Detection Of Treatment Failure Research Articles

Time-domain diffuse optical imaging technique for monitoring rheumatoid arthritis disease activity: experimental validation in tissue-mimicking finger phantoms

Objective. Effective treatment within 3–5 months of disease onset significantly improves rheumatoid arthritis (RA) prognosis. Nevertheless, 30% of RA patients fail their first treatment, and it takes 3–6 months to identify failure with current monitoring techniques. Time-domain diffuse optical imaging (TD-DOI) may be more sensitive to RA disease activity and could be used to detect treatment failure. In this report, we present the development of a TD-DOI hand imaging system and validate its ability to measure simulated changes in RA disease activity using tissue-mimicking finger phantoms. Approach. A TD-DOI system was built, based on a single-pixel camera architecture, and used to image solid phantoms which mimicked a proximal interphalangeal finger joint. For reference, in silico images of virtual models of the solid phantoms were also generated using Monte Carlo simulations. Spatiotemporal Fourier components were extracted from both simulated and experimental images, and their ability to distinguish between phantoms representing different RA disease activity was quantified. Main results. Many spatiotemporal Fourier components extracted from TD-DOI images could clearly distinguish between phantoms representing different states of RA disease activity. Significance. A TD-DOI system was built and validated using finger-mimicking solid phantoms. The findings suggest that the system could be used to monitor RA disease activity. This single-pixel TD-DOI system could be used to acquire longitudinal measures of RA disease activity to detect early treatment failure.

Unveiling challenges in real-time PCR strategies for detecting treatment failure: observations from clinical trials on chronic Chagas disease

Chagas disease (CD) caused by Trypanosoma cruzi remains a Neglected Tropical Disease with limited access to diagnosis and treatment, particularly for chronically infected patients. Clinical trials are underway to improve treatment using new drugs or different regimens, and Real-Time PCR is used to assess the parasitological response as a surrogate biomarker. However, PCR-based strategies have limitations due to the complex nature of T. cruzi infection. The parasite exhibits asynchronous replication, different strains and clones, and diverse tissue tropism, making it challenging to determine optimal timeline points for monitoring treatment response. This mini-review explores factors that affect PCR-based monitoring and summarizes the endpoints used in clinical trials for detecting treatment failure. Serial sampling and cumulative PCR results may improve sensitivity in detecting parasitemia and treatment failure in these trials.

Rise in alanine aminotransferase after HCV treatment is a highly sensitive screen for treatment failure.

Nucleic acid testing to confirm sustained virological response (SVR) after HCV therapy is technical, often expensive, and frequently unavailable where disease prevalence is highest. Alternative surrogate biomarkers merit evaluation. In a short-treatment trial in Vietnam (SEARCH-1; n = 52) we analysed how changes in alanine transaminase (ΔALT) and aspartate transaminase (ΔAST), from end of treatment (EOT) to EOT + 12 weeks, related to SVR, defined as HCV RNA < lower limit of quantification 12 weeks after EOT. In a separate UK trial (STOPHCV1; n = 202), we then tested the hypothesis that any elevation in ALT or AST between EOT and EOT12 is a sensitive screen for treatment failure. In SEARCH-1, among 48 individuals with data, 13 failed to achieve SVR. Median ΔALT and ΔAST were negative in cured patients but elevated when treatment failed [median ΔALT (IQR): -2 IU/L (-6, +2)] versus +17 IU/L (+7.5, +38) (p< 0.001). Amongst treatment failures, 12/13 had increase in ALT and 13/13 had increase in AST after EOT, compared with 12/35 in those cured. In STOPHCV1, 196/202 patients had evaluable data, of which 57 did not achieve SVR. A rise in ALT after EOT was 100% sensitive (95% C.I. [93.7 - 100%]) and 51% specific (42.4 - 59.7%) for detecting treatment failure. ΔAST >0 IU/L was 98.1% (89.9 - 99.9%) sensitive and 35.8% (27.3 - 45.1%) specific. A rise in ALT or AST after HCV therapy is a highly sensitive screen for treatment failure in mild liver disease. This finding could reduce costs and complexity of managing HCV.

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer.

