Estimating the HIV undiagnosed population in Catalonia, Spain: descriptive and comparative data analysis to identify differences in MSM stratified by migrant and Spanish-born population.

OBJECTIVE: Undiagnosed HIV continues to be a hindrance to efforts aimed at reducing incidence of HIV. The objective of this study was to provide an estimate of the HIV undiagnosed population in Catalonia and compare the HIV care cascade with this step included between high-risk populations. METHODS: To estimate HIV incidence, time between infection and diagnosis and the undiagnosed population stratified by CD4 count, we used the ECDC HIV Modelling Tool V.1.2.2. This model uses data on new HIV and AIDS diagnoses from the Catalan HIV/AIDS surveillance system from 2001 to 2013. Data used to estimate the proportion of people enrolled, on ART and virally suppressed in the HIV care cascade were derived from the PISCIS cohort. RESULTS: The total number of people living with HIV (PLHIV) in Catalonia in 2013 was 34 729 (32 740 to 36 827), with 12.3% (11.8 to 18.1) of whom were undiagnosed. By 2013, there were 8458 (8101 to 9079) Spanish-born men who have sex with men (MSM) and 2538 (2334 to 2918) migrant MSM living with HIV in Catalonia. A greater proportion of migrant MSM than local MSM was undiagnosed (32% vs 22%). In the subsequent steps of the HIV care cascade, migrants MSM experience greater losses than the Spanish-born MSM: in retention in care (74% vs 55%), in the proportion on combination antiretroviral treatment (70% vs 50%) and virally suppressed (65% vs 46%). CONCLUSIONS: By the end of 2013, there were an estimated 34 729 PLHIV in Catalonia, of whom 4271 were still undiagnosed. This study shows that the Catalan epidemic of HIV has continued to expand with the key group sustaining HIV transmission being MSM living with undiagnosed HIV.

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant.

BACKGROUND: We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. METHODS: The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. RESULTS: The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. CONCLUSIONS: Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.

Efficacy and safety of direct antiviral agents in a cohort of cirrhotic HCV/HIV-coinfected patients.

Background: New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients. Methods: A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated. Results: Patients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8-9.2; P = 0.004). Conclusions: In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness.

Safe Reduction in CD4 Cell Count Monitoring in Stable, Virally Suppressed Patients With HIV Infection or HIV/Hepatitis C Virus Coinfection.

BACKGROUND: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/µL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression. METHODS: The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. RESULTS: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to <200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/µL maintained counts ≥200 cells/µL. CONCLUSIONS: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/µL and HIV/HCV-coinfected patients with counts >350 cells/µL.

Insurability of HIV-positive people treated with antiretroviral therapy in Europe: collaborative analysis of HIV cohort studies.

OBJECTIVE: To increase equitable access to life insurance for HIV-positive individuals by identifying subgroups with lower relative mortality. DESIGN: Collaborative analysis of cohort studies. METHODS: We estimated relative mortality from 6 months after starting antiretroviral therapy (ART), compared with the insured population in each country, among adult patients from European cohorts participating in the ART Cohort Collaboration (ART-CC) who were not infected via injection drug use, had not tested positive for hepatitis C, and started triple ART between 1996-2008. We used Poisson models for mortality, with the expected number of deaths according to age, sex and country specified as offset. RESULTS: There were 1236 deaths recorded among 34,680 patients followed for 174,906 person-years. Relative mortality was lower in patients with higher CD4 cell count and lower HIV-1 RNA 6 months after starting ART, without prior AIDS, who were older, and who started ART after 2000. Compared with insured HIV-negative lives, estimated relative mortality of patients aged 20-39 from France, Italy, United Kingdom, Spain and Switzerland, who started ART after 2000 had 6-month CD4 cell count at least 350 cells/µl and HIV-1 RNA less than 104 copies/ml and without prior AIDS was 459%. The proportion of exposure time with relative mortality below 300, 400, 500 and 600% was 28, 43, 61 and 64%, respectively, suggesting that more than 50% of patients (those with lower relative mortality) could be insurable. CONCLUSION: The continuing long-term effectiveness of ART implies that life insurance with sufficiently long duration to cover a mortgage is feasible for many HIV-positive people successfully treated with ART for more than 6 months.

