Sustained Responders Research Articles

BDNF Genotype and Baseline Serum Levels in Relation to Electroconvulsive Therapy Effectiveness in Treatment-Resistant Depressed Patients.

Electroconvulsive therapy (ECT) represents one of the most effective therapies for treatment-resistant depression (TRD). The brain-derived neurotrophic factor (BDNF) is a neurotrophin implicated in major depressive disorder and in the effects of different therapeutic approaches, including ECT. Both BDNF peripheral levels and Val66Met polymorphism have been suggested as biomarkers of treatment effectiveness. The objective of this study was to test the potential of serum BDNF levels and Val66Met polymorphism in predicting ECT outcome in TRD patients. Seventy-four TRD patients scheduled to undergo ECT were included in the study. Illness severity was assessed through the Montgomery and Asberg Depression Rating Scale before beginning ECT (T0), the day after the end of ECT (T1), and 1 month after the end of ECT (T2). At T1, patients were classified as responders/nonresponders and remitters/nonremitters, whereas at T2, they were classified as sustained responders/nonresponders and sustained remitters/nonremitters. Serum concentrations of BDNF were measured at T0, and the BDNF Val66Met polymorphism was genotyped. No difference in BDNF concentrations was observed in responders versus nonresponders, in remitters versus nonremitters, in sustained responders versus sustained nonresponders, and in sustained remitters versus sustained nonremitters. No association of Val66Met polymorphism was detected with both the response and the remission status. Baseline serum BDNF levels and the BDNF Val66Met polymorphism showed no clinical utility in predicting ECT outcome in TRD patients.

A multicenter real-world review of 10kHz SCS outcomes for treatment of chronic trunk and/or limb pain.

ObjectivesHigh‐frequency spinal cord stimulation (HF‐SCS) at 10 kHz has proven to be efficacious in the treatment of chronic back and leg pain in a randomized, controlled, trial (SENZA‐RCT). However, large observational studies have yet to be published. Therefore, we performed a real‐world, multicenter, retrospective, review of therapy efficacy in 1660 patients with chronic trunk and/or limb pain.MethodsData were collected in a real‐world environment and retrospectively sourced from a global database. Included patients were trialed and/or permanently implanted with HF‐SCS at 10 kHz between April 2014 and January 2018. We evaluated responder rates at 3, 6, and 12 months post‐implantation. Response was defined as ≥50% pain relief from baseline. A last visit analysis included responder rate along with overall change in function, sleep, quality of life, and medication intake versus baseline.ResultsEighty‐four percent of our HF‐SCS‐treated patients had both chronic back and leg pain. At least 70% of patients reported response to therapy throughout 12 months of follow‐up. This sustained responder rate was corroborated by the last visit value (74.1%). Most patients reported concomitant improvements in function (72.3%), sleep (68.0%), and quality of life (90.3%) at their last visit versus baseline. Thirty‐two percent of patients reported decreased medication intake at their last visit.InterpretationSustained and effective pain relief was experienced by >70% of our HF‐SCS‐treated patients, consistent with the findings of a previously published randomized, controlled, trial. Our review provides complementary evidence to support the treatment of chronic back and leg pain with this therapy.

Electroacupuncture for Women with Chronic Severe Functional Constipation: Subgroup Analysis of a Randomized Controlled Trial.

Background Acupuncture has been found to be effective for treating chronic constipation. Objective The objective of this exploratory study was to evaluate the efficacy of electroacupuncture (EA) in the subgroup of women with chronic severe functional constipation. Methods This is a subgroup analysis of the multicenter, randomized, sham-acupuncture (SA) controlled trial. The efficacy of 822 (76%) female patients of the 1075 randomized patients with chronic severe functional constipation was evaluated. Patients were randomly assigned to receive 28 sessions of EA or SA over 8 weeks with 12 weeks' follow-up. This study focused on sustained complete spontaneous bowel movements (CSBMs) responders over the 8-week treatment. Results The primary outcome which was percentage of the sustained CSBMs responders for the subset of women with severe constipation was significantly higher in the EA group (24.3%) than in the SA group (8.1%) with difference of 13.1% (95%CI, 6.5% to 19.7%; P<0.001). As for the secondary outcomes, responders for ≥9 of 12 weeks of follow-up were higher in the EA group than in the SA group. Additionally, EA had significantly better improvement in mean weekly CSBMs, mean weekly spontaneous bowel movements (SBMs), and mean score changes of stool consistency and straining as well as quality of life of patients. The incidence of adverse events (AEs) related to acupuncture was rare and no statistical significance was found between two groups. Conclusion EA improved the spontaneity and the completeness of the bowel movement of women with severe functional constipation during 8-week treatment and the effect sustained for 12 weeks after stopping treatment.

