Likelihood Of Treatment Response Research Articles

Serum levels of fibrogenesis biomarkers reveal distinct endotypes predictive of response to weight loss in advanced nonalcoholic fatty liver disease.

NAFLD is associated with activation of fibroblasts and hepatic fibrosis. Substantial patient heterogeneity exists, so it remains challenging to risk-stratify patients. We hypothesized that the amount of fibroblast activity, as assessed by circulating biomarkers of collagen formation, can define a "high-risk, high-fibrogenesis" patient endotype that exhibits greater fibroblast activity and potentially more progressive disease, and this endotype may be more amendable to dietary intervention. Patients with clinically confirmed advanced NAFLD were prescribed a very low-calorie diet (VLCD) intervention (∼800kcal/d) to induce weight loss, achieved using total diet replacement. Serum markers of type III (PRO-C3) and IV collagen (PRO-C4) fibrogenesis were assessed at baseline every second week until the end of the VLCD, and 4 weeks post-VLCD and at 9 months follow-up. Twenty-six subjects had a mean weight loss of 9.7% with VLCD. This was associated with significant improvements in liver biochemistry. When stratified by baseline PRO-C3 and PRO-C4 into distinct fibrosis endotypes, these predicted substantial differences in collagen fibrogenesis marker dynamics in response to VLCD. Patients in the high activity group (PRO-C3 >11.4ng/mL and/or PRO-C4 >236.5ng/mL) exhibited a marked reduction of collagen fibrogenesis, ranging from a 40%-55% decrease in PRO-C3 and PRO-C4, while fibrogenesis remained unchanged in the low activity group. The biochemical response to weight loss was substantially greater in patients a priori exhibiting a high fibroblast activity endotype in contrast to patients with low activity. Thus, the likelihood of treatment response may be predicted at baseline by quantification of fibrogenesis biomarkers.

P183 Disease activity, comorbidities and functional status predict treatment response to biologic and targeted synthetic disease-modifying anti-rheumatic drugs in psoriatic arthritis

Abstract Background/Aims Much discussion surrounds the optimal therapeutic treatment plan for biologic and targeted synthetic disease modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) when treating psoriatic arthritis (PsA). The current study aims to identify predictors of treatment response among PsA patients initiating bDMARD/tsDMARD treatment, focusing on disease activity, functional status (Health Assessment Questionnaire, HAQ), and comorbidities. Methods The systematic review of clinical trials and observational studies used Medline, Embase and Cochrane databases. Eligible studies included full text papers with quantitative estimates of effect (or data to allow these to be computed). Papers also required a validated assessment of treatment response i.e., Minimal Disease Activity (MDA), or some other marker of treatment response such as treatment continuation. Case reports and conference abstracts were excluded. Results From 2824 articles identified, 27 were included. Across these, >15 different outcomes were used, and measured at > 10 different timepoints. There was consistent evidence to suggest that higher baseline disease activity was associated with a reduction in the likelihood of treatment response, see Table 1. Some studies reported up to 20% reduction in odds of LDA at 6 months associated with each 1 unit increase in DAPSA. Others demonstrated that patients with a high DAS28 (>3.2) experienced over a 90% reduction in the odds of MDA at 12 weeks. Eleven studies (from 15) demonstrated a significant association between baseline function and odds of treatment response. Each 1 unit increase in HAQ-DI decreased the odds of a good EULAR response at 3 months by up to 66%. The presence of comorbidities was also consistently associated with a decrease in treatment response. Studies showed that the presence of comorbidities at baseline lessened the odds of MDA at 6 months by up to 80%. Others reported that comorbidities were associated with a reduction in the odds of 5 year treatment persistence by up to 40%. Conclusion This review shows clear evidence of reduced bDMARD/tsDMARD response in PsA among patients with disease activity, poor function, and comorbidities. Clinicians should be aware of the reduced chances of treatment success and should consider early review of therapy, to consider whether treatment escalation or switching is required. Disclosure C. Addae-Kyereme: None. S. Lembke: None. G.J. Macfarlane: None. G.T. Jones: None.