Identification of recent HIV-1 infection among newly diagnosed cases in Catalonia, Spain (2006-08).

BACKGROUND: Quantification and description of patients recently infected by HIV can provide an accurate estimate of the dynamics of HIV transmission. Between 2006 and 2008 in Catalonia, we estimated the prevalence of recent HIV infection among newly diagnosed cases, described the epidemiological characteristics of the infection according to whether it was recent, long-standing or advanced, and identified factors associated with recent infection. METHODS: A Test for Recent Infection (TRI) was performed in serum samples from patients newly diagnosed with HIV. Two different TRI were used: the Vironostika-LS assay (January 2006-May 2007) and the BED-CEIA CEIA (June 2007 onwards). Samples were obtained within the first 6 months of diagnosis. Patients whose samples tested positive in the TRI were considered recently infected. RESULTS: Of 1125 newly diagnosed patients, 79.9% were men (median age, 35.4 years), 38.7% were born outside Spain, 48.9% were men who have sex with men (MSM) and 10.6% presented other sexually transmitted infections. The overall percentage of recent infection was 23.0%, which increased significantly, from 18.1% in 2006 to 26.2% in 2008. This percentage was higher for patients from South America (27.6%). Factors associated with recent infection were acquiring infection through sexual contact between MSM [odds ratio (OR) 2.0; 95% confidence interval (95% CI) 1.1-3.9], compared with acquiring infection through heterosexual relations and being under 30 years of age (OR 5.9; 95% CI 1.9-17.4), compared with being over 50 years of age. CONCLUSION: The highest percentage of recent infection was identified in MSM, suggesting either a higher incidence or a greater frequency of HIV testing. Information regarding testing patterns is necessary to correctly interpret data from recently infected individuals. Systems to monitor the HIV epidemic should include both parameters.

Prevalence of Transmitted Antiretroviral Resistance and Distribution of HIV-1Subtypes Among Patients with Recent Infection in Catalonia (Spain) between2003 and 2005

Los objetivos de este estudio fueron evaluar la prevalencia de las resistencias primarias transmitidas (RPT)y de subtipos de VIH-1 en pacientes recientemente infectados en Cataluña entre 2003 y 2005, y describirlas características de estos pacientes según la presencia o ausencia de RPT y el subtipo de VIH-1.Métodos: Después de la aplicación del algoritmo de pruebas serológicas para la seroconversión reciente al VIH (STARHS), alícuotas residuales de las muestras de suero de individuos recientemente infectados no tratados previamente con antirretrovirales fueron genotipados. Las secuencias FASTA se analizaron conel programa HIV db. Se utilizó el listado de mutaciones de la Organización Mundial de la Salud del 2009para estimar la prevalencia de resistencias transmitidas. Resultados: De 182 pacientes recientemente infectados, 14 (7,7%) presentaron RPT. Siete personas (3,8%)presentaban evidencias genotípica de RPT a los inhibidores de la transcriptasa inversa no análogos anucleósidos, 6 (3,3%) frente a inhibidores de la transcriptasa inversa análogos de nucleósidos, 3 (1,6%)frente a los inhibidores de la proteasa, y solo 2 personas (1,1%) presentaron RPT a más de una familia de medicamentos. Treinta y cinco (19,2%) pacientes estaban infectados con un subtipo no-B del VIH-1.Conclusión: Este es el primer estudio que estima la prevalencia de RPT en pacientes recientemente infectadosen Cataluña, y los resultados son similares a los de estudios realizados en otras regiones españolas. Para el adecuado seguimiento de estos parámetros es necesaria la vigilancia epidemiológica sistemática de las RPT (AU)

