Liver stiffness change with HCV cure in HIV-infected patients on non-nucleoside analogues.

BACKGROUND: Liver stiffness (LS) at sustained viral response (SVR) is strongly associated with a lower incidence of subsequent hepatic events. HIV NNRTIs may have a beneficial impact on fibrogenesis. OBJECTIVES: Our aim was to analyse the influence of NNRTI-based therapy on the change in LS from starting direct-acting antiviral (DAA) therapy to achieving SVR in HIV/HCV-coinfected patients. METHODS: Three hundred and thirteen HIV/HCV-coinfected patients who fulfilled the following criteria were included: (i) had achieved SVR with an IFN-free, DAA-including regimen; (ii) LS ≥9.5 kPa before therapy; (iii) LS measurement available at SVR; (iv) seronegative for HBsAg; and (v) ART containing 2 NRTIs plus either 1 NNRTI or 1 integrase inhibitor (INI) or 1-2 NRTIs plus 1 PI. LS changes were assessed. RESULTS: Seventy-four patients received NNRTI-based combinations [53 (71.6%) rilpivirine and 16 (21.6%) efavirenz] and 239 patients received other regimens. At baseline, the median (IQR) LS was 16.7 kPa (11.8-25.6) in the NNRTI group and 17.3 kPa (11.9-27.4) in the non-NNRTI group (P = 0.278). The median (IQR) percentage of LS decrease from baseline to SVR was 35.2% (18.2%-52.3%) for NNRTI-based therapy and 29.5% (10%-45.9%) for PI- or INI-based therapy (P = 0.018). In multivariate analysis, adjusted for sex, age, HCV genotype, NRTI backbone and propensity score for HIV therapy, NNRTI-based regimen use was associated with a higher LS decrease [ß = 11.088 (95% CI = 1.67-20.51); P = 0.021]. CONCLUSIONS: Treatment with NNRTI plus 2 NRTI combinations is associated with a higher LS decline than other ART combinations in HIV/HCV-coinfected patients receiving DAA-based therapy.

Carotid atherosclerosis in virologically suppressed HIV patients: comparison with a healthy sample and prediction by cardiovascular risk equations.

OBJECTIVES: To compare the prevalence of carotid atherosclerosis in virologically suppressed HIV patients with that of a community sample, and to evaluate the capacity of various cardiovascular risk (CVR) equations for predicting carotid atherosclerosis. METHODS: This was a cross-sectional study with two randomly selected groups: HIV patients from an HIV unit and a control group drawn from the community. Participants were matched by age (30-80 years) and sex without history of cardiovascular disease. Carotid plaque, common carotid intima-media thickness (cc-IMT) and subclinical atherosclerosis (carotid plaque and/or cc-IMT > 75th percentile) were assessed by carotid ultrasound. The Systematic Coronary Risk Evaluation (SCORE), Framingham, REGICOR, reduced Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D), and COMVIH equations were applied, and their abilities to predict carotid plaque were compared using the area under the curve (AUC). RESULTS: Each group included 379 subjects (77.8% men, age 49.7 years). Duration of antiretroviral therapy was 15.5 years. There were no differences between the groups for carotid plaque (HIV, 33.2%; control, 31.3%), mean cc-IMT (HIV, 0.63 mm; control, 0.61 mm) or subclinical atherosclerosis (HIV, 42.9%; control, 47.9%). Thymidine analogues were independently associated with subclinical atherosclerosis in HIV-infected patients. CVR equations revealed AUCs between 0.715 and 0.807 for prediction of carotid plaque; prediction was better in the control group and did not improve when HIV-adapted scales were used. CONCLUSIONS: The features of carotid atherosclerosis did not differ between the HIV-infected and the control group, although CVR equations were more predictive for carotid plaque in controls than in HIV-infected patients. HIV-specific equations did not improve prediction.

Primary resistance to integrase strand transfer inhibitors in Spain using ultrasensitive HIV-1 genotyping.

BACKGROUND: Transmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted. OBJECTIVES: We evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016. METHODS: Pre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%-19% of the virus population were considered to be low-frequency variants. RESULTS: From a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants. CONCLUSIONS: Transmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens.

Correction to: CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study.

Due to a production error the bottom portion of Figure 1 was omitted. The corrected figure is given below.

CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study.

