Timing and Determinants of Tuberculosis Treatment Interruption in Nairobi County, Kenya

Tuberculosis (TB) treatment is a key pillar in the management and control of TB. Service delivery within the treatment facilities plays an important role in ensuring treatment adherence by TB patients. A prospective cohort study involving 25 health facilities, 25 facility in-charge officers and 291 patients diagnosed as new sputum smear positive (SM+) between December 2014 and July 2015 was undertaken. The aim of the study was to estimate the median time to treatment interruption, associated factors and overall predictors of non-adherence to TB treatment. A total of 19 (6.5%) treatment interruptions were observed. The median time to default was 56 [95% CI, 36-105] days. Treatment in a non-public facility [AOR=0.210, 95% CI (0.046-0.952)] and facilities perceived to have adequate number of health care workers to offer Directly Observed Therapy (DOT) [AOR=0.195, 95% CI (0.068-0.56)] showed a lower odds of treatment interruption whereas attainment of secondary level education [AOR=5.28, 95% CI (1.18-23.59)] indicated a higher odds of treatment interruption. Non-clinical aspects of health care service delivery influence patient adherence to TB treatment. Health seeking behavior of groups considered to be high risk for treatment interruption should be incorporated into the design and delivery of TB treatment

Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption.

The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination

Timing and prognostic factors of tuberculosis treatment interruption

The global Tuberculosis epidemic (TB) poses a significant public health threat. While the consequences of TB treatment interruption are indisputable, the knowledge about the timing and prognostic factors of TB treatment interruption is fundamental. Despite a considerable amount of evaluation, the timing and prognostic factors of TB treatment interruption have been inconsistently identified from one study to another. Therefore, this study aimed to examine the evidence obtained from published literature on the timing and prognostic factors of TB treatment interruption at different points of the treatment course. In this review, three databases namely Pubmed, Scopus, and Science Direct were used to identify articles published from January 2003 to February 2018. This was based on the inclusion criteria and keywords including ‘default’, ‘survival time’, ‘tuberculosis’, and ‘treatment interruption’. The nine selected studies were prospective and retrospective cohort studies conducted in developing countries. The diversity of the study’s participants and TB treatment interruption definition were allowed, thus delineating a heterogeneous finding. This review suggests that the interruption predominantly occurred during the maintenance phase of treatment course. Despite the finding, a considerable gap in understanding the prognostic factors at different time points of TB treatment interruption was elicited. The heterogeneity across the studies may limit the inferences and warrant further evaluation. In essence, the time-related information should be integrated into framing impactful public health strategy, while a vigorous attempt on the evaluation of the cognitive, behavioural and psychosocial aspects may be beneficial

Plasticity of the Immune System in Children Following Treatment Interruption in HIV-1 Infection

It is intriguing that, unlike adults with HIV-1, children with HIV-1 reach a greater CD4+ T cell recovery following planned treatment cessation. The reasons for the better outcomes in children remain unknown but may be related to increased thymic output and diversity of T cell receptor repertoires. HIV-1 infected children from the PENTA 11 trial tolerated planned treatment interruption without adverse long-term clinical, virological, or immunological consequences, once antiretroviral therapy was re-introduced. This contrasts to treatment interruption trials of HIV-1 infected adults, who had rapid changes in T cells and slow recovery when antiretroviral therapy was restarted. How children can develop such effective immune responses to planned treatment interruption may be critical for future studies. PENTA 11 was a randomized, phase II trial of planned treatment interruptions in HIV-1-infected children (ISRCTN 36694210). In this sub-study, eight patients in long-term follow-up were chosen with CD4+ count>500/ml, viral load <50c/ml at baseline: four patients on treatment interruption and four on continuous treatment. Together with measurements of thymic output, we used high-throughput next generation sequencing and bioinformatics to systematically organize memory CD8+ and naïve CD4+ T cell receptors according to diversity, clonal expansions, sequence sharing, antigen specificity, and T cell receptor similarities following treatment interruption compared to continuous treatment. We observed an increase in thymic output following treatment interruption compared to continuous treatment. This was accompanied by an increase in T cell receptor clonal expansions, increased T cell receptor sharing, and higher sequence similarities between patients, suggesting a more focused T cell receptor repertoire. The low numbers of patients included is a limitation and the data should be interpreted with caution. Nonetheless, the high levels of thymic output and the high diversity of the T cell receptor repertoire in children may be sufficient to reconstitute the T cell immune repertoire and reverse the impact of interruption of antiretroviral therapy. Importantly, the effective T cell receptor repertoires following treatment interruption may inform novel therapeutic strategies in children infected with HIV-1

