Long-term evolution in liver fibrosis and immune profile after direct-acting antivirals therapy in hepatitis C virus-human immunodeficiency virus co-infected patients.

OBJECTIVE: Hepatitis C virus (HCV) therapy with direct-acting antivirals (DAA) achieves high rates of sustained virological response in people living with human immunodeficiency virus (HIV) (PLWH). Information on its long-term clinical impact is scarce. The aim of this study was to analyse liver fibrosis and immune response evolution after DAA treatment. METHODS: Retrospective, single centre cohort study of HIV-HCV co-infected patients treated with DAA between June 2013 and June 2018. We analysed the changes during follow up in liver fibrosis (assessed by transient elastography (TE), aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 scores) and immunity (CD4 and CD8 cells counts and CD4/CD8 ratio). RESULTS: We included 410 patients; 75% (308/407) men with a mean age of 50 years (SD 8); 78% (318/410) had long chronic HCV infection (median 21 years, interquartile range (IQR) 6-27 years) and 27% (107/393) had liver cirrhosis. Liver fibrosis improvement based on the decrease in TE value compared with the baseline occurred in 43% (131/302) of patients and 31% of patients based on biological scores (APRI: 124/398; FIB-4: 104/398) (p < 0.0001), being more frequent in those with advanced baseline fibrosis (83/144). The higher decrease was observed at 6 months after DAA therapy (-0.23; 95% CI -0.29 to -0.18), but a continuum in fibrosis regression of at least 30% from baseline value of TE was observed along the follow up (32% of patients at month 6, 51% at month 24 and 55% at month 48). Regarding the immunological profile, there was a significant decrease in CD8 counts at month 48 (-62.38; 95% CI -106.77 to -17.99; p 0.0001) and a progressive rise in the CD4/CD8 ratio after 24 months of follow up reaching an increment of +0.07 (95% CI 0.03-0.10, p 0.0001) at month 48. CONCLUSIONS: HCV treatment with DAA in PLWH is associated with significant progressive improvement in liver fibrosis and recovery of the immune system with an increase in the CD4/CD8 ratio in long-term follow up.

Response factors associated with electrocautery treatment of intra-anal high-grade squamous intraepithelial lesions in a population of HIV-positive men who have sex with men.

BACKGROUND: Ablative treatment of anal high-grade squamous intraepithelial lesions (HSIL) reduces the risk of progression to anal squamous cell carcinoma. OBJECTIVES: To identify factors that influence the response to treatment of anal HSIL by electrocautery ablation (ECA) in a population of HIV-positive men who have sex with men (MSM). DESIGN: Retrospective study of ECA treatment response in a prospectively followed anal dysplasia cohort. HIV-positive MSM diagnosed with anal HSIL were included. Demographic and HIV data were recorded. Response to treatment was assessed by biopsy after at least 18 months of follow-up. RESULTS: One hundred and twenty-eight HSILs in 91 men were included in this study. The overall response rate at 18 months was 70.3%. The number of electrocautery sessions required (2 ECA sessions vs 1: adjusted odds ratio [aOR] = 0.36 (95%CI 0.13-1.01); >=3 sessions vs 1: aOR = 0.10 (95%CI 0.04-0.29); p < 0.001]) and the history of previous HPV-related anal pathology (previous anal lesions vs no previous lesions AOR = 2.83 (95%CI 1.14-7.02), p = 0.024) were independently associated with response at 18 months. No serious adverse events were reported. CONCLUSIONS: Consideration should be given to alternative therapies in patients with unresolved HSIL after 1 ECA treatment.

Infective Endocarditis in Patients on Chronic Hemodialysis.

BACKGROUND: Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). OBJECTIVES: This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. METHODS: Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. RESULTS: A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p < 0.001). Cardiac surgery was less frequently performed among HD patients (30.6% vs. 46.2%; p < 0.001), whereas relapses were higher (9.4% vs. 2.7%; p < 0.001). Risk factors for 6-month mortality included Charlson score (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.11 to 1.44; p = 0.001), CNS emboli and other emboli (HR: 3.11; 95% CI: 1.84 to 5.27; p < 0.001; and HR: 1.73; 95% CI: 1.02 to 2.93; p = 0.04, respectively), persistent bacteremia (HR: 1.79; 95% CI: 1.11 to 2.88; p = 0.02), and acute onset heart failure (HR: 2.37; 95% CI: 1.49 to 3.78; p < 0.001). CONCLUSIONS: HD-IE is a health care-associated infection chiefly caused by S. aureus, with increasing rates of enterococcal IE. Mortality and relapses are very high and significantly larger than in non-HD-IE patients, whereas cardiac surgery is less frequently performed.

