Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up.

PURPOSE: Our aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors. METHODS: We included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004-2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors. RESULTS: Among 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use. CONCLUSION: Non-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.

Incidence of Anal Cancer and Related Risk Factors in HIV-Infected Patients Enrolled in the National Prospective Spanish Cohort CoRIS.

BACKGROUND: People living with HIV have an increased risk of anal cancer. OBJECTIVE: To estimate anal cancer incidence and related risk factors in a national cohort of HIV-infected patients. DESIGN: Prospective multicenter cohort study. SETTINGS: Multicenter study including patients from the Spanish HIV Research Network. PATIENTS: We collected data from 16,274 HIV-infected treatment-naive adults recruited from January 2004 to November 2020. MAIN OUTCOMES MEASURES: The primary outcome measures of this study were the incidence and prevalence of anal carcinoma. The secondary outcome measures included the associations between baseline and time-dependent covariables and the primary end point. RESULTS: Twenty-six cases of anal cancer were diagnosed, 22 of which were incident cases resulting in a cumulative incidence of 22.29 of 100,000 person-years, which was stable during the study period. At the end of the study, 20 of the 43 centers had screening programs for high-grade anal dysplasia. Patients with anal cancer were males (26/26; 100% vs 13,833/16,248; 85.1%), were mostly men who have sex with men (23/26; 88.5% vs 10,017/16,248; 61.6%), had a median age of 43 years (interquartile range, 35-51), were more frequently previously diagnosed with an AIDS-defining illness (9/26; 34.6% vs 2429/16,248; 15%), and had lower nadir CD4 cell counts (115 vs 303 µL). About a third (34.6%, 9/26) were younger than 35 years. In multivariable analysis, men who have sex with men and patients with previous AIDS-defining illness had an 8.3-fold (95% CI, 1.9-36.3) and 2.7-fold (95% CI, 1.1-6.6) increased HR for developing anal cancer, respectively. Patients with higher CD4 cell counts during the follow-up showed a 28% lower risk per each additional 100 CD4 cell/µL (95% CI, 41%-22%). LIMITATIONS: Lack of information on some potential risk factors, screening, and treatment of high-grade anal dysplasia were not uniformly initiated across centers during the study period. CONCLUSIONS: Although the overall incidence in our study was low, there was a significant number of patients younger than 35 years with anal cancer. In addition to age, other factors, such as men who have sex with men and patients with severe immunosuppression (current or past), should be prioritized for anal cancer screening. INCIDENCIA DEL CNCER DE ANO Y LOS FACTORES DE RIESGO RELACIONADOS CON PACIENTES INFECTADOS POR VIH INCLUIDOS EN LA COHORTE PROSPECTIVA NACIONAL ESPAOLA CORIS: ANTECEDENTES:Las personas portadoras del virus de la inmunodeficiencia humana tienen un mayor riesgo de cáncer anal.OBJETIVO:Nosotros queremos estimar la incidencia de cáncer anal y los factores de riesgo relacionados en una cohorte nacional española de pacientes infectados por VIH.DISEÑO:Estudio de cohortes de tipo multicéntrico y prospectivo.ÁMBITO:Se incluyeron pacientes de la Red Española de Investigación en VIH.PACIENTES:Recolectamos los datos de 16,274 adultos infectados por el VIH que nunca habían recibido tratamiento, reclutados desde enero de 2004 hasta noviembre de 2020.MEDIDAS DE RESULTADO PRINCIPALES:Las medidas de resultado primarias de este estudio fueron la incidencia y la prevalencia del carcinoma anal. Las medidas de resultado secundarias incluyeron las asociaciones entre las covariables basales y dependientes del tiempo y el criterio principal de valoración.RESULTADOS:Se diagnosticaron 26 casos de cáncer anal, de los cuales 22 fueron casos incidentales resultando con una incidencia acumulada de 22,29/100.000 personas-año que se mantuvo estable durante el período de estudio.Al final de nuestro estudio, 20 de los 43 centros referentes tenían programas de detección de displasia anal de alto grado. Los pacientes con cáncer anal eran hombres (26/26; 100% vs 13 833/16 248; 85,1%), en su mayoría hombres que mantenían sexo con otros hombres (23/26; 88,5% vs 10 017/16 248; 61,6%), la mediana de edad fue de 43 años (IQR: 3 -51), 34,6% (9/26) < 35 años, previa y frecuentemente diagnosticados con una enfermedad definitoria de SIDA (9/26; 34,6% vs 2429/16248; 15%) y que tenían un punto opuesto mucho más bajo en el recuentos de células CD4 (115 µL frente a 303 µL).En el análisis multivariable, los hombres que tenían relaciones sexuales con otros hombres y los pacientes con enfermedades definitorias de sida anteriores, tenían un aumento de 8,3 veces (IC del 95%: 1,9 a 36,3) y de 2,7 veces (IC del 95%: 1,1 a 6,6) en el cociente de riesgos instantáneos para desarrollar cáncer anal, respectivamente. Los pacientes con recuentos de células CD4 más altos durante el seguimiento mostraron un riesgo 28 % menor por cada 100 células CD4/µl adicionales (95% IC: 41%- 22%).LIMITACIONES:La falta de información sobre algunos factores potenciales de riesgo, la detección y el tratamiento de la displasia anal de alto grado no se iniciaron uniformemente en todos los centros durante el período de estudio.CONCLUSIONES:Si bien la incidencia general en nuestro estudio fue baja, hubo un número significativo de pacientes de <35 años con cáncer anal. Además de la edad, otros factores como los hombres que tienen sexo con hombres y los pacientes con inmunosupresión severa (actual o pasada) deben priorizarse para la detección del cáncer anal. ( Traducción-Dr. Xavier Delgadillo ).

Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer.

Human papillomavirus can cause preinvasive, high-grade squamous intraepithelial lesions (HSILs) as precursors to cancer in the anogenital area, and the microbiome is suggested to be a contributing factor. Men who have sex with men (MSM) living with human immunodeficiency virus (HIV) have a high risk of anal cancer, but current screening strategies for HSIL detection lack specificity. Here, we investigated the anal microbiome to improve HSIL screening. We enrolled participants living with HIV, divided into a discovery (n = 167) and validation cohort (n = 46), and who were predominantly (93.9%) cisgender MSM undergoing HSIL screening with high-resolution anoscopy and anal biopsies. We identified no microbiome composition signatures associated with HSILs, but elevated levels of microbiome-encoded proteins producing succinyl coenzyme A and cobalamin were significantly associated with HSILs in both cohorts. Measurement of these candidate biomarkers alone in anal cytobrushes outperformed anal cytology as a diagnostic indicator for HSILs, increasing the sensitivity from 91.2% to 96.6%, the specificity from 34.1% to 81.8%, and reclassifying 82% of false-positive results as true negatives. We propose that these two microbiome-derived biomarkers may improve the current strategy of anal cancer screening.

Contribution of Low CD4 Cell Counts and High Human Immunodeficiency Virus (HIV) Viral Load to the Efficacy of Preferred First-Line Antiretroviral Regimens for Treating HIV Infection: A Systematic Review and Meta-Analysis.

We assessed whether low CD4 count and high viral load (VL) affect the response to currently preferred ART. We performed a systematic review of randomized, controlled clinical trials that analyzed preferred first-line ART and a subgroup analysis by CD4 count (≤ or >200 CD4/µL) or VL (≤ or >100 000 copies/mL). We computed the odds ratio (OR) of treatment failure (TF) for each subgroup and individual treatment arm. Patients with ≤200 CD4 cells or VL ≥100 000 copies/mL showed an increased likelihood of TF at 48 weeks: OR, 1.94; 95% confidence interval (CI): 1.45-2.61 and OR, 1.75; 95% CI: 1.30-2.35, respectively. A similar increase in the risk of TF was observed at 96 weeks. There was no significant heterogeneity regarding integrase strand transfer inhibitor or nucleoside reverse transcriptase inhibitor backbone. Our results show that CD4 <200 cells/µL and VL ≥100,000 copies/mL impair ART efficacy in all preferred regimens.

