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INTRODUCTION: Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation. METHODS: Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2x upper limit of normal (ULN) and an ALT flare as ALT ≥5x ULN. RESULTS: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log10 IU/mL, an ALT flare was 15.6% with a median peak ALT x ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months. DISCUSSION: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year. [ABSTRACT FROM AUTHOR]

Summary: Thrombopoietin receptor agonists (TPO‐RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first‐line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end‐points included the sustained remission off‐treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)‐4, IL‐9 and IL‐17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor‐β levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation. [ABSTRACT FROM AUTHOR]

Cortical reactivation and regain of interareal functional connections have been linked to the recovery of hand grasping behavior after loss of sensory inputs in primates. We investigated contributions of neurons in two hierarchically organized somatosensory areas, 3b and S2, by characterizing local field potential (LFP) and multiunit spiking activity in five states (rest, stimulus-on, sustained, stimulus-off, and induced) and interareal communication after grasping behavior of dorsal column lesioned male squirrel monkeys had mostly recovered. Compared with normal cortex, fMRI, LFP, and spiking response magnitudes to step indentations were significantly weaker. The sustained component of the spiking recovered much better than the stimulus-off response. Correlation between overall spiking and γ LFP remained strong within each recovered areas 3b and S2. The interareal correlations of γ LFP were severely disrupted, except in the resting and stimulus-on periods. Interareal correlation of spiking was disrupted in the stimulus-off period only. In summary, submodality of low threshold mechanoreceptive neurons recovered differentially in input-deprived area 3b and S2 when impaired global hand grasping behavior returned. Slow-adapting-like neurons recovered, whereas rapid-adapting-like neurons did not. Interareal communications were also severely compromised. We propose that slow-adapting-like neurons and afferents in recovered area 3b and S2 mediate recovery of impaired grasping behavior after dorsal column tract lesion. [ABSTRACT FROM AUTHOR]

Background and Aim: In HBeAg negative chronic hepatitis B (CHB) patients, clinical relapse (CR) occurs more frequently, much earlier and often more severely after stopping tenofovir (TDF) and other nucleos(t)ide analogues (Nucs) than after stopping entecavir (ETV). It is unknown whether off‐Nuc hepatitis flare can be alleviated by switching from one Nuc to another. Methods: HBeAg‐negative CHB patients who had stopped Nuc according to the APASL stopping rule and had been followed‐up for > 48 weeks after Nuc cessation were recruited. Patients were classified as four groups: ETV monotherapy (mono‐ETV), TDF monotherapy (mono‐TDF), switched to ETV (switch‐ETV), and switched to TDF (switch‐TDF). Both switch groups had switched to the replacement Nuc > 12 weeks prior to end of therapy. Propensity score matching (PSM) was performed to minimize confounders among groups. Cox regression analysis was used to identify risks factors for off‐Nuc CR and flares. Results: A total of 1309 patients (1022 mono‐ETV, 219 mono‐TDF, 40 switch‐ETV and 28 switch‐TDF) were enrolled. The median time to CR was 39, 13, 38 and 14 weeks in mono‐ETV, mono‐TDF, switch‐ETV and switch‐TDF respectively (P < 0.001). After PSM, the mono‐ETV (adjusted HR: 0.39, P < 0.001) and switch‐ETV patients (adjusted HR: 0.41, P = 0.003) had both significantly later occurrence and lower rates of CR and flare. Conclusion: In summary, the incidence and timing of CR was determined by ETV or TDF in the last 3 months prior to end of treatment. Patients treated with non‐ETV‐Nuc switched to ETV > 12 weeks before end of the original Nuc therapy may reduce/defer CR. [ABSTRACT FROM AUTHOR]

Background: Clinical trials of allergen immunotherapy (AIT) may require up to 5 years to complete. These lengthy trials may be complicated by high and potentially differential dropouts, especially among participants who perceive that they are receiving placebo. We propose a three‐stage design in which the placebo group in Stage 1 crosses over to receive active treatment in Stage 2. In Stage 3, AIT is discontinued to determine whether benefit is maintained post‐treatment. We apply inferential statistics to support the three‐stage design for clinical trials to determine clinical efficacy, treatment response over time, and sustained response to AIT. Methods: The proposed framework constitutes a series of hypothesis tests for comparing treatment responses at the end of each stage. A simulation study was performed to illustrate the statistical properties under varying statistical missing mechanisms and effect sizes. Results: The statistical properties in terms of bias and statistical power were consistent with what are expected from conventional analyses. Specifically, the extent of bias depended on the missing mechanism and magnitude. The statistical powers were largely driven by effect and sample sizes as well as prespecified success margins. As an illustration, assuming relative treatment differences of 25% and stagewise dropout rate of 15%, a sample size of 200 per group may achieve 93% power to demonstrate a treatment effect and 60% power to demonstrate a maintained response post‐treatment. Conclusions: Inferential statistics support our proposed study design for evaluating benefits of AIT over time and inform clinical understanding and decisions. [ABSTRACT FROM AUTHOR]

Background & Aims: Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver‐related mortality. However, long‐term outcomes after pegylated interferon (PEG‐IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long‐term effectiveness and clinical outcomes of PEG‐IFN therapy. Methods: A total of 190 patients treated with PEG‐IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post‐treatment and defined as achieving both <2000 IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg‐positive group, and <2000 IU/mL HBV DNA in the HBeAg‐negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off‐therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. Results: The median follow‐up period was 7.2 years. Forty‐three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P <.001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non‐sustained responders (16.2% vs 2.5%, P =.01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. Conclusions: During long‐term follow‐up after PEG‐IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Chronic abdominal pain is frequently encountered at outpatient clinics where the traditional approach is to investigate visceral pathologies. Fifty percent of these patients are finally found to have abdominal wall pain which is generally secondary to entrapment of the anterior cutaneous nerve. This entity is identified by Carnett's sign. The treatment of choice is to infiltrate the painful points with lidocaine following which there is significant improvement in 85% to 90% of these patients. The duration of post-infiltration improvement is unknown. The objective of this work is to determine sustained response in one and two-year follow-up examinations. Materials and Methods: This is a retrospective cohort study conducted in the gastroenterology unit of the Clínica Fundadores. We included adult patients over 18 years of age who had received local injection treatment with 2% lidocaine without epinephrine and who had answered a telephone survey to assess the intensity of pain on an analogous scale. Results: Of the 360 eligible patients identified, 324 patients (90%) were interviewed by telephone. The average age of those interviewed was 57 years, and 87% were women. The average pain level prior to infiltration was 8.7 points. Following infiltration, the average intensity was 2.38 points (p <0.05). In 71% of patients, average pain intensity at a two year follow-up examination was 1.65 points (p <0.05), an 81% improvement in intensity (p = 0.001). Fibromyalgia had a positive association with sustained improvement in pain (p = 0.008). Conclusions: Infiltration of the abdominal wall with a local anesthetic produces a sustained response for up to two years in patients with chronic abdominal wall pain. [ABSTRACT FROM AUTHOR]

