Transmitted drug resistance to antiretroviral drugs in Spain during the period 2019-2021.

To evaluate the prevalence of transmitted drug resistance (TDR) to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTI, NNRTI), protease inhibitors (PI), and integrase strand transfer inhibitors (INSTI) in Spain during the period 2019-2021, as well as to evaluate transmitted clinically relevant resistance (TCRR) to antiretroviral drugs. Reverse transcriptase (RT), protease (Pro), and Integrase (IN) sequences from 1824 PLWH (people living with HIV) were studied. To evaluate TDR we investigated the prevalence of surveillance drug resistance mutations (SDRM). To evaluate TCRR (any resistance level ≥ 3), and for HIV subtyping we used the Stanford v.9.4.1 HIVDB Algorithm and an in-depth phylogenetic analysis. The prevalence of NRTI SDRMs was 3.8% (95% CI, 2.8%-4.6%), 6.1% (95% CI, 5.0%-7.3%) for NNRTI, 0.9% (95% CI, 0.5%-1.4%) for PI, and 0.2% (95% CI, 0.0%-0.9%) for INSTI. The prevalence of TCRR to NRTI was 2.1% (95% CI, 1.5%-2.9%), 11.8% for NNRTI, (95% CI, 10.3%-13.5%), 0.2% (95% CI, 0.1%-0.6%) for PI, and 2.5% (95% CI, 1.5%-4.1%) for INSTI. Most of the patients were infected by subtype B (79.8%), while the majority of non-Bs were CRF02_AG (n = 109, 6%). The prevalence of INSTI and PI resistance in Spain during the period 2019-2021 is low, while NRTI resistance is moderate, and NNRTI resistance is the highest. Our results support the use of integrase inhibitors as first-line treatment in Spain. Our findings highlight the importance of ongoing surveillance of TDR to antiretroviral drugs in PLWH particularly with regard to first-line antiretroviral therapy.

Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers.

OBJECTIVES: To assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk. METHODS: EPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs. RESULTS: Of 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00-1.98) for TDF + HCQ, 0.34 (0.00-2.06) for TDF, and 0.49 (0.00-2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21-1.00) for TDF + HCQ, 0.81 (0.44-1.49) for TDF, and 0.73 (0.41-1.38) for HCQ. Adverse events were generally mild. DISCUSSION: The target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo.

Vancomycin versus daptomycin for the treatment of confirmed gram-positive catheter-related bloodstream infections in oncology patients.

OBJECTIVE: To analyse the effectiveness and safety of daptomycin versus vancomycin on the management catheter-related bloodstream  nfections in oncology patients. METHOD: A retrospective study was carried out including all patients admitted  at the Medical Oncology Unit between 2010 and 2018 with positive blood  cultures confirmed catheter-related bloodstream infections due to gram- positive microorganism, who were treated with either vancomycin or  daptomycin. The primary end point was all cause 30-days mortality, 30-days  hospital readmission and length of hospital stay (length of hospital stay). Results: A total of 70 patients with catheter-related bloodstream infections were included in the present study: vancomycin was administered to  61.4% (n = 43) and daptomycin to 38.6% (n = 27) of  patients. 78.5% (n = 55) of isolated bacteria showed a vancomycin minimum  inhibitory concentration ≤ 1 µg/ml. No differences were observed  between the two groups of patients regarding the 30-day mortality rate rate  (32.6% [n = 14] versus 29.6% [n = 8]; p = 0.797), the 30-day re-admission rate (30.2% [n = 13] versus 29.6% [n = 8]; p = 0.957) or the length of  hospital stay (18.9 versus 16.5 days; p = 0.562). Nephrotoxicity rate was  equivalent in both groups: a 7% (n = 3) of vancomycin goup versus a 7.4% (n  = 2) of daptomycin group (p = 0.946). CONCLUSIONS: Our results show that both antibiotics are equivalent in their  safety and effectiveness. Therefore, vancomycin should continue being the  treatment of chose for gram-positive catheter-related bloodstream infections,  in particular at hospital centres with a low prevalence of strains that show  diminished susceptibility to vancomycin.