CINAMMON is a phase IV, open-label, single-arm, pilot study assessing maraviroc (MVC) in the central nervous system (CNS) when added to darunavir/ritonavir monotherapy (DRV/r) in virologically suppressed HIV-infected subjects. CCR5 tropic participants on DRV/r were recruited. Participants remained on DRV/r for 12 week (w) (control phase). MVC 150 mg qd was added w12-w36 (intervention phase). Lumbar puncture (LP) and neurocognitive function (Cogstate) examinations scheduled at baseline, w12 and w36; MRI before w12, again at w36. Primary endpoint was CSF inflammatory marker changes during intervention phase. Secondary endpoints included changes in NC function and MRI parameters. CSF/plasma DRV/r concentrations measured at w12 and w36, MVC at w36. Nineteen patients recruited, 15 completed (17M, 2F). Dropouts: headache (2), knee problem (could not attend, 1), personal reasons (1). Mean age (range) 45.4 years (27.2-65.1), 13/19 white, 10/19 MSM. No changes in selected CSF markers were seen w12-w36. Overall NC function did not improve w12-w36: total age adjusted z score improved by 0.27 (weighted paired t test; p = 0.11); for executive function only, age adjusted z score improved by 0.54 (p = 0.03). MRI brain parameters unchanged. DRV plasma:CSF concentration ratio unchanged between w12 (132) and w36 (112; p = 0.577, Wilcoxon signed-rank). MVC plasma:CSF concentration ratio was 35 at w36. No changes in neuroinflammatory markers seen. In this small study, addition of 24w MVC 150 mg qd to stable DRV/r monotherapy showed possible improvement in executive function with no global NC effect. Learning effect cannot be excluded. This effect should be further evaluated.

Genotypic tropism testing of proviral DNA to guide maraviroc initiation in aviraemic subjects: 48-week analysis of results from the PROTEST study.

OBJECTIVES: Maraviroc (MVC) is a suitable drug for aviraemic subjects on antiretroviral treatment (ART) developing toxicity. Its prescription requires prior tropism testing. It is unknown if proviral DNA genotypic tropism testing is reliable for guiding MVC initiation in aviraemic subjects, so this study was carried out to address this issue. METHODS: PROTEST was a phase 4, prospective, single-arm clinical trial carried out in 24 HIV care centres in Spain. MVC-naïve HIV-1-infected patients with HIV-1 RNA < 50 copies/mL on stable ART during the previous 6 months who required an ART change because of toxicity and who had R5 HIV, as determined by proviral DNA genotypic tropism testing, initiated MVC with two nucleoside reverse transcriptase inhibitors (NRTIs) and were followed for 48 weeks. Virological failure was defined as two consecutive viral load measurements > 50 copies/mL. RESULTS: Tropism results were available for 141 of 175 (80.6%) subjects screened: 60% had R5 and 85% of these (n = 74) were finally included in the study. Previous ART included protease inhibitors (PIs) in 62% of subjects, nonnucleoside reverse transcriptase inhibitors (NNRTIs) in 36%, and integrase inhibitors (INIs) in 2%. Main reasons for treatment change were dyslipidaemia (42%), gastrointestinal symptoms (22%) and liver toxicity (15%). MVC was given alongside tenofovir (TDF)/emtricitabine (FTC) (54%) and abacavir (ABC)/lamivudine (3TC) (40%) in most patients. Eighty-four per cent of patients maintained a viral load < 50 copies/mL to week 48, whereas 16% discontinued treatment: two withdrew informed consent, one had an R5 to X4 shift between screening and baseline, one was lost to follow-up, one developed an adverse event (rash), two died from non-study-related causes, and five developed protocol-defined virological failure. CONCLUSIONS: Initiation of MVC plus two NRTIs in aviraemic subjects based on genotypic tropism testing of proviral HIV-1 DNA is associated with low rates of virological failure for up to 1 year.

Elvitegravir concentrations in seminal plasma in HIV-1-infected men.

