Safe Discontinuation Research Articles

HBV RNA as a Biomarker for Safe Antiviral Discontinuation: A Prospective Study of Nucleos(t)ide Analogue Withdrawal.

Withdrawal of nucleos(t)ide analog (NA) therapy is associated with hepatitis B surface antigen (HBsAg) loss and sustained, off-therapy partial cure (normal ALT [≤30 U/L males, ≤20 U/L females) with HBV DNA <2000 IU/mL) but should be offered only to those most likely to benefit. HBVRNA may be useful for risk stratification. The Hepatitis B Research Network Immune-Active Trial prospectively evaluated treatment with tenofovir (TDF) for 192 weeks ± peginterferon-α (PegIFN) for initial 24 weeks followed by protocolized withdrawal of TDF amongst eligible participants (NCT01369212). HBV RNA was evaluated as predictor of ALT flares and sustained partial cure (HBV DNA<2000 IU/mL) 48 weeks after TDF withdrawal. Of 93 participants discontinuing TDF (52 in TDF+PegIFN and 41 in TDF alone), 52 (55.9%) had unquantifiable HBVRNA at end-of-treatment. ALT flares (>5xULN) at 48 weeks off-therapy occurred in 33.3%, with pre-treatment age (≥35 years) and quantifiable HBV RNA at end-of-treatment, the best predictors (AUROC 0.74 and 0.85, training and test set) of ALT flare. A total of 26 (28.3%) had sustained partial cure; 3 (11.5%) with ALT flare. Non-quantifiable HBVRNA and qHBsAg <100 IU/mL at end-of-treatment were the best predictors of sustained partial cure (AUROC 0.84 and 0.93, training and test set). If HBVRNA was quantifiable at end-of-treatment, the likelihood of sustained partial cure was only 3% whereas if HBV RNA was unquantifiable and qHBsAg <100 IU/mL, this likelihood was 73%. HBVRNA is a useful biomarker in predicting likelihood of achieving sustained partial cure and safe withdrawal of NAs.

Digoxin Discontinuation in Patients with HFrEF on Beta-Blockers: Implication for Future “Knock-Out Trials” in Heart Failure

Background: National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers. Methods: In OPTIMIZE-HF, of 2,477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for one-year outcomes were estimated. Results: Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85–1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85–1.25) or death (HR, 0.91; 95% CI, 0.72–1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25–2.04), 1.62 (1.18–2.22) and 1.43 (1.08–1.89). Conclusions: Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.

Non-Small Cell Lung Cancer Metastatic Without Oncogenic Alterations.

This overview provides a thorough review of current treatment approaches for first-line management of nononcogenic addicted non-small cell lung cancer. We also address pertinent clinical decision-making queries encountered in everyday practice, such as the optimal treatment strategy for PD-L1-high patients, predictive factors for response to immune checkpoint inhibitors (ICI) both in terms of patient and cancer characteristics, the potential benefits of dual checkpoint blockade, and the unresolved issue of safe discontinuation strategies for long-term responders. Around one in five patients falls into this latter category while the majority develop either primary or acquired resistance to ICI-based first-line therapy, necessitating effective subsequent lines of treatment. Docetaxel, with or without combination of antiangiogenic agents, serves as the backbone of treatment, although evidence in the post-ICI setting is limited. Given that an inflamed tumor microenvironment (TME) is crucial for ICI responses, targeting the TME in cases of acquired resistance alongside continued ICI administration appears rational, although clinical trials so far have failed to confirm this hypothesis. Antibody-drug conjugates have emerged as a promising treatment modality, offering the potential for reduced toxicity and improved efficacy by targeting specific cancer antigens. Moreover, several chemotherapy-free approaches are currently under investigation for treatment-naïve patients, including alternative ICI and drugs targeting epitopes on both cancer and immune cells.

Quantitative Measurement of Serum HBcrAg Can Be Used to Assess the Feasibility of Safe Discontinuation of Antiviral Therapy for Chronic Hepatitis B.