Circulating tumor DNA (ctDNA) has emerged as a promising tumor-specific biomarker in pancreatic cancer, but current evidence of the clinical potential of ctDNA is limited. In this study, we used comprehensive detection methodology to explore the utility of longitudinal ctDNA measurements in patients with advanced pancreatic cancer. A targeted eight-gene next-generation sequencing panel was used to detect point mutations and copy-number aberrations (CNA) in ctDNA from 324 pre-treatment and longitudinal plasma samples obtained from 56 patients with advanced pancreatic cancer. The benefit of ctDNA measurements to predict clinical outcome and track disease progression was assessed. We detected ctDNA in 35/56 (63%) patients at baseline and found that it was an independent predictor of shorter progression-free survival (PFS) and overall survival (OS). After initiation of treatment, ctDNA levels decreased significantly before significantly increasing by the time of progression. In some patients, ctDNA persistence was observed after the first chemotherapy cycles, and it was associated with rapid disease progression and shorter OS. Longitudinal monitoring of ctDNA levels in 27 patients for whom multiple samples were available detected progression in 19 (70%) patients. The median lead time of ctDNA measurements on radiologically determined progression/time of death was 19 days (P = 0.002), compared with 6 days (P = 0.007) using carbohydrate antigen 19-9. ctDNA is an independent prognostic marker that can be used to detect treatment failure and disease progression in patients with advanced pancreatic cancer.

1249. Rise in ALT after Hepatitis C Treatment is a Highly Sensitive Marker of Treatment Failure

Abstract Background Hepatitis C nucleic acid testing to confirm sustained virological response (SVR) after antiviral treatment is technical and expensive, hampering scale-up and decentralisation of care in resource-poor settings. Serial liver function testing may offer a cheaper means of screening for treatment failure. Methods In an HCV treatment shortening study in Vietnam (n=51), we analysed whether a change in ALT or AST from EOT to EOT+ 12 weeks (ΔALT; ΔAST) was a sensitive surrogate for HCV RNA in detecting treatment failure. We compared ΔALT and ΔAST between cures (38) and failures (13), and assessed sensitivity, specificity and area under receiver-operator curves (AUROC) vs gold standard HCV RNA. We validated our findings in a second, larger study population from a UK treatment shortening study (n=202). Both study populations had mild liver disease, and all participants were treated with 4-8 weeks direct acting antiviral therapy. Results In Vietnam, among 46 HCV genotype 1 or 6-infected individuals who supressed ALT on therapy, 11 failed to achieve SVR. Median ΔALT was -1 IU/L in cures vs +24 IU/L in treatment failures (p&amp;lt; 0.001). Increase in ALT (ΔALT &amp;gt; 0) after end-of-treatment was 100% (95% C.I. [66.4 – 100]) sensitive and 48% [26.8 – 69.4] specific vs HCV RNA in identifying failures (AUROC = 0.99). These results were validated among 193 genotype 1 or 4-infected individuals who supressed ALT on treatment in a UK study (in which 60 failed to achieve SVR). Median ΔALT was +1 IU/L in cures vs +45 IU/L in treatment failures (p&amp;lt; 0.001). ΔALT &amp;gt; 0 was 100% sensitive (95% C.I. [94.6 – 100]) and 47% [38.3-56.3] specific (AUC = 0.98). ΔAST performed similarly. Figure 1Change in ALT from EOT to EOT+12 in cures and from EOT to start of retreatment (EOT+6 to 24) in treatment failures in a) Vietnam study b) UK study Conclusion ΔALT from EOT to EOT+12 is a highly sensitive screen for identifying DAA treatment failures. Using this strategy, only around half of treated individuals require HCV RNA testing 12 weeks after end of treatment, offering substantial benefits in terms of cost reductions and decentralisation of care. Disclosures All Authors: No reported disclosures.

Patterns of care for non-metastatic castration-resistant prostate cancer: A population-based study.

ObjectivesTo describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous ADT for the treatment of non‐metastatic castration‐resistant prostate cancer (nmCRPC).Patients and MethodsThis was a retrospective, longitudinal, population‐based study of administrative health data from 2008 to 2019. Men 65 years and older receiving continuous androgen deprivation therapy (ADT) with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2‐year look‐back window was used to assess patterns of care leading up to CRPC as well as baseline covariates.ResultsAt a median follow‐up of 40.1 months, 944 patients with nmCRPC were identified. Their median time from initiation of continuous ADT to CRPC was 26.0 months. 60.7% of patients had their PSA measured twice or fewer in the year prior to index, and 70.7% patients did not receive any imaging in the year following progression to CRPC. Throughout the study period, 921/944 (97.6%) patients with CRPC progressed to high‐risk (HR‐CRPC) with PSA doubling time ≤ 10 months, of which more than half received fewer than three PSA tests in the year prior to developing HR‐CRPC, and 30.9% received no imaging in the subsequent year.ConclusionPSA testing and imaging studies are underutilized in a real‐world setting for the management of nmCRPC, including those at high risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging and detection of treatment failure and/or metastases, thereby delaying the necessary treatment intensification with life‐prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patient outcomes.