Predictive factors associated with three years of response to HbA1c goals with exenatide QW or insulin glargine: Post-hoc analysis of the DURATION-3 study.

This post-hoc analysis of the DURATION-3 study aimed to identify factors associated with sustained glycaemic response with exenatide once weekly (QW) or insulin glargine (IG) among patients with type 2 diabetes. Response was defined as achieving treatment target of HbA1c <7.0% (<53 mmol/mol) at Week 26; sustained responders maintained the treatment target for ≥80% of remaining visits, including one during the final 6 months. Of 467 patients, 287 (61.5%) completed 156 weeks of treatment. At Week 26, 175 patients (61.0%) (exenatide QW, n = 95; IG, n = 80) achieved an HbA1c response. At Week 156, 84 of 175 responders (48.0%) had sustained response, with more sustained responders with exenatide QW (22.7% vs 13.9% with IG; P < 0.03). Logistic regression identified three predictors of sustained response: (a) exenatide QW vs IG treatment (odds ratio, 2.584 [95% confidence interval, 1.288-5.187]; P = 0.0075), (b) lower HbA1c at Week 26 (0.139 [0.053-0.366]; P < 0.0001), and (c) lower fasting serum glucose at Week 26 (0.693 [0.541-0.888]; P = 0.0037). A regression model was used to estimate the likelihood of sustained response with either treatment. This analysis provides a helpful tool for predicting sustained response with exenatide QW or IG.

Discovery of Biomarkers for Clinical Response to Radiotherapy in HCC via Deep Immunoprofiling of Peripheral Blood

Introduction: Hepatocellular carcinoma (HCC) is a highly malignant primary liver tumour which ranks third as the cause of cancer-related deaths worldwide. Yttrium-90 (Y90)-radioembolisation (RE) is a form of localised radiotherapy recommended for intermediate and inoperable liver tumors. Y90-RE has been shown to downsize tumors and delay disease progression. Despite its short half-life (∼64 hrs), Y90 induces sustained therapeutic effects months after delivery, which may be linked to a systemic immune response. Method: Tumour tissues from treatment-naïve (control) or Y90 treated HCC patients (n=7 each) were subjected to Next-Generation-Sequencing (NGS). Tumor-infiltrating leukocytes (TILs) and isolated peripheral blood mononuclear cells (PBMCs) obtained at various time-points post-treatment were analysed using time-of-flight mass cytometry (CyTOF). Random Forests predictive model based on CyTOF data was used to predict response outcome for each patient. Result: CyTOF data from TILs isolated post-Y90-RE suggested presence of local immune activation, observed by the increased expression of granzyme B and infiltration of CD8+T cells, CD56+NK cells and CD8+CD56+NKT cells. NGS data revealed that post-Y90-RE tumors upregulated genes involved in innate and adaptive immune activation and also chemokines, CCL5 and CXCL16, which corresponded with recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumors. Comparing PBMCs obtained pre- and post-Y90-RE, an increase in TNFα on both the CD8+ and CD4+T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE was observed, which suggest at systemic immune activation. Y90-RE responders exhibited higher percentage of PD-1+/Tim-3+CD8+T cells co-expressed homing receptors, CCR5 and CXCR6. A prediction model was built to identify sustained responders to Y90-RE based on the immune profiles from pre-treatment PBMCs. Conclusion: Deep-immunophenotyping of tumour and systemic environment revealed immune activation that corresponded to sustained response to Y90-RE observed in HCC patients. Potential biomarkers associated with a positive clinical response were also identified and used to build a prediction model.