Abstract 5459: Association between stomatitis and treatment efficacy with novel TROP2-directed antibody drug conjugate (ADC), datopotamab deruxtecan, in patients with metastatic cancer

Abstract Background: Incidence of toxicity with immunotherapy has been correlated with likelihood of treatment response (Hussaini, Cancer Treat Rev 2021; Schuell, Br J Cancer 2005). However, this phenomenon has not yet been demonstrated with antibody-drug conjugates. Datopotamab deruxtecan (Dato-DXd) is a novel ADC composed of an anti-Trop2 monoclonal antibody, a stable tetrapeptide-based cleavable linker, and a topoisomerase-I inhibitor payload (Bardia, Annals of Onc 2021). Early phase studies have demonstrated significant activity in heavily pretreated patients with metastatic non-small cell lung cancer (NSCLC) and metastatic breast cancer (MBC). Stomatitis was a common treatment-emergent adverse event (TEAE) observed in clinical trials. We conducted a study to evaluate the association between incidence of stomatitis and treatment response with Dato-DXd and evaluate the impact of steroid mouthwash. We hypothesized that presence and grade of mucositis would correlate with observed treatment efficacy. Methods: We included all patients treated at one academic institution (Massachusetts General Hospital) with Dato-DXd. Stomatitis was assessed by NCI-CTCAE V5.0. Objective Response Rate (ORR) was assessed by RECIST criteria with independent radiology review. Use of mouthwash was evaluated by secondary review and categorized as primary or secondary prophylaxis. A time-to-event analysis was performed to evaluate the time to onset of stomatitis. Results: 60 patients, including 19 with MBC and 41 with NSCLC, were treated with Dato-DXd between June 2018-September 2022. The median age of patients was 64 and 41/60 patients were female. The median time to onset of mucositis was 14 days (95% CI 12-42 days). There was no significant difference in incidence of stomatitis between the MBC and NSCLC cohorts. Compared to patients who had progressive disease (PD), patients who had a partial response (PR) or stable disease (SD) were 11 times more likely to have stomatitis (OR 11.0, 95% CI 3.61-44.01, p<0.001). Later in the trial (January 2020 onward), 28 patients received primary steroid prophylaxis - excluding these patients, those who were found to have PR/SD were 8.8 times more likely to develop stomatitis compared to patients who had PD (OR 8.8, 95% CI 1.5-73.3, p=0.023). Conclusion: The development of stomatitis may be associated with higher likelihood of therapeutic efficacy. Given that these findings are a hypothesis-generating post-hoc exploratory analysis from a single institution, this requires validation in larger studies before drawing strong conclusions and impacting clinical decision making. Further research is also needed evaluate the relationship between TEAEs and therapeutic efficacy with other ADCs. Citation Format: Rachel O. Abelman, Laura M. Spring, Phoebe K. Ryan, Geoffrey Fell, Dejan Juric, Rebecca S. Heist, Aditya Bardia. Association between stomatitis and treatment efficacy with novel TROP2-directed antibody drug conjugate (ADC), datopotamab deruxtecan, in patients with metastatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5459.

Evolution of ultrasound in giant cell arteritis.

Ultrasound (US) is being increasingly used to diagnose Giant Cell Arteritis (GCA). The traditional diagnostic Gold Standard has been temporal artery biopsy (TAB), but this is expensive, invasive, has a false-negative rate as high as 60% and has little impact on clinical decision-making. A non-compressible halo with a thickened intima-media complex (IMC) is the sonographic hallmark of GCA. The superficial temporal arteries (STA) and axillary arteries (AA) are the most consistently inflamed arteries sonographically and imaging protocols for evaluating suspected GCA should include at least these two arterial territories. Studies evaluating temporal artery ultrasound (TAUS) have varied considerably in size and methodology with results showing wide discrepancies in sensitivity (9–100%), specificity (66–100%), positive predictive value (36–100%) and negative predictive value (33–100%). Bilateral halos increase sensitivity as does the incorporation of pre-test probability, while prior corticosteroid use decreases sensitivity. Quantifying sonographic vasculitis using Halo Counts and Halo Scores can predict disease extent/severity, risk of specific complications and likelihood of treatment response. Regression of the Halo sign has been observed from as little as 2 days to as late as 7 months after initiation of immunosuppressive treatment and occurs at different rates in STAs than AAs. US is more sensitive than TAB and has comparable sensitivity to MRI and PET/CT. It is time-efficient, cost-effective and allows for the implementation of fast-track GCA clinics which substantially mitigate the risk of irreversible blindness. Algorithms incorporating combinations of imaging modalities can achieve a 100% sensitivity and specificity for a diagnosis of GCA. US should be a standard first line investigation in routine clinical care of patients with suspected GCA with TAB reserved only for those having had a normal US in the context of a high pre-test probability.