Hepatitis B virus (HBV) infection is a serious global health problem, and chronic HBV infection significantly increases the risk of liver fibrosis, cirrhosis, and even hepatocellular carcinoma in patients. Current first-line therapeutics such as nucleos(t)ide analogues and interferons are unable to completely clear cccDNA, so the vast majority of patients need to take long-term or even lifelong medication. However, long-term virological and biochemical responses can be achieved in some patients after drug withdrawal. Successfully screening these patients with drug withdrawal advantages is difficult. Hepatitis-B-core-related antigen (HBcrAg) is a new HBV serological marker that which can reflect the level and transcription activity of cccDNA in hepatocytes. Therefore, HBcrAg has potential value in guiding patients in drug withdrawal. This review summarizes previous reports on HBcrAg and evaluates the application value of HBcrAg in safe drug discontinuation.

KIR-генетические факторы и ответ на терапию ингибиторами тирозинкиназ при хроническом миелоидном лейкозе

The development of tyrosine kinase inhibitors (TKIs) and their introduction into clinical practice considerably improved the prognosis for chronic myeloid leukemia (CML) patients. About 50 % of patients with achieved deep molecular response are eligible for safe TKI discontinuation. Despite these advances, no reliable biomarkers are known to predict a response and sustaining treatment-free remission after TKI withdrawal. As TKIs do not destroy leukemic stem cells, which can be responsible for relapse, critical importance in CML is attached to natural killers (NK-cells) having antitumor activity. Functional activity of NK-cells is evaluated by expression level and repertoire of killer cell immunoglobulin-like receptors (KIR). Current studies demonstrate that a patient’s KIR genotype affects the probability of achieving early and deep molecular responses to first- and second-generation TKIs, progression-free and overall survivals, and sustaining treatment-free remission. On that ground, KIR-genetic factors can be regarded as promising predictors of response to TKI therapy in CML. Early clinical studies, which dealt with monoclonal antibodies blocking the inhibitory KIR in order to increase NK-cell activity, revealed an acceptable safety profile and efficacy in some hematological diseases (such as acute myeloid leukemia, multiple myeloma, Т-cell lymphoma) if used in combination with cytostatic drugs or antitumor monoclonal antibodies. KIR genotype determination can contribute to the development of effective therapies of this malignant hematological tumor.

A US payer perspective health economic model assessing value of monitoring disease activity to inform discontinuation and re-initiation of DMT in multiple sclerosis

Objectives: We evaluate the potential clinical and cost impacts of discontinuing disease-modifying therapy (DMT) in people with multiple sclerosis (PwMS) when age-related immunosenescence can reduce DMT efficacy while increasing associated risks. Methods: A Markov model simulated clinical and cost impacts to the patient and payers when a proportion of eligible patients with relapsing remitting multiple sclerosis (RRMS) discontinue DMT. Eligibility was defined as age >55 years, an RRMS diagnosis of >5 years, and no history of relapses for 5 years. Increasing the proportion of eligible patients willing to discontinue therapy was also modeled. Clinical and cost inputs were from published literature. Results: Difference in EDSS progression between eligible patients who did and did not attempt discontinuation was not significant. After 1 year of eligibility, per-patient costs were $96k lower in the cohort that attempted discontinuation; however a higher proportion of relapses were seen in this group. When the proportion of patients willing to discontinue DMT increased, clinical findings remained consistent while the average cost per patient decreased. Conclusion: While there are increased clinical and cost benefits as more eligible patients attempt discontinuation, the risk of relapses can increase. Timely disease monitoring is required to manage safe DMT discontinuation.

Characteristics and Attendance of Patients Eligible for the PASS Clinic: A Transition of Care Model After Acute Symptomatic Seizures.