Objectives: The objectives of this study were to assess the prevalence of transmitted HIV-1 drug resistances(TDR) and HIV-1 subtypes in recently infected patients in Catalonia between 2003 and 2005 and to describe the characteristics of these patients according to the presence or absence of TDR and HIV-1subtype.Methods: After application of the Serological Testing Algorithm for Recent HIV Seroconversion (STARHS),residual aliquots of serum samples from recently infected antiretroviral-naïve individuals were genotyped. FASTA sequences were analyzed using the HIVDB Program. The World Health Organization 2009List of Mutations for Surveillance of Transmitted HIV-1 Drug Resistant HIV Strains was used to estimate the prevalence of TDR. Results: Of 182 recently infected patients, 14 (7.7%) presented TDR. Seven (3.8%) had genotypic evidence of TDR against non-nucleoside reverse transcriptase inhibitors, 6 (3.3%) against nucleoside reverse transcriptase inhibitors, 3 (1.6%) against protease inhibitors (PIs), and only 2 individuals (1.1%) presented TDR against more than one class of drugs. Thirty-five (19.2%) patients were infected with a non-B HIV-1subtype.Conclusion: This is the first study to estimate the prevalence of TDR in recently infected patients in Catalonia. The results are similar to those of studies performed in other Spanish regions. Correct monitoring of these parameters requires systematic epidemiologic surveillance of transmitted resistance (AU)

Prevalence of transmitted antiretroviral resistance and distribution of HIV-1 subtypes among patients with recent infection in Catalonia (Spain) between 2003 and 2005.

OBJECTIVES: The objectives of this study were to assess the prevalence of transmitted HIV-1 drug resistances (TDR) and HIV-1 subtypes in recently infected patients in Catalonia between 2003 and 2005 and to describe the characteristics of these patients according to the presence or absence of TDR and HIV-1 subtype. METHODS: After application of the Serological Testing Algorithm for Recent HIV Seroconversion (STARHS), residual aliquots of serum samples from recently infected antiretroviral-naïve individuals were genotyped. FASTA sequences were analyzed using the HIVDB Program. The World Health Organization 2009 List of Mutations for Surveillance of Transmitted HIV-1 Drug Resistant HIV Strains was used to estimate the prevalence of TDR. RESULTS: Of 182 recently infected patients, 14 (7.7%) presented TDR. Seven (3.8%) had genotypic evidence of TDR against non-nucleoside reverse transcriptase inhibitors, 6 (3.3%) against nucleoside reverse transcriptase inhibitors, 3 (1.6%) against protease inhibitors (PIs), and only 2 individuals (1.1%) presented TDR against more than one class of drugs. Thirty-five (19.2%) patients were infected with a non-B HIV-1 subtype. CONCLUSION: This is the first study to estimate the prevalence of TDR in recently infected patients in Catalonia. The results are similar to those of studies performed in other Spanish regions. Correct monitoring of these parameters requires systematic epidemiologic surveillance of transmitted resistance.

Once- or twice-daily dosing of nevirapine in HIV-infected adults: a population pharmacokinetics approach.