Clinical characteristics and prognosis of HCC occurrence after antiviral therapy for HCV patients between sustained and non-sustained responders

Hepatitis C virus (HCV)-infected patients who achieved sustained virologic response (SVR) may still develop hepatocellular carcinoma (HCC). The characteristic of HCC and the prognosis between SVR and non-SVR patients were not well known. Among 1884 HCV-infected patients who were treated with pegylated IFN plus ribavirin therapies, 122 patients developed HCC during follow-up were enrolled in this study. Laboratory data were collected before and at least 1 year after IFN-based therapy, as well as the latest follow-up. Both SVR and non-SVR patients had similar risk factors to develop HCC, but with a little difference. Liver cirrhosis plays a key role in HCC occurrence in both groups. Among the patients who developed HCC, non-SVR patients had significantly higher total bilirubin, higher FIB-4, lower pre-treatment platelet count, higher pre-treatment AFP levels and higher proportion of cirrhosis than SVR patients before occurrence of HCC. After curative treatment, SVR patients had lower recurrence and longer overall survival than non-SVR patients by Kaplan-Meier analysis. Multivariate analysis revealed that APRI ≥0.7 was the independent risk factor for HCC recurrence; and AFP ≥20ng/ml post IFN therapy, as well as HCC recurrence were the independent risk factors of mortality. Liver cirrhosis plays a key role in HCC occurrence after antiviral therapies. SVR patients may have lower HCC recurrence and longer survival rates than non-SVR patients. Only APRI was associated with HCC recurrence; and post-IFN AFP and HCC recurrence were predictive of subsequent mortality independently.

Safety of monitoring antiretroviral therapy response in HIV-1 infection using CD4+ T cell count at long-term intervals.

The latest Brazilian guideline recommended the reduction of routine CD4+ T cell counts for the monitoring of patients with human immunodeficiency virus type 1 (HIV-1) under combination antiretroviral therapy (cART). The aim of this study was to evaluate the safety of monitoring response to cART in HIV-1 infection using routine viral load at shorter intervals and CD4+ T cell count at longer intervals. CD4+ T cell counts and HIV-1 viral load were evaluated in 1,906 HIV-1-infected patients under cART during a three-year follow-up. Patients were stratified as sustained, non-sustained and non-responders. The proportion of patients who showed a CD4+ T > 350cells/µL at study entry among those with sustained, non-sustained and non-responders to cART and who remained with values above this threshold during follow-up was 94.1%, 81.8% and 71.9%, respectively. HIV-1-infected patients who are sustained virologic responders and have initial CD4+ T cell counts > 350cells/µL showed a higher chance of maintaining the counts of these cells above this threshold during follow-up than those presenting CD4+ T ≤ 350cells/µL (OR = 39.9; 95%CI: 26.5-60.2; p < 0.001). This study showed that HIV-1-infected patients who had sustained virologic response and initial CD4+ T > 350cells/µL were more likely to maintain CD4+ T cell counts above this threshold during the next three-year follow-up. This result underscores that the evaluation of CD4+ T cell counts in longer intervals does not impair the safety of monitoring cART response when routine viral load assessment is performed in HIV-1-infected patients with sustained virologic response.

Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis

BackgroundThe therapeutic options for treatment-resistant depression (TRD) encompass a range of neuromodulatory techniques, including repetitive transcranial magnetic stimulation (rTMS). While rTMS is safe and has documented short-term efficacy, durability of antidepressant effects is poorly established. ObjectiveAssess existing evidence regarding durability of rTMS-induced antidepressant response. MethodsWe performed a systematic review of studies reporting antidepressant outcome measures collected three or more months after the end of an induction course of rTMS for depression. Among responders to the induction course, we used a meta-analytic approach to assess response rates at 3 (m3), 6 (m6) or 12 (m12) months after induction, and studied predictors of responder rates using meta-regression. ResultsNineteen studies published between 2002 and 2018 were included. Eighteen were eligible for analysis at m3 (732 patients) and m6 (695 patients) and 9 at m12 (247 patients). Among initial responders, 66.5% sustained response at m3 (95% CI = 57.1–74.8%, I2 = 27.6%), 52.9% at m6 (95% CI = 40.3–65%, I2 = 0%), and 46.3% at m12 (95% CI = 32.6–60.7%, I2 = 0%), in the absence of any major bias. Random-effects meta-regressions further demonstrated that a higher proportion of women, as well as receipt of maintenance treatment, predicted higher responder rates at specific time-points. ConclusionsrTMS is a durable treatment for depression, with sustained responder rates of 50% up to 1 year after a successful induction course of treatment. Maintenance treatment may enhance the durability of the antidepressant effects of rTMS, and should be considered in clinical practice, as well as systematically explored in future clinical trials.