Most acute symptomatic seizure (ASyS) patients stay on antiseizure medications (ASM) long-term, despite low epilepsy development risk. The Post-Acute Symptomatic Seizure (PASS) clinic is a transition of care model for ASyS patients who individualize ASM management with the goal of a safe deprescription. We evaluated patients discharged on ASMs after a witnessed or suspected ASyS to analyze their PASS clinic visit attendance and its predictors. A single-center, retrospective cohort study of adults without epilepsy who were discharged from January 1, 2019, to September 30, 2019, on first-time ASMs due to witnessed or suspected ASyS (PASS clinic-eligible). We fit a cause-specific Cox proportional hazards model to analyze factors associated with PASS clinic attendance, which depends on survival in this patient population that has a high early postdischarge mortality (a competing risk). We checked for multicollinearity and the assumption of proportional hazards. Among 307 PASS clinic-eligible patients, 95 (30.9%) attended the clinic and 136 (44.3%) died during a median follow-up of 14 months (interquartile range = 2-34). ASyS occurred in 60.2% (convulsive 47%; electrographic 26.7%) of patients. ASMs were continued in the absence of ASyS or epileptiform abnormalities (EAs) in 27% of patients. Multivariable analysis revealed that the presence of EAs (HR = 1.69, 95% CI 1.10-2.59), PASS clinic appointments provided before discharge (HR = 3.39, 95% CI 2.15-5.33), and less frequently noted ASyS etiologies such as autoimmune encephalitis (HR = 2.03, 95% CI 1.07-3.86) were associated with an increased clinic attendance rate. Medicare/Medicaid insurance (HR = 0.43, 95% CI 0.24-0.78, p = 0.005) and the presence of progressive brain injury (i.e., tumors; HR = 0.55, 95% CI 0.32-0.95, p = 0.032) were associated with reduced rate of PASS clinic attendance. Our real-world data highlight the need for appropriate postdischarge follow-up of ASyS patients, which can be fulfilled by the PASS clinic model. Modest PASS clinic attendance can be significantly improved by adhering to a structured discharge planning process whereby appointments are provided before discharge. Future research comparing patient outcomes, specifically safe ASM discontinuation in a PASS clinic model to routine clinical care, is needed.

Safe discontinuation of psychotropic drugs in older people? : New evidence and practical approach

Many older patients are permanently prescribed one or more psychotropic drugs for treatment of symptoms, such as behavioral and psychological symptoms in dementia, depressive symptoms, anxiety, and insomnia. They therefore contribute to the risk of polypharmacy. Recently, deprescribing studies have been published in order to clarify if inadequate medications can be safely discontinued. This mini-review summarizes the study results and derives practical recommendations for routine use. A literature search was carried out in PubMed for clinical studies on deprescribing in association with psychotropic substances. After removal of duplications, 12heterogeneous clinical studies were identified and reduction of psychotropic substances could be successfully achieved in 8studies. In four of these studies psychological, behavioral and functional endpoints were reported. Criteria for successful deprescribing of sedatives were in particular motivation, information and sufficient cooperation of the patients and for antipsychotic drugs in people with dementia, the sustainable establishment of nonpharmaceutical treatment strategies. Deprescribing was not attempted in cases of ahistory of severe chronic mental illness and in cases of severe behavioral symptoms in dementia. Evidence for antidepressants was not sufficient to extract practical recommendations. Safe deprescribing of antipsychotic drugs in patients with dementia is justified if non-pharmacological treatment options are sustainably implemented, and for sedative drugs in well-informed, highly motivated and cooperative patients.

Shared Decision Making and Cardioneuroablation Allow Discontinuation of Permanent Pacing in Patients with Vagally Mediated Bradycardia.

Safe discontinuation of pacemaker therapy for vagally mediated bradycardia is a dilemma. The aim of the study was to present the outcomes of a proposed diagnostic and therapeutic process aimed at discontinuing or not restoring pacemaker therapy (PPM) in patients with vagally mediated bradycardia. The study group consisted of two subgroups of patients with suspected vagally mediated bradycardia who were considered to have PPM discontinued or not to restore their PPM if cardioneuroablation (CNA) would successfully treat their bradycardia. A group of 3 patients had just their pacemaker explanted but reimplantation was suggested, and 17 patients had preexisting pacemakers implanted. An invasive electrophysiology study was performed. If EPS was negative, extracardiac vagal nerve stimulation (ECVS) was performed. Then, patients with positive ECVS received CNA. Patients with an implanted pacemaker had it programmed to pace at the lowest possible rate. After the observational period and control EPS including ECVS, redo-CNA was performed if pauses were induced. The decision to explant the pacemaker was obtained based on shared decision making (SDM). After initial clinical and electrophysiological evaluation, 17 patients were deemed eligible for CNA (which was then performed). During the observational period after the initial CNA, all 17 patients were clinically asymptomatic. The subsequent invasive evaluation with ECVS resulted in pause induction in seven (41%) patients, and these patients underwent redo-CNA. Then, SDM resulted in the discontinuation of pacemaker therapy or a decision to not perform pacemaker reimplantation in all the patients after CAN. The pacemaker was explanted in 12 patients post-CNA, while in 2 patients explantation was postponed. During a median follow-up of 18 (IQR: 8-22) months, recurrent syncope did not occur in the CNA recipients. Pacemaker therapy in patients with vagally mediated bradycardia could be discontinued safely after CNA.