Baseline parameters and the prediction of treatment failure in patients with intravenous drug use-associated spinal epidural abscesses.

Despite the increasing incidence of spinal epidural abscess (SEA), the baseline parameters potentially predictive of treatment failure remain poorly characterized. In this study, the authors identify the relevant baseline parameters that predict multimodal treatment failure in patients with either intravenous drug use (IVDU)-associated SEA or non-IVDU-associated SEA. The authors reviewed the electronic medical records of a large institutional series of consecutive patients with diagnosed SEA between January 2011 and December 2017 to characterize epidemiological trends as well as the complement of baseline measures that are predictive of failure after multimodal treatment in patients with and without concomitant IVDU. The independent impact of clinical and imaging factors in detecting treatment failure was assessed by performing stepwise binary logistic regression analysis. A total of 324 consecutive patients with diagnosed SEA were identified. Overall, 226 patients (69.8%) had SEA related to other causes and 98 (30.2%) had a history of recent IVDU. While non-IVDU SEA admission rates remained constant, year-over-year admissions of patients with IVDU SEA nearly tripled. At baseline, patients with IVDU SEA were distinct in many respects including younger age, greater unemployment and disability, less frequent diabetes mellitus (DM), and more frequent methicillin-resistant Staphylococcus aureus infection. However, differences in length of stay, loss to follow-up, and treatment failure did not reach statistical significance between the groups. The authors constructed independent multivariate logistic regression models for treatment failure based on identified parameters in the two cohorts. For the non-IVDU cohort, the authors identified four variables as independent factors: DM, hepatitis B/C, osteomyelitis, and compression deformity severity. In contrast, for patients with IVDU, the authors identified three variables: albumin, endocarditis, and endplate destruction. Receiver operating characteristic and area under the curve (AUC) analyses were undertaken for the multivariate models predicting the likelihood of treatment failure in the two cohorts (AUC = 0.88 and 0.89, respectively), demonstrating that the derived models could adequately predict the risk of multimodal treatment failure. Treatment failure risk factor point scales were derived for the identified variables separately for both cohorts. Patients with IVDU SEA represent a unique population with a distinct set of baseline parameters that predict treatment failure. Identification of relevant prognosticating factors will allow for the design of tailored treatment and follow-up regimens.

Patterns of care for patients with non-metastatic castration-resistant prostate cancer: Population-based study in Ontario, Canada.

53 Background: To describe patterns of practice of PSA testing and imaging for Ontario men receiving continuous androgen deprivation therapy (ADT) for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Methods: This was a retrospective, longitudinal, population-based study of administrative health data from 2008 to 2019. Men &gt; 65 years old receiving continuous ADT with documented CRPC were included. An administrative proxy definition was applied to capture patients with nmCRPC patients and excluded those with metastatic disease. Patients were indexed upon progression to CRPC and were followed until death or end of study period to assess frequency of monitoring with PSA tests and conventional imaging. A 2-year look-back window was used to assess patterns of care leading up to CRPC, as well as baseline covariates. Results: At a median follow-up of 40 months, 944 patients with CRPC were identified. Their median time from initiation of ADT to CRPC was 26 months, 61% of patients had their PSA measured twice or fewer in the year prior to index and 71% patients did not receive any imaging in the year following progression to CRPC. Almost all patients (98%, n = 921/944) in the study progressed to high-risk CRPC (HR-CRPC) during the study period, of which more than half received fewer than 3 PSA tests in the year prior to progression to HR-CRPC, and 31% received no imaging in the subsequent year. Conclusions: PSA testing and imaging studies are under-utilized in a real-world setting for the management of nmCRPC, including those at high-risk of developing metastatic disease. Infrequent monitoring impedes proper risk stratification, disease staging, detection of treatment failure and/or metastases, likely delaying necessary treatment intensification with life-prolonging therapies. Adherence to guideline recommendations and the importance of timely staging should be reinforced to optimize patients’ outcome.