Treatment of juvenile localized scleroderma: current recommendations, response factors, and potential alternative treatments.

Juvenile localized scleroderma (jLS) is a chronic autoimmune and fibrosing disease associated with a high risk for functional impairment. Antifibrotic options are limited, so current treatment strategies are focused on disease activity control. Pediatric rheumatologists are in consensus on the need to treat with systemic immunosuppressants, in particular, methotrexate. However, more than 30% of patients fail initial methotrexate treatment. This review provides an update on current management and reviews reports on potential alternative treatments. An overview of current treatment recommendations and its efficacy are discussed. Recent studies have identified several factors associated with likelihood of treatment response. These include time to initiation of treatment, certain subtypes, and extracutaneous involvement. Findings from recent reports of alternative systemic immunomodulators, including biologic medications, will be summarized. Methotrexate treatment has greatly improved outcome for most jLS patients but a substantial portion have refractory cutaneous and/or extracutaneous disease. Treatment response factors are being identified, which could lead to improved management strategies. Recent studies provide further support on mycophenolate mofetil as an alternative treatment. Data on biologic therapies is encouraging, with data suggesting efficacy for many extracutaneous manifestations but more studies are needed to evaluate these and other options for jLS.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Antecedent infections and vaccinations in chronic inflammatory demyelinating polyneuropathy: A European collaborative study.

Chronic inflammatory demyelinating polyneuropathy (CIDP) may be rarely preceded by infection. A causative link remains unproven, in contrast to Guillain-Barré syndrome (GBS), which is commonly postinfectious with well-demonstrated pathophysiological mechanisms of molecular mimicry following Campylobacter jejuni enteritis. Uncommonly, infections are reported before the onset of CIDP. In this study we aimed to determine the frequency and characteristics of CIDP occurring after antecedent infections or vaccinations in two large European cohorts. We reviewed the records of 268 subjects with "definite" or "probable" CIDP from the Inflammatory Neuropathy Clinic, Birmingham, UK (129 subjects), and from the Serbian national CIDP database (139 subjects). Twenty-five of 268 (9.3%) subjects had a respiratory or gastrointestinal infection in the 6 weeks preceding CIDP onset, and 3 of 268 (1.1%) had received an influenza vaccination. CIDP disease onset occurred at a younger age (mean [standard deviation], 44.25[17.36] years vs 54.05[15.19] years; P < .005) and acute-onset CIDP was more common (42.9% vs 12.1%; odds ratio, 5.46; 95% confidence interval, 2.35-12.68; P < .001) in subjects with preceding infections or vaccinations. No differences in CIDP subtype, rates of cerebrospinal fluid protein level elevation, disability, or likelihood of treatment response, were observed. Antecedent infections or vaccinations may precede about 10% of cases of CIDP and are more common in younger subjects. Acute-onset CIDP is more frequent after antecedent events. These findings may suggest specific pathophysiological mechanisms in such cases.

Novel application of Kaplan-Meier methods to model tolerance for nonadherence to imatinib in patients with chronic myeloid leukemia (CML) in the ADAGIO study.