Utility of Procalcitonin in Clinical Practice

The rise of multi-resistant infections and complications associated with the overuse of antibiotics has led to the implementation of antibiotic stewardship strategies as a marker of patient safety and quality. Using biomarkers that can accurately predict the presence or absence of bacterial infection, thus signaling the need for antibiotic use, or supporting appropriate and safe discontinuation, has become an increasingly relevant strategy for antibiotic stewardship. Evidence supporting procalcitonin for antimicrobial stewardship has focused mostly on lower respiratory tract infections and sepsis. This review discusses the most relevant evidence to support the use of procalcitonin in clinical practice.

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome.

Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for adults. In these patients, treatment with rituximab allows safe discontinuation of steroids, but long-term efficacy is variable, and some patients experience NS relapses after B cell reconstitution. In this study, we aimed to determine disease-associated changes in the B and T cell phenotype of adult patients with SDND/FRNS after steroid-induced remission. We also investigated whether any of these changes in immune cell subsets could discriminate between patients who developed NS relapses after steroid-sparing treatment with rituximab from those who did not. Lymphocyte subsets in SDNS/FRNS patients (n = 18) were compared to those from patients with steroid-resistant NS (SRNS, n = 7) and healthy volunteers (HV, n = 15). Before rituximab, SDND/FRNS patients showed increased frequencies of total and memory B cells, mainly with a CD38-negative phenotype. Within the T-cell compartment, significantly lower levels of FOXP3+ regulatory T cells (Tregs) were found, mostly due to a reduction in CD45RO+ memory Tregs compared to both SRNS and HV. The levels of CD45RO+ Tregs were significantly lower at baseline in patients who relapsed after rituximab (n = 9) compared to patients who did not (n = 9). In conclusion, patients with SDND/FRNS displayed expansion of memory B cells and reduced memory Tregs. Treg levels at baseline may help identify patients who will achieve sustained remission following rituximab infusion from those who will experience NS relapses.

Novel Virus Air Sampler Based on Electrostatic Precipitation and Air Sampling of SARS-CoV-2.

The assessment of airborne viruses in air is a critical step in the design of appropriate prevention and control measures. Hence, herein, we developed a novel wet-type electrostatic air sampler using a viral dissolution buffer containing a radical scavenging agent, and verified the concentration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the air of hospital rooms inhabiting coronavirus disease 2019 (COVID-19) patients and public areas. RNA damage caused by corona discharge was negligible when Buffer AVL was used as the collecting electrode. The viral RNA concentration in the air of the room varied by patient: 3.9 × 103 copy/m3 on the 10th day after onset in a mild case and 1.3 × 103 copy/m3 on the 18th day in a severe case. Viral RNA levels were 7.8 × 102 and 1.9 × 102 copy/m3 in the air of the office and food court, respectively, where people removed their masks when eating and talking, but it remained undetected in the station corridor where all the people were wearing masks. The assessment of airborne SARS-CoV-2 RNA using the proposed sampler can serve as a basis for the safe discontinuation of COVID-19 isolation precautions to identify exposure hotspots and alert individuals at increased infection risks.

Self-reported reasons for discontinuation or continuation of antipsychotic medication in individuals with first-episode schizophrenia.