OBJECTIVES: The aim of this study was to develop and validate a population pharmacokinetic model for nevirapine in a population of HIV-infected adults and to evaluate the influence of nevirapine dosing regimen and patient characteristics on nevirapine trough concentration. METHODS: HIV-infected adults receiving oral nevirapine for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and nevirapine concentrations in plasma were determined by HPLC. Pharmacokinetic parameters, inter-individual variability and residual error were estimated using non-linear mixed effects modelling. The influence of patient characteristics on the pharmacokinetics of nevirapine was explored, and the predictive performance of the final model was evaluated in an external data set of observations. RESULTS: Totals of 40 and 18 Caucasian patients were included in two data sets for model building and model validation, respectively. A mono-compartmental model with first-order absorption and elimination best described the pharmacokinetics of nevirapine. Body weight influenced oral clearance (CL/F) and volume of distribution (V/F). The estimated population pharmacokinetic parameters (inter-individual variability) for an individual weighing 70 kg were CL/F 2.95 L/h (24%), V/F 95.2 L (30%) and k(a) 1.8 h(-1) (96%). The final model predicted nevirapine concentrations in the external model-validation data set with no systematic bias and adequate precision. Bayesian estimates of nevirapine trough concentrations were lower when nevirapine was administered once instead of twice daily, and nearly half of the patients weighing 90 kg had drug concentrations <3.0 mg/L when nevirapine was dosed once daily. CONCLUSIONS: A population model to describe the pharmacokinetics of nevirapine was developed and validated in HIV-infected patients. Body weight influenced CL/F and V/F. Based on Bayesian estimates of individual nevirapine concentrations, twice- instead of once-daily administration of nevirapine would be more optimal in patients weighing >70 kg.

Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain).

OBJECTIVE: We analyze the factors related to progression to AIDS or death in HIV-infected patients from the Proyecto para la Informatización del Seguimiento Clínico epidemiológico de los pacientes con Infección por VIH/SIDA (PISCIS) Cohort and we assess the optimal time to initiate highly active antiretroviral therapy (HAART) taking lead time into account. METHODS: We selected naive patients who were AIDS-free and initiated HAART after January 1998. Statistical analyses were performed using Cox proportional hazards models. Lead time was defined as the time it took the deferred group with an early disease stage to reach the later stage. The analysis accounting for lead time was performed using multiple imputation methods based on estimates from the pre-HAART period as described elsewhere. RESULTS: Multivariate analysis on 2035 patients (median follow-up = 34.3 months) showed significantly higher hazard ratios (HRs) for a CD4 count <200 cells/microL (HR = 3.79, 95% confidence interval [CI]: 2.18 to 6.57), HIV-1 RNA level >100,000 copies/mL (HR = 1.84, 95% CI: 1.26 to 2.69), and hepatitis C virus (HCV) coinfection (HR = 2.40, 95% CI: 1.65 to 3.49), whereas a lower risk was found for those who started HAART between January 2001 and June 2004 (HR = 0.55, 95% CI: 0.30 to 0.90). When lead time and unseen events were included, we found a higher risk of progression to AIDS among patients who deferred treatment when the CD4 count reached <200 cells/microL (HR = 2.97, 95% CI: 1.91 to 4.63) and 200 to 350 cells/microL (HR = 1.85, 95% CI: 1.03 to 3.33) compared with those who started treatment with CD4 counts from 200 to 350 cells/microL and >350 cells/microL, respectively. CONCLUSIONS: Advanced HIV disease, HCV coinfection, and early HAART period were determinants of AIDS progression or death. Lead-time analysis in asymptomatic HIV-infected patients suggests that the best time to start HAART is before the CD4 count falls to lower than 350 cells/microL.

[Impact of a clinical self-evaluation intervention on the appropriateness of hospital stays]. / Impacto de una intervención de autoevaluación clínica sobre la adecuación de la estancia hospitalaria.

AIM: To assess the impact of an intervention on inappropriate hospital stays (IHS) in acute-care hospitals in Catalonia (Spain) with the aim of testing the hypothesis that a simple intervention (adeQhos) reduces the proportion of IHS. METHODS: A pre-test/post-test study was performed through the <> questionnaire. Two intervention groups (internal medicine and general surgery) and 2 control groups (other medical specialities, orthopedics) were compared in 10 acute-care hospitals in Catalonia. The same evaluators assessed appropriateness of hospital stays before and after the intervention, using the Appropriateness Evaluation Protocol. RESULTS: A total of 1,594 pre-test stays and 1,495 post-test stays were reviewed. Of all the stays reviewed (day before discharge), 41.1% were inappropriate. The intervention was applied to 4,613 stays. There was a significant increase of IHS in the medicine control group (from 39.7 to 48.6%), and no decrease in the intervention groups (internal medicine [from 46.7 to 50.6%] or general surgery [from 27.2 to 31.2%]). The correlation between the intensity of the intervention and the difference in IHS before and after the intervention was r = -0.373 (p = 0.106). The intensity of intervention differed among the hospitals. In hospitals with an intensity of intervention > 60%, the proportion of IHS decreased by 10.7 points in internal medicine and by 4.8 points in general surgery, while the proportion of IHS increased in the control groups. CONCLUSIONS: The prevalanece of IHS the day before discharge in the hospitals studied was high (41.1%). No significant decrease in IHS was observed after a low-intensity intervention.