OBJETIVO: Analizar la eficacia y seguridad de la daptomicina frente a la  vancomicina en el tratamiento de las infecciones del torrente sanguíneo asociadas a catéter vascular en pacientes oncológicos.Método: Se realizó un estudio retrospectivo que incluyó a los pacientes ingresados en la Unidad de Oncología-Médica entre 2010-2018 con infección del torrente sanguíneo asociada a catéter vascular causada por  grampositivos, y que fueron tratados con vancomicina o daptomicina. Como  objetivos principales se determinaron la tasa de mortalidad por todas las  causas a los 30 días, el reingreso hospitalario a los 30 días y la duración de la  estancia hospitalaria. RESULTADOS: El estudio incluyó 70 pacientes con infecciones del torrente sanguíneo asociadas a catéter vascular: el 61,4% (n = 43) recibió  vancomicina y el 38,6% (n = 27) daptomicina. El 78,5% (n = 55) de las  bacterias aisladas presentaron una concentración mínima inhibitoria de  vancomicina ≤ 1 µg/ml. No se observaron diferencias entre ambos grupos de  pacientes en cuanto a la tasa de mortalidad a 30 días (32,6% [n = 14]  frente al 29,6% [n = 8]; p = 0,797), la tasa de reingreso a 30 días (30,2% [n  = 13] frente al 29,6% [n = 8]; p = 0,957) o la duración de la hospitalización (18,9 frente a 16,5 días; p = 0,562). La tasa de nefrotoxicidad fue equivalente  en ambos grupos: 7% (n = 3) para vancomicina frente al 7,4% (n = 2) para  daptomicina (p = 0,946). CONCLUSIONES: Nuestros resultados muestran que ambos antibióticos son equivalentes en su seguridad y eficacia. Por ello, vancomicina debería seguir siendo el tratamiento de elección para la infección del torrente sanguíneo asociada a catéter vascular, especialmente en centros con  una baja prevalencia de cepas con una susceptibilidad disminuida a  ancomicina.

Vancomicina frente a daptomicina como tratamiento de las bacteriemias asociadas a catéter y causadas por grampositivos en el paciente oncológico / Vancomycin versus daptomycin for the treatment of confirmed gram-positive catheter-related bloodstream infections in oncology patients

Objetivo: Analizar la eficacia y seguridad de la daptomicina frente ala vancomicina en el tratamiento de las infecciones del torrente sanguíneoasociadas a catéter vascular en pacientes oncológicos.Método: Se realizó un estudio retrospectivo que incluyó a los pacientesingresados en la Unidad de Oncología-Médica entre 2010-2018 coninfección del torrente sanguíneo asociada a catéter vascular causadapor grampositivos, y que fueron tratados con vancomicina o daptomicina.Como objetivos principales se determinaron la tasa de mortalidad portodas las causas a los 30 días, el reingreso hospitalario a los 30 días yla duración de la estancia hospitalaria.Resultados: El estudio incluyó 70 pacientes con infecciones del torrentesanguíneo asociadas a catéter vascular: el 61,4% (n = 43) recibió vancomicinay el 38,6% (n = 27) daptomicina. El 78,5% (n = 55) de las bacteriasaisladas presentaron una concentración mínima inhibitoria de vancomicina≤ 1 μg/ml. No se observaron diferencias entre ambos grupos depacientes en cuanto a la tasa de mortalidad a 30 días (32,6% [n = 14] frente al 29,6% [n = 8]; p = 0,797), la tasa de reingreso a 30 días (30,2%[n = 13] frente al 29,6% [n = 8]; p = 0,957) o la duración de la hospitalización(18,9 frente a 16,5 días; p = 0,562). La tasa de nefrotoxicidadfue equivalente en ambos grupos: 7% (n = 3) para vancomicina frente al7,4% (n = 2) para daptomicina (p = 0,946).Conclusiones: Nuestros resultados muestran que ambos antibióticos sonequivalentes en su seguridad y eficacia. Por ello, vancomicina deberíaseguir siendo el tratamiento de elección para la infección del torrentesanguíneo asociada a catéter vascular, especialmente en centros con unabaja prevalencia de cepas con una susceptibilidad disminuida a vancomicina.

Objective: To analyse the effectiveness and safety of daptomycin versusvancomycin on the management catheter-related bloodstream infectionsin oncology patients.Method: A retrospective study was carried out including all patientsadmitted at the Medical Oncology Unit between 2010 and 2018 withpositive blood cultures confirmed catheter-related bloodstream infectionsdue to gram-positive microorganism, who were treated with either vancomycinor daptomycin. The primary end point was all cause 30-daysmortality, 30-days hospital readmission and length of hospital stay (lengthof hospital stay).Results: A total of 70 patients with catheter-related bloodstream infectionswere included in the present study: vancomycin was administeredto 61.4% (n = 43) and daptomycin to 38.6% (n = 27) of patients.78.5% (n = 55) of isolated bacteria showed a vancomycin minimuminhibitory concentration ≤ 1 μg/ml. No differences were observed betweenthe two groups of patients regarding the 30-day mortality rate rate (32.6% [n = 14] versus 29.6% [n = 8]; p = 0.797), the 30-day re-admissionrate (30.2% [n = 13] versus 29.6% [n = 8]; p = 0.957) or the lengthof hospital stay (18.9 versus 16.5 days; p = 0.562). Nephrotoxicity ratewas equivalent in both groups: a 7% (n = 3) of vancomycin goup versus a7.4% (n = 2) of daptomycin group (p = 0.946).Conclusions: Our results show that both antibiotics are equivalent intheir safety and effectiveness. Therefore, vancomycin should continuebeing the treatment of chose for gram-positive catheter-related bloodstreaminfections, in particular at hospital centres with a low prevalence ofstrains that show diminished susceptibility to vancomycin.