PSS8 - Cost Per-Responder Analysis of Secukinumab Compared to Other Biologics for Treatment of Moderate to Severe Psoriasis Patients in Saudi Arabia

Secukinumab 300 mg, a fully human interleukin-17A antibody, has demonstrated superior and sustained efficacy in treatment of adults with moderate to severe psoriasis over other biologic treatments. The analysis compared the cost per responder of secukinumab (SEC) as first-line biologic treatment versus adalimumab (ADA), etanercept (ETN), infliximab (INF), ustekinumab (UST) and placebo. A 52-week decision-tree model reflecting response to treatment defined as Psoriasis Area Severity Index (PASI) reduction of ≥90%, from a mixed-treatment comparison, led into a Markov model to evaluate the cost per response for each treatment. Responders (PASI≥90) at week 16 continued the initial treatment. Non-responders and drop-outs were switched to standard of care. Analyses were conducted for responders at week 16, week 52 and for sustained responders between weeks 16 and 52, from a Saudi Arabian perspective over a 1-year time horizon. Costs for each treatment included the drug and resource costs, obtained from the Saudi Food and Drug Authority website and national sources respectively, for 2018. No discount was applied. SEC 300 mg had the lowest cost per PASI≥90 responder at 52 weeks (SAR148,952), compared with UST (SAR166,923), INF (SAR175,876), ADA (SAR198,825) or ETN (SAR228,029). Likewise, SEC had the lowest cost per sustained 52-week PASI≥90 responder (SAR80,648) and ADA the highest (SAR105,023). At week 16, cost per PASI≥90 responder was lower for SEC (SAR64,326) versus ADA (SAR 86,785), ETN (SAR115,804) and INF (SAR86,160) except UST (SAR61,035). Sensitivity analysis supported the robustness of the results. Secukinumab as first-line biologic treatment of adults with moderate to severe psoriasis has the lowest cost per PASI≥90 responder compared with other biologic treatments in Saudi Arabia over 1 year.

Impact of Non-Adherence and Flare Resolution on the Cost-Effectiveness of Treatments for Gout: Application of a Linked Pharmacometric/Pharmacoeconomic Model.

Dual urate-lowering therapy (ULT) with lesinurad in combination with either allopurinol or febuxostat is an option for patients with gout unsuccessfully treated on either monotherapy. Treatment failure is often a result of poor medication adherence. Imperfect adherence in clinical trials may lead to biased estimates of treatment effect and confound the results of cost-effectiveness analyses. To estimate the impact of varying medication adherence on the cost effectiveness of lesinurad dual therapy and estimate the value-based price of lesinurad at which the incremental cost-effectiveness ratio is equalto £20,000 per quality-adjusted life-year (QALY). Treatment effect was simulated using published pharmacokinetic-pharmacodynamic models and scenarios representing adherence in clinical trials, routine practice, and perfect use. The subsequent cost and health impacts, over the lifetime of a patient cohort, were estimated using a bespoke pharmacoeconomic model. The base-case incremental cost-effectiveness ratios comparing lesinurad dual ULT with monotherapy ranged from £39,184 to £78,350/QALY gained using allopurinol and £31,901 to £124,212/QALY gained using febuxostat, depending on the assumed medication adherence. Results assuming perfect medication adherence imply a per-quarter value-based price of lesinurad of £45.14 when used in dual ULT compared with allopurinol alone and £57.75 compared with febuxostat alone, falling to £25.41 and £3.49, respectively, in simulations of worsening medication adherence. The estimated value-based prices of lesinurad only exceeded that which has been proposed in the United Kingdom when assuming both perfect drug adherence and the eradication of gout flares in sustained treatment responders.

Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma

ObjectivesYttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained...