Many individuals with schizophrenia discontinue initially prescribed antipsychotics. Knowledge on reasons for discontinuation among individuals with first-episode schizophrenia is sparse. We aimed to describe reasons for discontinuation and continuation, differences between individuals discontinuing and continuing, and factors predicting reasons for discontinuation or continuation. This was a prospective cohort study with a post hoc design. Individuals with first-episode schizophrenia were included from early intervention teams in Denmark from 2009-2012. Sociodemographic and clinical variables were collected at baseline and reasons for discontinuation and continuation of antipsychotics were assessed at 3.5-year follow-up. Among 215 patients, 76 reported reasons for discontinuation and 139 for continuation. The most frequent reasons for discontinuation were "side effects" and "patient believed he/she no longer needed the medication because he/she was now better". The most frequent reasons for continuation were "benefits for positive symptoms" and "another person told them to". Individuals who discontinued antipsychotics were at baseline younger, had longer DUP, less negative symptoms, better social function, lower compliance, higher self-belief of coping, and fewer used antipsychotics compared to those continuing antipsychotics. The effect of antipsychotics is the main reason to continue, whereas side effects were the main reason to discontinue. Knowledge of reasons to discontinue or continue is helpful in shared decision-making, identifying individuals with high odds of discontinuation, improving adherence, and helping with safe discontinuation.

Correlation between serum quantitative HBsAg and HBV DNA levels in chronic hepatitis B patients

Background/Aim. Quantitative hepatitis B virus (HBV) surface antigen (qHBsAg) has become increasingly wide-spread in the last few years in both diagnostic and therapeutic protocols for HBV infection. Numerous studies have proposed it as a surrogate marker for covalently closed circular DNA (cccDNA). The aim of the study was to determine the correlation between qHBsAg and HBV DNA viremia in untreated patients. Methods. The study included 112 untreated patients diagnosed with chronic HBV infection. Demographic and other data from medical records and laboratory analyses, taken as part of routine chronic HBV infection diagnosis with the determination of qHBsAg and HBV DNA viremia, were recorded for all patients. Results. The average age of the patients included in the study was 48.27 ? 15.14 years; males (58%) were more represented. qHBsAg levels had a high-intensity positive correlation with HBV DNA viremia. The concentration of qHBsAg, HBV DNA viremia, and the concentrations of alanine aminotransferase and aspartate aminotransferase showed statistically significantly higher values in HBV e antigen (HBeAg)-positive than in HBeAg-negative patients. Conclusion. Our study showed that qHBsAg has a high-intensity positive correlation with HBV DNA viremia. The use of qHBsAg is essential for determining the phase of chronic HBV infection, assessment of the success and length of treatment, as well as for safe discontinuation of antiviral therapy with a lower risk of relapse.

Abstract 15031: Anticoagulation Status and Risk of Stroke Following Leak-Closure Procedure for Residual Leak After Occlusion of the Left Atrial Appendage in Patients With Atrial Fibrillation

Introduction: Studies have shown a correlation between leaks following left atrial appendage occlusion procedure and thromboembolic (TE) events. Hypothesis: We investigated the benefits of leak-closure in terms of safe discontinuation of oral anticoagulation (OAC) and minimization of the stroke-risk. Methods: Consecutive patients undergoing leak-closure procedure at our institution were included in the analysis. Procedures included closure with endovascular coils or Amplatzer plug or by using radiofrequency ablation (RFA). Persistence of the leak was verified by multiplane transesophageal echocardiogram (TEE) using color Doppler. Follow-up TEE were performed 60 ± 15 days post-procedure to evaluate LAA closure and patients were kept on OAC until then. After confirmation of closure, they were transitioned to ASA 81 mg/day. All patients were monitored quarterly for thromboembolic (TE) events. Results: A total of 139 post-Watchman patients undergoing leak-closure were included in the analysis (RFA: 10, Amplatzer plug: 5, coil-closure: 124). Pre-coil closure TE events were reported in 7 (5%) subjects. Moderate (3-4 mm) and severe (≥5 mm) leak were detected in 118 (85%) and 21 (15%) patients respectively. After the leak-closure procedure, complete sealing of the leak was confirmed at the follow-up TEE in 138 (99.2%) patients. Figure 1 shows significant reduction in TE events following the leak-closure procedure (p=0.031). During the 2-year follow-up period, six deaths were reported due to unrelated causes. Of the remaining 133 subjects, two patients were on DAPT because of history of coronary artery disease, two with prior stroke were on half-dose OAC and the remaining 129 (95.8%) were on ASA 81 mg/day. No TE events were reported in patients that transitioned to ASA. Conclusions: In this series, successful percutaneous leak-closure not only minimized the risk of stroke but also enabled the majority of patients to discontinue OAC without any TE events.