Psychological distress in women and men living with HIV in Spain: a cross-sectional telephone survey.

BACKGROUND: Psychological distress includes a broader range of experiences, varying from less severe symptoms of depression and anxiety to severe psychiatric disease. Global estimates for depression and anxiety in 2017 were 3.4% and 3.8%, respectively. While for people living with HIV, global estimates were 16% and 33%, respectively. OBJECTIVE: We aimed to determine the prevalence of psychological distress by gender and associated characteristics in patients living with HIV. METHODS: A cross-sectional study was conducted within the Spanish HIV Research Network CoRIS. Participants were interviewed by telephone between 2010 and 2014 about their psychological distress, sociodemographics, drug consumption, self-perceived health and combined antiretroviral therapy (cART) adherence. Laboratory tests and medical history details were collected from CoRIS. Logistic regression was used to identify characteristics associated with psychological distress. FINDINGS: We interviewed 99 women and 464 men, both living with HIV. A greater proportion of women (51, 51.5%) reported psychological distress than men (179, 38.6%; p<0.01). Non-adherence to cART (OR 4.6 and 2.3, 95% CI 1.4‒15.1 and 1.3‒4.2) and non-use of cART (8.4 and 1.8, 2.2‒32.4 and 1.1‒2.8) were related to psychological distress in women and men, respectively. Spending little time in leisure-based physical activity was related to psychological distress in women (3.1, 1.1‒9.0). Living alone (2.0, 1.3‒3.0) and being unemployed (2.3, 1.4‒3.6) were related to psychological distress in men. CONCLUSIONS AND CLINICAL IMPLICATIONS: As people living with HIV have a high prevalence of psychological distress, their regular screening appointments should include psychological assessment. A gendered approach is needed to detect and manage psychological distress.

Sexual behaviour and poor hygiene are related to recent hepatitis a virus community outbreaks

OBJECTIVES: there has been a global increase in the incidence of hepatitis A infection. The aim of this study was to examine the characteristics of the increase in our region and the degree of adherence to the recommended hygienic measures after discharge from hospital. METHODS: demographic, clinical and biochemical variables were collected from patients with acute hepatitis A in our health area. The patients were grouped as follows: January 2010 to December 2016 (historical cohort) and January 2017 to October 2017 (recent cohort). A phylogenetic analysis was also performed in the recent cohort. One month after discharge, bacterial growth was evaluated by a culture of the dominant hand imprint and were compared with a control group. RESULTS: a total of 110 cases were registered with a median age of 36.3 years (range 3-89) and 77.3 % were male. The incidence was 0.82/100,000 inhabitants/year and 22.75/100,000 inhabitants/year in the historical and recent cohorts, respectively. Patients in the recent cohort were more frequently male (52.6 % vs. 82.4 %, p = 0.008) and younger (51.7 [3-89] vs. 33.4 [4-74] years, p < 0.001). In addition, 63.8 % of the recent cohort were men who had sex with other men and had unsafe sexual practices (37.5 %). Phylogenetic analysis showed a predominance of genotype A and a high frequency of the VRD 521-2016 sequence. A higher growth of enterobacteria was observed in patients with hepatitis A compared to the control group (7.3 % vs. 1.2 %, p = 0.005), despite specific hygienic measures given at discharge. CONCLUSIONS: a recent outbreak of hepatitis A in our area was related with gender, younger age and sexual practices. Hepatitis A infected subjects showed a poor adherence to hygienic measures. Our data suggests the need for policies that encourage preventive actions, particularly vaccination in this high-risk group

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Sexual behaviour and poor hygiene are related to recent hepatitis a virus community outbreaks.