Rapid and sustained clinical responses are critical in improving long-term outcomes in epilepsy. While a 50 % reduction from baseline in standardized seizure frequency (SSF) is often cited as a measure of clinically meaningful efficacy, sustained response (SR) is an alternative method that allows the assessment of onset and durability of the response. Time to sustained response in SSF of ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % was assessed for pooled data from 3 similar randomized clinical trials of adjunctive eslicarbazepine acetate (ESL). Patients with focal seizures on stable doses of 1–2 antiseizure medications were randomized to placebo, ESL 800 mg/day, or ESL 1200 mg/day. SR50, SR75, SR90, and SR100 were defined as a ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % reduction, respectively, in SSF compared to baseline occurring anytime during the 12-week maintenance period, sustained through the end of the maintenance period. Safety signals were assessed for patients with SR50 onset within the first 2 weeks of the maintenance period (early responders) and any point following the first 2 weeks (later responders). A total of 1221 patients were included in this analysis. SR50 was achieved as early as Day 1 (placebo, 4.7 %; ESL 800 mg/day, 8.8 %; ESL 1200 mg/day, 10.4 %). After 84 days, SR50 was achieved by 32.1 % of the placebo group, 46.9 % of the ESL 800 mg/day group (p = 0.0002 vs placebo), and 53.7 % of the ESL 1200 mg/day group (p < 0.0001 vs placebo). Both ESL groups demonstrated earlier SR50 onset compared with placebo (p < 0.0001). Time to SR50 onset was not statistically different between the 800 and 1200 mg/day ESL dose groups. SR75 (p = 0.0001), SR90 (p = 0.0019), and SR100 (p = 0.0014) were achieved significantly earlier in the ESL 1200 mg/day groups vs placebo. SR75 was achieved significantly earlier in the ESL 800 mg/day group vs placebo (p = 0.0188), while achievements of SR90 (p = 0.0525) and SR100 (p = 0.0540) trended toward earlier occurrence. A greater proportion of patients in the ESL groups compared to the placebo group achieved an SR50 during the maintenance period, and those patients in the ESL groups also achieved SR50 and SR75 sooner than placebo treated patients. Additionally, patients treated with the higher ESL dose achieved SR90 and SR100 sooner than those treated with placebo. [ABSTRACT FROM AUTHOR]

Background: Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose.Study Design and Methods: Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3-8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications.Results: Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p < 0.001). Sustained pain freedom was significantly higher in patients treated with lasmiditan versus placebo at 24 hours: 200 mg: 21.2%; 100 mg: 16.9%; 50 mg: 17.4%; placebo: 10.3% (all p < 0.01); and at 48 hours: 200 mg: 18.4%; 100 mg: 15.2%; 50 mg: 14.9%; placebo: 9.6% (all p < 0.05). Similar sustained benefits of lasmiditan versus placebo at 24 and 48 hours were noted for most bothersome symptom-free, total migraine-free and disability-free responses. Modified sustained pain freedom at 24 hours was also observed in significantly higher proportions of lasmiditan-treated patients versus placebo: 200 mg: 27.0%; 100 mg: 21.7%; 50 mg: 21.7%; placebo: 12.9% (all p < 0.01).Conclusion: Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses.Clinicaltrials.gov Identifier Numbers: SAMURAI: NCT02439320; SPARTAN: NCT02605174. [ABSTRACT FROM AUTHOR]

Cessation of nucleos(t)ide analogue (Nuc) therapy in HBeAg‐negative patients may increase HBsAg loss rate in patients with sustained remission (SR) and non‐retreated clinical relapsers (CR). To investigate and compare the HBsAg kinetics from end of treatment (EOT) to HBsAg loss in these patients, serial serum samples after EOT from 36 SR and 12 CR with HBsAg loss (study group) and an 1:1 matched control who remained HBsAg‐seropositive (control group) were assayed retrospectively for quantitative HBsAg (qHBsAg). The results showed that study group SR and CR had comparable EOT features except SR had lower EOT qHBsAg (67.5 vs 350.5 IU/mL; P = 0.02; < 100 IU/mL: 58.3% vs 25%; P = 0.09). All showed gradual qHBsAg decrease then "precipitous HBsAg decline" (>0.5 log10 IU/mL in 1 year) prior to HBsAg loss. Patients with EOT qHBsAg <100 showed earlier (<12 months) "precipitous HBsAg decline" (91.7% vs 58.3%; P = 0.017) and sooner HBsAg loss (5.5 vs 21.9 months; P = 0.026). The control group also showed gradual qHBsAg decrease but less frequent "precipitous HBsAg decline" (39.6% vs 100%; P < 0.001) which occurred later (15.1 vs 5.7 months; P = 0.003) and was less steep (slope −0.6 vs −1.65 log10 IU/mL/year; P < 0.001). HBsAg loss was achieved in 92.9% of the patients with "precipitous HBsAg decline" >0.76 log10IU/mL in 1 year. In conclusion, both the SR and CR groups showed gradual HBsAg decrease followed by a "precipitous HBsAg decline", which is a prerequisite for HBsAg loss. Lower EOT HBsAg in the SR group and qHBsAg <100 IU/mL may reflect better immune control hence followed by sooner HBsAg loss. [ABSTRACT FROM AUTHOR]

Background: Daratumumab, a human CD38 monoclonal antibody that has direct on-tumor and immunomodulatory mechanisms of action, demonstrated clinical benefit as monotherapy or in combination with established regimens in patients with multiple myeloma with one or more prior lines of therapy. Case presentation: A male patient, who was 70 years of age at the time of diagnosis of multiple myeloma in 2011, relapsed after five lines of therapy, including autologous stem cell transplantation. The patient's disease, which was considered high risk with a deletion of chromosome 17p, advanced quickly and was triple refractory 2 years after diagnosis leaving few treatment options. He was treated with daratumumab monotherapy in the SIRIUS clinical trial resulting in a stringent complete response and clearance of minimal residual disease. The duration of the patient's clinical response is now over 3.5 years without relapse, compared with a median of 7.6 months for similarly treated patients. The patient's immunophenotype revealed CD8+ T-cell expansion, clonal expansion of the T-cell receptor repertoire and decreases in regulatory T cells during daratumumab therapy, suggesting a robust adaptive immune response. This immune response was still present 32 months into daratumumab therapy. Conclusions: The results from this case report showed that a patient with advanced multiple myeloma, who had exhausted all treatment options with existing regimens, mounted an ongoing, deep and durable response to daratumumab monotherapy. Further investigation of the immunologic profile provided additional patient-level evidence of an immunomodulatory mechanism of action of daratumumab. [ABSTRACT FROM AUTHOR]

Background & Aims It is uncertain if nucleos(t)ide analogue (NA)-induced hepatitis B surface antigen (HBsAg) seroclearance is durable. We investigated the impact of hepatitis B surface antibody (anti-HBs) and duration of consolidation antiviral therapy on the durability of HBsAg seroclearance. Methods A territory-wide cohort study was conducted using data from the Hospital Authority, Hong Kong. We identified all subjects with positive HBsAg between January 1, 2000 and August 31, 2016. NA use, liver biochemistries, serial HBsAg and anti-HBs results were retrieved. The primary endpoint was confirmed HBsAg seroclearance, defined least two negative HBsAg test results, with the last HBsAg test being negative in patients with chronic hepatitis B (CHB). Results A total of 4,080 CHB patients were included for analysis. In patients with spontaneous HBsAg seroclearance (n = 3,563), 1,771 patients (49.7%) had confirmed HBsAg seroclearance and 75 patients (2.1%) had HBsAg seroreversion. In patients with NA-induced HBsAg seroclearance (n = 475), 320 patients (67.4%) had confirmed HBsAg seroclearance and 14 patients (2.9%) had HBsAg seroreversion. The five-year cumulative probability of confirmed HBsAg seroclearance was comparable in patients with spontaneous and NA-induced HBsAg seroclearance (88.1% vs. 92.2%; Log-rank test, p = 0.964); it was also similar in patients with or without anti-HBs in NA-treated patients (95.4% vs. 95.5%, Log-rank test, p = 0.602). HBsAg seroreversion was only observed in 3 (2.0%) patients who had received consolidation therapy for 6–12 months and none of those who had received it for ≥12 months. Conclusions NA-induced HBsAg seroclearance is as durable as spontaneous HBsAg seroclearance. NA-treated patients may not need to have positive anti-HBs before stopping treatment. Longer consolidation NA treatment may result in more durable HBsAg seroclearance. Lay summary We investigated 4,080 patients with hepatitis B surface antigen (HBsAg) seroclearance. HBsAg seroreversion occurred in 2.1% of patients with spontaneous and 2.9% of those with nucleos(t)ide analogues-induced HBsAg seroclearance. [ABSTRACT FROM AUTHOR]