Study on the approach to HIV: health management and the healthcare process in Spain.

INTRODUCTION: HIV continues to represent a problem of great relevance for public health in Spain. This study aims to carry out an analysis that will provide in-depth knowledge of the resources, clinical care, and management during the diagnosis, follow-up, and treatment phases of HIV infection in Spain. METHODS: In the first phase, a multidisciplinary Scientific Committee designed an information collection tool in the form of a survey. In the second phase, carried out in the autonomous communities of Andalusia, Catalonia, and La Rioja, a multidisciplinary group of 42 experts, representatives of the public administration, clinical profiles, and representatives of NGOs in the field of HIV answered the survey. RESULTS: The assessment of HIV resources is generally positive. As regards diagnosis, the experts considered that there was good coordination between Primary and Hospital care. Regarding treatment, the evaluations reflected good opinions on therapeutic conciliation and adherence, with a negative opinion in the evaluation of drug interactions with antiretroviral treatment. Regarding follow-up, the perception expressed was disparate concerning the coordination between Hospital and Primary Care as well as the adaptation of care to chronicity, aging, fragility, mental health, and oncological processes. CONCLUSION: There are certain processes that can be improved in the management of HIV infection in people with HIV in Spain, including protocols for follow-up and coordination between primary and hospital care in the treatment and follow-up of the disease.

Frequency and characteristics of HTLV in migrants: results from the +Redivi collaborative network in Spain.

INTRODUCTION: The objective of this study was to describe the main characteristics of migrants diagnosed with human T-lymphotropic virus (HTLV) infection within the +Redivi Spanish network. METHODS: Patients with a diagnosis of HTLV type 1 or 2 in +Redivi from October 2009 to December 2020 were included. Diagnosis was based on positive HTLV serology (enzyme-linked immunosorbent assay (ELISA)/chemiluminescent immunoassay (CLIA)) with line immunoassay (LIA)/Western blot with/without polymerase chain reaction (PCR). RESULTS: A total of 107/17 007 cases (0.6%) had a final diagnosis of HTLV infection: 83 (77.67%) HTLV-1 infections, 6 (5.6%) HTLV-2 infections and 18 (16.8%) non-specified. The majority (76, 71%) were female, median age was 42 years and median time from arrival to Spain until consultation was 10 years. The group included 100 (93.5%) immigrants and 7 (6.6%) visiting friends and relatives (VFR)-immigrants. Most patients were from South America (71, 66.4%), followed by Sub-Saharan Africa (15, 14%) and Central America-Caribbean (13, 12.1%). Around 90% of patients were asymptomatic at presentation and diagnosed as part of screening programs. Median duration of follow-up was 5 years (IQR 2-7). Regarding HTLV-associated conditions, 90 patients (84.2%) had none, 7 (6.5%) had tropical spastic paraparesis , 5 (4.7%) had other associated conditions (dermatitis, uveitis, pulmonary disease), 3 (2.8%) had other neurological symptoms and 2 (1.9%) had adult T-cell leukaemia/lymphoma. No patients with HTLV-2 had HTLV-associated conditions. Four patients (3.7%) died. Concomitant diagnoses were found in 41 (38.3%) patients, including strongyloidiasis in 15 (14%) and HIV co-infection in 4 (3.7%). In 70% of patients, screening of potential contacts was not performed/recorded. CONCLUSIONS: HTLV infections (the majority due to HTLV-1) were mainly diagnosed in asymptomatic migrants from Latin America (generally long-settled immigrants and the majority female with the consequent implications for screening/prevention). A high rate of association with strongyloidiasis was found. In the majority, screening of potential contacts was not performed, representing a missed opportunity for decreasing the under diagnosis of this infection.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men.