Confirmation of infantile spasms resolution by prolonged outpatient EEGs.

ObjectiveThere is no consensus on the type or duration of the posttreatment EEG needed for assessing treatment response for infantile spasms (IS). We assessed whether outpatient electroencephalograms (EEGs) are sufficient to confirm infantile spasms (IS) treatment response.MethodsThree‐year retrospective review identified new‐onset IS patients. Only presumed responder to IS treatment at 2 weeks with a prolonged (>90 minutes) outpatient EEG to assess treatment response and at least 3‐month follow‐up were included. Hypsarrhythmia, electroclinical spasms, and sleep were evaluated for the first hour and for the duration of the EEG.ResultsWe included 37 consecutive patients with new‐onset IS and presumed clinical response at 2 weeks posttreatment. Follow‐up outpatient prolonged EEGs (median: 150 minutes, range: 90‐240 minutes) were obtained 14 days (IQR: 13‐17) after treatment initiation. EEGs detected ongoing IS in 11 of 37 (30%) presumed early responders. Prolonged outpatient EEG had a sensitivity of 85% (confidence interval [CI] 55%‐98%) for detecting treatment failure. When hypsarrhythmia and/or electroclinical spasms were not seen, EEG had a negative predictive value 92% (CI: 75%‐99%) for confirming continued IS resolution. Outpatient EEG combined with clinical assessment, however, identified all treatment failures at 2 weeks. Compared with the entire prolonged EEG, the first‐hour recording missed IS in 45% (5/11). While sleep was captured in 95% (35/37) of the full EEG recording, the first hour of recording captured sleep in only 54% (20/37).SignificanceInfantile spasms treatment response can be confirmed with a clinical history of spasm freedom and an outpatient prolonged EEG without evidence for ongoing spasms (hypsarrhythmia/electroclinical spams on EEG). Outpatient prolonged EEG, but not routine EEGs, represents an alternative to inpatient long‐term monitoring for IS posttreatment EEG follow‐up.

Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients

BackgroundHead and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy.MethodsPlasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry.ResultsTEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival.ConclusionsMonitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.

Virologic response of treatment experienced HIV-infected Ugandan children and adolescents on NNRTI based first-line regimen, previously monitored without viral load

BackgroundMany HIV-infected African children gained access to antiretroviral treatment (ART) through expansion of PEPFAR programs since 2004 and introduction of “Test and Treat” WHO guidelines in 2015. As ART access increases and children transition from adolescence to adulthood, treatment failure is inevitable. Viral load (VL) monitoring in Uganda was introduced in 2016 replacing clinical monitoring. However, there’s limited data on the comparative effectiveness of these two strategies among HIV-infected children in resource-limited settings (RLS).MethodsHIV-infected Ugandan children aged 1–12 years from HIV-care programs with > 1 year of first-line ART using only immunologic and clinical criteria to monitor response to treatment were screened in 2010. Eligible children were stratified by VL ≤ 400 and > 400 copies/ml randomized to clinical and immunological (control) versus clinical, immunological and VL monitoring to determine treatment failure with follow-up at 12, 24, 36, and 48 weeks. Plasma VL was analyzed retrospectively for controls. Mixed-effects logistic regression models were used to compare the prevalence of viral suppression between study arms and identify factors associated with viral suppression.ResultsAt baseline all children (n = 142) were on NNRTI based ART (75% Nevirapine, 25% efavirenz). One third of ART-experienced children had detectable VL at baseline despite high CD4%. Median age was 6 years (interquartile range [IQR]: 5–9) and 43% were female. Overall, the odds of viral suppression were not different between study arms: (arm by week interaction, p = 0.63), adjusted odds ratio [aOR]: 1.07; 95%CI: 0.53, 2.17, p = 0.57) and did not change over time (aOR: 0 vs 24 week: 1.15; 95% CI: 0.91, 1.46, p = 0.24 and 0 vs 48 weeks: 1.26; 95%CI: 0.92, 1.74, p = 0.15). Longer duration of a child’s ART exposure was associated with lower odds of viral suppression (aOR: 0.61; 95% CI: 0.42, 0.87, p < .01). Only 13% (9/71) of children with virologic failure were switched to second-line ART, in spite of access to real-time VL.ConclusionWith increasing ART exposure, viral load monitoring is critical for early detection of treatment failure in RLS. Clinicians need to make timely informed decisions to switch failing children to second-line ART.Trial registrationClinicalTrials.gov NCT04489953, 28 Jul 2020. Retrospectively registered. (https://register.clinicaltrials.gov).