Background and Aims Previous studies suggested spontaneous seroclearance of hepatitis B surface antigen (HBsAg) was still associated with an increased risk of hepatocellular carcinoma (HCC), in patients ⩾50 years of age. This study aimed to evaluate the risk of HCC after HBsAg seroclearance and the impact of gender on HCC. Methods All chronic hepatitis B patients under medical care in Hospital Authority, Hong Kong who had cleared HBsAg between January 2000 and August 2016 were identified. The age of the patient at HBsAg seroclearance, gender, and subsequent development of HCC were analyzed. Results A total of 4,568 patients with HBsAg seroclearance were identified; 793 (17.4%) were treated by nucleos(t)ide analogues and 60 (1.3%) had received interferon treatment. At a median (interquartile range) follow-up of 3.4 (1.5–5.0) years, 54 patients developed HCC; cumulative incidences of HCC at 1, 3 and 5 years were 0.9%, 1.3% and 1.5%, respectively. Age above 50 years (adjusted hazard ratio 4.31, 95% confidence interval 1.72–10.84; p = 0.002) and male gender (2.47, 1.24–4.91; p = 0.01) were two independent risk factors of HCC. Female patients aged ⩽50 years (n = 545) had zero risk of HCC within 5 years of follow-up. Male patients aged ⩽50 years (n = 769), female patients aged >50 years (n = 1,149) and male patients aged >50 years (n = 2,105) had a 5-year cumulative incidence of HCC 0.7%, 1.0% and 2.5%, respectively. Similar findings were observed in patients with spontaneous and antiviral treatment-induced HBsAg seroclearance. Conclusions Female patients aged 50 years or below have zero risk of HCC after HBsAg seroclearance, whereas female patients aged above 50 years and all male patients are still at risk of HCC. Lay summary: We investigated 4,568 patients with hepatitis B surface antigen (HBsAg) seroclearance. Female patients aged 50 years or below have zero risk of hepatocellular carcinoma (HCC) after HBsAg seroclearance, whereas female patients aged above 50 years and all male patients are still at risk of HCC. [ABSTRACT FROM AUTHOR]

Objective: This paper prospectively evaluates the long-term follow-up [mean ± standard deviation (SD) duration: 89.7±19.4 months] data of 15 patients (13 females and 2 males) with refractory symptomatic immune thrombocytopenia (ITP) treated with rituximab. Materials and Methods: Rituximab was administered at 375 mg/m2 weekly for a total of 4 doses. Complete response (CR) was defined as a platelet count of ≥100,000/mm³ and partial response (PR) asa platelet count of ≥30,000/mm³ but less than 100,000/mm³. Early response (ER) and late response (LR) were defined as response within 42 days and after 42 days of initiation of rituximab therapy, respectively. Sustained response (SR) was defined as response lasting for at least 6 months. Results: Mean age (±SD) at the start of rituximab was 46.6±11.3 years. Mean platelet count (±SD) prior to rituximab treatment was 17,400±8878/mm³. The mean time (±SD) between rituximab therapy and response to rituximab in early responders and late responders was 1.8±1 .3 weeks and 10±2.8 weeks, respectively. Mean durations (±SD) of ER and LR were 51 ±47.2 months and 6±4.2 months, respectively. Seven of the 15 patients (46.7%) showed an initial response to rituximab (5 ER and 2 LR). The rate of SR over 6 months was 26.7% (4/15). Among the responders to rituximab, 3 (3/7, 42.9%) maintained their response 1 year after rituximab treatment and 2 (2/7, 28.6%) had ongoing response 5 years after initiation of rituximab. Two of the 7 patients (28.6%) still maintained their response 98 months after initiation of rituximab. All 5 initial responders with subsequent relapse achieved response from subsequent treatment modalities (3 CR, 2 PR). Conclusion: Our data confirm, over a long period of observation, that rituximab is safe and effective in the management of patients with chronic refractory primary ITP. [ABSTRACT FROM AUTHOR]

Finite treatment with nucleos(t)ide analogues (NAs) remains a great challenge for chronic hepatitis B in the clinic. This study aimed to investigate the relationship between intrahepatic quasispecies heterogeneity and the NAs off-treatment outcomes in a prospective cohort. Eighteen HBeAg-positive patients with chronic hepatitis B who achieved the cessation criteria underwent liver biopsy, and stopped treatment thereafter. Patients were followed up prospectively for 1 year. The reverse transcriptase (RT) gene of intrahepatic hepatitis B virus (HBV) was cloned and sequenced. Intrahepatic quasispecies heterogeneity and specific gene mutations were analysed using bioinformatic methods. Ten patients achieved sustained response, and eight patients developed viral relapse. The intrahepatic quasispecies Shannon entropy and nucleotide diversity within either RT or the surface (S) region of patients with sustained response were significantly higher (p < 0.05) than those of patients who had a viral relapse. Intrahepatic quasispecies Shannon entropy at the nucleotide level predicted the sustained off-treatment response (area under receiver operating characteristics curve 0.925; 95% CI 0.807–1.000; p 0.003). More positive selection sites and N -glycosylation mutations within the S region were found in patients with sustained response than in the patients with viral relapse (p < 0.01). Most of the positive selection sites in patients with sustained response were located in reported HLA-I-restricted or HLA-II-restricted epitopes. Intrahepatic quasispecies heterogeneity at the end of treatment was correlated with off-treatment outcomes in HBeAg-positive patients with chronic hepatitis B. More immune escape mutations were found within the S region in patients with sustained response. The higher intrahepatic quasispecies heterogeneity indicated a more robust immune control over HBV, which in turn maintained a sustained response after withdrawal of NAs. [ABSTRACT FROM AUTHOR]

Background Recent studies have shown that antiviral treatment discontinuation is safe and associated with virologic remission in HBeAg-negative patients. However, the period of viral suppression and follow-up in these studies was relatively short. Objectives To investigate whether continuous viral suppression with tenofovir disoproxil fumarate for more than 7 years is associated with HBsAg loss and sustained response after treatment discontinuation and receiving a full course of hepatitis B vaccination. Study design Patients with HBeAg-negative chronic HBV infection and more than 7 years of persistent viral suppression with tenofovir therapy were selected for treatment discontinuation and HBV vaccination. Follow-up with monthly ALT, HBV–DNA, and HBsAg determinations lasted 72 weeks. In patients with viral relapse, the viral quasispecies in the overlapping reverse transcriptase and small surface protein regions was analysed by ultra-deep pyrosequencing. Results Eight of 17 HBeAg-negative patients accepted tenofovir discontinuation: 5 patients achieved sustained response (persistent HBV–DNA levels <2000 IU/mL and normal ALT) despite an initial virologic relapse, one lost HBsAg, and two needed re-treatment. All patients with an on-treatment HBsAg level decline >5000 IU/mL achieved sustained response. Patients with HBsAg level <100 IU/mL during an ALT flare after antiviral discontinuation achieved sustained response. Significant changes were seen in the composition of the HBV quasispecies, and half the patients showed changes in HBV genotype. Conclusions Even though the majority of patients presented an initial relapse with selection of HBV variants, most achieved sustained response. Changes in HBsAg levels on and off treatment may be useful for predicting the likelihood of virologic remission. [ABSTRACT FROM AUTHOR]