OBJECTIVES: there has been a global increase in the incidence of hepatitis A infection. The aim of this study was to examine the characteristics of the increase in our region and the degree of adherence to the recommended hygienic measures after discharge from hospital. METHODS: demographic, clinical and biochemical variables were collected from patients with acute hepatitis A in our health area. The patients were grouped as follows: January 2010 to December 2016 (historical cohort) and January 2017 to October 2017 (recent cohort). A phylogenetic analysis was also performed in the recent cohort. One month after discharge, bacterial growth was evaluated by a culture of the dominant hand imprint and were compared with a control group. RESULTS: a total of 110 cases were registered with a median age of 36.3 years (range 3-89) and 77.3 % were male. The incidence was 0.82/100,000 inhabitants/year and 22.75/100,000 inhabitants/year in the historical and recent cohorts, respectively. Patients in the recent cohort were more frequently male (52.6 % vs. 82.4 %, p = 0.008) and younger (51.7 [3-89] vs. 33.4 [4-74] years, p < 0.001). In addition, 63.8 % of the recent cohort were men who had sex with other men and had unsafe sexual practices (37.5 %). Phylogenetic analysis showed a predominance of genotype A and a high frequency of the VRD 521-2016 sequence. A higher growth of enterobacteria was observed in patients with hepatitis A compared to the control group (7.3 % vs. 1.2 %, p = 0.005), despite specific hygienic measures given at discharge. CONCLUSIONS: a recent outbreak of hepatitis A in our area was related with gender, younger age and sexual practices. Hepatitis A infected subjects showed a poor adherence to hygienic measures. Our data suggests the need for policies that encourage preventive actions, particularly vaccination in this high-risk group.

The algorithm used for the interpretation of doravirine transmitted drug resistance strongly influences clinical practice and guideline recommendations.

OBJECTIVES: We report the results of the reverse transcriptase (RT)/protease (PR) transmitted drug resistance (TDR) prevalence study in 2018, focusing on doravirine resistance-associated mutations and the differences observed when Stanford or French National Agency for AIDS Research (ANRS)/Spanish Network of AIDS Research (RIS)/IAS-USA resistance interpretation algorithms are used to describe clinically relevant resistance. METHODS: We used the WHO 2009 list to investigate the prevalence of NNRTI, NRTI and PI TDR, in treatment-naive HIV-1-infected patients, adding mutations E138A/G/K/Q/R, V106I, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F in RT. The prevalence of doravirine resistance-associated mutations, as described by Soulie et al. in 2019, was evaluated. Clinically relevant TDR was investigated using the latest versions of ANRS, RIS, IAS-USA and Stanford algorithms. RESULTS: NNRTI mutations were detected in 82 of 606 (13.5%) patients. We found 18 patients (3.0%) with NRTI mutations and 5 patients (0.8%) with PI mutations. We detected 11 patients harbouring doravirine resistance-associated mutations (prevalence of 1.8%). Furthermore, we observed important differences in clinically relevant resistance to doravirine when ANRS/RIS (0.7%), IAS-USA (0.5%) or Stanford algorithms (5.0%) were used. V106I, which was detected in 3.8% of the patients, was the main mutation driving these differences. V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients. CONCLUSIONS: The prevalence of NRTI and PI TDR remains constant in Spain. Doravirine TDR is very infrequent by RIS/ANRS/IAS-USA algorithms, in contrast with results using the Stanford algorithm. Further genotype-phenotype studies are necessary to elucidate the role of V106I in doravirine resistance.

Surveillance of transmitted drug resistance to integrase inhibitors in Spain: implications for clinical practice.

BACKGROUND: Integrase strand-transfer inhibitors (INSTIs) constitute at present one of the pillars of first-line ART. OBJECTIVES: To study the prevalence of and the trend in transmitted drug resistance (TDR) to INSTIs in ART-naive patients in Spain. METHODS: During the period 2012-17, 1109 patients from CoRIS were analysed. The Stanford algorithm v8.7 was used to evaluate TDR and transmission of clinically relevant resistance. To describe individual mutations/polymorphisms, the most recent IAS list (for INSTIs) and the 2009 WHO list update (for the backbone NRTIs used in combination with INSTIs in first-line treatment) were used. RESULTS: Clinically relevant resistance to the INSTI class was 0.2%: T66I, 0.1%, resistance to elvitegravir and intermediate resistance to raltegravir; and G163K, 0.1%, intermediate resistance to raltegravir and elvitegravir. No clinical resistance to dolutegravir or bictegravir was observed. The prevalence of INSTI TDR following the IAS-USA INSTI mutation list was 2.6%, with no trend towards changes in the prevalence throughout the study period. The overall prevalence of NRTI WHO mutations was 4.3%, whereas clinically relevant resistance to tenofovir, abacavir and emtricitabine/lamivudine was 1.7%, 1.9% and 0.7%, respectively. CONCLUSIONS: Given the low prevalence of clinically relevant resistance to INSTIs and first-line NRTIs in Spain, it is very unlikely that a newly diagnosed patient will present with clinical resistance to a first-line INSTI-based regimen. These patients may not benefit from INSTI and NRTI baseline resistance testing.

Reproductive history before and after HIV diagnosis: A cross-sectional study in HIV-positive women in Spain.