Immunovirological treatment outcomes after 2 years of antiretroviral therapy in children living with the human immune deficiency virus in Lagos Nigeria

Background/objective: The World Health Organization (WHO) recommends routine assessment of antiretroviral treatment outcomes to detect treatment failure early and prevent the development of drug resistance. The aim of this study was to describe treatment outcomes of antiretroviral therapy (ART) over 2 years in children living with the human immune deficiency virus enrolled in the paediatric HIV clinic at the Lagos UniversityTeaching Hospital (LUTH).Materials and methods: This was a retrospective study of antiretroviral treatment outcomes in 278 children receiving antiretroviral therapy at the paediatric HIV clinic of LUTH. Demographic, clinical and laboratory data were retrospectively collected from clinical records of pediatric patientswho received antiretroviral therapy for 2 years ( from November 2015 to December 2017) . Virological failure was defined as viral load &gt; 400 copies/ml and immunological failure was defined as a CD4 count &lt;100 cells/mm3 or CD4 % &lt;15% after receiving antiretroviral agents for 12 months. Data was analysed using graph pad prism version 5.0.Results: After 12 months on antiretroviral therapy (ART), 101 (36%) had virological failure while 14 (5%) and 36 (13%) failed immunologically [CD4 count &lt;100 cells/mn3 and CD4 &lt;15% respectively]. Virological blips were observed at 24 months in 6.1% of patients while immunovirological discordance occurred in 30% of patients (poor virological clearance despite good immunological recovery) . High baseline viral load (&gt;5000 copies/ml), poor adherence (&lt;95%) and low baseline CD4 counts (101-249 cells/mn3) were significantly associated with virological failure, while low baseline CD4 counts (&lt;350 cells/mn3) and poor adherence (&lt;95%) were significantly associated with immunologic failure.Conclusion: The treatment outcomes observed in this study are similar to those reported in earlier studies. At 1 and 2 years of antiretroviral therapy , there was immune restoration however 101 (36%) and 87 (31%) respectively had virological failure despite good adherence to therapy and good Immunological restoration. This calls for early initiation and switch to second and third line drugs .&#x0D; Key words: Human immunodeficiency virus (HIV), zidovudine, lamivudine, nevirapine, virological blips, immunovirological discordance , children, Nigeria.

Trends in CD4 and viral load testing 2005 to 2018: multi-cohort study of people living with HIV in Southern Africa.

IntroductionThe World Health Organization (WHO) recommends a CD4 cell count before starting antiretroviral therapy (ART) to detect advanced HIV disease, and routine viral load (VL) testing following ART initiation to detect treatment failure. Donor support for CD4 testing has declined to prioritize access to VL monitoring. We examined trends in CD4 and VL testing among adults (≥15 years of age) starting ART in Southern Africa.MethodsWe analysed data from 14 HIV treatment programmes in Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in 2005 to 2018. We examined the frequency of CD4 and VL testing, the percentage of adults with CD4 or VL tests, and among those having a test, the percentage starting ART with advanced HIV disease (CD4 count <200 cells/mm3) or failing to suppress viral replication (>1000 HIV‐RNA copies/mL) after ART initiation. We used mixed effect logistic regression to assess time trends adjusted for age and sex.ResultsAmong 502,456 adults, the percentage with CD4 testing at ART initiation decreased from a high of 78.1% in 2008 to a low of 38.0% in 2017; the probability declined by 14% each year (odds ratio (OR) 0.86; 95% CI 0.86 to 0.86). Frequency of CD4 testing also declined. The percentage starting ART with advanced HIV disease declined from 83.3% in 2005 to 23.5% in 2018; each year the probability declined by 20% (OR 0.80; 95% CI 0.80 to 0.81). VL testing after starting ART varied; 61.0% of adults in South Africa and 10.7% in Malawi were tested, but fewer than 2% were tested in the other four countries. The probability of VL testing after ART start increased only modestly each year (OR 1.06; 95% CI 1.05 to 1.06). The percentage with unsuppressed VL was 8.6%. There was no evidence of a decrease in unsuppressed VL over time (OR 1.00; 95% CI 0.99 to 1.01).ConclusionsCD4 cell counting declined over time, including testing at the start of ART, despite the fact that many patients still initiated ART with advanced HIV disease. Without CD4 testing and expanded VL testing many patients with advanced HIV disease and treatment failure may go undetected, threatening the effectiveness of ART in sub‐Saharan Africa.