Background & Aims We assessed predictors of response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a in routine clinical practice. Methods Ninety-five HBeAg-negative patients received peginterferonalfa-2a for 48 weeks and were followed-up for 48 weeks post-treatment. Serum HBsAg and HBV DNA levels were monitored during and after therapy with valid commercial assays. Sustained response (SR) was defined as HBV DNA <2000 IU/ml at study week 96. Results Twenty-two patients (23%) achieved SR and nine (9.5%) lost HBsAg. HBsAg decline was more profound in patients with SR. HBsAg decline ≥10% from baseline to week 24 was significantly associated with SR [81% (17/21) vs 37% (21/57); Odds ratio: 7.286 (2.162-24.552), P = 0.001]. The PARC rule (no decrease in HBsAg and <2 log drop in HBV DNA at week 12) was evaluated in a subset of 47 patients. Among eight patients who fulfilled the PARC rule, none achieved SR. Of the 39 patients who did not fulfil the PARC rule, 24 (62%) had HBsAg decline of ≥10% at week 24 (12 achieved SR) and 15 (38%) had HBsAg decline of <10% (1 achieved SR; negative predictive value: 93%). Conclusions In HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a, HBsAg decline >10% at 24 weeks is significantly associated with SR. The combination of the PARC rule and week 24 decline in HBsAg can identify almost two-thirds of patients who are unlikely to achieve SR. Clinicaltrials.gov identifier: NCT01283074. [ABSTRACT FROM AUTHOR]

Eltrombopag is effective and safe in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy. However, when eltrombopag is discontinued, platelet counts usually return to baseline within 2 weeks. Here, we describe the clinical characteristics of the, to the best of our knowledge, largest case series of patients with ITP, who presented sustained responses after discontinuing eltrombopag ( n = 12). The median time from diagnosis to eltrombopag initiation was 24 months (range, 1-480). The median number of prior therapies was 5 (range, 1-7), and the median duration of eltrombopag treatment was 5 months (range, 1-13). Three patients received eltrombopag for only 1 month. The treatment was well-tolerated. The median (range) follow-up of this case series was of 7 months (6-20), during which all patients maintained a safe platelet count without the need for anti-ITP treatment. The communication of such cases may support the conduction of new studies to investigate which predictive factors could identify ITP patients with sustained responses after discontinuing eltrombopag without additional therapy. The need of long-term use of eltrombopag should be re-examined. [ABSTRACT FROM AUTHOR]

Thrombopoietin mimetics are new treatment options for patients with immune thrombocytopenia (ITP). Because of their mechanism of action, long-term administration was envisioned in order to maintain effective thrombopoiesis. We report on 30 romiplostim treated patients: 13/27 responders (48%) achieved stable platelet counts on a mean romiplostim dose of 2.43 µg/kg and were able to stop romiplostim after a mean of 44.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 26 months (range 12-52). No bleeding events occurred during the observational period. No specific patient's features nor pattern of early response seemed to predict for sustained response. However, patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Our observations support feasibility of romiplostim safe suspension in a relevant proportion of ITP patients. [ABSTRACT FROM AUTHOR]

Background Although electroconvulsive therapy (ECT) is the most effective acute antidepressant intervention, sustained response rates are low. It has never been systematically assessed whether psychotherapy, continuation ECT, or antidepressant medication is the most efficacious intervention to maintain initial treatment response. Methods In a prospective, randomized clinical trial, 90 inpatients with major depressive disorder (MDD) were treated with right unilateral ultra-brief acute ECT. Electroconvulsive therapy responders received 6 months guideline-based antidepressant medication (MED) and were randomly assigned to add-on therapy with cognitive-behavioral group therapy (CBT-arm), add-on therapy with ultra-brief pulse continuation electroconvulsive therapy (ECT-arm), or no add-on therapy (MED-arm). After the 6 months of continuation treatment, patients were followed-up for another 6 months. The primary outcome parameter was the proportion of patients who remained well after 12 months. Results Of 90 MDD patients starting the acute phase, 70% responded and 47% remitted to acute ECT. After 6 months of continuation treatment, significant differences were observed in the three treatment arms with sustained response rates of 77% in the CBT-arm, 40% in the ECT-arm, and 44% in the MED-arm. After 12 months, these differences remained stable with sustained response rates of 65% in the CBT-arm, 28% in the ECT-arm, and 33% in the MED-arm. Conclusions These results suggest that ultra-brief pulse ECT as a continuation treatment correlates with low sustained response rates. However, the main finding implicates cognitive-behavioral group therapy in combination with antidepressants might be an effective continuation treatment to sustain response after successful ECT in MDD patients. [ABSTRACT FROM AUTHOR]

Background: Migraine is the most common neurological condition in developed countries. The abortive treatment of migraine attacks is important both for quality of life and costs associated with illness. Triptans, serotonin 5-HT1B/1D receptor agonists, effectively relieve the pain, disability, and associated symptoms of migraine while improving healthrelated quality of life. Although a number of direct head-to-head triptan comparisons have been made, data for all possible permutations are not available, and unlikely to ever be so, although in clinical practice such information would be useful. Objective: We aimed to determine the relative efficacy of all available triptans to abort migraine headache among patients with previous adequate response to migraine treatments. Methods: We included only double-blinded randomized clinical trials comparing triptans to either placebo or another triptan. Our primary outcomes were pain-free response at two hours and 24-hour sustained pain-free response, and our secondary outcomes were headache response at two hours and 24-hour sustained headache response. We used Bayesian multiple treatment comparison meta-analyses of seven triptans used in adult patients to abort migraine attacks. We applied a random-effects analysis with meta-regression adjusting for dose. Results are reported as odds ratios with 95% credible intervals. Results: We included data from 74 randomized clinical trials. All triptans were significantly superior to placebo for all outcomes, with the exception of naratriptan for 24-hour sustained pain-free response. Eletriptan consistently yielded the highest treatment effect estimates. For the two-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, almotriptan, naratriptan, and frovatriptan for at least one of the two outcomes. Rizatriptan yielded the second highest treatment effects followed by zolmitriptan. For the 24-hour endpoints, eletriptan was statistically significantly superior to sumatriptan, rizatriptan, almotriptan, and naratriptan for at least one of the two outcomes. Frovatriptan data were not available at that endpoint. Further, the probability that eletriptan is the most likely of all triptans to produce a favorable outcome was 68% for pain-free response at two hours, and 54% for 24-hour sustained pain-free response. Conclusion: Triptans appear to offer differing treatment effects. In the populations studied eletriptan was most likely to produce pain-free responses that were sustained. [ABSTRACT FROM AUTHOR]

