Discontinuation of maintenance therapy against toxoplasma encephalitis in AIDS patients with sustained response to anti-retroviral therapy

Discontinuation of maintenance therapy against toxoplasma encephalitis (TE) for individuals infected with human immunodeficiency virus (HIV) who are receiving successful anti-retroviral therapy is considered safe. Nevertheless, there are few published studies concerning this issue. Within the setting of the Swiss HIV Cohort Study, this report describes a prospective study of discontinuation of maintenance therapy against TE in patients with a sustained increase of CD4 counts to > 200 cells/microL and 14% of total lymphocytes, and no active lesions on cerebral magnetic resonance imaging (MRI). In addition to clinical evaluation, cerebral MRI was performed at baseline, and 1 and 6 months following discontinuation. Twenty-six AIDS patients with a history of TE agreed to participate, but three patients (11%) could not be enrolled because they still showed enhancing cerebral lesions without a clinical correlate. One patient refused MRI after 6 months while clinically asymptomatic. Among the remaining 22 patients who discontinued maintenance therapy, one relapsed after 3 months. During a total follow-up of 58 patient-years, there was no TE relapse among the patients who had remained clinically and radiologically free of relapse during the study. Thus, discontinuation of maintenance therapy against TE was generally safe, but may fail in a minority of patients. Patients who remain clinically and radiologically free of relapse at 6 months after discontinuation are unlikely to experience a relapse of TE.

Dissociated lateralization of transient and sustained blood oxygen level-dependent signal components in human primary auditory cortex

Among other auditory operations, the analysis of different sound levels received at both ears is fundamental for the localization of a sound source. These so-called interaural level differences, in animals, are coded by excitatory-inhibitory neurons yielding asymmetric hemispheric activity patterns with acoustic stimuli having maximal interaural level differences. In human auditory cortex, the temporal blood oxygen level-dependent (BOLD) response to auditory inputs, as measured by functional magnetic resonance imaging (fMRI), consists of at least two independent components: an initial transient and a subsequent sustained signal, which, on a different time scale, are consistent with electrophysiological human and animal response patterns. However, their specific functional role remains unclear. Animal studies suggest these temporal components being based on different neural networks and having specific roles in representing the external acoustic environment. Here we hypothesized that the transient and sustained response constituents are differentially involved in coding interaural level differences and therefore play different roles in spatial information processing. Healthy subjects underwent monaural and binaural acoustic stimulation and BOLD responses were measured using high signal-to-noise-ratio fMRI. In the anatomically segmented Heschl's gyrus the transient response was bilaterally balanced, independent of the side of stimulation, while in opposite the sustained response was contralateralized. This dissociation suggests a differential role at these two independent temporal response components, with an initial bilateral transient signal subserving rapid sound detection and a subsequent lateralized sustained signal subserving detailed sound characterization.

Levocetirizine is an effective treatment in patients suffering from chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled, parallel, multicenter study

BACKGROUND: Chronic idiopathic urticaria (CIU) is defined by the almost daily presence of urticaria for at least 6 weeks without an identifiable cause. Symptoms include short-lived wheals, itching, and erythema. CIU impedes significantly a patient's quality of life (QoL). Levocetirizine is an antihistamine from the latest generation approved for CIU. AIM: To investigate the efficacy of levocetirizine, 5 mg, and placebo for the symptoms and signs of CIU, as well as for the QoL and productivity. METHODS: The primary criteria of evaluation were the pruritus severity scores over 1 week of treatment and over 4 weeks. The QoL was assessed via the Dermatology Life Quality Index (DLQI). RESULTS: Baseline pruritus severity scores were comparable in the two treatment groups (2.06+/-0.58). After 1 week, levocetirizine was superior to placebo and demonstrated a considerable efficacy (difference=0.78, P<0.001). This efficacy was maintained over the entire study period (4 weeks, P<0.001). The number and size of wheals were considerably reduced compared with placebo over 1 week and over the total treatment period (P sustained response, but also by an important improvement in QoL.

Abatacept in the Treatment of Severe, Longstanding, and Refractory Uveitis Associated with Juvenile Idiopathic Arthritis.

OBJECTIVE Abatacept (ABA), a selective T cell costimulation modulator that binds to CD80 and CD86 on antigen-presenting cells, was investigated for its antiinflammatory effect in treating severe chronic uveitis associated with juvenile idiopathic arthritis (JIA). METHODS Our retrospective study was conducted by members of the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC). Patients with JIA who are receiving ABA treatment for active uveitis were included. In all patients, uveitis had been refractory to previous topical and systemic corticosteroids, immunosuppressives, and at least 1 tumor necrosis factor-α inhibitor. A standardized protocol was used to document uveitis (MIWGUC) and arthritis. Baseline visit and visits at 3, 6, 9, and 12 months before and after ABA start were evaluated. Primary outcome measure was defined as achievement of uveitis inactivity; secondary outcome measures were tapering of corticosteroid and/or immunosuppressive treatment, and occurrence of complications. RESULTS In all, 21 patients (16 female) with active uveitis (n = 21) and arthritis (n = 18) were included (mean age 11.8 ± 3.6 yrs). In 7 of 18 patients with active arthritis at baseline, inactivity was achieved following ABA treatment. Uveitis inactivity was achieved in 11 patients, but recurred later in 8 of them, and remained active in another 10 cases. Systemic corticosteroids or immunosuppression were tapered in 3 patients, but uveitis recurred in all of them during further followup. Ocular complications secondary to uveitis were present in 17 patients at baseline, while 3 patients developed new ocular complications during followup. CONCLUSION A sustained response to ABA was uncommon in patients with severe and refractory uveitis.

Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis

Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death.

Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis

BACKGROUND: Clinical outcomes of chronic hepatitis C infection in patients with advanced fibrosis include liver failure, hepatocellular carcinoma, and death. OBJECTIVE: To investigate whether sustained virologic response to treatment for hepatitis C is associated with improved clinical outcomes. DESIGN: Retrospective cohort study. SETTING: 5 hepatology units of tertiary care centers in Europe and Canada caring for patients with chronic hepatitis C treated between 1990 and 2003. PATIENTS: Consecutively treated patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6). MEASUREMENTS: Sustained virologic response, defined as absence of detectable hepatitis C virus RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver failure, and hepatocellular carcinoma. RESULTS: Of 479 patients, 29.6% had sustained virologic response and 70.3% did not. Median follow-up was 2.1 years (interquartile range, 0.8 to 4.9 years). Four patients with and 83 without sustained virologic response had at least 1 outcome event. Sustained virologic response was associated with a statistically significant reduction in the hazard of events (adjusted hazard ratio, 0.21 [95% CI, 0.07 to 0.58]; P = 0.003). The effect was largely attributable to a reduction in liver failure, which developed in no patients with and 42 patients without sustained virologic response (5-year occurrence, 0% vs. 13.3% [CI, 8.4% to 18.2%]; unadjusted hazard ratio, 0.03 [CI, 0.00 to 0.91]). LIMITATIONS: Because few events occurred in the sustained virologic response group, the study had limited ability to detect differences between groups in individual outcomes. In addition, the study was retrospective; selection and survival biases may therefore influence estimates of effect. CONCLUSION: Sustained virologic response to treatment is associated with improved clinical outcomes, mainly prevention of liver failure, in patients with chronic hepatitis C and advanced fibrosis.

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

BACKGROUND Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). METHODS We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). RESULTS SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. CONCLUSION In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients

Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi

Objective  Malnutrition is common in HIV-infected children in Africa and an indication for antiretroviral treatment (ART). We examined anthropometric status and response to ART in children treated at a large public-sector clinic in Malawi. Methods  All children aged <15 years who started ART between January 2001 and December 2006 were included and followed until March 2008. Weight and height were measured at regular intervals from 1 year before to 2 years after the start of ART. Sex- and age-standardized z-scores were calculated for weight-for-age (WAZ) and height-for-age (HAZ). Predictors of growth were identified in multivariable mixed-effect models. Results  A total of 497 children started ART and were followed for 972 person-years. Median age (interquartile range; IQR) was 8 years (4–11 years). Most children were underweight (52% of children), stunted (69%), in advanced clinical stages (94% in WHO stages 3 or 4) and had severe immunodeficiency (77%). After starting ART, median (IQR) WAZ and HAZ increased from −2.1 (−2.7 to −1.3) and −2.6 (−3.6 to −1.8) to −1.4 (−2.1 to −0.8) and −1.8 (−2.4 to −1.1) at 24 months, respectively (P < 0.001). In multivariable models, baseline WAZ and HAZ scores were the most important determinants of growth trajectories on ART. Conclusions  Despite a sustained growth response to ART among children remaining on therapy, normal values were not reached. Interventions leading to earlier HIV diagnosis and initiation of treatment could improve growth response.

A genetic validation study reveals a role of vitamin D metabolism in the response to interferon-alfa-based therapy of chronic hepatitis C

Background To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. Methodology/Principal Findings Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome. Conclusions/Significance Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.

Effects of low abdominal blood flow and dobutamine on blood flow distribution and on the hepatic arterial buffer response in anaesthetized pigs

Low cardiac output impairs the hepatic arterial buffer response (HABR). Whether this is due to low abdominal blood flow per se is not known. Dobutamine is commonly used to increase cardiac output, and it may further modify hepatosplanchnic and renal vasoregulation. We assessed the effects of isolated abdominal aortic blood flow changes and dobutamine on hepatosplanchnic and renal blood flow. Twenty-five anesthetized pigs with an abdominal aorto-aortic shunt were randomized to 2 control groups [zero (n = 6) and minimal (n = 6) shunt flow], and 2 groups with 50% reduction of abdominal blood flow and either subsequent increased abdominal blood flow by shunt reduction (n = 6) or dobutamine infusion at 5 and 10 microg kg(-1) min(-1) with constant shunt flow (n = 7). Regional (ultrasound) and local (laser Doppler) intra-abdominal blood flows were measured. The HABR was assessed during acute portal vein occlusion. Sustained low abdominal blood flow, by means of shunt activation, decreased liver, gut, and kidney blood flow similarly and reduced local microcirculatory blood flow in the jejunum. Shunt flow reduction partially restored regional blood flows but not jejunal microcirculatory blood flow. Low-but not high-dose dobutamine increased gut and celiac trunk flow whereas hepatic artery and renal blood flows remained unchanged. Neither intervention altered local blood flows. The HABR was not abolished during sustained low abdominal blood flow despite substantially reduced hepatic arterial blood flow and was not modified by dobutamine. Low-but not high-dose dobutamine redistributes blood flow toward the gut and celiac trunk. The jejunal microcirculatory flow, once impaired, is difficult to restore.