Predicting treatment failure in regular care Internet-Delivered Cognitive Behavior Therapy for depression and anxiety using only weekly symptom measures.

Therapist guided Internet-Delivered Cognitive Behavior Therapy (ICBT) is effective, but as in traditional CBT, not all patients improve, and clinicians generally fail to identify them early enough. We predict treatment failure in 12-week regular care ICBT for Depression, Panic disorder and Social anxiety disorder, using only patients' weekly symptom ratings to identify when the accuracy of predictions exceed 2 benchmarks: (a) chance, and (b) empirically derived clinician preferences for actionable predictions. Screening, pretreatment and weekly symptom ratings from 4310 regular care ICBT-patients from the Internet Psychiatry Clinic in Stockholm, Sweden was analyzed in a series of regression models each adding 1 more week of data. Final score was predicted in a holdout test sample, which was then categorized into Success or Failure (failure defined as the absence of both remitter and responder status). Classification analyses with Balanced Accuracy and 95% Confidence intervals was then compared to predefined benchmarks. Benchmark 1 (better than chance) was reached 1 week into all treatments. Social anxiety disorder reached Benchmark 2 (> 65%) at week 5, whereas Depression and Panic Disorder reached it at week 6. For depression, social anxiety and panic disorder, prediction with only patient-rated symptom scores can detect treatment failure 6 weeks into ICBT, with enough accuracy for a clinician to take action. Early identification of failing treatment attempts may be a viable way to increase the overall success rate of existing psychological treatments by providing extra clinical resources to at-risk patients, within a so-called Adaptive Treatment Strategy. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

BCR-ABL1 and beyond

Chronic myeloid leukaemia (CML) is characterised by the BCR-ABL1 fusion, which causes activated and abnormal cell signalling. If untreated, CML progresses to a rapidly fatal acute leukaemia at a median of 3 years. BCR-ABL1 can be superbly targeted by tyrosine kinase inhibitor drugs and most patients now have a life expectancy approaching that of the general population. However, about 20% of patients fail therapy and require a rapid change of treatment to avoid the risk of disease progression and death. Molecular monitoring of BCR-ABL1 transcript levels using quantitative PCR is now the recommended monitoring strategy and can detect treatment failure and emerging drug resistance. Acquired resistance is most frequently associated with mutations in the BCR-ABL1 kinase domain that interfere with drug binding. These are detected in ∼50% of resistant patients, but the other resistance mechanisms are not well understood. Data is emerging from next-generation sequencing studies that somatic variants in cancer-related genes occur at a high frequency at drug resistance. Furthermore, these mutations have also been detected in some patients at diagnosis and are associated with a poor outcome. Next-generation sequencing may provide important prognostic information for CML patients at diagnosis and resistance and identify targets for therapy.

Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma \u2013 results of a prospective biomarker study

BackgroundMetastasized or unresectable melanoma has been the first malignant tumor to be successfully treated with checkpoint inhibitors. Nevertheless, about 40–50% of the patients do not respond to these treatments and severe side effects are observed in up to 60%. Therefore, there is a high need to identify reliable biomarkers predicting response.Tumor Mutation Burden (TMB) is a debated predictor for response to checkpoint inhibitors and early measurement of ctDNA can help to detect treatment failure to immunotherapy in selected melanoma patients. However, it has not yet been clarified how TMB and ctDNA can be used to estimate response to combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma.Patients and methodsIn this prospective biomarker study, we included 35 melanoma patients with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy. In all patients, a tumor panel of 710 tumor-associated genes was applied (tumor vs. reference tissue comparison), followed by repetitive liquid biopsies. Cell-free DNA was extracted and at least one driver mutation was monitored. Treatment response was evaluated after about three months of therapy.ResultsTMB was significantly higher in responders than in nonresponders and TMB > 23.1 Mut/Mb (TMB-high) was associated with a survival benefit compared to TMB ≤ 23.1 Mut/Mb (TMB-low or TMB-intermediate). Furthermore, a > 50% decrease of cell-free DNA concentration or undetectable circulating tumor DNA (ctDNA), measured by tumor-specific variant copies/ml of plasma at first follow-up three weeks after treatment initiation were significantly associated with response to combined immunotherapy and improved overall survival, respectively. It is noticeable that no patient with TMB ≤ 23.1 Mut/Mb and detectable or increasing ctDNA at first follow-up responded to immunotherapy.ConclusionHigh TMB, > 50% decrease of cell-free DNA concentration, and undetectable ctDNA at first follow-up seem to be associated with response and overall survival under combined immunotherapy. The evaluation of ctDNA and cell-free DNA three weeks after treatment initiation may be suitable for early assessment of efficacy of immunotherapy.