E157Q integrase strand-transfer inhibitor substitution in patients with acute/recent HIV infection.

OBJECTIVES: Integrase strand-transfer inhibitor (InSTI)-based regimens are the preferred combinations for naïve HIV-infected individuals. Polymorphic substitutions that reduce InSTIs activity have been described, with E157Q being one of the most frequently found. This study aimed to evaluate the prevalence of E157Q substitution in newly diagnosed acute/recent HIV cases and the presence of transmission clusters. DESIGN: Prospective cohort study in patients with acute/recent HIV infection. METHODS: Genotypic drug resistance tests were performed in all consecutive patients prospectively enrolled with a documented infection of less than 6 months from May 2015 to May 2017. Sequences were obtained by ultra-deep sequencing. Phylogenetic inferences were performed using maximum likelihood trees constructed with Mega 6.06. Bootstrap values of 75% or greater were defined for cluster assignment. Follow-up was, at least, 1 year. RESULTS: In six out of 67 consecutive patients (8.95%, 95% confidence interval 4.17-18.19) with acute/recent HIV infection, strains carrying the E157Q InSTI substitution were detected. All cases were MSM patients infected with subtype B strains. No other resistance substitutions were detected in these cases. Median viral load was 5.33 (interquartile range: 4.54-5.71) log10 copies/ml and, in all cases, the mutational viral load was high (>95%). Three cases were included in transmission clusters. Three cases responded to dolutegravir-based regimens; nonnucleoside reverse transcriptase inhibitor-based regimens were used for the other case(s). CONCLUSION: E157Q substitution, reducing raltegravir and elvitegravir activity, was frequently found in acute/recent HIV cases. All cases were infected with subtype B, and some were included in clusters. Cases treated with dolutegravir-based regimens had good virological response.

Polypharmacy and potential drug-drug interactions in an HIV-infected elderly population.

OBJECTIVE: Comorbidities associated with the ageing of the HIV+ population may require chronic treatment. Our aim is to determine the degree of polypharmacy and the number of potential drug-drug interactions, as well as the relationship between both variables in a HIV-infected population over the age of 65. METHODS: Descriptive transversal study targeting HIV+ patients aged ≥65, attended in a Spanish hospital in 2014. The prevalence of polypharmacy (≥5 drugs) and potential drug-drug interactions were assessed, and also risk factors associated with such. RESULTS: 265 subjects aged ≥65 years were identified, 197 of whom were on antiretroviral treatment and had data about their electronic prescription. 93% were polymedicated. The patients whose antiretroviral treatment included a non-nucleoside reverse transcriptase inhibitor (NNRTI) demonstrated a fourfold probability of being polymedicated. 65% of the patients showed at least one potential drug-drug interaction and 6.6% a severe potential drug-drug interaction. The risk of interaction was significantly associated with the number of prescribed drugs (incidence rate ratio per prescribed drug, CI 95%: 1.18 (1.14;1.22; p<0.0001) and with the use of protease inhibitors (PI) (incidence rate ratio, CI 95%: 1.65 (1.28;2.11; p=0.0001)). CONCLUSION: Polypharmacy has a high prevalence and is more common in patients treated with NNRTI. The number of potential drug-drug interactions increase with the number of prescribed drugs and is higher in those patients on PI.