Background: The durability of off-treatment virologic responses has not been fully elucidated in chronic hepatitis B (CHB) patients who have previously achieved complete virologic suppression with nucleos(t)ide analog (NA) therapy. This study aimed to assess off-treatment virologic relapse rates and to characterize the outcomes of subsequent re-treatment in CHB patients who have discontinued oral NA following complete virologic suppression. Methods: Ninety-five CHB patients who showed complete virologic suppression were withdrawn from NAs: entecavir, lamivudine, and clevudine in 67, 15, and 13 patients, respectively. Consolidation therapy was given for 6 and 12 months for HBeAg-positive and -negative CHB, respectively, before cessation. Virologic relapse was managed with the same NA that had induced complete virologic response before discontinuation. Results: The cumulative rates of virologic relapse at 12 and 24 months were 73.8% and 87.1%, respectively. The relapse rates were independent of HBeAg positivity, HBeAg seroconversion, and type of oral NA. In a multivariate analysis, duration of oral NA therapy was the only significant predicting factor associated with off-treatment virologic relapse. Although the majority of patients regained complete virologic suppression, some patients did not respond to re-treatment with the initial NA and developed genotypic resistance. Conclusions: NA consolidation therapy for 6 and 12 months is associated with high off-treatment virologic relapse in HBeAg-positive and -negative CHB patients, respectively. Drugs with high genetic barriers to resistance should be considered as a rescue therapy for off-treatment relapse in CHB. [ABSTRACT FROM AUTHOR]

Abstract: Background: Clinical trials are not generally powered to analyze outcomes such as sustained response. We evaluated sustained response rates for patients with major depressive disorder receiving quetiapine XR as monotherapy or adjunct therapy. Method: Post hoc analyses of pooled data from four previously reported randomized, placebo-controlled studies of quetiapine XR 150 and 300mg/day as monotherapy or adjunct therapy to ongoing antidepressant. Sustained response rates (≥50% reduction in MADRS total score at specific timepoint and each subsequent visit until Week 6) were calculated at Weeks 1, 2, and 4; rates were compared using a Cochran–Mantel–Haenszel analysis. Results: In the monotherapy studies, the proportion of patients experiencing sustained response was greater with quetiapine XR 150mg/day versus placebo at Week 2 (20.0% vs. 13.3%; p<0.05) and Week 4 (33.3% vs. 23.3%; p<0.01) (observed cases [OC]). The corresponding sustained response rates for quetiapine XR 300mg/day were 18.0% (p=0.104) and 29.7% (p=0.063), respectively (OC). The proportion of patients experiencing sustained response was greater in the adjunct studies versus placebo at Weeks 2 and 4 for quetiapine XR 150 (Week 2, 30.1% vs. 15.2%, p<0.001; Week 4, 40.1% vs. 32.0%, p<0.05) and 300mg/day (Week 2, 29.0% vs. 15.2%, p<0.001; Week 4, 42.0% vs. 32.0%, p<0.05) (OC). Limitations: Post hoc analyses, acute treatment period; no active comparator. Conclusions: Quetiapine XR as monotherapy (150mg/day at Weeks 2 and 4) or adjunct to ongoing antidepressant therapy (150 and 300mg/day at Weeks 2 and 4) increased sustained response rates versus placebo. [Copyright &y& Elsevier]

Background: The prevalence of chronic hepatitis C virus (HCV) infection in the Italian correctional population is estimated to be around 38%. In this setting HCV infection treatment is controversial because of several factors such as active drug substance abuse, psychiatric illness, length of treatment, risk of re-infection, poor adherence and low success rate.Methods: A retrospective data review of 159 inmates, positive for anti-Hepatitis C virus (HCV) antibody, evaluated to National Institute for Infectious Diseases "L. Spallanzani" (INMI) from January 2006 to December 2009, was conducted to evaluate rate of completion (feasibility) and outcome efficacy of chronic Hepatitis C Virus (HCV) infection treatment with Pegylated Interferon and Ribavirin in five correctional facilities in Rome.Results: Of the 159 inmates evaluated in the study period, 50, all male (median age 39 years) were treated. Twenty patients (40%) did not complete treatment: 15 showed no response and therapy was stopped, 5 patients (10%) interrupted treatment because of adverse reactions. The global feasibility was 60%. The overall sustained virologic response (SVR) was 50% (32% for genotype 1 and 68% for genotype other than 1). The main predictors of SVR at the Multivariable Logistic Regression Odds Ratio (MLR-OR) were a better pretreatment histological diagnosis (absence of bridging fibrosis or cirrhosis [MLR-OR 11.85; 95% CI 1.96-71.62) and a HCV genotype other than 1 (MLR-OR 5.87; 95% CI 1.49-23.17).Conclusions: Chronic HCV infection treatment in correctional facilities is feasible and effective and should be strongly recommended, in combination with preventive measures, in appropriately screened patients because it represents an important opportunity to treat a population with a high prevalence of chronic HCV infection among whom treatment options post incarceration may be limited. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B ( CHB) in serum HBeAg negative patients is a difficult to cure, progressive disease leading to end-stage liver disease and hepatocellular carcinoma. Currently, there are two different treatment strategies for such patients: a finite course of Pegylated interferon (PEG- IFN) or long-term administration of the more potent and less resistance-prone nucleot(s)ide analogues ( NUC), i.e. entecavir and tenofovir. Although NUC may ensure persistent viral suppression by preventing disease progression in most patients, they require lifelong administration with the hypothetical disadvantages of cost, lack of long-term safety data and, most important, the null rates of HBsAg seroclearance. On the other hand, 1 year of PEG- IFN has the advantage of providing an immune-mediated control of hepatitis B virus ( HBV) infection, with the possibility of achieving a sustained off-treatment response in 20% of the patients, ultimately leading to HBsAg loss in approximately 50% of these. However, these sustained response rates can be significantly increased by carefully selecting candidates for PEG- IFN therapy based upon baseline ALT and HBV DNA levels, viral genotype and IL28B polymorphisms, by extending PEG- IFN therapy beyond 48 weeks and, most importantly, by applying early on-treatment stopping rules based upon HBsAg kinetics. Overall, PEG- IFN is an ideal treatment strategy in selected patients with HBeAg-negative CHB, because of its well-recognized and predictable safety profile and a unique mechanism of antiviral activity leading to long-lasting immune control. Because of these features, new therapeutic trials based upon a combination of PEG- IFN and third generation NUC such as entecavir and tenofovir, in both naïve and NUC-exposed patients, are ongoing to further increase the rates of HBsAg seroclearance, which remains the 'ideal end-point' in all HBeAg-negative CHB subjects. [ABSTRACT FROM AUTHOR]

Hepatitis C virus contact and infection show three different phenotypes: spontaneous viral clearance (SVC), chronic hepatitis C (CHC) and sustained virological response (SVR) following antiviral treatment. Many factors, including genetics, influence the evolution of these three phenotypes. We performed a literature search (PubMed) up to 31 January 2010 without language restriction to identify relevant studies on genes and hepatitis C. Additional studies were sought by reviewing the reference lists of the identified articles. Meta-analysis (using Meta-disk 1.4) was conducted to evaluate the association of single nucleotide polymorphism (SNP) in the IL28B region and SVR. The candidate gene approach showed strong relationships between human leucocyte antigen class II (DQB10301 and DRB11101) and SVC. A cirrhosis risk score involving 7 SNPs has been validated recently. The set of odds ratios of studies demonstrated an association between SNP (rs12987960/rs8099917) in the IL28B and SVR in CHC treated with peginterferon plus ribavirin (OR: 4.6; 95% CI: 2.9-7.3). The overall distribution of protective allele correlated with ethnic differences in SVR (Asians, Europeans, Hispanic and Afro-Americans) together with SVC, but not with fibrosis stage or viral load. These polymorphisms did not influence SVR in very-easy-to-treat patients such as genotype 2/3, rapid virological responders or patients with acute hepatitis C. While the genetic fingerprint for fibrosis progression remains elusive, IL28b polymorphism predicts SVC and SVR. However, nearly half of patients achieving SVR did not show favourable genotype. Further genetic signals are warranted to complete the puzzle of factors influencing hepatitis C. [ABSTRACT FROM AUTHOR]