The aim of this study is to examine the reproductive history of human immunodeficiency virus (HIV)-positive women, before and after HIV diagnosis, to describe the characteristics of women with pregnancies after HIV diagnosis, and to assess the prevalence of mother-to-child transmission.A cross-sectional study was performed among women within reproductive ages (18-49) selected from the cohort in the Spanish AIDS Research Network (CoRIS). A descriptive analysis of the pregnancy outcomes was made according to women's serostatus at the moment of pregnancy and association of women's characteristics with having pregnancy after HIV diagnosis was evaluated using logistic regression models.Overall, 161 women were interviewed; of them, 86% had been pregnant at least once and 39% after HIV diagnosis. There were 347 pregnancies, 29% of them occurred after HIV diagnosis and in these, 20% were miscarriages and 29% were voluntary termination of pregnancy. There were 3 cases of mother-to-child transmission among the 56 children born from HIV-positive mothers; in these cases, women were diagnosed during delivery. Having a pregnancy after HIV diagnosis was more likely when the younger women were at the time of diagnosis: odds ratio (OR) = 1.29 (95% confidence interval 0.40-4.17) for 25 to 29 years old, OR = 0.59 (0.15-2.29) for 30 to 34 years old, OR = 0.14 (0.03-0.74) for ≥35 years old, compared with those <25 years at diagnosis, who were diagnosed for ≥5 years (OR = 5.27 [1.71-16.18]), who received antiretroviral treatment at some point (OR = 9.38 [1.09-80.45]), and who received information on reproductive health (OR = 4.32 [1.52-12.26]).An important number of pregnancies occurred after HIV diagnosis, reflecting a desire for motherhood in these women. Reproductive and sexual health should be tackled in medical follow-ups.

Safety, efficacy, and persistence of emtricitabine/tenofovir versus other nucleoside analogues in naive subjects aged 50 years or older in Spain: the TRIP study.

OBJECTIVES: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred combination ART (cART) for these patients have been described. Our study compares emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) versus other nucleoside reverse transcriptase inhibitor (NNRTI) regimens in HIV ART-naïve patients who are ≥50 years. DESIGN: National, retrospective cohort analysis of patients who were ≥50 years old when they began the first cART (January 1, 2006 to December 31, 2009). METHODS: We compared safety, effectiveness, and persistence of treatment in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitor (PI) versus NNRTI users and lopinavir/r versus efavirenz users. RESULTS: We included 161 patients: median age was 54.6 years, 83% were men, median CD4 count was 191 cells/µL, median viral load was 4.7 log, and median follow-up was 19 months (maximum, 48 months). Of these participants, 112 started with FTC/TDF and 49 with other nucleotide reverse transcriptase inhibitors (NRTIs). During follow-up, 21.9% of subjects developed at least one laboratory event ≥grade 3, 5.6% interrupted cART due to adverse events,19.3% had virologic failure, and 49.1% modified cART. There were no statistically significant differences between FTC/TDF and non-FTC/TDF users for any output except for persistence: The proportion of subjects who changed cART was 71.4% for non-FTC/TDF users and 38.6% for FTC/TDF users (log rank 0.001; adjusted hazard ratio, 2.10; 95% CI, 1.34-3.29). CONCLUSIONS: In a population of HIV-infected subjects who were ≥50 years old, our study suggests that the use of FTC/TDF is generally safe and effective, with a longer persistence as compared to other regimens.

Durability of first ART regimen and risk factors for modification, interruption or death in HIV-positive patients starting ART in Europe and North America 2002-2009.

OBJECTIVES: To estimate the incidence of and risk factors for modifications to first antiretroviral therapy (ART) regimen, treatment interruption and death. METHODS: A total of 21 801 patients from 18 cohorts in Europe and North America starting ART on regimens including at least two nucleoside reverse transcriptase inhibitors and boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor during 2002-2009 were included. Incidence of modifications (change of drug class, substitution/addition within class, or switch to nonstandard regimen), interruption or death and associations with patient characteristics were estimated using competing-risks methods. RESULTS: During median 28 months follow-up, 8786 (40.3%) patients modified first ART, 2346 (10.8%) interrupted and 427 (2.0%) died before changing regimen. Three-year cumulative percentages of modification, interruption and death were 47, 12 and 2%, respectively. After adjustment, rates of interruption were highest for IDUs and lowest for MSM, and higher for patients starting ART with CD4 cell count above 350 cells/µl than other patients. Compared to efavirenz, patients on lopinavir and other protease inhibitors had higher rates of modification and interruption, on atazanavir had lower rates of class change, and on nevirapine higher rates of interruption. Those on tenofovir/emtricitabine backbone had lowest rates of substitutions and switches to nonstandard regimen, and on abacavir/lamivudine lowest rates of interruption. Rates of substitution and switches to nonstandard regimen were lower in 2006-2009. CONCLUSION: Rates of modification and interruption were high, particularly in the first year of ART. Decreased rates of substitutions or switches to nonstandard regimen in recent years may be linked to greater use of well tolerated once-daily drugs.