Objetivo: Las comorbilidades asociadas al envejecimiento de la población VIH+ pueden requerir tratamientos crónicos. Nuestro objetivo es determinar el grado de polifarmacia y el número de interacciones farmacológicas potenciales, así como la relación entre ambas variables en un grupo de población VIH+ mayor de 65 años.Métodos: Estudio descriptivo transversal en pacientes VIH+≥65 años atendidos en un hospital español en 2014. Se evaluó la prevalencia de polimedicación (≥5 fármacos) y se analizaron las interacciones farmacológicas potenciales y los factores de riesgo asociados a ellas.Resultados: Se identificaron 265 sujetos ≥65 años, de los cuales 197 recibían tratamiento antirretroviral y tenían datos en la receta electrónica. El 93% estaban polimedicados. Los pacientes cuyo tratamiento antirretroviral incluía un inhibidor de la transcriptasa inversa no nucleósido (ITINN) presentaban una probabilidad cuatro veces mayor de estar polimedicados. El 65% de los pacientes presentó al menos una interacción potencial y el 6,6% una interacción potencial grave. El riesgo de interacciones se asoció significativamente al número de fármacos prescritos (razón de tasas de incidencia por fármaco prescrito con IC 95%: 1,18 (1,14;1,22; p<0.0001)) y a los inhibidores de la proteasa (IP) (razón de tasas de incidencia IC 95%: 1,65 (1,28;2,11; p=0,0001)).Conclusión: La prevalencia de la polifarmacia es muy alta y más frecuente en los pacientes tratados con ITINN. El número de interacciones farmacológicas potenciales aumenta con el número de fármacos prescritos y es mayor en los pacientes tratados con IP.

Markers of deep infiltrating endometriosis in patients with ovarian endometrioma: a predictive model.

OBJECTIVE: The purpose of the study was to develop an easily applicable predictive model to predict deep infiltrating endometriosis in patients with ovarian endometrioma. STUDY DESIGN: We performed a retrospective analysis of 178 consecutive women with ovarian endometrioma who underwent surgery, with histological confirmation and complete removal of endometriosis in the Hospital Clinic of Barcelona. Several markers were prospectively obtained and compared between the group of patients presenting deep infiltrating endometriosis associated with ovarian endometrioma and women with only ovarian endometrioma. Multiple logistic regression analysis was performed to create a model to predict the presence of deep infiltrating endometriosis and internal validation was later performed. RESULTS: Of the 178 patients studied, 80 (45%) were classified in the ovarian endometrioma group and 98 (55%) in the group of patients presenting deep infiltrating endometriosis associated with ovarian endometrioma. The independent variables to predict deep infiltrating endometriosis were: at least one previous pregnancy, a past history of surgery for endometriosis and the mean endometriosis-associated pelvic pain score. The area under the ROC curve was 0.91 (95% confidence interval: 0.86-0.94), with an optimal cut-off of the predicted probability of 0.54. The sensitivity of the model was 80% and the specificity 84%. CONCLUSIONS: This model predicts the development of deep infiltrating endometriosis in patients with ovarian endometriomas allowing prioritization of women for referral to specialized centers.

Altered Hypercoagulability Factors in Patients with Chronic Chagas Disease: Potential Biomarkers of Therapeutic Response.

Thromboembolic events were described in patients with Chagas disease without cardiomyopathy. We aim to confirm if there is a hypercoagulable state in these patients and to determine if there is an early normalization of hemostasis factors after antiparasitic treatment. Ninety-nine individuals from Chagas disease-endemic areas were classified in two groups: G1, with T.cruzi infection (n = 56); G2, healthy individuals (n = 43). Twenty-four hemostasis factors were measured at baseline. G1 patients treated with benznidazole were followed for 36 months, recording clinical parameters and performance of conventional serology, chemiluminescent enzyme-linked immunosorbent assay (trypomastigote-derived glycosylphosphatidylinositol-anchored mucins), quantitative polymerase chain reaction, and hemostasis tests every 6-month visits. Prothrombin fragment 1+2 (F1+2) and endogenous thrombin potential (ETP) were abnormally expressed in 77% and 50% of infected patients at baseline but returned to and remained at normal levels shortly after treatment in 76% and 96% of cases, respectively. Plasmin-antiplasmin complexes (PAP) were altered before treatment in 32% of G1 patients but normalized in 94% of cases several months after treatment. None of the patients with normal F1+2 values during follow-up had a positive qRT-PCR result, but 3/24 patients (13%) with normal ETP values did. In a percentage of chronic T. cruzi infected patients treated with benznidazole, altered coagulation markers returned into normal levels. F1+2, ETP and PAP could be useful markers for assessing sustained response to benznidazole.