OBJECTIVES: The aim of the study was to quantify elvitegravir (EVG) concentrations in the semen of HIV-1-infected men receiving antiretroviral therapy (ART) consisting of an elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) single-tablet regimen. METHODS: A phase IV, cross-sectional study was carried out including HIV-1-infected male adults with suppressed plasma HIV-1 RNA who switched ART to EVG/COBI/FTC/TDF. Total EVG concentrations at the end of the dosing interval (C24 h ) and HIV-1 RNA were measured in paired seminal plasma (SP) and blood plasma (BP) samples 4 weeks after switching to EVG/COBI/FTC/TDF. Validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify EVG concentrations, and HIV-1 RNA was determined by real-time polymerase chain reaction (PCR). RESULTS: Ten men were included. Their median age was 40 years (range 24-47 years), the median time on ART was 50 months (range 10-186 months), the median time with plasma HIV-1 RNA < 40 copies/mL was 37 months (range 7-113 months), and the median CD4 count was 737 cells/µL (range 190-1122 cells/µL). Four weeks after switching to EVG/COBI/FTC/TDF, all subjects had HIV-1 RNA < 40 copies/mL in both BP and SP. Median EVG C24 h was 277 ng/mL (range 64.8-1790 ng/mL) in BP and 169 ng/mL (range 12.8-792 ng/mL) in SP. A significant correlation was observed between BP and SP EVG concentrations (Spearman rho 0.952; P < 0.001). The median SP:BP EVG concentration ratio was 0.39 (range 0.20-0.92). EVG C24 h in SP was at least 23-fold the in vitro protein-unbound 50% effective response (EC50 ) of HIV-1 clinical isolates (0.04-0.55 ng/mL). In all but one individual, EVG C24 h in SP was also higher than the blood plasma protein binding-adjusted 95% inhibitory concentration (IC95 ) of wild-type HIV-1 (45 ng/mL). CONCLUSIONS: Seminal EVG concentrations in HIV-infected men treated with EVG/COBI/FTC/TDF sufficed to contribute to maintaining HIV-1 RNA suppression in this compartment.

Improvement of lipoatrophy by switching from efavirenz to lopinavir/ritonavir.

OBJECTIVE: To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy. METHODS: Ninety-six-week phase IV, open-label, multicentre, pilot randomized trial. HIV-infected patients with moderate/severe lipoatrophy at one or more body sites despite long-term thymidine NRTI-free therapy were randomized to continue their efavirenz (EFV)-based antiretroviral regimen or to switch from EFV to lopinavir/ritonavir (LPV/r). The primary endpoint was the absolute change in limb fat mass measured by dual X-ray absorptiometry from baseline to 96 weeks. Changes in other body fat measurements, subjective perception of lipoatrophy, subcutaneous fat gene expression and plasma lipids were also assessed. RESULTS: Thirty-three patients (73% men, median age 52 years) were recruited. At 96 weeks, absolute limb fat mass increased in the LPV/r arm vs. the EFV arm (estimated difference +1082.1 g; 95% CI +63.7 to +2103.5; P = 0.04); this difference remained significant after adjustment by gender, age, fat mass, body mass index and CD4 cell count at baseline. Subjective lipoatrophy perception scores also improved in the LPV/r arm relative to the EFV arm. Adipogenesis, glucose and lipid metabolism, and mitochondrial gene expression increased in the LPV/r arm compared with the EFV arm at 96 weeks. HDL cholesterol decreased in the LPV/r arm relative to the EFV arm. CONCLUSIONS: Switching from EFV to LPV/r in HIV-infected patients with lipoatrophy may offer further limb fat gain beyond thymidine NRTI discontinuation, although this strategy decreased plasma HDL cholesterol and caused changes in subcutaneous fat gene expression that may be associated with increased insulin resistance.

The helminth community of the wood mouse Apodemus sylvaticus from the Erro River valley, Navarre, Spain.

The helminth fauna of the wood mouse, Apodemus sylvaticus, in the Erro River valley (Navarre, Spain) was investigated from a total of 150 mice between February 2001 and July 2002. An overall prevalence of 90.7% was recorded and up to 14 helminth species identified. The most prevalent species was the nematode Heligmosomoides polygyrus (78.0%), whereas Syphacia stroma was the species with the highest median abundance (19.8). The detection of Calodium hepaticum, Rodentolepis straminea and the larvae of Hydatigera taeniaeformis are significant, since these helminth species could be considered potential human parasites. The helminth infracommunity comprised no more than five species. A significant predominance of monoxenous species was detected. Statistically significant differences were also found between prevalences, helminth abundance, species richness and helminth diversity of sub-populations of the wood mouse determined by host age and season of capture, which agree with most of the studies carried out on this host. This study will shed light on the helminth community of the wood mouse from a region of Spain which has not previously been documented.