BACKGROUND: While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL). METHODS: We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. RESULTS: We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728-.882). CONCLUSIONS: We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.

Imported cysticercosis in Spain: A retrospective case series from the +REDIVI Collaborative Network.

BACKGROUND: Neurocysticercosis (NCC) is the most common parasitic neurological disease worldwide and a major cause of epilepsy. Spain is the country reporting the highest number of NCC imported cases in Europe. METHODOLOGY: Retrospective case series of NCC patients registered in the +REDIVI Network from October 1, 2009 to July 2018. A specific questionnaire, including clinical and diagnostic characteristics, was created and sent to the collaborator centers. RESULTS: 46 cases were included in the analysis. 55% were male, mean age of 40 years. 95.6% were migrants. The median duration since migration from an endemic area was 10 years. Predominant nationalities were Ecuadorians (50%) and Bolivians (30.4%). Frequent locations were parenchymal (87%), subarachnoid (26.1%) and intraventricular cysts (10.9%). Serological analysis was performed in 91.3%, being 54.8% positive. Most prevalent clinical manifestations were persistent headache (60.9%), epilepsy (43.5%) and visual changes (13%). Patients were mainly treated with albendazole (76.1%), corticosteroids (67.4%), and anticonvulsionants (52.2%). 82.5% had a favorable clinical outcome. CONCLUSIONS: Most NCC cases were long-standing migrants. Few clinical differences were observed depending on the cysticerci location. The treatment was often not according to current recommendations, and no uniform criteria were followed when it came to the therapeutic regimen. NCC case management in Spain (including clinician awareness and laboratory capacity improvements) needs to be strengthened.

Screening for Trypanosoma cruzi infection in immigrants and refugees: Systematic review and recommendations from the Spanish Society of Infectious Diseases and Clinical Microbiology.

BackgroundChagas disease has spread beyond its original borders on the American continent with migration. It can be transmitted from mother to child, through organ transplantation and transfusion of blood and blood products. It is necessary to determine when to screen for this infection.AimOur objective was to evaluate the appropriateness of screening for Trypanosoma cruzi infection in Latin American migrants and their descendants.MethodsWe reviewed the literature using rigorous criteria. The quality of evidence was ranked according to the GRADE classification. An evidence to decision framework was adopted to provide information on the most relevant aspects necessary to formulate recommendations.ResultsThe 33 studies evaluated revealed a prevalence of T. cruzi infection among Latin American migrants in Europe of 6.08% (95% confidence interval (CI): 3.24-9.69; 28 studies). Vertical transmission occurred in three of 100 live births (95% CI: 1-6; 13 studies). The prevalence of cardiovascular disease was 19% (95% CI: 13-27; nine studies), including only 1% severe cardiac events (95% CI: 0-2; 11 studies). The overall quality of evidence was low because of risk of bias in the studies and considerable heterogeneity of the evaluated populations. The recommendations took into account economic studies on the value of screening strategies and studies on acceptability of screening and knowledge of the disease in the affected population.ConclusionsWe identified five situations in which screening for T. cruzi infection is indicated. We recommend screening persons from endemic areas and children of mothers from these areas.

Chagas disease.

Chagas disease is an anthropozoonosis from the American continent that has spread from its original boundaries through migration. It is caused by the protozoan Trypanosoma cruzi, which was identified in the first decade of the 20th century. Once acute infection resolves, patients can develop chronic disease, which in up to 30-40% of cases is characterised by cardiomyopathy, arrhythmias, megaviscera, and, more rarely, polyneuropathy and stroke. Even after more than a century, many challenges remain unresolved, since epidemiological control and diagnostic, therapeutic, and prognostic methods must be improved. In particular, the efficacy and tolerability profile of therapeutic agents is far from ideal. Furthermore, the population affected is older and more complex (eg, immunosuppressed patients and patients with cancer). Nevertheless, in recent years, our knowledge of Chagas disease has expanded, and the international networking needed to change the course of this deadly disease during the 21st century has begun.