Integrated Molecular Analysis Identifies Replicative Stress As Sensitizer to Imetelstat Therapy in AML

Telomerase activation enables replicative immortality in the majority of cancers including acute myeloid leukemia (AML). Imetelstat competitively inhibits telomerase activity with recently reported clinical efficacy in myelodysplasia and myelofibrosis. Here we show final results on a randomized preclinical trial in AML patient-derived xenografts (PDX; n = 30 individual AML; each treated with imetelstat vs. vehicle control; n = 6 per condition). Using drug sensitivity scores (DSS) to define in vivo PDX responses, we provide integrated phenotypic, cytogenetic, genomic and transcriptomic analysis of samples to understand AML response to imetelstat. We use this mechanistic insight to rationally sequence induction chemotherapy with imetelstat to optimize in vivo responses, even in initially poorly responding samples.Methods: An AML PDX cohort was established using bone marrow (BM) or peripheral blood (PB) samples collected from 30 AML patients and transplanted into NOD/SCID/IL2gR-/-/hIL3,CSF2,KITLG (NSGS; n = 12 recipients / AML patient sample). AML onset was defined by reconstitution of BM and spleen with CD45+ CD33+ donor cells, circulating blasts, anemia (HCT < 35%) or thrombocytopenia (PLT < 400 x 10^6/ml). After initial engraftment was confirmed by PB chimerism (> 1%), recipients were treated with imetelstat (15 mg/kg I.P.) or control every 48 - 72h.Results: Across the entire cohort, survival was improved for imetelstat- vs. PBS-treated PDX (Median survival PBS: 88d, Imetelstat: 138d; Hazard ratio PBS: 2.87; 2.20 to 3.74; Cox proportional hazards model: p < 0.0001), however there were clear differences in the quality and duration of response to imetelstat treatment. In order to quantify the sensitivity of each individual AML patient sample to therapy, DSS were derived using the area under the curve of PB donor chimerism in PBS versus imetelstat-treated recipients (Mean DSS entire cohort: 3.21 ± 0.36). DSS positively correlated with survival benefit (R square: 0.87), and values higher than 2.3 gained at least 30 days of survival benefit. Based on DSS, AML patient samples were grouped into “Sustained” (17 AML patient samples; 57%) or “Poor” responders (13 AML patient samples; 43%) with DSS 2.3 as cut-off value. European LeukemiaNet 2017 adverse prognostic samples were trend-wise enriched in poor vs. sustained responders to imetelstat (83.3% poor vs. 16.7% sustained response; p = 0.06, Fisher's exact test). RNA sequencing and mutational profiling was performed on all baseline AML samples. Differential expression analysis revealed a gene signature specifically expressed in sustained compared to poor responders (p < 0.05; log2FC > 1.5; 109 annotated genes) that was functionally annotated in replicative stress including nucleosome (p = 0.01), transcription factor activity (p = 0.04), and sequence-specific DNA binding (p = 0.04).We therefore examined whether the induction of replicative stress could sensitize response to imetelstat therapy. Seven independent AML patient samples with poor response to imetelstat monotherapy were transplanted into NOD.Rag1-/-Il2Rg-/-/ hIL3,CSF2,KITLG (NRGS). Mice received standard induction chemotherapy intravenously as a cytarabine (Arac; 50 mg/kg) and doxorubicin (Doxo; 1.5 mg/kg) 5+3 dosing regimen followed by continuous imetelstat therapy vs. imetelstat alone, standard induction chemotherapy alone, or vehicle control (n = 6 / group, n = 24 / AML sample). Combination therapy significantly prolonged overall survival (Median survival: Control: 38.5d; Imetelstat: 41d; Arac+Doxo: 61d; Arac+Doxo + Imetelstat: 71d post-start of treatment; Hazard ratio Arac+Doxo alone vs. Arac+Doxo+Imetelstat: 2.34; 1.19 to 4.586; Cox proportional hazards model: p < 0.001).In summary, imetelstat prolonged overall survival in a large cohort of AML PDX. In 57% (17 out of 30 individual AML patient samples), sustained responses to imetelstat were associated with marked improvements in survival and a baseline replicative stress-annotated transcriptional signature. The rational sequencing of standard induction chemotherapy to induce replicative stress provides proof-of-concept to sensitize imetelstat-resistant AML patient samples and suppress expansion and prevent relapse in AML. DisclosuresLane:novartis: Consultancy; janssen: Consultancy, Research Funding.

Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment.

The introduction of direct-acting antivirals (DAA) has increased sustained virological response (SVR) rates in patients with advanced liver disease and chronic hepatitis C(CHC)infection. At present, data on clinical outcome and long-term durability of viral eradication after successful DAA therapy are scarce. To evaluate the long-term success of viral eradication in patients with advanced fibrosis or cirrhosis treated with DAAs. Five hundred and fifty-one patients with advanced fibrosis (n=158) or cirrhosis (CPS-A:317,CPS-B/C:76) and SVR after interferon and ribavirin-free DAA therapy treated between October 2013 and April 2016 were studied with a median follow-up of 65.6 (13.0-155.3) weeks. Only patients without hepatocellular carcinoma (HCC) at baseline and without liver transplantation were included. Twelve patients (2.2%) died during follow-up: the mortality rate was 0.6% in F3, 2.2% in CPS-A and 5.3% in CPS-B/C patients (P=.08). During follow-up 36 patients with cirrhosis (9.1%) developed a liver related event, including 16 with de-novo HCC (4.1%). Seven patients were transplanted at a median of 9.7 (range 3.8-21.7) months after EOT. History of decompensation was significantly associated with liver related events during follow-up (HR 7.9; 95% CI 2.7-22.6; P<.001), and with mortality (HR 5.5; 95% CI 1.5-20.2, P=.01). Eradication of HCV by DAA therapy was durable irrespective of the DAA combination used. Most of the cured patients had an excellent long-term clinical prognosis. Nevertheless, the risk of new occurrence of HCC remains worrisome and thus regular surveillance is obligatory even after clinical stabilization and improvement of the patient.

Abstract IA37: Prevention of Hepatocellular Carcinoma (HCC) with antiviral therapy

Abstract On a world-wide basis, chronic viral hepatitis accounts for nearly 75% of all cases of HCC. One of the important implications of this is that HCC may be more readily preventable either by vaccination or with anti-viral therapy. Antiviral therapy against hepatitis B has largely evolved away from using alpha interferon to nucleoside analogues. Lamivudine is the nucleoside analogue agent that has been best studied in preventing HCC. In a large prospective, randomized placebo-controlled trial of lamivudine therapy in patients with advanced liver disease associated with HBV infection, 3.9% of patients receiving lamivudine developed HCC compared to 7.4% on placebo (p=0.047) (1). More recently entecavir and tenofovir have become widely used as the main antiviral agents to control HBV infection. Both agents appear to be very effective in controlling HBV infection but data on their ability to reduce the risk of HCC are controversial. At least two meta-analyses have been done of the anti-cancer benefits of antiviral therapy. Chronic HCV infection appears to be associated with about 30% of HCCs worldwide but in some regions including Europe and the United States it is the leading underlying cause of HCC. The evidence is substantial that effective treatment of hepatitis C can reduce the risk of HCC. The HALT-C Trial was a large randomized controlled trial carried out at multiple sites within the United States, enrolling more than 1,000 patients and randomized patients with HCV infection and advanced fibrosis (bridging hepatic fibrosis or cirrhosis) to receive long-term maintenance therapy with a low dose of peginterferon alfa or to remain untreated for a period of 4 years (2). The initial report from this study showed that antiviral therapy did not reduce the rate of either hepatic decompensation or HCC but an analysis of liver related outcomes after 7 to 8 years of follow up among patients who did not respond to therapy colleagues found that patients who achieved viral cure had significantly lower rates of hepatic decompensation, liver transplantation, or HCC than patients with remained non-responders to interferon (3). This was confirmed in other large cohort studies from several countries in Europe and Canada and meta-analyses. In summary, antiviral treatment for viral hepatitis appears to have benefits in decreasing the risk of HCC in chronically infected patients. This benefit is most pronounced in patients with chronic hepatitis C and advanced hepatic fibrosis or cirrhosis in patients achieving viral clearance and seems much more marginal in patients with chronic hepatitis B where antiviral therapy usually results in viral suppression rather than elimination.