Impacto de una intervención de autoevaluación clínica sobre la adecuación de la estancia hospitalaria / Impact of a clinical self-evaluation intervention on the appropriateness of hospital stays

Objetivo: Evaluar el impacto de una intervención sobre la proporción de estancias inapropiadas (EI), para contrastar la hipótesis de que una intervención sencilla de información y participación (adeQhos®) permite reducir la proporción de EI. Método: Estudio pre/postintervención mediante el cuestionario «adeQhos®», que compara 2 grupos experimentales (medicina, cirugía) y 2 grupos control (otras especialidades médicas, cirugía ortopédica y traumatología), en 10 hospitales de agudos de Cataluña. Los mismos revisores evaluaron la adecuación mediante el Appropriateness Evaluation Protocol, antes y después de la intervención. Resultados: Se revisaron 1.594 estancias antes de la intervención y 1.495 después. El 41,1% de todas las estancias revisadas (día previo al alta) resultaron inapropiadas. La intervención se realizó sobre 4.613 estancias. Hubo un incremento significativo de EI en el grupo control de medicina (del 39,7 al 48,6%), mientras que en los grupos de intervención no se observó ninguna disminución (en medicina del 46,7 al 50,6%, y en cirugía del 27,2 al 31,2%). Sin embargo, la correlación entre la intensidad de la intervención y las diferencias de EI antes y después fue de r = -0,373 (p = 0,106). La intensidad de la intervención fue desigual en los diferentes hospitales; en los que presentaban una intensidad de intervención > 60% el porcentaje de EI disminuyó 10,7 puntos en medicina y 4,8 en cirugía, mientras que en los grupos control aumentó. Conclusiones: La prevalencia de EI en el día previo al alta en los hospitales estudiados fue considerablemente alta (del 41,1%). No se observó ninguna reducción significativa de la inadecuación hospitalaria tras una intervención de baja intensidad

Aim: To assess the impact of an intervention on inappropriate hospital stays (IHS) in acute-care hospitals in Catalonia (Spain) with the aim of testing the hypothesis that a simple intervention (adeQhos®) reduces the proportion of IHS. Methods: A pre-test/post-test study was performed through the «adeQhos®» questionnaire. Two intervention groups (internal medicine and general surgery) and 2 control groups (other medical specialities, orthopedics) were compared in 10 acute-care hospitals in Catalonia. The same evaluators assessed appropriateness of hospital stays before and after the intervention, using the Appropriateness Evaluation Protocol. Results: A total of 1,594 pre-test stays and 1,495 post-test stays were reviewed. Of all the stays reviewed (day before discharge), 41.1% were inappropriate. The intervention was applied to 4,613 stays. There was a significant increase of IHS in the medicine control group (from 39.7 to 48.6%), and no decrease in the intervention groups (internal medicine [from 46.7 to 50.6%] or general surgery [from 27.2 to 31.2%]). The correlation between the intensity of the intervention and the difference in IHS before and after the intervention was r = -0.373 (p = 0.106). The intensity of intervention differed among the hospitals. In hospitals with an intensity of intervention > 60%, the proportion of IHS decreased by 10.7 points in internal medicine and by 4.8 points in general surgery, while the proportion of IHS increased in the control groups. Conclusions: The prevalanece of IHS the day before discharge in the hospitals studied was high (41.1%). No significant decrease in IHS was observed after a low-intensity intervention

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis.