Incidencia y factores de riesgo de carcinomas definitorios de SIDA en una cohorte de pacientes con infección por VIH: importancia de la definición de casos incidentes / Incidence and risk factors of AIDS-defining cancers in a cohort of HIV-positive adults: Importance of the definition of incident cases

Introducción El objetivo de este estudio es analizar la incidencia y factores de riesgo para el desarrollo de carcinomas definitorios de SIDA (CDS), e investigar el efecto de diferentes definiciones de casos incidentes. Métodos Se diseñó un estudio de cohortes. Se analizaron incidencia y factores de riesgo mediante regresión de Poisson. Se realizó el análisis para tres definiciones de casos incidentes: retraso de 0, 14 y 30 días desde la inclusión en la cohorte. Resultados Se incluyeron 6393 sujetos con infección por VIH. La incidencia de CDS cambió según las definiciones de casos incidentes (retraso 0, 14 y 30 días). Diferentes factores se asociaron con el riesgo de CDS para diferentes definiciones de casos incidentes. Para el retraso 0, el riesgo de sarcoma de Kaposi (KS) y linfoma no Hodgkin (LNH) fue mayor para valores de CD4 <200/ml. La terapia HAART se asoció a un menor riesgo de LNH y SK. Los hombres que tienen sexo con hombres tuvieron mayor riesgo de SK. SK y LNH no se asociaron con carga viral, género, hepatitis B o C. Para los retrasos de 14 y 30 días, los resultados fueron similares; sin embargo, la hepatitis C se asoció de forma significativa con el LNH. Conclusiones Nuestro estudios muestra la importancia de la definición de casos incidentes en los estudios de cohortes. Diferentes definiciones pueden influir en la estimación de la incidencia de CDS y en el análisis de los factores de riesgo (AU)

Background The aim of this study was to investigate the incidence and risk factors for the development of AIDS-defining cancers (ADCs); and to investigate the effect of making different assumptions on the definition of incident cases. Methods A multicentre cohort study was designed. Poisson regression was used to assess incidence and risk factors. To account for misclassification, incident cases were defined using lag-times of 0, 14 and 30 days after enrolment. Results A total of 6393 HIV-positive subjects were included in the study. The incidences of ADCs changed as the lag periods were varied from 0 to 30 days. Different risk factors emerged as the definition of incident cases was changed. For a lag time of 0, the risk of Kaposi sarcoma [KS] and non-Hodgkin lymphoma [NHL] increased at CD4 counts <200/ml. HAART was associated with lower risk of NHL and KS. Men who had sex with men had a higher risk of KS. KS and NHL were not associated with viral load, gender, or hepatitis B or C. The results were similar for a lag-time of 14 and 30 days; however, hepatitis C was significantly associated with NHL. Conclusions This analysis shows the importance of the definition of incident cases in cohort studies. Alternative definitions gave different incidence estimates, and may have implications for the analysis of risk factors (AU)

Bone alterations in hepatitis C virus infected patients.

BACKGROUND AND AIMS: Most studies have shown that patients with chronic hepatitis C virus (HCV) infection are affected by osteoporosis. However, liver function impairment and deranged nutrition may both play a role in the bone alterations observed. In some works no osteoporosis was found, and some cases of osteosclerosis have been reported. The aim of the study is to assess bone alterations in treatment-naïve, well-nourished HCV patients, in order to discern whether or not HCV infection causes osteoporosis. METHODS: Whole-body bone densitometry and assessment of T-score at lumbar spine and hip were performed to 40 patients and 40 age- and sex-matched controls, with a Lunar Prodigy Advance (General Electric, Piscataway, NJ, USA). All the patients underwent liver biopsy. Nutritional evaluation was performed by subjective nutritional assessment, body mass index (BMI), and densitometric assessment of total lean mass and total fat mass. Serum osteocalcin, osteoprotegerin, RANKL, PTH, crosslaps, vitamin D3, testosterone, IGF-1, and estradiol were determined. RESULTS: Patients did not show differences in total bone mineral density (BMD) or T-score with controls. On the contrary, about a third of them showed positive T scores. Patients showed lower IGF-1, vitamin D3 and testosterone, but higher telopeptide levels, and a trend to higher osteoprotegerin levels. Multivariate analyses disclosed that age, sex, and total lean mass were the only parameters independently related with BMD. CONCLUSIONS: Therefore, chronic HCV infection in well nourished patients with preserved liver function does not cause osteoporosis.

Incidence and risk factors of AIDS-defining cancers in a cohort of HIV-positive adults: Importance of the definition of incident cases.

