.83]; P = .002), and age at initiation of HAART (AHR, 1.06 per year; 95% CI, 1.02–1.09; P = .001). Initial antiretroviral regimen chosen was not associated with different risk of clinical progression. Conclusions Patients with sustained virologic response on HAART have a low mortality rate over time. Long-term outcome of these patients is driven by immunologic response at the end of the first year of therapy and age at the time of HAART initiation, but not by the initial antiretroviral regimen selected.

Contribution of Interferon gamma release assays testing to the diagnosis of latent tuberculosis infection in HIV-infected patients: A comparison of QuantiFERON-TB Gold In Tube, T-SPOT.TB and tuberculin skin test

BackgroundDiagnosis and treatment of latent tuberculosis infection (LTBI) is the most effective strategy to control tuberculosis (TB) among patients with HIV infection. The tuberculin skin test (TST) was the only available method to identify LTBI. The aim of the present work was to evaluate the usefulness of the interferon-gamma release assays (IGRAs): QuantiFERON-tuberculosis (TB) Gold-In-Tube test (QFG) and T-SPOT.TB for the diagnosis of LTBI in a diverse cohort of HIV-infected patients.MethodsA prospective study was carried out in consecutive patients cared for in a single institution in Spain from January 2009 to October 2010. IGRAs and TST were performed simultaneously. TST induration ≥ 5 mm was considered positive.ResultsQFG, T-SPOT.TB and TST were performed in 373 subjects. Median CD4 cell count was 470/μl with a median nadir of 150/μl. TST, QFG and T-SPOT.TB were positive in 13.3%, 7.5% and 18.5% cases respectively. Among 277 patients with neither past or current TB nor previous treatment for LTBI and who had TST results, a positive TST result was obtained in 20 (7.2%) cases. When adding QFG results to TST, there were a total of 26 (8.6%) diagnoses of LTBI. When the results of both IGRAs were added, the number of diagnoses increased to 54 (17.9%) (incremental difference: 10.7% [95% confidence interval [CI]:5.3-16.2%] [p < 0.001]), and when both IGRAs were added, the number of diagnoses reached 56 (18.5%) (incremental difference: 11.3% [95% CI:5.7%–16.9%] [p < 0.001]). Patients with a CD4 cell count greater than 500 cells/μl and prior stay in prison were more likely to have a diagnosis of LTBI by TST and/or QFG and/or T-SPOT.TB (adjusted odds ratio [aOR]: 3.8; 95% CI, 1.4 – 9.9; and aOR: 3.3; 95% CI, 1.3 – 8.3, respectively).ConclusionsIGRAs were more sensitive than TST for diagnosis of M. tuberculosis infection in HIV-infected patients. Dual sequential testing with TST and IGRAs may be the optimal approach for LTBI screening in this population.

Endothelial function is impaired in HIV-infected patients with lipodystrophy

BACKGROUND Data supporting a link between body-fat distribution changes and cardiovascular disease risk in HIV-infected patients are scarce and contradictory. We evaluated endothelial dysfunction, an early event in the development of atherosclerosis, and pro-atherosclerotic plasma biomarkers in HIV-infected patients with lipodystrophy. METHODS HIV-infected patients with and without lipodystrophy were prospectively enrolled. Endothelial function was measured through flow-mediated dilatation (FMD) of the brachial artery. Plasma levels of several biomarkers of inflammation, endothelial activation and coagulation associated with adipose tissue and endothelial dysfunction were determined. RESULTS The study included 110 patients, 55 of them with lipodystrophy. FMD was significantly lower in patients with lipodystrophy than in those without lipodystrophy (median [IQR] 3.1% [0.4-8.9] versus 6.3% [3.3-10.7]; P=0.004). Patients with isolated lipoatrophy exhibited the lowest FMD (2.6% [0-6.6]; P(Kruskal-Wallis)=0.02). Lipodystrophy was associated with significantly higher plasma levels of interleukin 6 (IL-6) and plasminogen activator inhibitor 1 (PAI-1) and lower levels of adiponectin; severe lipodystrophy was associated with higher concentrations of vascular cell adhesion molecule 1 (sVCAM-1). There was an inverse correlation between FMD and IL-6 (Spearmans rho =-0.26; P=0.007). In a multivariate regression model with the lowest quartile of FMD as the dependent variable and lipodystrophy, traditional cardiovascular risk factors, 10-year Framingham risk score, pro-atherosclerotic biomarkers and HIV-related variables as predictors, the only independent predictor of endothelial dysfunction was lipodystrophy (odds ratio 5.22, 95% confidence interval 1.76-15.46; P=0.003). CONCLUSIONS Lipodystrophy is associated with endothelial dysfunction, independently of the presence of traditional cardiovascular risk factors. This finding and the accompanying profile of pro-atherosclerotic biomarkers support an increased cardiovascular risk in HIV-infected patients with lipodystrophy.