7038 Background: Although adherence to imatinib treatment has been shown to be critical for attaining treatment response among patients with CML, some studies have suggested a 7.3-9.9% nonadherence tolerance margin before loss of treatment effects. We aimed to model probabilistically the margin of tolerance required to ensure treatment response among patients prescribed imatinib and the margin, if any, before treatment response is at risk. Methods: We performed a post hoc analysis of the ADAGIO study conducted in Belgium on 169 evaluable patients ( Blood 2009). Using the pill count ratio as, what in conventional survival analysis would be, the time variable, we modeled the cumulative likelihood of treatment response as a function of increasing pill count adherence. We applied Kaplan-Meier methods to model the likelihood of complete cytogenetic (CCyR), complete hematological (CHR), major molecular (MMR) and optimal (OR) (as defined by the European Leukemia Net) response as a function of 90-day pill count adherence. Kaplan-Meier methods thus estimated the tolerance for nonadherence to imatinib by calculating the 1 minus Kaplan-Meier estimate for treatment response. Results: Analyses (see Table) showed that ̃100% adherence of prescribed dose is associated with probabilities (rounded) of 0.84 for CHR, 0.83 for CCyR, 0.82 for OR, and 0.77 for MMR; compared to, 0.37 (CHR and CCyR), 0.35 (OR), and 0.39 (MMR) at 90% adherence. (of 0.7698 (MMR). Increasing the intake of imatinib from 90% to 100% of the prescribed dose increased the likelihood of the various treatment responses by 1.95 to 2.35-fold. Conclusions: Our findings challenge any previously estimated tolerance for nonadherence. There is virtually no margin for nonadherence if the objective is to optimize the likelihood of treatment response, and only a minimal margin to avoid impaired treatment response. Under such adherence, response rates similar to those in the pivotal IRIS trial can be obtained. Clinicians must assess and promote patient adherence, and patients must be perfectly adherent.[Table: see text]

Digital phenotyping in psychiatry

Digital phenotyping represents a new approach aimed at measuring the human behavior by using smartphones and personal device sensors, smartphone apps, keyboard interaction, and various features of subject’s voice and speech. Data collected by a digital phenotyping smartphone application are divided into two categories: a) active data (i.e., those usually collected by using a survey modality) which require an ‘active participation’ from the subject to be generated; and, b) passive data (for instance, those data collected by using Global Positioning System (GPS) traces), usually collected without any participation or action from the subject. Digital phenotyping may theoretically enhance clinicians’ ability to early identify, diagnose and manage any mental health conditions and favoured a more personalized diagnostic and therapeutic approach to several mental conditions. The innovative and insightful approach applied by the digital phenotyping appears to find an interesting and useful application in the field of psychiatry. The digital phenotyping is in line with the new paradigm of the precision psychiatry, i.e. the new approach performed to help clinicians in customizing a psychiatric treatment for each patient, by integrating information about individual phenotypes and genotypes with biographical, clinical and biological data. A precision psychiatry approach would ideally allow clinicians to tailor clinical decision-making and stratify patients to each available treatment according to each one’s likelihood of treatment response and prognosis. Our aims are at providing a comprehensive panorama on evidence-based applications of digital phenotyping in psychiatry.DisclosureNo significant relationships.

Trends in patient misperception and decisional regret during treatment for advanced cancer: A prospective study.

e24190 Background: Cancer patients receiving palliative therapy often misperceive the likelihood of benefits and toxicity. Change in misperception during treatment and decisional regret after has not been studied. We assessed shifts in perception of treatment outcomes and decisional regret after treatment in a single-center prospective study. Methods: We enrolled patients with advanced solid cancer starting palliative intent treatment. At baseline, both patients and their treating physicians were asked about their perceived likelihood of treatment response, symptom palliation, survival benefit, and treatment toxicity on scale of 0-100% at start of treatment and at follow-up. The Signed Rank tested whether patient perception changed significantly over time. After treatment, patients alive and not in hospice were asked about their decision to undergo treatment. Results: Of 122 patients with baseline estimates, 65% completed at least one follow-up survey while undergoing treatment. At enrollment, respondents’ mean age was 65 years (range: 32–89); 54% were male. Compared to baseline, there was no change in patients’ perceptions of treatment response, survival benefit, toxicity (all P≥0.52) at follow-up; a trend toward change in perceived curative potential (P = 0.06); an increase (of 7 points) of perceived likelihood of symptom relief (P = 0.04). Perceived likelihood of treatment response and symptom relief increased (both P &lt; 0.03) among patients whose baseline estimates of treatment response were lower than or similar to their physicians’ estimates. Conversely, perceived likelihood of treatment response (P = 0.01) and curative potential (P = 0.02) decreased among patients with more optimistic estimates than their physicians’. Of the surviving 63 patients, 33 (52%) completed the end of treatment survey, 24 were unreachable and 6 declined. Median time of survey response was at 41.2 weeks (IQR: 36.4 – 47.9). Nearly all (95%) agreed that treatment was the right decision. None regretted their choice; 79% agreed they would make the same choice if they had to do it again; 12% agreed that treatment did them a lot of harm. Conclusions: Patients’ perceptions of treatment response converged during therapy as compared to their physicians at baseline. Of surviving patients surveyed, none regretted their decision to receive palliative cancer treatment. Treatment expectations evolve over time, highlighting opportunities for enhanced communication and patient education beyond initial consent procedures.