Introduction: Several studies have reported that interferon therapy increases elimination rate of HBeAg and anti-HBe seroconversion in chronic hepatitis B (CHB) patients. We aimed to evaluate long-term results of interferon-α treatment in HBeAg positive CHB patients in a country with exclusively D genotype.Methods: Seventy-one naive CHB patients (M/F 61/10, mean age 29±12 years, range 16-62) treated with 6 months of interferon-α 2b, 10 MU tiw and had a consequent untreated follow-up period of at least 10 years with positive response were identified and their data were reviewed. The therapy response was defined as HBeAg seroconversion with undetectable HBV-DNA. The responders were followed-up at 3-6-month intervals.Results: Twenty-eight (39%) patients achieved HBeAg seroconversion (25 within the therapy, 3 within the consequent 12 months off-treatment follow-up). The responders were followed-up with a mean period of 152 months (range 123-181). In the follow-up period, 21/25 (84%) initial responders relapsed. On the other hand, 3 patients who did not respond at the end of therapy sustained the response during follow-up. Hence 21/28 total responders relapsed (75%), either with HBeAg reversion (3, 14.3%) or HBV-DNA elevation over 2000 IU/ml (or its equivalent in other types of definitions) and ALT elevation (18, 85.7%). The sustained response was present in 7 patients (9.8%). Serious side effects precluding completion of treatment occurred in three patients (4.2%). In multivariate analysis none of the pre-treatment parameters appeared to be significant in predicting response.Conclusion: Sustained response to interferon treatment is low in HBeAg positive CHB patients with genotype D. [ABSTRACT FROM AUTHOR]

Objectives. Longer lamivudine (LAM) consolidation therapy after hepatitis B e antigen (HBeAg) seroconversion has been demonstrated to reduce the cumulative relapse rate. However, the optimal interval of LAM consolidation therapy remains controversial. We evaluated the post-treatment durability of LAM-induced HBeAg seroconversion and the length of LAM consolidation therapy required to maintain sustained HBeAg seroconversion. Material and methods. This retrospective study included 401 naive HBeAg-positive chronic hepatitis B patients who were treated with LAM 100 mg daily for at least 24 weeks (range 24–258 weeks). Among them, 124 patients who achieved a complete response (HBeAg seroconversion, alanine aminotransferase normalization, hepatitis B virus DNA < 200 copies/ml) at the end of LAM therapy were followed up for at least 48 weeks (range 48–350 weeks). Results. Of the 124 complete responders, 42 (33.87%) achieved a sustained response (persistent response ≥ 48 weeks). However, the cumulative relapse rates at 48 and 96 weeks post-treatment were 54.03% and 68.4%, respectively. Multivariate analysis revealed pretreatment age ≤ 34 years [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.40–3.62; p < 0.001] and LAM consolidation therapy ≥ 48 weeks (HR 2.44; 95% CI 1.35–4.40; p = 0.003) to be independent factors for predicting a sustained response. Conclusions. LAM-induced HBeAg seroconversion is not durable in Taiwan. However, a duration of LAM consolidation therapy > 48 weeks may be favorable for maintaining durable HBeAg seroconversion. [ABSTRACT FROM AUTHOR]

Neural representations of even temporally unstructured stimuli can show complex temporal dynamics. In many systems, neuronal population codes show ‘progressive differentiation’, whereby population responses to different stimuli grow further apart during a stimulus presentation. Here we analysed the response of auditory cortical populations in rats to extended tones. At onset (up to 300 ms), tone responses involved strong excitation of a large number of neurons; during sustained responses (after 500 ms) overall firing rate decreased, but most cells still showed statistically significant rate modulation. Population vector trajectories evoked by different tone frequencies expanded rapidly along an initially similar trajectory in the first tens of milliseconds after tone onset, later diverging to smaller amplitude fixed points corresponding to sustained responses. The angular difference between onset and sustained responses to the same tone was greater than between different tones in the same stimulus epoch. No clear orthogonalization of responses was found with time, and predictability of the stimulus from population activity also decreased during this period compared with onset. The question of whether population activity grew more or less sparse with time depended on the precise mathematical sense given to this term. We conclude that auditory cortical population responses to tones differ from those reported in many other systems, with progressive differentiation not seen for sustained stimuli. Sustained acoustic stimuli are typically not behaviorally salient: we hypothesize that the dynamics we observe may instead allow an animal to maintain a representation of such sounds, at low energetic cost. [ABSTRACT FROM AUTHOR]

Abstract: Background: Viral genomic mutations have become increasingly recognized as being associated with the outcome of chronic HBV infection. However, the role of viral mutations as a predictor of response to pegylated-interferon (PEG-IFN) therapy has so far remained unclear. Study design: Viral mutations in the enhancer II/basal core promoter (BCP)/precore and the pre-S regions were characterized by direct sequencing in pretreatment serum samples of 50 patients with chronic hepatitis B (33 HBeAg-positive and 17 HBeAg-negative), who were treated for 48 weeks with PEG-IFN alpha-2b. Results: Sustained virological response at 48 weeks post treatment, defined as HBeAg seroconversion and HBV DNA<2000IU/mL for HBeAg-positive patients, and HBV DNA<200IU/mL for HBeAg-negative patients, was achieved in 12 (36.4%) and 6 (35.3%) of HBeAg-positive and HBeAg-negative patients, respectively. Response to PEG-IFN therapy correlated to low pretreatment HBsAg level but did not correlate with HBV genotype, pretreatment alanine transaminase and HBV DNA levels. In HBeAg-positive hepatitis, PEG-IFN response correlated with the appearance of double BCP mutations (A1762T/G1764A) at baseline (P =0.041). In the HBeAg-negative group, response to PEG-IFN therapy was associated with the presence of pre-S mutation/deletions (P =0.028). Multivariate analysis identified low pretreatment HBsAg level as an independent factor associated with SVR in both groups. Conclusions: Pretreatment quantitative HBsAg determination is useful for predicting response to PEG-IFN therapy. The presence of double BCP and pre-S mutation/deletions at entry may be associated with a high rate of antiviral response in HBeAg-positive and HBeAg-negative hepatitis, respectively. [Copyright &y& Elsevier]

Abstract: Frequency tuning of auditory cortical neurons is typically determined by integrating spikes over the entire duration of a tone stimulus. However, this approach may mask functionally significant variations in tuning over the time course of the response. To explore this possibility, frequency response functions (FRFs) based on population multiunit activity evoked by pure tones of 175 or 200ms duration were examined within four time windows relative to stimulus onset corresponding to “on” (10–30ms), “early sustained” (30–100ms), “late sustained” (100–175ms), and “off” (185–235 or 210–260ms) portions of responses in primary auditory cortex (A1) of 5 awake macaques. FRFs of “on” and “early sustained” responses displayed a good concordance, with best frequencies (BFs) differing, on average, by less than 0.25 octaves. In contrast, FRFs of “on” and “late sustained” responses differed considerably, with a mean difference in BF of 0.68 octaves. At many sites, tuning of “off” responses was inversely related to that of “on” responses, with “off” FRFs displaying a trough at the BF of “on” responses. Inversely correlated “on” and “off” FRFs were more common at sites with a higher “on” BF, thus suggesting functional differences between sites with low and high “on” BF. These results indicate that frequency tuning of population responses in A1 may vary considerably over the course of the response to a tone, thus revealing a temporal dimension to the representation of sound spectrum in A1. [Copyright &y& Elsevier]