BACKGROUND AND OBJECTIVE: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. RESULTS: Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively). CONCLUSION: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Results of a study of prolonging treatment with pegylated interferon-alpha2a plus ribavirin in HIV/HCV-coinfected patients with no early virological response.

OBJECTIVE: To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR). METHODS: Patients received pegylated interferon (peg-INF)-alpha2a 180 microg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm). RESULTS: One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+ T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load >800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%. CONCLUSIONS: This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.

Long-term safety and efficacy of nevirapine-based approaches in HIV type 1-infected patients.

Using a multicenter, cross-sectional, observation study, the long-term safety, metabolic profile, and viral efficacy of nevirapine (NVP)-based approaches in HIV-1-infected patients treated for at least 2 years were assessed. For 4 months, all consecutive HIV-1-infected patients who had been receiving an NVP-containing regimen for at least 2 years were recruited. A total of 613 patients were included with a median follow-up period of 43 months (IQR: 31-51). At baseline, 24.5% (150 patients) were treatment naive, 41.5% (254 patients) switched for simplification purposes, and 34% (209 patients) were failing HAART. Increases by five times or more in AST/ALT values were observed in fewer than 2% of patients. Only 5.7% of all adverse events reported during the investigation were attributable to NVP. The percentage of patients with normal HDL cholesterol levels rose from 17.7% at baseline to 35.4% at the last visit. At the latest time point available for analysis, 76% of naive and 74% of those who had switched had HIV-1 RNA loads of <50 copies/ml, while 59% of salvage patients achieved this level of viral suppression. Factors associated with viral suppression at the latest visit were adequate adherence (OR: 2.58, 95% CI: 0.85-7.78, p < 0.001), first-line treatment (OR: 3.02, 95% CI: 1.52-6.00, p = 0.002), and baseline CD4 cells >400 cells/microl (OR: 2.34, 95% CI: 1.22-4.47, p = 0.010). Exposure to nevirapine for up to 4 years is safe. Liver toxicity is infrequent and generally mild. HDL cholesterol levels consistently increase over time and viral suppression is maintained.

Short communication. Baseline factors associated with haematological toxicity that leads to a dosage reduction of pegylated interferon-alpha2a and ribavirin in HIV- and HCV-coinfected patients on HCV antiviral therapy.

OBJECTIVE: To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients. DESIGN: Multicentre, prospective, observational study. SETTING: Eleven hospitals in Spain during the period 2002-2003. SUBJECTS AND METHODS: One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-alpha2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm(3) (neutrophil-endpoint) and a platelet count below 50,000/mm(3) (platelet-endpoint). RESULTS: Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (+/-3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46-9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31-8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm(3) (HR: 3.59; 95% CI: 1.77-7.28) and baseline weight <60 kg (HR: 2.21; 95% Cl: 1.04-4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm(3) decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint. CONCLUSIONS: Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.

[Clinical-epidemiological characteristics and antiretroviral treatment trends in a cohort of HIV infected patients. The PISCIS Project]. / Características clinicoepidemiológicas y tendencias en el tratamiento antirretroviral de una cohorte de pacientes con infección por el virus de la inmunodeficiencia humana. Cohorte PISCIS.