A novel approach to quantitatively synthesize subgroup findings from multiple trials.

e14081 Background: The identification of characteristics that stratify patients according to the likelihood of treatment response is a key goal of precision oncology research. Within randomized trials, effect modification is typically examined through subgroup analyses or the inclusion of an interaction term(s) in a multivariable regression model. To date, systematic reviews of such findings have relied upon qualitative summaries or subgroup-specific meta-analyses. Such approaches are problematic because they do not quantify the magnitude or the degree of uncertainty in the difference in the treatment effects between subgroups. To address this gap, we propose a novel approach that can be used to quantitatively pool subgroup findings from multiple trials. Methods: Our procedure is focused on the estimation of the pooled difference between the subgroup-specific treatment effects within a two-stage meta-analysis. In the first stage, the magnitude and standard error of the difference between the subgroup-specific treatment effects is estimated for each study. When studying relative effect measures, this difference can be estimated on the log-scale, e.g., study-specific difference = log(RRsubgroup A) – log(RRsubgroup B). The standard error of this difference can then be estimated using subgroup-specific 95% CIs. A meta-analysis of the study-specific differences is then conducted. When the differences are estimated on the log-scale, the pooled quantity can be re-expressed as the ratio of the subgroup specific ORs, RRs, or HRs whereby a ratio equal to 1.00 indicates that the subgroup-specific estimates are equal in magnitude. Results: Case-studies and empirical simulations highlighting the application of our approach will be presented. Potential extensions of this methodology will also be discussed. Such extensions include the use of dose-response models to address subgroup categories of a continuous variable and the inclusion of three or more treatments within a network meta-analysis. Conclusions: This method may help to better identify and quantify the degree of heterogeneity of subgroup differences across trials, particularly in settings where the number of patients within each trial is limited.

Role of tissue plasminogen activator and plasminogen activator inhibitor as potential biomarkers in psychosis.

The identification of biological markers for psychosis has an impact on its diagnosis, prognosis, and likelihood of treatment response. Tissue plasminogen activator (tPA) is involved in important functions such as synaptic plasticity, long-term potentiation and neurogenesis. Plasminogen activator inhibitor (PAI-1) is the most important inhibitor of tPA. Preliminary studies have shown that schizophrenia patients have lower tPA and higher PAI-1 levels than the general population. The association of tPA and PAI-1 abnormalities with psychotic spectrum disorders, however, remains elusive. Our primary objective was to assess the plasma levels of tPA and PAI-1 in patients experiencing acute psychotic episodes as compared to those in healthy controls. In this prospective case-control study, we collected peripheral blood samples from psychiatric inpatients and healthy age, gender and race-matched subjects and determined plasma levels of tPA and PAI-1 by enzyme-linked immune-absorbent assays. Plasma levels of PAI-1 in patients with schizoaffective disorder were significantly lower as compared to those in control subjects (P = 0.03). tPA was lower in cases as compared to controls although it did not reach statistical significance. Asian patients and controls had lower PAI-1 levels. Further, Asian patients with schizoaffective disorder had significantly lower PAI-1 level compared to Asian patients with schizophrenia. Our results indicate that patients with schizoaffective disorder have lower PAI-1 levels than those with schizophrenia, affective psychosis, and healthy controls. Further studies are warranted to explore the potential of PAI-1 as a biomarker for diagnosing schizoaffective disorder.

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders.

We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability. We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo-controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12weeks. Meta-analysis included 57 trials (N=16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects. SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not.

Genetic Factors That Affect Spontaneous Clearance of Hepatitis C or B Virus, Response to Treatment, and Disease Progression

Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment.

Risks and benefits of phase 1 clinical trial participation.