Screening for precancerous anal lesions with P16/Ki67 immunostaining in HIV-infected MSM.

BACKGROUND: Screening of anal cancer in HIV-infected MSM with anal cytology results in high rates of false positive results and elevated burden of high-resolution anoscopies. High-risk HPV up-regulates p16 and Ki67 expression in epithelial cells. We assessed the usefulness of P16/Ki-67 immunostaining cytology for the diagnosis of precancerous anal lesions. METHODOLOGY: Cross-sectional multicenter study. Concomitant anal liquid cytology with p16/Ki-67 immunostaining and HRA with biopsy of acetowhite lugol-negative lesions was performed in HIV-infected MSM. We compared the diagnostic performance of an abnormal anal cytology and p16/Ki-67 immunostaining relative to HRA-guided biopsy by logistic regression and comparison of ROC areas. RESULTS: We included 328 HIV-infected MSM. HSIL was histologically diagnosed in 72 subjects (25.1%), and 2 (0.6%) were diagnosed with anal cancer. An abnormal cytology showed a sensitivity of 95.6% and a specificity of 58.8% for the diagnosis of biopsy-proven HSIL. P16/Ki67 positivity was associated with the presence of biopsy-proven HSIL (P trend = 0.004) but with low sensitivity (41.2%) and specificity (71%). The combination of standard cytology with P16/Ki67 immunostaining did not increment the predictive value of standard cytology alone (AUC 0.685 vs. 0.673, respectively, P = 0.688). CONCLUSION: In HIV-infected MSM P16/Ki67 immunostaining does not improve the diagnostic accuracy of anal cytology, which shows a high sensitivity yet poor specificity. Other approaches aimed at improving the diagnostic accuracy of current techniques for the diagnostic of precancerous HSIL are warranted.

Topical cidofovir to treat high-grade anal intraepithelial neoplasia in HIV-infected patients: a pilot clinical trial.

OBJECTIVE: To evaluate the efficacy of 1% topical cidofovir cream for the treatment of anal high-grade squamous intraepithelial lesions (HSILs) in HIV-infected individuals. DESIGN: Single-arm, open-label, pilot clinical trial. METHODS: The study medication was applied intraanally three times per week for 4 weeks. Lesions were assessed with high-resolution anoscopy and biopsy at weeks 12 and 24. The primary endpoint was complete remission (CR) at week 12, defined as clinical and histological remission. We also evaluated partial remission defined as regression to low-grade squamous intraepithelial lesion. RESULTS: We included 17 HIV-infected patients with intraanal HSIL. Median (interquartile range) age was 36 years (28-41), median (interquartile range) CD4 cell count was 545 cells/µl (358-630), and viral load was less than 50  copies/ml in 93.7%. Two patients were lost to follow-up, one of them did not apply treatment. At 12 weeks, in the intention-to-treat population, 10 out of 16 patients [62.5%; 95% confidence interval (CI), 38.2-85.7%] had achieved CR. At 24 weeks, seven of the 10 patients (70%; 95% CI, 47-93%) remained in CR, but two out of 10 patients (20%; 95% CI, 0-40%) presented HSIL. One patient did not attend the visit at 24 weeks. Three patients with persistent HSIL at 12 weeks improved at 24 weeks (partial response in one and CR in two). The mean number of human papillomavirus genotypes decreased from 5.2 to 2.7 at 12 weeks (P = 0.002). Local adverse effects were frequent (81%), although there were no discontinuations because of adverse events. CONCLUSION: One percent topical cidofovir could be an appropriate alternative therapy in HIV-infected patients with anal HSIL. CLINICAL TRIAL: gov unique identifier: NCT01946009.

Old and new challenges in Chagas disease.

Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected disease, which can lead to cardiomyopathy, arrhythmias, megaviscera, and more rarely, polyneuropathy in up to 30-40% of patients around 20 to 30 years after acute infection. Although it is endemic in the Americas, global population movements mean that it can be located wherever migrants from endemic areas settle. The disease was first described 100 years ago and still challenges clinicians worldwide, since diagnostic, therapeutic, and prognostic methods remain insufficient. Furthermore, factors such as HIV co-infection, immunosuppressive drugs, transplantation, and neoplastic disease can alter the natural course of the infection. We present the case of a Bolivian woman with chronic T cruzi infection diagnosed at our clinic in Madrid, Spain, who subsequently developed non-Hodgkin lymphoma. Our report illustrates the challenges of an increasingly common infection seen in non-endemic countries, and highlights both daily management dilemmas and associated difficulties that arise.

[How is the implementation of the new legal framework for health care affecting HIV-infected immigrants in an irregular situation in Spain?]. / ¿Cómo está afectando la aplicación del nuevo marco legal sanitario a la asistencia de los inmigrantes infectados por el VIH en situación irregular en España?

INTRODUCTION: The entry into force of Royal Decree (RD) 16/2012 in Spain in September 2012 led to the exclusion of the group of irregular immigrants from the National Healthcare System. With this work, GESIDA attempts to measure the impact of the entry into force of the RD in relation to its application by the Autonomous Communities (CCAA), and how it has affected the health care of irregular immigrants infected with HIV. METHODS: Information was requested from the 17 CCAA of the existence of measures to ensure the care and treatment of people with HIV infection that were left unprotected because of the implementation of the RD. Likewise, a survey was conducted on health professionals and NGOs involved in the care of these people, to find out how it has affected the implementation of the RD to their daily healthcare work and the availability of information on regulations to implement it. RESULTS: The response of the CCAA was variable, hardly contributing, in some cases, to mitigate the negative effect of the RD. To this is added a complex bureaucracy to access the benefits offered by some regions, often inaccessible to the most vulnerable subjects. Lack of information for health-care professionals and NGOs involved in the care of immigrants, hinders access of this population to health care and the establishment of control measures for diseases with an impact on the public health. CONCLUSIONS: The RD 16/2012 has had a negative impact on daily healthcare working, generating the appearance of deep inequities throughout the country.

Dried blood as an alternative to plasma or serum for Trypanosoma cruzi IgG detection in screening programs.

Trypanosoma cruzi serological screening is recommended for people potentially exposed to this parasite in countries where Trypanosoma cruzi is endemic and those where it is not endemic. Blood samples on filter paper may be a practical alternative to plasma/serum for antibody detection. Using the Architect Chagas assay, we detected the presence of IgG against T. cruzi in matched serum and dried blood spots (DBS) collected from 147 patients residing in Madrid, Spain, who had potential previous exposure to T. cruzi. The κ statistic for the DBS/serum proportion of agreement for the detection of antibodies against T. cruzi was 0.803, considering an S/CO (assay result unit; chemiluminescent signal from the sample [S] divided by the mean chemiluminescent signal for the three calibrators used in the test [CO]) cutoff value of ≥1.00. The relative sensitivity of the Architect test using DBS increased from 95.2% to 98.8% when the cutoff was lowered from ≥1.00 to ≥0.88, while the relative specificity decreased from 84.1% to 71.6%. Overall, the median S/CO values for DBS were significantly lower than those for serum (2.6 versus 6.5; P < 0.001). Discrepancies that occurred with the use of DBS included 10 false positives (with low S/CO values in 9 cases [median, 2.13]) and 4 false negatives, with mean S/CO values of 0.905 (gray zone). Using DBS plus a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) may be a simple and reliable method for detecting IgG against T. cruzi when blood sampling by venipuncture is not feasible. This method may also reduce the false-negative rates observed with some rapid diagnostic tests. The lower relative sensitivity compared to the reference method may be increased by lowering the optical density threshold.

Nifurtimox therapy for Chagas disease does not cause hypersensitivity reactions in patients with such previous adverse reactions during benznidazole treatment.