International controlled trials have demonstrated increasing sustained virological response (SVR) rates to interferon-based therapies in hepatitis-C-treated patients. Response rates of 6–20% in the era of interferon monotherapy are compared with 42–82% with pegylated interferon plus ribavirin. The virological durability of the SVR is unknown and the optimal follow-up for these patients is unclear. The aim of our study was to determine SVR rates and the durability of the response to interferon-based therapies in the clinical setting. From our database of 1540 hepatitis C patients, 344 treatment courses of at least 12 weeks duration were identified, including interferon monotherapy (175 patients), interferon plus ribavirin (96 patients) and peginterferon plus ribavirin (73 patients). Interferon monotherapy was associated with an SVR rate of 5% in 103 genotype 1 patients and 25% in 72 genotype 2/3 patients. Response rates were higher ( P < 0.001) with interferon plus ribavirin—41% in 34 genotype 1 patients and 73% in 62 genotype 2/3 patients—and with peginterferon plus ribavirin—47% in 47 genotype 1 patients and 79% in 26 genotype 2/3 patients. Of 147 patients with an SVR, 146 (>99%) remained hepatitis C virus PCR negative during a mean 2.3 years (range 0.3–10.3) of follow-up. In conclusion, with advances in therapies, we are achieving higher response rates in hepatitis C patients treated in the clinical setting. We can now expect an SVR in over half of the treated patients. Importantly, the response is durable and medium and long-term follow-up of these patients are of low yield and largely unnecessary. [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of the present study was to determine whether a 24-week course of combination therapy with ribavirin and high-dose interferon-α2b (IFN-α2b) could provide an acceptable treatment efficacy in chronic hepatitis C (CHC). Methods: Seventy-six patients with CHC whose serum hepatitis C virus (HCV) RNA levels were more than 100 kIU/mL on quantitative polymerase chain reaction (PCR) assay were included. The patients were assigned to two different dose groups of IFN-α2b: group A ( n = 39) received 6 MU and group B ( n = 37) received 10 MU. Each group received the dose daily for 14 days then three times per week for a total of 24 weeks. In addition, HCV genotype 1b patients in group A and group B were classified into group C ( n = 20) and D ( n = 29), respectively. All patients received 600 or 800 mg ribavirin per day. Results: Sustained response rates in group A were significantly higher than those in group B (66.7% vs 35.1%, intent-to-treat, P = 0.0060). However, sustained response rates in group C were not different from those in group D (45.0% vs 20.7%, intent-to-treat, P = 0.0696). The proportion of patients who discontinued the treatment or reduced drug dosage because of adverse events was significantly higher in group B than in group A (27.0% vs 7.69%, P = 0.0224). Conclusion: A 24-week course of combination therapy with ribavirin and 6 MU IFN-α2b had an acceptable efficacy with fewer adverse events than that with ribavirin and 10 MU IFN-α2b in CHC. [ABSTRACT FROM AUTHOR]

Background. Interferon (IFN) is expected to prevent the progression of hepatitis C virus infection to cirrhosis and the development of hepatocellular carcinoma (HCC), but there have been several reports of the development of HCC after a sustained response to IFN. Our aim was to elucidate the incidence and clinical features of, and risk factors for, HCC in sustained responders to IFN, taken for the treatment of chronic hepatitis C. Methods. We designed a retrospective cohort study conducted at 16 major Hospitals. Th subjects were a total of 1056 patients showing sustained responses, 29 of whom developed HCC. Results. The incidence of HCC per 100 person-years was 0.56 (95% confidence interval, 0.35-0.76) in sustained responders. By the Cox proportional hazard model, we found that older age, higher serum aspartate aminotransferase level, and lower platelet count before IFN therapy were independent risk factors associated with the development of HCC. A risk index of HCC development, based on the coefficients of these risk factors, was used to classify patients into three groups, with low, intermediate, and high risk. The incidence rates of HCC for these three groups were 0.11, 0.44, and 1.98 per 100 person-years, respectively. The median period to the development of HCC was 4.6 years (range, 1.4-9.0 years), and there were no other specific clinical features of the HCC that developed in these patients. Conclusions. This study suggests that the risk of development of HCC is not completely eliminated in sustained responders to IFN. these findings may be useful in determining a follow-up strategy after a sustained response to IFN. [ABSTRACT FROM AUTHOR]

Although psychophysical studies have revealed involvement of spectral edges in auditory perception, little is known about neural processing. This study investigates how spectral edges are processed in neurons of alert cat primary-auditory-cortex (A1) with sustained response property. Stimuli are low-pass, high-pass and band-pass tones with sharp spectral edges whose edge-frequencies were systematically shifted, constructing edge-frequency response functions. Pure- and two-tone stimuli served to delineate excitatory and inhibitory subfields of the frequency response field (FRF). Based on the response function characteristics, cells were divided into edge-sensitive and edge-insensitive cells: the edge sensitive cells had narrow tuning to the high-edge (type-II cells) or low-edge (type-III cells) frequencies, while the edge insensitive cells were driven by any static stimuli with energy on FRF (type-I) or only very narrowband stimuli with energy confined to FRF (type-IV cells). Edge-sensitive cells showed a close correlation between the best frequencies of the single-frequency (BFSF) and edge-frequency (BFEF) response functions and between their half-height bandwidths, suggesting that the edge-frequency identification is processed along the tonotopic axis in A1. BFSF shifted (mean 0.11 octaves) into the stimulus band from the BFEF (closely corresponding to pitch shift into stimulus band from the edge frequency in human psychophysical data of edge-pitch), suggesting central mechanism of edge-pitch sensation. Type-I cells had non-significant inhibitory subfields of FRF; type-II cells had the significant inhibitory subfield on the higher frequency side; type-III cells, on the lower frequency side; and type-IV cells, on both sides, suggesting that the inhibitory mechanism characterizes the cell-type specific spectral-edge sensitivity. [Copyright &y& Elsevier]

One hundred and forty-one patients with chronic hepatitis C virus (HCV) infection treated with 6 MIU of interferon (IFN)-α2b for 24 weeks were studied to compare pretreatment viral dynamics during 1 month before the initiation of treatment (ΔHCV) with other predictive factors. The patients were classified into three groups according to ΔHCV: the Increase group (ΔHCV >0.20 log copies/ml/month), the Stable group (−0.20≤ΔHCV≤0.20 log copies/ml/month) and the Decrease group (ΔHCV<−0.20 log copies/ml/month). The sustained response (SR) rates were 0/40 (0%) in the Increase group, 6/54 (11.1%) in the Stable group and 25/47 (53.2%) in the Decrease group (P<0.0001). Based on the HCV RNA level at baseline, the SR rates were lower in the Increase group than that in the Decrease group in less than 5.0 log copies/ml (0% vs. 100.0%, P=0.0132) and at 5.00–5.49 log copies/ml (0% vs. 81.8%, P=0.0270), respectively. The pretreatment HCV RNA decrease was determined as independent predictors of SR by multivariable logistic regression analysis (P<0.0001). For serial assays of HCV RNA during treatment, there was not significant difference in mean HCV RNA level at baseline but was significantly different on day 14 between the Decrease and the Nondecrease groups (1.15 vs. 2.21 log copies/ml, P=0.0417). These results suggest that ΔHCV is independently associated with the IFN response and is useful for determining the indication of IFN treatment. [Copyright &y& Elsevier]