The results from phase 1 clinical trials can allow new treatments to progress further in drug development or halt that process altogether. At the forefront of phase 1 clinical trials is the safety of every patient participant, which is particularly true when testing new oncologic treatments in which patients may risk potentially toxic treatments in the hope of slowing the progression of or even curing their disease. We explore the benefits and risks that patients experience when participating in phase 1 clinical trials. Rules and regulations have been put into place to protect the safety and interests of patients while undergoing clinical trials. Selecting patients with cancer who will survive long enough to accrue data for these trials continues to be challenging. New prognostic models have been validated to help health care professionals select those patients who will likely benefit from participation in phase 1 trials. There also are long-lasting positive and negative impacts on those patients who choose to participate in phase 1 clinical trials. Modern phase 1 clinical trials represent a therapeutic option for many patients who progress through frontline therapy for their malignancies. Recent phase 1 clinical trials testing targeted therapies have increased responses in many diseases in which other lines of therapy have failed. Patients still face many risks and benefits while enrolled in a phase 1 trial, but the likelihood of treatment response in the era of rational, targeted therapy is increased when compared with the era of cytotoxic therapy.

Predictors of Treatment Outcomes in ANCA-Associated Vasculitis with Severe Kidney Failure

In ANCA-associated GN, severe renal dysfunction portends a poor prognosis for renal recovery and patient survival. This study evaluated the prognostic factors affecting renal and patient outcomes in patients presenting with severe kidney failure to guide immunosuppressive therapy. This study retrospectively evaluated clinical and histopathologic characteristics of 155 patients who underwent biopsy between October 1985 and February 2011 (median eGFR at presentation, 7.1 ml/min per 1.73 m(2); 87% required hemodialysis), all treated with immunosuppressive medications. Three outcomes of interest were measured: patient survival, renal survival, and treatment response (defined as dialysis-free survival without active vasculitis by 4 months after biopsy). Competing risk, Cox, and logistic regression analyses were conducted for each outcome measure. Within 4 months after biopsy, treatment response was attained in 51% of patients, 35% remained on dialysis, and 14% died. In a competing risk analysis, estimated cumulative incidence rates of ESRD and disease-related mortality were 26% and 17% at 1 year and 32% and 28% at 5 years, respectively. Cyclophosphamide therapy and treatment response by 4 months were independently associated with patient and renal survival, adjusting for the percentage of normal glomeruli, histopathologic chronicity index score, and baseline clinical characteristics. Only 5% of patients still dialysis dependent at 4 months subsequently recovered renal function. Low chronicity index score (odds ratio [OR], 1.16; 95% confidence interval [95% CI], 1.04 to 1.30, per unit decrease) and baseline eGFR>10 ml/min per 1.73 m(2) (OR, 2.77; 95% CI, 1.09 to 7.01) were significantly associated with treatment response by 4 months. Among cyclophosphamide-treated patients, the likelihood of treatment response was >14% even with highest chronicity index score and eGFR<10 ml/min per 1.73 m(2). Although low baseline renal function and severe renal scarring are associated with lower treatment response rate, no "futility" threshold could be identified. Conversely, continued immunosuppressive therapy beyond 4 months is unlikely to benefit patients who remain dialysis dependent.

Plasma fibrinogen: now also an antidepressant response marker?

Major depressive disorder (MDD) is one of the leading causes of global disability. It is a risk factor for noncompliance with medical treatment, with about 40% of patients not responding to currently used antidepressant drugs. The identification and clinical implementation of biomarkers that can indicate the likelihood of treatment response are needed in order to predict which patients will benefit from an antidepressant drug. While analyzing the blood plasma proteome collected from MDD patients before the initiation of antidepressant medication, we observed different fibrinogen alpha (FGA) levels between drug responders and nonresponders. These results were replicated in a second set of patients. Our findings lend further support to a recently identified association between MDD and fibrinogen levels from a large-scale study.