Protocolo del estudio: abordaje del sobrepeso en Atención Primaria. Papel de la entrevista motivacional / Tackling child overweight in Primary Care: the role of motivational interviewing

Objetivo: plantear un programa de intervención sobre el sobrepeso, desarrollado por los profesionales de Atención Primaria (AP), basado en la entrevista motivacional. Analizar las variaciones del Z score del índice de masa corporal (IMC), del patrón nutricional, del nivel de actividad física y la concordancia entre dos diferentes escalas para ese fin. Metodología: diseño: estudio de intervención en niños entre 6 y 12 años que en el control del programa de salud infantil de los seis años tengan un IMC > P85 y < P95), pertenecientes a cinco consultas de Pediatría de AP. Serán excluidos los que tengan una obesidad secundaria o aquellos en los que no sea posible realizar un seguimiento adecuado. Se les realizará una intervención de seis sesiones basadas en la entrevista motivacional y se realizará una encuesta nutricional y dos de actividad física, en el momento basal, a los cuatro meses y al final de la intervención. Análisis estadístico: los factores que se asocian con los cambios pre- y posintervención se estudiarán mediante modelos de regresión multivariante. La concordancia entre las escalas de actividad física se estudiará con el índice de Kappa. Los análisis estadísticos se realizarán con el software SPSS® versión 2. Limitaciones: la falta de habilidad en la técnica de la entrevista motivacional por parte de los pediatras. Para superar dicha limitación se ha proyectado realizar un taller de formación específica a los participantes. Otra limitación es la falta de grupo control (AU)

Objective: the primary objective is to assess the impact of a programme for tackling child overweight based on motivational interviewing, by measuring changes in the body mass index Z-scores, eating patterns and physical activity levels. The agreement between two physical activity questionnaires will also be assessed. Methods: we propose to carry out an interventional study on children aged between 6 and 12 years old. All children from five paediatric doctor's lists at the participating primary care health centres identified as overweight in the 6-year-old health check-up will be candidates for this study (body mass index >85th percentile and < 95th percentile). Children with secondary obesity or those who would not be properly followed-up will be excluded from the study. A six-session intervention based on motivational interviewing, will be performed. A nutrition and physical activity questionnaire will be administered at baseline, at 4months and at the end of the intervention. Factors associated to pre-post changes will be studied via multivariate regression models. The agreement between the physical activity questionnaires will be assessed with the Kappa coefficient. Statistical analysis will be performed using SPSS version 21. The greatest limitation of this study is the lack of skills for motivational interviewing among the participating clinicians. To address this limitation, the participating clinicians will attend specific workshops on motivational interviewing focused on child obesity. Another limitation is the lack of a control group (AU)

Abacavir/lamivudine plus darunavir/ritonavir in routine clinical practice: a multicentre experience in antiretroviral therapy-naive and -experienced patients.

OBJECTIVES: To present clinical experience with a regimen including abacavir/lamivudine + darunavir/ritonavir in a cohort of HIV-1-infected patients. METHODS: A retrospective, multicentre cohort study, including all consecutive adult HIV-1-infected patients who started abacavir/lamivudine + darunavir/ritonavir from April 2008 to December 2010 and had at least one follow-up visit. The primary endpoint was HIV-1 viral load (VL) <40 copies/mL at week 48. RESULTS: One hundred and eighty-three patients (42 naive and 141 experienced) from 19 hospitals in Spain were studied. The median follow-up was 26.7 (0.5-58.6) months, 79.8% were men, the median age was 47.1 (21.4-80.5) years, 26.2% had AIDS and 38.8% were positive for hepatitis C virus. At baseline, the median CD4 count was 246 cells/mm(3) in naive patients and 393 cells/mm(3) in experienced patients and the median VL was 4.80 and <1.59 log copies/mL, respectively. At week 48, 81.8% of naive patients and 84.2% of experienced patients receiving the regimen reached a VL <40 copies/mL, whereas at 96 weeks this occurred in 90.5% and 92.8%, respectively. CD4 cell count increases at 48 and 96 weeks were +176.5 and +283.5 cells/mm(3) in naive patients and +74.9 and +93 cells/mm(3) in experienced patients, respectively. Overall, 86 (47%) patients discontinued the study regimen, in many cases possibly related to non-medical reasons, such as drug switches to reduce cost or changes in address due to economic constraints. Three patients died of causes unrelated to therapy and 19 (10.4%) discontinued the regimen due to adverse events. CONCLUSIONS: In our cohort, abacavir/lamivudine + darunavir/ritonavir was safe, well tolerated and achieved high rates of virological suppression. In a proportion of patients, discontinuation of this effective regimen was possibly due to non-medical reasons.