Currently, only two drugs are approved for treating Trypanosoma cruzi infection: benznidazole and nifurtimox. Adverse reactions are frequent with both drugs: they have chemical similarities and common metabolic pathways making cross reactions a possibility. Our objective was to describe the safety/tolerability profile of nifurtimox in patients who had previously discontinued benznidazole due to hypersensitivity reactions. We performed a prospective observational study from September 2009 to December 2011. Patients who discontinued benznidazole therapy due to hypersensitivity reactions (HR) and were later treated with nifurtimox were included. HR to benznidazole were defined as presence of a rash with or without mucosal involvement, fever or laboratory abnormalities (such as eosinophilia, leucopaenia or impaired liver function tests). The drugs were prescribed for 60 days (benznidazole) or 60-90 days (nifurtimox). The National Cancer Institute criteria (CTCAE, 2006, Version 3.0) were used for grading and reporting of adverse reactions (AR). Eighteen patients (16 females, two males, median age 35.5 years, range 15-50 years) with asymptomatic late chronic infection, were included. Median time between benznidazole interruption and start of therapy with nifurtimox was 121.5 days (IQR 72-223 days). Fifteen patients (83.3%) developed an AR to nifurtimox, gastrointestinal complaints and anorexia being the most common, and 13 patients (72%) completed the treatment schedule. Five patients interrupted therapy (27.8%) mainly because of gastrointestinal intolerance and/or nervous system toxicity. Only one patient developed skin lesions, a mild maculopapular rash not requiring specific therapy or treatment withdrawal. There was no severe AR. Nifurtimox as second line therapy in patients who discontinued benznidazole specifically due to HR appears to be safe and does not seem to be associated with a higher incidence of AR.

[Assessment of the impact of the new health legislation on illegal immigrants in Spain: the case of human immunodeficiency virus infection]. / Evaluación del impacto del nuevo marco legal sanitario sobre los inmigrantes en situación irregular en España: el caso de la infección por el virus de la inmunodeficiencia humana.

The immigrant population in Spain, whether legal or not, has been entitled to healthcare under the same conditions as the Spanish population since the year 2000. The entry into vigour of the Royal Decree-Law 12/2012 of 20 April has significantly restricted this right, so that unauthorized or non-resident foreigners may now only receive emergency care, if they are under 18 or pregnant women. Out of an estimated 459,909 illegal immigrants in our country, 2,700 to 4,600 are probably infected with HIV; 1,800 to 3,220 know that they are infected, and 80% of the latter could receive antiretroviral treatment. The Royal Decree-Law is likely to cause many undesirable consequences in this population infected with HIV: increasing mortality, promoting the emergence of opportunistic diseases, increasing hospital admissions, increasing infections in the population (by HIV and other pathogens), or contributing to mother to child transmission of HIV. The expected increase in morbidity and mortality will be a greater cost in patient care, a cost which will be significantly higher in the more immunosuppressed patients. Therefore, the enforcement of the Royal Decree-Law will be much less cost-effective in the short term than was expected, and will negatively affect our country's public health, especially for those patients infected with HIV who will not be covered, thus increasing healthcare medium to long term costs, and moving away from the international health goals that were established.

Evaluation of nitazoxanide for the treatment of disseminated cystic echinococcosis: report of five cases and literature review.

We aimed to evaluate the effectiveness of nitazoxanide in disseminated cystic echinococcosis (DCE) that failed to respond to surgical and antiparasitic therapy. We report on seven patients (five of them with bony involvement): two cases from the literature and five patients who were included in a compassionate trial of nitazoxanide therapy in our hospital. Median follow-up time until nitazoxanide therapy was 12 years and all patients had received prior medical treatment and extensive surgery. Nitazoxanide (500 mg/12 h) in combination with albendazole, with/without praziquantel, was administered for 3-24 months. Three patients improved: one with muscle involvement (clinico-radiological response), one with lung involvement (radiological response), and another with soft tissue and bony involvement (clinico-radiological response of soft tissue cysts). There was one discontinuation after 15 days of starting therapy. Nitazoxanide combination therapy could have a role in the treatment of DCE when there is no bony involvement. Long-term safety profile seems to be favorable.