Estrategia terapéutica en hipertensión arterial pulmonar

Research and the advances in treatment of pulmonary arterial hypertension can lead to a change in the natural history of this disease. The basis of the treatment is the use of specific pulmonary vasodilators, although other measures need to be taken into account such as physical activity, psychological support, anticoagulant and diuretic treatment, oxygen therapy, contraceptive use. Prior to any type of specific treatment, a study is required on the acute vaso-reactivity of the pulmonary vascular bed, since patients with a positive response could benefit from treatment with calcium antagonists. In the case of a negative response or on not being sustained responders, there are now drugs available for the three main metabolic pathways implicated in the development of the disease. These include prostanoids (epoprosterenol, treprostinil and iloprost, selexipag), endothelin receptor antagonists or ERA (bosentan, macitentan and ambrisentan), phosphodiesterase-5 inhibitors or PDE5 (sildenafil and tadalafil), and guanylate cyclase stimulators (riociguat). The choice of initial drug, whether single therapy or in combination, will depend on multiple factors such as functional class, comorbidities, interactions with other drugs, tolerability and safety, and finally the availability and preferences.

Low-Dose Linaclotide (72 μg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

Objectives:Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-μg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-μg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-μg linaclotide dose in CIC patients.Methods:This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 μg or 145 μg, or placebo for 12 weeks. The primary endpoint, 12-week complete spontaneous bowel movement (CSBM) overall responder, required patients to have ≥3 CSBMs and an increase of ≥1 CSBM per week from baseline in the same week for ≥9 of 12 weeks of the treatment period. Secondary endpoints included 12-week change from baseline in bowel (SBM and CSBM frequency, stool consistency, straining) and abdominal (bloating, discomfort) symptoms, monthly CSBM responders, and 12-week CSBM responders among patients who averaged >1 SBM/week at baseline. Sustained response (12-week CSBM overall responders who met weekly criteria for 3 of the 4 final weeks (weeks 9–12) of treatment) was evaluated as an additional endpoint. Adverse events (AEs) were monitored.Results:The intent-to-treat population included 1,223 patients (mean age=46 years, female=77%, white=71%). The primary endpoint was met by 13.4% of linaclotide 72-μg patients vs. 4.7% of placebo patients (P<0.0001, odds ratio=3.0; statistically significant controlling for multiplicity). Sustained response was achieved by 12.4% of linaclotide 72-μg patients vs. 4.2% of placebo patients (nominal P<0.0001). Linaclotide 72-μg patients met 9-of-10 secondary endpoints vs. placebo (P<0.05; abdominal discomfort, P=0.1028). Patients treated with linaclotide 145 μg also improved CIC symptoms for the primary (12.4%) and sustained responder endpoint parameters (11.4%) and for all 10 of the secondary endpoint parameters including abdominal discomfort (P<0.05). Diarrhea, the most common AE, was mild in most instances and resulted in discontinuation of 0, 2.4%, and 3.2% of patients in the placebo, linaclotide 72-μg, and linaclotide 145-μg groups, respectively.Conclusions:Once-daily linaclotide 72 μg significantly improved CIC symptoms in both men and women with a low rate of discontinuation due to diarrhea over 12 weeks of treatment.

Long-term follow-up of patients with chronic hepatitis C treated with α-interferon and ribavirin antiviral therapy: clinical and fibrosis impact of treatment response.

The slow progression of chronic hepatitis C (CHC) infection requires long observation periods to detect clinical changes. We compare the incidence of clinical events, hepatocellular carcinoma (HCC), overall mortality, liver-related mortality, and fibrosis progression between patients with a sustained virological response (SVR) and nonresponders (NR) after a 13-year follow-up period. One hundred and eighty-two CHC patients, who received interferon and ribavirin treatment between 1996 and 2000, were included. Clinical events were evaluated during follow-up. At the end of follow-up, transient elastography was used to assess fibrosis progression. Of the 182 patients, 46.7% (n=85) achieved an SVR. Twenty-seven patients developed hepatic decompensation (one SVR) and 15 developed HCC (three SVR). Twenty-nine patients died (eight SVR). Twelve of the 29 deaths were liver related (two SVR). Independent factors associated with hepatic decompensation were NR to treatment [hazard ratio (HR)=23.35; 95% confidence interval (CI): 2.90-189.25; P=0.003], advanced fibrosis at baseline (HR=9.11; 95% CI: 4.13-20.09), and treatment delay after diagnosis (HR=1.02; 95% CI: 1.00-1.03; P=0.012). Only the latter two were associated with HCC development and liver-related mortality. An assessment of liver fibrosis was performed on 125 patients (66 SVR). Fibrosis values were significantly lower in SVR patients, showing less progression to advanced stages of fibrosis [SVR: 6.6 (2.8); 95% CI: 5.8-7.3] than NR [NR: 14.0 (11.1); 95% CI: 11.1-16.9; P<0.001]. In patients with CHC, SVR is durable and reduces clinical events. The risk of HCC development is lower, but not eliminated. Sustained responders showed fibrosis stabilization or improved fibrosis values.