First-line antiretroviral treatment and virological response among HIV adult patients at an accredited HIV care center, Cameroon

BackgroundViral load (VL) monitoring in the clinical follow-up of HIV patients to detect treatment failure is not routinely offered in Cameroon. The study was designed to characterize virological response on antiretroviral treatment (ART) among adults living with HIV and to identify predictors of virological failure (VF).MethodsBetween November 2014 and January 2016, a prospective, population-based cohort study was conducted among HIV-positive adults under first-line treatment and monitored at the Accredited HIV Care Center (AHCC) of Laquintinie Hospital of Douala. Clinical and biological data at the initiation of ART were collected from patients’ medical records. HIV VL at 12 and 24 months after the patient started treatment on ART were performed using quantitative real-time PCR protocol with the generic HIV Roche TaqMan assay. Descriptive and logistic regression analysis were performed in Stata SE11 version in data analysis.ResultsOverall 150 (45.5%) of 330 adults living with HIV were tested with at least one VL, and of these patients, 51 (34.0%) were tested with two VL during the followed-up. The VF was observed in 13 of 51 (25.5%) patients and among them, 8 (61.5%) switched to second-line ART regimens. Thirty-five (68.6%) of the 51 patients had an undetectable VL at the first VL measurement, and seven (13.7%) patients subsequently developed viral load rebound (VLR) on tritherapy. Using a multivariate analysis, the risk of VF was seven times higher in HIV adults who did not respect the medication hours (OR = 7.38, 95%CI = 1.56–34.90, p = 0.012) and eleven times higher in patients with none or primary school education (OR = 11.38, 95% CI = 2.41–53.76, p = 0.002).ConclusionLow education level and poor adherence are the main risk factors for VF. Strengthening therapeutic failure prevention strategies and routine VL surveillance would allow early detection of VF and contribute in achieving the third goal of UNAIDS which recommends “90–90-90” targets for People Living with HIV in resource-limited settings.

Predictors of triple therapy treatment failure among H. pylori infected patients attending at a tertiary hospital in Northwest Tanzania: a prospective study

BackgroundHelicobacter pylori (H.pylori) infection is a common medical problem in resource limited areas. The treatment outcome after triple therapy has not been well studied in developing countries and preliminary data suggests a high rate of treatment failure. This study investigated the triple therapy treatment failure rate and associated factors among dyspeptic patients receiving H. pylori first line therapy at a tertiary hospital, Tanzania.MethodsA prospective study in the Gastroenterology unit of the Bugando Medical Centre (BMC) was conducted between October 2015 and May 2017. All dyspeptic patients with stool antigen tests positive for H.pylori were given first line therapy, and stool antigen testing was repeated within 7 days and 5 weeks after completion of the treatment. Biopsies were taken before initiation of therapy and analysed for clarithromycin and quinolone resistance mutations using polymerise chain reaction (PCR) and sequencing. Adherence and other social-demographic characteristics were documented.ResultsA total of 210 patients were enrolled; the median age was 35 years (interquartile range, 27–48). First line treatment failure as defined by positive stool antigen 5 weeks post treatment was observed in 65/210 (31%) of patients. Independent predictors of first line treatment failure were presence of clarithromycin resistance mutations (OR: 23.12, 95% CI (9.38–56.98), P < 0.001) and poor adherence (OR: 7.39, 95% CI (3.25–16.77), P < 0.001). The sensitivity and specificity of stool antigen testing within 7 days after completion therapy in detecting treatment failure was 100 and 93.2%, respectively.ConclusionNearly one-third of patients with clarithromycin resistance mutations and poor adherence develop first line treatment failure. Routine stool antigen testing within seven days after completion of therapy can be considered in order to initiate second line treatment early to prevent associated morbidities.