BACKGROUND: The aim of this study was to investigate the incidence and risk factors for the development of AIDS-defining cancers (ADCs); and to investigate the effect of making different assumptions on the definition of incident cases. METHODS: A multicentre cohort study was designed. Poisson regression was used to assess incidence and risk factors. To account for misclassification, incident cases were defined using lag-times of 0, 14 and 30 days after enrolment. RESULTS: A total of 6393 HIV-positive subjects were included in the study. The incidences of ADCs changed as the lag periods were varied from 0 to 30 days. Different risk factors emerged as the definition of incident cases was changed. For a lag time of 0, the risk of Kaposi sarcoma [KS] and non-Hodgkin lymphoma [NHL] increased at CD4 counts <200/ml. HAART was associated with lower risk of NHL and KS. Men who had sex with men had a higher risk of KS. KS and NHL were not associated with viral load, gender, or hepatitis B or C. The results were similar for a lag-time of 14 and 30 days; however, hepatitis C was significantly associated with NHL. CONCLUSIONS: This analysis shows the importance of the definition of incident cases in cohort studies. Alternative definitions gave different incidence estimates, and may have implications for the analysis of risk factors.

Clinical, virological and biochemical evidence supporting the association of HIV-1 reverse transcriptase polymorphism R284K and thymidine analogue resistance mutations M41L, L210W and T215Y in patients failing tenofovir/emtricitabine therapy.

BACKGROUND: Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. RESULTS: The cross-sectional study carried out with > 200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. CONCLUSIONS: Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.

Drug resistance mutations in HIV-infected patients in the Spanish drug resistance database failing tipranavir and darunavir therapy.

The presence of resistance mutations in patients failing tipranavir or darunavir was examined at the national drug resistance database of the Spanish AIDS Research Network. Although mutations emerging during tipranavir and darunavir failures differed considerably, cross-resistance was found in up to half of the patients tested. Interestingly, mutation 54L, which is associated with tipranavir hypersusceptibility, was selected in half of the darunavir failures. Thus, resistance testing seems mandatory to ensure the benefit of the sequential use of these drugs.

An epidemiologic study to determine the prevalence of the HLA-B*5701 allele among HIV-positive patients in Europe.

OBJECTIVES: HLA-B*5701 is a major histocompatibility complex class I allele associated with an immunologically-mediated hypersensitivity reaction to abacavir. The objectives of this study were to evaluate HLA-B*5701 prevalence among European, HIV-1-infected patients and to compare the local and central laboratory screening results. METHODS: Data were combined from six multicentre, prospective studies involving 10 European countries in which HIV-1-infected patients (irrespective of treatment experience or previous HLA-B*5701 screening), >or=18 years of age, were evaluated for HLA-B*5701 carriage, determined by the central and local laboratory methods. RESULTS: A total of 9720 patients from 272 centres were included in the analysis. The overall estimate of HLA-B*5701 prevalence in Europe was 4.98%, with country-specific estimates ranging from 1.53 to 7.75%. HLA-B*5701 prevalence was highest in the self-reported white population (6.49%) and lowest in the black population (0.39%). Local laboratory results had a high specificity (99.9%) and sensitivity (99.2%) when compared with the central laboratory results. CONCLUSION: This study supports data from previous studies regarding the prevalence of HLA-B*5701 in the HIV population and the variation of HLA-B*5701 prevalence between different racial groups. The high specificity and sensitivity of local laboratory results, suggests that clinicians can be confident in using local laboratories for pretreatment HLA-B*5701 screening. However, it is essential that local laboratories participate in HLA-B*5701-specific quality assurance programs to maintain 100% sensitivity. In HIV-infected patients, pretreatment HLA-B*5701 screening may allow more informed decisions regarding abacavir use and has the potential to significantly reduce the frequency of abacavir-related hypersensitivity reactions and costs associated with managing these reactions.

Cytokines and lipid peroxidation in alcoholics with chronic hepatitis C virus infection.

A major cause of liver cirrhosis and hepatocarcinoma is chronic infection by hepatitis C virus. Ethanol consumption is the most significant environmental factor that exacerbates the progression of chronic hepatitis C to liver cirrhosis and hepatocarcinoma, perhaps due to increased cytokine secretion together with increased lipid peroxidation. In this study, we compare the intensity of lipid peroxidation (estimated as malondialdehyde (MDA) serum levels), the antioxidant status, (measured as glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities in red blood cells), and levels of cytokines derived from Th1 cells (such as interferon gamma (IFNG)), Th2 cells (such as interleukin (IL)-4), Th3 cells (such as transforming growth factor beta (TGF-beta)), and IL-6, IL-8, and tumor necrosis factor (TNF)-alpha in patients affected by chronic hepatitis C virus infection, 26 drinkers of alcohol and 40 nondrinkers of alcohol. Patients showed significantly higher TNF-alpha (Z = 4.92, P < 0.001), IL-8 (Z = 4.95, P < 0.001), IFNG (Z = 2.81, P = 0.005), TGF-beta (t = 2.12, P = 0.037), MDA (Z = 5, P < 0.001), but lower IL-6 (Z = 3.61, P < 0.001) and GPX (F = 4.30, P < 0.05) than controls, whereas no differences were observed regarding IL-4 (Z = 0.35, P = 0.72), GPX and SOD activities. Alcoholics showed significantly higher TNF-alpha, but lower IL-4, MDA, and GPX, than nonalcoholics. TNF-alpha was significantly related to albumin and prothrombin activity, whereas TGF-beta was significantly related to MDA levels. Thus, cytokine secretion is altered in HCV infection. This alteration mainly consists of a stimulation of Th1 cytokines and an inhibition--or at least, no stimulation--of Th2 cytokines; these changes are especially marked among alcoholics with HCV infection, and are accompanied by raised TGF-beta.