Desmopressin in haemophilia: The need for a standardised clinical response and individualised test regimen.

Due to interindividual variation in desmopressin response, non-severe haemophilia A patients require desmopressin testing prior to therapeutic treatment. However, adequate response or frequency of blood sampling is not standardised in international guidelines. Consequently, various definitions and blood sampling protocols are currently applied. Interestingly, sustainability of desmopressin response is not incorporated into these definitions. To study desmopressin response rates in a cohort of non-severe haemophilia A patients using currently accepted desmopressin response definitions. This, in order to formulate a standardised, uniform response which includes information on sustainability and to design a standardised blood sampling protocol. Currently used desmopressin responses in non-severe haemophilia A patients were derived from a literature search. Actual desmopressin response rates were individualised in 105 non-severe HA patients from the Erasmus University Medical Centre and classified according to current varying definitions. Five response definitions were evaluated, three of which included only factor VIII (FVIII):C cut-off levels and two also incorporated FVIII:C-fold increase over baseline. C-fold increase showed no association with desmopressin response sustainability. C 1hour after infusion (<0.30, ≥0.30-0.49, ≥0.50-0.79 and ≥0.80IU/mL) was, however, indicative of desmopressin response after 6hours. We suggest standardised desmopressin response based on clinically relevant FVIII:C levels, e.g. 0.30 and 0.50IU/mL. In addition, patients with <0.30IU/mL FVIII:C after 1hour (non-responder) or ≥0.80IU/mL (sustained responder) do not require subsequent blood sampling. However, patients with ≥0.30-0.79IU/mL FVIII:C after 1hour should undergo blood sampling after 6hours to additionally determine response sustainability.

Improvements in brain and behavior following eradication of hepatitis C.

Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV- controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV- controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.

Increased Spontaneous Programmed Cell Death Is Associated with Impaired Cytokine Secretion in Peripheral Blood Mononuclear Cells from Hepatitis C Virus-Positive Patients.

Peripheral blood mononuclear cells (PBMCs) play a critical role in clearing hepatitis C virus (HCV). PBMC defects have been linked with HCV infection; however, the underlying mechanisms remain obscure. We hypothesized that PBMCs of HCV-infected patients are more susceptible to programmed cell death (PCD), and are therefore unable to clear HCV. We compared spontaneous PBMC PCD and cytokine [interleukin (IL)-1, -6, -8, -10, and -12] secretion between untreated (naive) HCV+ and treated [sustained responder (SR)] patients with HCV, and HCV- healthy controls. Spontaneous PBMC PCD was assessed by annexin-V fluorescein isothiocyanate/propidium iodide staining, and cytokine levels were measured by cytometric bead array. Differences between groups were analyzed through paired and nonpaired t tests and Mann-Whitney U test. The rate of spontaneous PCD was higher in PBMCs of naive HCV+ patients (p < 0.0001) and SR-HCV patients (p < 0.002) than in HCV- controls. Significantly low levels of IL-8, -6, and -10 were detected in the supernatant of cell cultures of PBMCs from naive HCV+ (p < 0.05) and SR-HCV (p < 0.05) patients relative to HCV- controls. There was no difference between the naive HCV+ and SR-HCV groups in terms of PBMC PCD rate or cytokine levels. The present findings indicate that HCV infection is associated with increased PBMC susceptibility to PCD and decreased production of IL-8, -6, and -10.