Impact of prior pneumococcal vaccination on clinical outcomes in HIV-infected adult patients hospitalized with invasive pneumococcal disease.

BACKGROUND: Recent studies in hospitalized patients with community-acquired pneumonia have found a lower risk of bacteraemia and better clinical outcomes in patients who had previously received the 23-valent pneumococcal polysaccharide vaccine (PPV) in comparison with unvaccinated individuals. The aim of this study was to assess the influence of prior PPV on clinical outcomes in HIV-infected adult patients hospitalized with invasive pneumococcal disease (IPD). METHODS: This was an observational study of all consecutive HIV-infected adults hospitalized with IPD from January 1996 to October 2007 in three hospitals in Spain. Baseline characteristics and clinical outcome-related variables were compared according to prior PPV vaccination status. RESULTS: A total of 162 episodes of IPD were studied. In 23 of these (14.2%), patients had previously received PPV. In both vaccinated and unvaccinated patients, most of the causal serotypes were included in the 23-valent PPV (76.9% and 84.1%, respectively). Overall, 25 patients (15.4%) died during hospitalization, 21 patients (13%) required admission to an intensive care unit (ICU) and 34 patients (21%) reached the composite outcome of death and/or admission to the ICU. None of the 23 patients who had previously received PPV died or required ICU admission, in comparison with 25 (18%; P=0.026) and 21 (15.1%; P=0.046), respectively, of the unvaccinated patients. The length of hospital stay for vaccinated patients was significantly shorter (8.48 vs. 13.27 days; P=0.011). CONCLUSIONS: Although 23-valent PPV failed to prevent IPD in some HIV-infected patients, vaccination produced beneficial effects on clinical outcomes by decreasing illness severity and mortality related to IPD.

Bacterial pneumonia in HIV-infected patients: use of the pneumonia severity index and impact of current management on incidence, aetiology and outcome.

OBJECTIVES: Despite a recent decrease, bacterial pneumonia (BP) is still the most common admission diagnosis in HIV patients. We analyse BP incidence, characteristics and prevention measures. METHODS: Observational study of all patients hospitalized for BP in a tertiary hospital in Barcelona, Spain, from January 2000 to December 2005. Demographic and HIV-related data, BP risk factors, characteristics of BP and outcomes are analysed. RESULTS: One hundred and eighty-six BP episodes in 161 patients were included; patients were mainly male (73.7%) and intravenous drug users (73.7%). A decrease in BP incidence was seen during the study period, especially in vaccinated patients. The most commonly isolated microorganism was Streptococcus pneumoniae (31.7%), followed by Legionella pneumophila (5.9%). Legionella pneumophila was more likely in patients with undetectable viral load, higher CD4 cell counts or prior vaccination. Highly active antiretroviral therapy, cotrimoxazole prophylaxis and pneumococcal vaccination did not have a significant influence on bacteraemia rate, in-hospital complications or BP mortality. High Pneumonia Severity Index (PSI) predicted mortality accurately [relative risk 15.2, 95% confidence interval 3.2-71.7; P=0.001]. Mortality was 9.1%, but was significantly higher in patients with CD4 counts under 200 cells/microL (P=0.022). CONCLUSIONS: A decline in BP incidence was seen during the study period. Combining CD4 cell count and PSI score could become a good strategy in deciding which patients have to be hospitalized.

Abuso y dependencia de sustancias en el trastorno bipolar / Substance abuse and substance dependence in bipolar disorder

Objetivo: la asociación entre las conductas adictivas y el trastorno bipolar ha sido ampliamente estudiada por diferentes autores a lo largo del tiempo sin embargo, los resultados de las causas de dicha asociación no son concluyentes. Material y métodos: en el presente artículo se revisa la literatura publicada sobre este tema prestando especial atención a la comorbilidad del alcoholismo con el trastorno bipolar y las implicaciones diagnósticas, terapéuticas y pronosticas que conllevan dicha asociación. Resultados: el trastorno bipolar es la patología del eje I más frecuentemente asociada al consumo de alcohol y drogas, y esta asociación es más frecuente en las fases maniacas que en las depresivas. Conclusiones: con frecuencia la comorbilidad dificulta el diagnóstico y empeora el pronóstico. Habitualmente los tratamientos convencionales son menos efectivos (AU)