Introducción del sistema europea de transferencia de créditos (ECTS) en la Facultad de Medicina de La Laguna / Introduction of the European Credit Transfer System (ECTS) in the medical school of the University of La Laguna

Para la convergencia europea se deben modificar los planes de estudios de las facultades de medicina de forma que el Sistema de Transferencia de Créditos Europeo (ECTS) esté incorporado a los nuevos planes del estudio antes del 2010 Objetivos: Experimentar la introducción del ECTS en el segundo cuatrimestre de quinto curso, modificando la metodología docente. Diseño del estudio: Se adaptaron los programas teóricos y prácticos y se establecieron unos objetivos docentes y un sistema de evaluación para las asignaturas de Patología Médica de la Sangre y de la Hematopoyesis, de las Enfermedades Infecciosas y del Sistema Endocrino y Nutrición, Pediatría y Patología Quirúrgica de Cara, Cuello, Mama y Glándulas Endocrinas. Se realizaron encuestas a los alumnos en el transcurso de cuatrimestre, utilizando para las respuestas una escala de tipo Likert con cinco grados. Se analizó la priorización de las competencias genéricas y específicas de los alumnos. Para el análisis de los resultados se aplicaron pruebas no paramétricas. Resultados: Los 37 créditos actuales se transformaron en 29.5 ECTS, con 736.5 horas de trabajo para los alumnos. Se redujeron los programas teóricos de 186 lecciones en total a 134 (reducción del 27.96 %). Los alumnos prepararon y presentaron 58 casos clínicos bajo la supervisión de sus tutores. Los profesores consideraron que el aprendizaje teórico había sido similar al de cursos anteriores (66.6 %) y el práctico había sido mejor (73.3 %). El 73.3 % de los alumnos contestaron que el proyecto debía mejorarse, mediante la reducción de la carga de trabajo de los alumnos y mejora del sistema de evaluación. Los alumnos apreciaron de forma estadísticamente significativa que mejoró la docencia práctica y su capacidad para preparar y presentar casos clínicos. El rendimiento académico de los alumnos fue significativamente mejor que el de los alumnos del curso anterior. Los estudiantes estuvieron de acuerdo con la prioridad de competencias de la CND para 9/9 de las generales y 4/17 de las específicas. Conclusiones: La introducción experimental del ECTS mejoró el rendimiento académico, la formación práctica y el autoaprendizaje de los alumnos. La experiencia fue satisfactoria para profesores y alumnos. La estimación de la carga de trabajo de los alumnos fue subestimada (AU)

Introduction: To comply with the requirements of European convergence, faculties of medicine must modify their curricula and incorporate the European Credit Transfer System (ECTS) before 2010. Objectives: To test the introduction of ECTS in the 2nd term of the 5th year medicine course and the appropriately modified teaching methodology. Study design: Theoretical and practical programs were adapted; academic objectives and student evaluation system were established for the following subjects: medical pathology of blood and haematopoiesis, infectious diseases and endocrine system and nutrition, paediatrics and surgical pathology of the face, neck, breast and endocrine glands. Students were surveyed during the term, using a 5-point Likert-type scale. We recorded student priorities for general and specific parameters, and the results were analyzed using non-parametric tests. Results: Thirty-seven credits were converted into 29.5 ECTS credits, representing 736.5 student working hours. The theory program was reduced from 186 to 134 lectures (a reduction of 28%). Students presented 58 tutor-supervised clinical cases. The teaching staff considered that learning of theory was similar to previous years (66.6%) but that practical learning improved (73.3%). Most students (73.2%) thought the program should be improved, especially the examination system, and the workload reduced. Students reported a statistically significant improvement in practical teaching and in their capacity to present clinical cases. Academic performance was significantly higher than that of the 5th year students the previous year. Students agreed with the National Deans Conference priorities for the 9/9 general and 4/17 specific competences. Conclusions: Introducing ECTS improved academic performance, practical training and self-learning. The project proved satisfactory for staff and students. Student workload was underestimated in the new plan (AU)