Pregnancy and malaria exposure are associated with changes in the B cell pool and in plasma eotaxin levels.

Pregnancy triggers immunological changes aimed to tolerate the fetus, but its impact on B lymphocytes is poorly understood. In addition, exposure to the Plasmodium parasite is associated with altered distribution of peripheral memory B cell (MBC) subsets. To study the combined impact of high malaria exposure and pregnancy in B cell subpopulations, we analyzed PBMCs from pregnant and nonpregnant individuals from a malaria-nonendemic country (Spain) and from a high malaria-endemic country (Papua New Guinea). In the malaria-naive cohorts, pregnancy was associated with a significant expansion of all switched (IgD(-)) MBC and a decrease of naive B cells. Malaria-exposed women had more atypical MBC and fewer marginal zone-like MBC, and their levels correlated with both Plasmodium vivax- and Plasmodium falciparum-specific plasma IgG levels. Classical but not atypical MBC were increased in P. falciparum infections. Moreover, active atypical MBC positively correlated with proinflammatory cytokine plasma concentrations and had lower surface IgG levels than the average. Decreased plasma eotaxin (CCL11) levels were associated with pregnancy and malaria exposure and also correlated with B cell subset frequencies. Additionally, active atypical and active classical MBC expressed higher levels of eotaxin receptor CCR3 than the other B cell subsets, suggesting a chemotactic effect of eotaxin on these B cell subsets. These findings are important to understand immunity to infections like malaria that result in negative outcomes for both the mother and the newborn and may have important implications on vaccine development.

The model for end-stage liver disease score is the best prognostic factor in human immunodeficiency virus 1-infected patients with end-stage liver disease: a prospective cohort study.

End-stage liver disease (ESLD) has become the main cause of mortality in patients coinfected by human immunodeficiency virus (HIV) and hepatitis B virus or hepatitis C virus in developed countries. The aim of this study was to describe the natural history of and prognostic factors for ESLD, with particular attention paid to features affecting liver transplantation. This was a prospective cohort study in 2 Spanish community-based hospitals performed between 1999 and 2004. One hundred four consecutive patients with cirrhosis and a first clinical decompensation of their chronic liver disease or hepatocellular carcinoma were included in the study. During a median follow-up of 10 months (endpoint: death, liver transplantation, or the last checkup date), 61 patients (59%) died. The probability of mortality (Kaplan-Meier method) at 1, 2, and 3 years was 43% [95% confidence interval (CI), 34%-60%], 59% (95% CI, 48%-70%), and 70% (95% Cl, 59%-81%), respectively. In a multivariate analysis, the Model for End-Stage Liver Disease (MELD) score and the inability to reach an undetectable plasma HIV-1 RNA viral load at any time during follow-up were the only variables independently associated with the risk of death (P < 0.001). Fifteen (14%) of the 104 patients were accepted for liver transplantation, although only 5 underwent the procedure, and 10 died while on the waiting list. The waiting list mortality rate in patients with a MELD score < 20 and in patients with a MELD score >20 was 58% and 100%, respectively (median follow-up, 5 months). In conclusion, HIV-1-infected patients with ESLD, especially those with poorly controlled HIV and a high MELD score, have a poor short-term outcome. The MELD score may be useful in deciding whether to indicate liver transplantation in these patients. However, because only a small proportion of the patients in this study were considered candidates for liver transplantation and most died while on the waiting list, few received a transplant.

Health care-associated native valve endocarditis: importance of non-nosocomial acquisition.

BACKGROUND: The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. OBJECTIVE: To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. DESIGN: Prospective cohort study. SETTING: 61 hospitals in 28 countries. PATIENTS: Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. MEASUREMENTS: Clinical and echocardiographic findings, microbiology, complications, and mortality. RESULTS: Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). LIMITATIONS: Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. CONCLUSION: More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. PRIMARY FUNDING SOURCE: None.

Prevalence and clinical relevance of occult hepatitis B in the fibrosis progression and antiviral response to INF therapy in HIV-HCV-coinfected patients.

Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies (HBcAb) and HBV DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. This situation has been frequently described in patients with chronic hepatitis C virus (HCV) infection. The objective of this study was to evaluate the prevalence of occult hepatitis B in HIV-HCV-coinfected patients and its clinical relevance in liver histology and viral response after interferon therapy for HCV. A total of 238 HIV-HCV-infected patients,negative for HBsAg, were included. Serum samples were analyzed for the presence of HBV DNA and HBcAb.HBV DNA quantification was determined with the Cobas TaqMan HBV Test (detection limit 6 IU/ml). Data from liver biopsy and laboratory tests were also analyzed. HBcAb resulted in 142 (60%) patients, being the independent associated factors: male gender, previous history of intravenous drug use, age, CD4 count,and HAV antibody presence. Among 90 HBcAb patients that we could analyze, HBV DNA was positive in 15 (16.7% of occult hepatitis B infection in this group, and 6.3% in the whole HIV-HCV cohort studied). No baseline factors, liver histology, or HCV therapy response were related to the presence of HBV DNA. We found that occult hepatitis B is a frequent condition present in at least 6.3% of our HCV-HIV patients and in more than 16% of those with HBcAb. Despite the high prevalence, this phenomenon does not seem to affect the clinical evolution of chronic hepatitis C or modify the viral response to interferon-based HCV therapies

The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients.

BACKGROUND: Stavudine (d4T)-containing regimens are associated with a potential for lipoatrophy and dyslipidaemia. We assessed the safety and efficacy of reducing the dose of stavudine compared with switching to tenofovir or maintaining the standard dose of d4T. METHODS: Clinically stable HIV-infected patients receiving antiretroviral therapy containing stavudine 40 mg twice daily with a plasma HIV RNA < 200 copies/ml for at least 6 months were randomized to maintain stavudine 40 mg twice daily (d4T40 arm), to reduce to 30 mg twice daily (d4T30 arm), or to switch from d4T to tenofovir (TDF arm). RESULTS: Fifty-eight (93% male) patients were included: 22 in the d4T40 arm, 19 in the d4T30 arm and 17 in TDF arm. At baseline, median time on d4T was 6 years (interquartile range [IQR] 2.6-7.1), median age 43 years (IQR 36-51) and median CD4+ T-cell count was 587/mm3 (IQR 329-892). At week 24, median limb fat changes (g) were as follows: d4T40 = -182 (95% CI: -469- -5); d4T30 = 527 (95% CI: -343-694); and TDF = 402 (95% CI: 130-835; d4T40 versus TDF, P = 0.0003). Significant differences between median values of laboratory parameters were detected: triglycerides (mg/dl): d4T40 = 19; d4T30 = -23 and TDF = -79 (d4T40 versus TDF, P = 0.03); and total cholesterol (mg/dl): d4t40 = 22, d4T30 = -4, and TDF = -28 (d4T40 versus TDF, P = 0.04). No significant difference was observed in mitochondrial function assessed in peripheral blood mononuclear cells. CONCLUSIONS: Although both strategies were associated with a trend toward a decrease in plasma lipids and an increase in body fat, the only significant changes were observed among those who switched to tenofovir.

Noninvasive diagnosis of hepatic fibrosis in HIV/HCV-coinfected patients.