1962 AGE, GENDER AND NOCTURNAL URGENCY SEVERITY PREDICT RESPONSE TO ANTIMUSCARINIC TREATMENT

INTRODUCTION AND OBJECTIVES: Nocturnal urinary urgency significantly impacts quality of life in patients with overactive bladder. To date, only 1 prospective study has demonstrated antimuscarinic efficacy for reducing nocturnal urgency episodes. Data on predictors of positive treatment outcomes would help identify patients who would most likely benefit from antimuscarinic pharmacotherapy. We examined the impact of sex, age and baseline nocturnal urgency on the response to fesoterodine (FESO) in overactive bladder (OAB) subjects with nocturnal urgency. METHODS: Eligible subjects aged 18 years with self-reported OAB symptoms, including nocturnal urgency, were randomized to receive fesoterodine or PBO for 12 wk if they had 2-8 nocturnal urgency episodes/24 h at baseline and a 35% reduction of nocturnal urgency episodes during a 2-week, single-blind PBO run-in. Following 1:1 randomization, FESO 4 mg (n 463) or PBO (n 474) was administered once daily for 4 weeks, followed by optional escalation to 8 mg for the remaining 8 weeks at the discretion of the investigator. For this post-hoc analysis, a logistic regression model was used to assess whether treatment, sex, age and number of baseline nocturnal urgency episodes predicted the likelihood of response, defined as a reduction from baseline of 1 micturition-related nocturnal urgency episodes/24 h at week 12. Missing data were imputed with the last observation carried forward method. RESULTS: Nocturnal urgency episodes were significantly reduced following fesoterodine treatment (P 0.0034; Figure). Women (P 0.0225) were more likely to show a treatment response than men to respond to fesoterodine. Greater number of baseline nocturnal urgency episodes (P 0.0001) was also associated with an increased likelihood of treatment response. Older age (P 0.0123) was associated with a slightly decreased likelihood of treatment response. CONCLUSIONS: Treatment, sex, age, and number of nocturnal urgency episodes at baseline significantly predicted the likelihood of response in subjects with OAB and nocturnal urgency.

Patients’ Willingness to Accept the Risks and Benefits of New Treatments for Chronic Hepatitis C Virus Infection

BackgroundSome patients with chronic hepatitis C virus (HCV) infection forego treatment due to concerns about treatment efficacy, treatment duration, and side effects.ObjectiveThe purpose of this study was to quantify patient preferences among possible outcomes associated with new, direct-acting antiviral agents (DAAs) for the treatment of HCV infection and determine which treatment features are most important to patients in making treatment decisions.MethodsAdult participants with a self-reported physician diagnosis of HCV infection in five countries completed a web-enabled, choice-format conjoint analysis survey. The survey presented participants with 20 treatment-choice questions. Each treatment-choice question included a pair of hypothetical treatment profiles with varying levels of six attributes: treatment duration; chance of getting rid of the virus completely (i.e. likelihood of a sustained virologic response [SVR]); weeks on an additional, third medicine (i.e. a DAA); risk of a severe rash; risk of severe anemia; and number of times a day the third medicine is taken. Treatment-choice questions were based on a predetermined experimental design with known statistical properties. Random-parameters logit was used to estimate preference weights for all attribute levels and the mean relative importance of each attribute.Results284 participants completed the survey. Likelihood of an SVR was the most important outcome to participants, followed by severe anemia risk, severe rash risk, therapy type (a combination of total weeks of treatment and weeks on the third medicine), and dosing of the third medicine. Controlling for other factors, preferences were similar across all therapy types examined.ConclusionPatients with HCV infection indicate a willingness to accept an increased risk of side effects for sufficient improvement in the likelihood of treatment response.Electronic Supplementary MaterialSupplementary material is available for this article at 10.1007/BF03262498 and is accessible for authorized users.

Clinical drivers in naïve patient eligibility for treatment of chronic hepatitis C

Hepatitis C virus (HCV) infection represents a major health problem, being a leading cause of cirrhosis and liver transplantation worldwide. Viral eradication achieved by Peginterferon and Ribavirin therapy is the only therapeutic option that can prevent fibrosis progression in chronic hepatitis and liver-related complications in cirrhotic patients. Unfortunately, the occurrence of potentially serious side effects argues against universal treatment of HCV-infected patients. Indeed most scientific societies suggest that eligibility for therapy be based on baseline factors, the so called clinical drivers for treatment eligibility. Current international guidelines recommend focusing on the severity of liver disease, likelihood of treatment response in terms of chances of sustained virological response (SVR) to antiviral therapy and risk of serious adverse events when making treatment decisions. However, evidence exists that treatment may benefit also patients with mild fibrosis and that baseline predictions of a SVR are inaccurate because of the key role of HCV kinetics while on-therapy. An extended treatment programme is further supported by the fact that an increase in the number of patients treated would ultimately result in a long-term reduction of liver-related deaths.