BACKGROUND AND OBJECTIVE: The aims of this study were to describe the process of implementation of the PISCIS cohort, and to describe the clinical and epidemiological characteristics and trends of antiretroviral treatment (ART) among patients enrolled from 1998 through 2003. PATIENTS AND METHOD: Prospective cohort study of HIV-infected patients aged > or = 16 years newly attended in 10 Catalonian hospitals and one Balearic Islands hospital. Analysis were done using the Mantel's chi2 test for trend. RESULTS: A total of 5,968 patients (mean age 39 yrs; 75% men) were recruited with a mean follow-up of 26.4 months (13,130 person-years). A total of 2,763 patients were newly diagnosed and among these, the most frequent transmission route was the heterosexual one (43%), followed by homosexual (31%). We observed an increasing trend in the proportion of persons < 35 years and immigrants. Among newly diagnosed, 43% had < 200 CD4 T cells/microl in the nearest determination from HIV diagnosis. In the year 2003, 83% of patients were on ART. A decrease of the protease inhibitor-based regimen (from 85% in 1998 to 25% in 2003; p < 0.001) and an increase of nucleoside and non-nucleoside analogue reverse transcriptase inhibitors-containing regimens were observed over time among naive patients who started ART with three or more drugs. CONCLUSIONS: HIV infected patients' cohorts are feasible in our setting and are an important tool in clinical and public health. The heterosexual route of transmission was the most frequent among newly diagnosed patients. The diagnosis delay is high and, on the other hand, ARV regimens have been changing according to the recommended guidelines.

Características clinicoepidemiológicas y tendencias en el tratamiento antirretroviral de una cohorte de pacientes con infección por el virus de la inmunodeficiencia humana. Cohorte PISCIS / Clinical-epidemiological characteristics and antiretroviral treatment trends in a cohort of HIV infected patients. The PISCIS Project

FUNDAMENTO Y OBJETIVO: Los objetivos de este estudio fueron describir el proceso de implementación de la cohorte PISCIS y las características clínico epidemiológicas y las tendencias en el tratamiento antirretroviral (TARV) de los pacientes con infección por el virus de la inmunodeficiencia humana (VIH) incluidos desde 1998 hasta 2003.PACIENTES Y MÉTODO: Estudio de cohorte prospectivo de pacientes con infección por el VIH de 16 años de edad o mayores atendidos en primera visita en 10 hospitales de Cataluña y uno de las Baleares. El análisis estadístico de las tendencias se realizó mediante el test de la χ2 de Mantel. RESULTADOS: Se incluyó a un total de 5.968 pacientes (edad media: 39,5 años; 75% varones) con un tiempo medio de seguimiento de 26,4 meses (13.130 personas-año). Del total, 2.763 fueron nuevos diagnósticos, en los que la vía de transmisión más frecuente fue la heterosexual (43%), seguida de la homosexual (31%). Se observó una tendencia significativamente creciente en la proporción de sujetos de edad inferior a 35 años e inmigrantes. Un 43% tenían una cifra de linfocitos CD4 inferior a 200 células/µl en la determinación más cercana al diagnóstico de la infección por el VIH. Del total, un 87% estaban en TARV en el año 2003. Entre los pacientes no tratados previamente que iniciaron pautas de TARV con 3 o más fármacos, se observó una disminución de las pautas que incluían inhibidores de la proteasa (del 85% en 1998 al 25% en 2003; p < 0,001), mientras que aumentaron otras que contenían inhibidores de la transcriptasa inversa no análogos y análogos de los nucleósidos. CONCLUSIONES: Las cohortes de pacientes con infección por el VIH son viables en nuestro medio y tienen gran utilidad clínica y en salud pública. La vía de transmisión más frecuente entre los nuevos diagnósticos es la heterosexual, el retraso en el diagnóstico es elevado y las pautas de TARV han ido cambiando para adaptarsea las recomendadas por las guías