Effects of delays to response blocking when used as treatment for problem behavior maintained by automatic reinforcement

Response blocking and response interruption are common interventions for problem behavior maintained by automatic reinforcement in the treatment literature, but these interventions may be extremely challenging for caregivers to implement with fidelity (i.e., immediately blocking each instance). We evaluated the effects of challenges to the procedural integrity of response blocking and interruption procedures upon the maintenance of treatment effects for problem behavior maintained by automatic reinforcement for two young men by measuring aberrant behavior under several conditions including a baseline condition, an immediate response blocking or interruption condition, and delayed response blocking or interruption conditions (e.g., 3-s, 15-s, and 30-s delays). The results indicated that even brief delays to implementing blocking and interruption severely compromised treatment efficacy

A protocol on information-motivation-behavioural skills risk of intensive phase treatment interruption among pulmonary tuberculosis patients in urban districts, Selangor

Introduction: Despite advancement of treatment modalities, Tuberculosis (TB) treatment interruption rate has globally accelerating, calling for greater framework shifting towards psychosocial intervention. Similarly, Selangor state had reported the perturbing TB treatment interruption rate, which was figured persistently above 10% in the interval year of 2014 to 2018, thus signifies an empirical assessment on Information-Motivation-Behavioural skills (IMB) determinants of TB intensive phase treatment. This study aims to determine the time to intensive phase TB treatment interruption and its prognostic factors among newly diagnosed pulmonary Tuberculosis (PTB) smear positive patients in urban district Selangor. Methods: A multi-centric prospective cohort study will recruit 695 newly diagnosed PTB smear positive patients at treatment centres in urban districts, Selangor. This study will utilize validated self-administered questionnaire and standardised data collection form (PROFORMA). At baseline, we will elicit information on IMB models constructs, additionally on socio-demographics, health service factors and clinical characteristics. Meanwhile, four points follow up will be executed to retrieve information on treatment status and time varying effects of body weight, treatment side effects, symptoms improvement and internalised stigma. Finally, survival analysis will be computed to identify the time to intensive phase treatment interruption and its prognostic factors. Conclusion: This study will enlighten IMB model determinants of intensive phase treatment interruption, hence to endeavour psychosocial elements in designing time relevant public health strategies in TB case management

Effects of 2, 4, 5-Trichlorophenoxyacetic Acid on Swiss-Webster Mice

Pure and Commercial samples of the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5- T) were tested on Swiss-Webster mice for: (1) interruption of the estrus cycle and (2) teratogenic effects. The estrus cycle of mice administered Commercial 2,4,5-T was interrupted in 42.9% of the animals and in 12.5% of the animals given Pure 2,4,5-T. No fetal abnormalities were found in pregnant animals treated with Commercial or Pure 2,4,5-T. Fetal resorptions were found in both treatment groups. Treatment with Pure 2,4,5-T produced a significant decrease in viable fetal weight and increased fetal deaths

Implications of therapy interruption on monthly migraine days and modified migraine disability assessment in patients treated with erenumab for chronic and episodic migraine: SQUARE study interim results.

BACKGROUND There are limited real-world data in Switzerland examining the impact of erenumab, a fully human IgG2 monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor, on migraine-related quality of life. OBJECTIVE This 18-month interim analysis of 172 patients with episodic or chronic migraine from the SQUARE study provides first prospective insights on the impact of mandatory erenumab treatment interruption, following Swiss-reimbursement requirements, in a real-world clinical setting in Switzerland. FINDINGS Recruited patients receiving 70 or 140 mg erenumab underwent treatment interruption on average 11.2 months after therapy onset with a mean duration of 4 months. There were sustained improvements in mean monthly migraine days (MMD) and migraine disability (mMIDAS) during initial treatment with erenumab. Treatment interruption was associated with a temporary worsening of condition. Symptoms ameliorated upon therapy reuptake reaching improvements similar to pre-break within 3 months. CONCLUSIONS Treatment interruption was associated with a temporary worsening of condition, which improved again after therapy restart

Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BackgroundIn the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study.Patients and methodsPatients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations.ResultsThe safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%).ConclusionsMost EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education.Trial registration numberNCT00863655