Background: Although hepatocellular carcinoma does develop after sustained response to interferon (IFN) in patients with chronic hepatitis C, details on the clinical prognosis have not been elucidated yet. Patients and Methods: Among 12 patients with liver cancer arising after hepatitis C virus (HCV) elimination, 10 patients with potentially curative ablation were prospectively analyzed. Matched control patients were chosen from a patient list of surgical resection on the basis of age, sex, cancer stage, and severity of liver disease. Control patients were recruited with a ratio of 1:4, and all the control patients had positive HCV-RNA. Results: One (10.0%) of 10 patients with virus elimination and 31 (77.5%) of 40 control patients eventually developed cancer recurrence during the same follow-up period. Cancer recurrence rates of the 10 cases and 40 controls were 10.0 and 55.3% at the 3rd year, and 10.0 and 72.2% at the 5th year, respectively. The recurrence rate in the 10 cases of virus elimination was significantly lower than that of control patients (p = 0.012). Conclusion: Although hepatocellular carcinogenesis after elimination of HCV-RNA by IFN treatment did rarely occur, the recurrence rate after radical therapy was significantly lower than that of untreated or non-responsive patients.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: The best treatment for chronic hepatitis C patients who do not respond to interferon is still unknown. Reported rates of response to treatment vary as the result of heterogeneous definitions of non-responders and small study size.Methods: One hundred nineteen hepatitis C virus (HCV) RNA-positive non-responders to high-dose interferon monotherapy received alpha-interferon, 5 MU tiw plus oral ribavirin, 1000–1200 mg/day for 48 weeks (Group A, n=74) or alpha-interferon, 5 MU daily for 4 weeks, followed by 5 MU tiw plus oral ribavirin, 1000–1200 mg/day for 44 weeks (Group B, n=45) according to the Institution where they were followed. Persistently normal alanine aminotransferase and negative HCV RNA up to 72 weeks from treatment onset defined a sustained response.Results: Eighteen patients discontinued treatment (13 developed anemia, two mucositis, one granulocytopenia; two were dropouts), none for serious adverse events. There were 24 (20%) sustained responders, with similar final response rates in Groups A and B. Sustained response was more frequent in patients aged ≤40 years (36% vs. 13%; P=0.006) and in those with non-1 genotype (44% vs. 14%; P=0.002). Among genotype 1 patients, the younger ones showed higher response rates (32% vs. 7%; P=0.005). Compared with patients harboring non-1 genotypes, the odds ratio of being a non-responder was 1.68 (confidence interval (CI): 0.53–5.37; P=0.381) in younger genotype 1 patients and 9.53 (CI: 2.84–32; P<0.001) in older genotype 1 patients.Conclusions: Chronic hepatitis C patients who are non-responders to interferon monotherapy and infected by non-1 genotypes should undergo re-treatment with combination therapy. Treatment should be extended to younger genotype 1 patients who are more susceptible to liver disease worsening because of longer life expectancy and have a higher probability of being long lasting responders than their older counterparts. [Copyright &y& Elsevier]

The treatment of chronic hepatitis C with a standard regimen of therapy with interferon (IFN) alpha for 6 months results in a sustained response (SR) in a minority of patients with high levels of HCV-RNA. The aim of this study was to assess whether a high dose of IFN and IFN beta induction/IFN alpha therapy increase efficacy, and to identify the determinants or predictive factors of SR in patients with IFN resistant chronic hepatitis C. In 99 patients with high levels of HCV-RNA (>1 Meq/ml), we compared the efficacy of IFN beta induction/IFN alpha therapy (n=50) and IFN alpha monotherapy (n=49). HCV-RNA clearence was observed in 22 patients (44%) in IFN beta induction/IFN alpha group and 11 (22.4%) in IFN alpha monotherapy group at 7 days after the start of treatment, there were significant difference between these two groups (P=0.0327); in 26 (52%) and 13 (26.5%) at the end of treatment, there were significant difference between these two groups (P=0.0134); in 9 (18%) and 3 (6.1%) at 6 months after the end of treatment, there was no difference between these two groups (P=0.1212), respectively. SR was observed in 9 (18%) and non-response in 41 (82%) with the IFN beta induction/IFN alpha therapy, and in 3 (6.1%) and 46 (93.9%) with IFN alpha monotherapy, respectively. IFN beta induction/IFN alpha therapy was better than IFN alpha monotherapy by HCV-RNA clearance at 7 days after the start of treatment and at the end of treatment, but there was no significant difference between these two groups at 6 months after the end of treatment. IFN beta induction/IFN alpha therapy was superior to IFN alpha monotherapy in the treatment of chronic hepatitis C, and this therapy may be recommended for patients with high levels of HCV-RNA of chronic hepatitis C. [Copyright &y& Elsevier]

Abstract Background and Aims Consensus interferon (CIFN) is a newly developed type I interferon. The aim of this study was to investigate the safety and efficacy of CIFN in the treatment of patients with chronic hepatitis C and to determine the predictors for sustained response. Methods Patients were randomized to receive 3 μg or 9 μg CIFN three times a week for 24 weeks, followed by 24 weeks of observation. Efficacy was assessed by normalization of serum transaminase levels and disappearance of serum hepatitis C virus (HCV)-RNA at the end of treatment and at 24 weeks after stopping treatment. Histologic response was defined as a decrease of at least two points in the Knodell necroinflammatory score at week 48 and was compared with baseline. Results There were no serious adverse effects related to CIFN therapy. Overall, 44% of patients receiving 3 μg and 48% of patients receiving 9 μg had normalization of serum transaminase levels and disappearance of HCV viremia at the end of treatment. At 24 weeks after stopping treatment, 16% of patients in receiving 9 μg and 12% of patients receiving 3 μg had sustained responses. The histologic responses in patients receiving 9 μg and those receiving 3 μg were 60% and 36%, respectively. The necroinflammatory score was significantly reduced from baseline to week 48 in both groups. In addition, bodyweight < 60 kg and pretreatment serum HCV-RNA level < 0.5 MEq/mL can serve as predictors for sustained response to CIFN treatment. Conclusions These findings suggest that 9 μg CIFN is safe and effective in the treatment of patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Abstract Background: α-Interferons are the accepted therapy for patients infected with chronic hepatitis C virus (HCV) in China. However, consensus interferon (CIFN) for HCV treatment is effective in patients with chronic hepatitis C from Western countries. Methods: This randomized, controlled trial was conducted to determine the safety and efficacy of CIFN at two doses, and to compare it with α-2a-interferon (IFN-α-2a) in Chinese patients with chronic HCV. Interferon-naive patients with chronic HCV infection (n = 187) were randomly chosen to receive 15 μg CIFN or 9 μg or 3 MU IFN-α-2a subcutaneously, three times a week for 24 weeks, followed by a 24 week observation period. Efficacy was evaluated by the normalization of serum alanine aminotransferase (ALT) and the non-detectability disappearance of serum HCV-RNA by using reverse-transcription–polymerase chain reaction. The safety of CIFN was evaluated by recording the type and severity of adverse effects. Results: The combined ALT and HCV-RNA end-of-treatment and sustained responses were observed to be greater for treatment with 15 μg CIFN (59.0% and 55.7%, respectively) compared to IFN α-2a (36.1% and 39.3%, respectively; P = 0.01 for the end-of-treatment, P = 0.07 for the sustained response). The combined ALT and HCV-RNA end-of-treatment and sustained responses for treatment with 9 μg CIFN (both 49.2%) were higher than those for IFN-α-2a (not statistically significant). Data were analyzed by using a logistic-multiple-variate regression model, which indicated that the higher IFN dose (15 μg or 9 μg CIFN vs 3 MU IFN-α-2a; P < 0.01) appeared to be associated with a better sustained response. The type, frequency and severity of adverse effects were comparable across treatment groups. Conclusions: Consensus interferon appears to be safe and effective at concentrations of 9 and 15 μg, but 15 μg CIFN may be more effective than 3 MU IFN-α-2a, without increased toxicity. [ABSTRACT FROM AUTHOR]