BACKGROUND: Several serum markers reflecting extracellular matrix status have been correlated with liver fibrosis in non-HIV-infected patients with chronic hepatitis C infection. These indexes have been less examined in HIV/HCV-coinfected individuals. OBJECTIVE: We aimed to evaluate the predictive value of serum markers for liver fibrosis in HIV-infected patients with chronic hepatitis C virus (HVC). METHODS: Serum levels of metalloproteinases 1 and 2 (MMP-1 and -2), tissue inhibitors of matrix metalloproteinases (TIMP-1), procollagen type III N-terminal peptide (PIIINP), and hyaluronic acid (HA) were measured in HIV-infected patients with chronic hepatitis C at the time of obtaining a liver biopsy and before the consideration of anti-hepatitis C therapy. RESULTS: One hundred and nineteen consecutive HIV-HVC coinfected patients were included. TIMP-1 (r = 0.6; P < 0.001), TIMP-1/MMP-1 ratio (r = 0.5; P < 0.001), TIMP-1/MMP-2 ratio (r = 0.3; P < 0.001), MMP-2 (r = 0.2; P = 0.044), PIIINP (r = 0.4; P < 0.001), and HA (r = 0.5; P < 0.001) were positively and significantly correlated with the fibrosis stage. In the multivariate analysis, TIMP-1 (odds ratio [OR] = 1.004, 95% confidence interval [CI]: 1.002 to 1.006, P = 0.001) and HA >95 microg/dL (OR = 6.041, 95% CI: 1.184 to 30.816, P = 0.031) were independently associated with liver fibrosis. The area under the curve of score to discriminate mild (F0-F1) from significant (F2-F4) fibrosis in the received-operating analysis using the variables TIMP-1 and HA was 0.84, with a sensitivity of 72.9% and a specificity of 83.1%. CONCLUSION: TIMP-1 and HA were quite sensitive and specific for predicting the degree of liver fibrosis in HIV-infected patients with chronic hepatitis C. These parameters may become a noninvasive alternative to liver biopsy when the degree of liver fibrosis needs to be estimated.

Periannular complications in infective endocarditis involving prosthetic aortic valves.

The periannular extension of infection in prosthetic valve endocarditis (PVE) is a serious complication of infective endocarditis associated with high mortality. Periannular lesions in PVE occasionally rupture into adjacent cardiac chambers, leading to aortocavitary fistulae and intracardiac shunting. It is unknown whether the prognosis of patients with aortocavitary fistulae is worse than that of those with nonruptured abscesses. The aims of this study were to determine the distinctive clinical characteristics of patients with PVE and either aortocavitary fistulization or nonruptured abscesses. In a retrospective multicenter study of >872 PVE episodes, 150 patients (17%) with periannular complications in PVE in the aortic position were identified (29 with aortocavitary fistulization and 121 with nonruptured abscesses). Early-onset PVE was present in 73 patients (49%). Rates of heart failure (p = 0.09), ventricular septal defect (p <0.01), and third-degree atrioventricular block (p = 0.07) were higher in patients with fistulization. Surgical treatment was undertaken in 128 patients (83%). In-hospital mortality in the overall population was 39%. Multivariate analysis identified heart failure (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.6 to 6.8), renal failure (OR 2.5, 95% CI 1.2 to 5.2), and co-morbidity (OR 2.4, 95% CI 1.1 to 5.1) as independent risk factors for death. Fistulous tract formation was not associated with increased in-hospital mortality (OR 1.6, 95% CI 0.7 to 3.7). The actuarial 5-year survival rate in surgical survivors was 100% in patients with fistulae and 78% in patients with nonruptured abscesses (log-rank p = 0.14). In conclusion, aortocavitary fistulous tract formation in PVE complicated with periannular complications is associated with higher rates of heart failure, ventricular septal defect, and atrioventricular block than nonruptured abscesses. Despite the frequent complications, fistulous tract formation in the current era of infective endocarditis is not an independent risk factor for mortality.

Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002.

BACKGROUND: Triple-combination antiretroviral therapy (CART) for human immunodeficiency virus infection has been in use for almost a decade, but the extent to which treatment success has changed is uncertain. We examined risk of initial virological failure of CART according to the year of starting therapy. METHODS: We included subjects from 5 complete clinic cohorts in Europe and Canada who started CART without previous antiretroviral therapy from 1996 to 2002 with 1 or more pre-CART viral load (VL) measurement and CD4 count. Based on the first VL measurement from 6 to 12 months after CART initiation, virological failure was defined as a VL of more than 500 copies/mL. We used the following 3 inclusion strategies: (1) including all subjects, with missing VL measurement counted as virological failure (n = 3825; strategy A); (2) including all subjects with VL measurement (n = 3120; strategy B); and (3) including all subjects receiving antiretroviral therapy at VL measurement (n = 2890; strategy C). RESULTS: From 1996 to 2002, risk of virological failure fell from 38.9% to 24.8% for strategy A, 28.4% to 12.0% for strategy B, and 22.8% to 8.2% for strategy C. Estimated relative reductions in risk (95% confidence interval) over the 7-year period, adjusted for cohort, demographic factors, pre-CART VL and CD4 count, and previous AIDS, were 48% (39%-56%), 64% (53%-73%), and 79% (69%-85%) for strategies A, B, and C, respectively. Reductions in risk were greatest from 1996 to 1999, with weaker trends subsequently. Trends remained but were attenuated after further adjustment for the starting regimen. CONCLUSIONS: Over a 7-year period of CART use in clinical practice, risk of initial virological failure of treatment has halved at least. These data suggest the trend is due to improvements in CART regimens and greater effectiveness of their use.

Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy.

BACKGROUND: Pre-eclampsia and/or fetal death have increased sharply in HIV-infected pregnant women receiving HAART. METHODS: The occurrence of pre-eclampsia or fetal death was analysed in women who delivered after at least 22 weeks of gestation for all women (January 2001 until July 2003) and for HIV-infected women (November 1985 until July 2003). RESULTS: In 2001, 2002 and 2003, the rates per 1000 deliveries of pre-eclampsia and fetal death, respectively, remained stable in all pregnant women at 25.4, 31.9 and 27.7 (P = 0.48) and 4.8, 5.8, and 5.0 (P = 0.89) (n = 8768). In 1985-2000 (n = 390) to 2001-2003 (n = 82), rates per 1000 deliveries in HIV-infected women rose from 0.0 to 109.8 (P < 0.001) for pre-eclampsia and from 7.7 to 61.0 (P < 0.001) for fetal death. In all pregnant women, factors associated with pre-eclampsia or fetal death were multiple gestation [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.3-5.6; P < 0.001], HIV infection (adjusted OR, 4.9; 95% CI, 2.4-10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58-0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46-0.90; P = 0.010). The use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7-18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054-0.627; P = 0.007) were risk factors in HIV-infected women. CONCLUSIONS: HIV infection treated with HAART prior to pregnancy was associated with a significantly higher risk for pre-eclampsia and fetal death.

Clinical characteristics and outcome of aortic endocarditis with periannular abscess in the International Collaboration on Endocarditis Merged Database.

The aims of this study were to determine the clinical characteristics and outcome of patients who had definite infective endocarditis (IE) complicated by aortic ring abscess formation that was detected with transesophageal echocardiography (TEE) and to determine the prognostic significance of abscess formation in aortic valve IE. Patients who had aortic valve IE were selected from the International Collaboration on Endocarditis Merged Database (ICE-MD) if they underwent TEE. Among 311 patients who had definite aortic valve IE, 67 (22%) had periannular abscesses. They were more likely to have infection in the setting of a prosthetic valve (40% vs 19%, p <0.001) and coagulase-negative staphylococcal IE (18% vs 6%, p < 0.01) and less likely to have streptococcal IE than were patients who did not develop abscess (28% vs 46%, p = 0.01). Systemic embolization, central nervous system events, and heart failure did not differ between those who developed abscess and those who did not, but power was limited. Patients who had abscess were more likely to undergo surgery (84% vs 36%, p <0.001), and their in-hospital mortality rate was higher (19% vs 11%, p = 0.09). Multivariate analysis of prognostic factors of mortality in aortic IE identified age (odds ratio [OR] 1.6, 95% confidence interval [CI]1.2 to 2.1), Staphylococcus aureus (S. aureus) infection (OR 2.4, 95% CI 1.1 to 5.2), and heart failure (OR 2.9, 95% CI 1.4 to 6.1) as variables that were independently associated with increased risk of death. Periannular abscess formation showed a nonsignificant trend toward an increased risk of death (OR 1.9, 95% CI 0.9 to 3.8). Multivariate analysis of prognostic factors of mortality in complicated aortic IE with abscess formation identified S. aureus infection (OR 6.9, 95% CI 1.6 to 29.4) as independently associated with increased risk of death. In conclusion, in the current era of TEE and high use of surgical treatment, periannular abscess formation in aortic valve IE is not an independent risk factor for mortality. S. aureus infection is an independent prognostic factor for mortality in patients who have abscess formation.