Tracking endocrine resistance in estrogen-receptor positive breast cancer in ctDNA.

e14550 Background: Endocrine therapy is the standard of care treatment for patients with estrogen-receptor positive advanced breast cancer, owing to improved tolerability and comparable efficacy to that of cytotoxic chemotherapy. Half of such cancers will progress through first line therapy (primary endocrine resistance) and half will progress after an initial period of disease control (secondary or acquired endocrine resistance). A significant challenge is to test for and identify biomarkers which can guide the likely success of endocrine therapy as a single agent or in combination with small molecule inhibitors.This is particularly challenging where metastatic deposits reside at sites where biopsy is difficult. Potential biomarkers indicative of resistance to endocrine therapy have been identified and can be detected in circulating tumour DNA (ctDNA). CtDNA is shed from tumours and is detectable in a cancer patient’s bloodstream. Information on mutational profiles can guide an oncologist in the selection of targeted therapy in addition to hormonal therapy. Methods: We have analysed formalin-fixed paraffin-embedded(FFPE) tumour samples and longitudinal liquid biopsies from 19 patients who were treated with fulvestrant in combination with a novel inhibitor of the PIK3CA/AKT pathway with next-generation sequencing using a targeted 44-gene panel. Mutations identified using this technique were tracked during the course of treatment using droplet-digital PCR(ddPCR). Results: 57 samples were tested using a 44-gene panel; 19 FFPE tumour samples and matched ctDNA samples were obtained prior therapy and ctDNA samples at disease progression. Mutations detected in PIK3CA, AKT1, ESR1and TP53 genes were trackable in longitudinal ctDNA samples using ddPCR. The association between ctDNA dynamics and outcome will be presented. Conclusions: Multiple mutations that enable the early detection of treatment failure and resistance can be tracked in ctDNA. Investigating the clinical utility of ctDNA is paramount.

Predictors of treatment failure, time to switch and reasons for switching to second line antiretroviral therapy in HIV infected children receiving first line anti-retroviral therapy at a Tertiary Care Hospital in Ethiopia

BackgroundTreatment failure and delay in switching to second line regimen are major concerns in the treatment of HIV infected children in a resource limited setting. The aim of this study was to determine the prevalence and predictors of first line antiretroviral therapy (ART) regimen failure, reasons and time taken to switch to second line antiretroviral (ARV) medications after treatment failure among HIV-infected children.MethodsA retrospective cohort study was conducted February 2003 to May 2018 in HIV-clinic at Tikur Anbessa Specialized Hospital (TASH), Ethiopia. All HIV infected children ≤15 years of age and who were taking first line ART for at least 6 months were included. Data abstraction format was used to collect the data from patients’ chart and registry. Binary and multivariable logistic regression statistics were used.ResultsOut of 318 enrolled HIV-infected children, the prevalence of treatment failure was found to be 22.6% (72/318), among these 37 (51.4%) had only immunologic failure, 6 (8.3%) had only virologic failure and 24 (33.3%) had both clinical and immunological failure. The mean time taken to modify combination antiretroviral therapy (cART) regimen was 12.67 (4.96) weeks after treatment failure was confirmed. WHO Stage 3 and 4 [Adjusted Odds Ratio (AOR), 3.64, 95% CI 1.76–7.56], not having both parents as primary caretakers [AOR, 2.72 95% CI, 1.05–7.06], negative serology of care takers [AOR, 2.69 95% CI, 1.03–7.03], and cART initiation at 11 month or younger were predicting factors of treatment failure. Of the 141 (47.9%) children who had regimen switching or substitution, treatment failure (44.4%) and replacement of stavudine (d4T) (30.8%) were major reasons. Only 6.6% patients had received PMTCT service.ConclusionOne fifth of the patients had experienced treatment failure. Advanced WHO stage at baseline, not being taken care of by mother and father, negative sero-status caretakers, and younger age at initiation of cART were the predictors of treatment failure. PMTCT service uptake was very low. There was a significant time gap between detection of treatment failure and initiation of second line cART. Half of the patients encountered regimen switching or substitution of cART due to treatment failure and replacement of stavudine (d4T).