BACKGROUND AND OBJECTIVE: The aims of this study were to describe the process of implementation of the PISCIS cohort, and to describe the clinical and epidemiological characteristics and trends of antiretroviral treatment(ART) among patients enrolled from 1998 through 2003.PATIENTS AND METHOD: Prospective cohort study of HIV-infected patients aged ≥ 16 years newly attended in 10Catalonian hospitals and one Balearic Islands hospital. Analysis were done using the Mantel’s χ2 test for trend. RESULTS: A total of 5,968 patients (mean age 39 yrs; 75% men) were recruited with a mean follow-up of 26.4months (13,130 person-years). A total of 2,763 patients were newly diagnosed and among these, the most frequent transmission route was the heterosexual one (43%), followed by homosexual (31%). We observed an increasing trend in the proportion of persons < 35 years and immigrants. Among newly diagnosed, 43% had <200 CD4 T cells/µl in the nearest determination from HIV diagnosis. In the year 2003, 83% of patients were on ART. A decrease of the protease inhibitor-based regimen (from 85% in 1998 to 25% in 2003; p < 0.001)and an increase of nucleoside and non-nucleoside analogue reverse transcriptase inhibitors-containing regimens were observed over time among naïve patients who started ART with three or more drugs. CONCLUSIONS: HIV infected patients’ cohorts are feasible in our setting and are an important tool in clinical and public health. The heterosexual route of transmission was the most frequent among newly diagnosed patients. The diagnosis delay is high and, on the other hand, ARV regimens have been changing according to the recommended guidelines

Adecuación de la estancia hospitalaria en un servicio de medicina interna de un hospital comarcal / Appropiateness of hospital stain in a general hospital´s internal medicina service

Objetivo: Valorar la utilidad del protocolo adeQhos® para conocer la tasa de estancias inadecuadas en un servicio de medicina e identificar sus causas. Material y método: Se analizaron las estancias que generaron los pacientes ingresados en el servicio de medicina interna del Hospital General de Vic entre el 12 de diciembre de 2002 y el 3 de enero de 2003. Resultados: Se analizaron 963 estancias hospitalarias, con un 19,6 por ciento de estancias inadecuadas con diferencias significativas entre los profesionales participantes. Los motivos de inadecuación fueron atribuibles al propio médico y al proceso de alta hospitalaria. Conclusiones: El adeQhos® es un instrumento útil para disponer de forma ágil y rápida de datos globales acerca de la adecuación de las estancias hospitalarias (AU)

Alternation of antiretroviral drug regimens for HIV infection. A randomized, controlled trial.

BACKGROUND: Mathematical modeling has suggested that alternating antiretroviral regimens while patients' viral load remains suppressed would minimize HIV resistance mutations. OBJECTIVE: To compare alternation of antiretroviral regimens with the current standard of switching regimens after viral load rebound. DESIGN: Randomized, multicenter, open-label, pilot trial. SETTING: 15 outpatient HIV clinics in Spain and Argentina. PATIENTS: 161 HIV-1-infected, antiretroviral-naive persons. INTERVENTION: Patients were assigned to continuously receive stavudine, didanosine, and efavirenz (standard of care, regimen A) or zidovudine, lamivudine, and nelfinavir (standard of care, regimen B) until virologic failure, or to alternate between those two regimens every 3 months while viral load was suppressed (regimen C). MEASUREMENTS: Time to virologic failure, percentage of patients with undetectable plasma viremia over 48 weeks, CD4 and CD8 cell counts, adverse events, emergence of drug resistance, drug adherence, and quality of life. RESULTS: Patients receiving standard-of-care regimens A and B did not differ. Virologic failure over 48 weeks was delayed in the alternating therapy group compared with the pooled standard-of-care group (incidence rate, 1.2 events/1000 person-weeks [95% CI, 0.3 to 3.6 events/1000 person-weeks] vs. 4.8 events/1000 person-weeks [CI, 2.9 to 7.4 events/1000 person-weeks]; P = 0.01). Genotypic drug resistance emerged in 79% of patients in the standard-of-care group who experienced on-therapy treatment failure. Patients in the standard-of-care and alternating therapy groups had similar CD4 cell counts, frequency of adverse events, reported drug adherence, and quality of life. CONCLUSIONS: Virologic outcome was better with alternating therapy than with the current standard of care, while adverse events and adherence were similar. The strategy of alternating therapy merits further investigation.