Incidence and risk factors for mitochondrial toxicity in treated HIV/HCV-coinfected patients.

BACKGROUND: Coinfection with hepatitis C virus (HCV) and HIV is not uncommon and therapies for both infections are currently available. A major drawback, however, could be a potentially higher risk for mitochondrial toxicity (MT), defined as the elevation of pancreatic enzymes or lactate levels due to the nucleoside analogue reverse transcriptase inhibitors contained in both therapies. METHODS: Prospective analyses of clinical and laboratory data, including plasma lactate levels and pancreatic enzymes, of 113 consecutive HIV/HCV-coinfected patients were assigned to receive ribavirin (RBV) plus interferon (IFN)-alpha. RESULTS: Fourteen patients (12%) showed increased levels of amylase/lipase and/or hyperlactataemia. No patient developed clinical pancreatitis. Four patients with hyperlactataemia had clinical symptoms of lactic acidosis and recovered uneventfully by 2 weeks after treatment withdrawal. The variables significantly associated with MT in the univariate analysis were: therapy with didanosine (ddl), ddl plus stavudine (d4T), previous history of diabetes and the baseline lactate level. However, ddl use was the only independent risk factor for MT identified in the multivariate analysis. MT was not associated with gender, age, alcohol consumption, type of IFN, degree of steatosis and fibrosis in liver biopsy, presence of lipodystrophy, CD4+ cell count, HCV or HIV viral load, mitochondrial DNA and COXII-expression in liver tissue, or antiretroviral therapy containing d4T or protease inhibitors. CONCLUSIONS: 12% of HIV/HCV-coinfected patients receiving IFN plus RBV concomitantly with highly active antiretroviral therapy developed laboratory markers of MT. Although most of cases were asymptomatic, our study suggests that concomitant use of RBV plus ddl should be avoided, and that routine monitoring of lactate and pancreatic enzymes may be recommended.

Aorto-cavitary fistulous tract formation in infective endocarditis: clinical and echocardiographic features of 76 cases and risk factors for mortality.

AIMS: To investigate the clinical features, echocardiographic characteristics, management, and prognostic factors of mortality of aorto-cavitary fistulization (ACF) in infective endocarditis (IE). Extension of infection in aortic valve IE beyond valvular structures may result in peri-annular complications with resulting necrosis and rupture, and subsequent development of ACF. Aorto-cavitary communications create intra-cardiac shunts, which may result in further clinical deterioration and haemodynamic instability. METHODS AND RESULTS: In a retrospective multi-centre study over 4681 episodes of IE, a total of 76 patients with ACF [1.6%, confidence interval (CI) 95%: 1.2-2.0%] diagnosed by echocardiography or during surgery were identified. Fistulae were found in 1.8% of cases of native valve IE and in 3.5% of cases of prosthetic valve IE from the general population and in 0.4% of drug abusers. PVE was present in 31 (41%) cases of ACF. Transthoracic and transoesophageal echocardiography detected the fistulous tracts in 53 and 97% of cases, respectively. Peri-annular abscesses were detected in 78% of cases, fistulae originated in similar rates from the three sinuses of Valsalva, and the four cardiac chambers were equally involved in the fistulous tracts. Heart failure (HF) developed in 62% of cases and surgery was performed in 66 (87% CI 95% 77-93%) patients with a mortality of 41% (95% CI 30-53%) in the overall population. Multivariate analysis identified HF (OR 3.4, CI 95% 1.0-11.5), prosthetic IE (OR 4.6, CI 95% 1.4-15.4) and urgent or emergency surgical treatment (OR 4.3, CI 95% 1.3-16.6) as variables significantly associated with an increased risk of death. Major complications during follow-up (death, re-operation, or re-admission for HF) among the five operative survivors with residual fistulae occurred in 20 and 100% of patients at 1 and 2 years, respectively. CONCLUSION: Aorto-cavitary fistulous tract formation is an uncommon but extremely serious complication of IE. In-hospital mortality was exceptionally high despite aggressive management with surgical intervention in the majority of patients. Prosthetic IE, urgent surgery, and the development of HF identify the subgroup of patients with IE and ACF that have significantly increased risk of in-hospital death.