Avis d’experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d’un trouble bipolaire traitées par valproate

IntroductionThe perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. MethodsA panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. ResultsFirst of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. ConclusionAlthough the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant.

The Long-Acting Cabotegravir Tail as an Implementation Challenge: Planning for Safe Discontinuation.

The long-acting feature of cabotegravir, an integrase-inhibitor highly effective in preventing acquisition of HIV in adolescents and adults, is both its greatest strength and a challenge to its implementation. Cab-LA is administered at 8-week intervals (after an initial loading dose) but has a long, variable drug "tail" that may leave users vulnerable to future drug resistance if they contract HIV during this critical period. The potential for cab-LA to meaningfully contribute to ending the HIV Epidemic is hindered by, among other factors, limited resources to guide patients and providers on how to safely discontinue injections. We suggest three key strategies to overcome this specific challenge: (1) Comprehensive patient education and counseling about the drug tail; (2) Training and coaching PrEP care teams, including clinical and non-clinical staff, on communication around the tail; (3) Adherence support strategies, including monitoring of cabotegravir drug levels after discontinuation, for a personalized medicine approach to safe discontinuation.

Postoperative Antibiotics and Time to Reach Discharge Criteria after Appendectomy for Complex Appendicitis

Introduction: Postoperative antibiotic treatment is indicated for 3–5 days following appendectomy for complex appendicitis. However, meeting discharge criteria may allow for safe discontinuation of antibiotics and discharge. This study assessed the association between time to reach discharge criteria and duration of postoperative antibiotic use and length of stay. Methods: This is a multicenter retrospective cohort study including patients who underwent appendectomy for complex appendicitis and received postoperative antibiotics for >24 h. Main outcome measures were time to reach discharge criteria, duration of postoperative antibiotic use, length of hospital stay, and postoperative infectious complications. Discharge criteria were defined as absence of fever (temperature ≤38°C) for 24 h, ability to tolerate oral intake, and pain controlled by oral analgesics. Results: Between May 2014 and January 2015, 124 patients were included. Time to reach discharge criteria was 2 days (interquartile range [IQR] 1–3). Patients received postoperative antibiotics and were in hospital for a median of 5 (IQR 3–5) and 5 (IQR 4–6) days, respectively. Infectious complications occurred in 12% and did not differ between patients reaching discharge criteria before or after 2 postoperative days. Discussion: Discharge criteria were met by a median of 2 days after appendectomy for complex appendicitis. This suggests that postoperative antibiotics duration and thereby hospital stay can be reduced. In daily practice, prescribed antibiotics are not reduced in total days given. Prospective studies that evaluate limited postoperative antibiotic use, based on these criteria, are necessary.

Serum Pregenomic RNA Combined With Hepatitis B Core-Related Antigen Helps Predict the Risk of Virological Relapse After Discontinuation of Nucleos(t)ide Analogs in Patients With Chronic Hepatitis B.

Background and AimCessation of nucleos(t)ide analogs (NAs) therapy in patients with chronic hepatitis B (CHB) is uncommon. Although criteria for discontinuation appear in some guidelines, the indicators for assessing discontinuation of NAs are limited, whether NAs can be safely ceased remains a difficult clinical issue. Our study aimed to investigate the role of serum pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) at the end of treatment (EOT) in guiding the safe discontinuation of NAs in CHB patients.MethodsThis is a retrospective study, clinical data of all CHB patients who discontinued NAs treatment at West China Hospital between June 2020 and January 2021 were collected, including EOT pgRNA, HBcrAg, hepatitis B surface antigen (HBsAg), etc. All patients should meet the Asian-Pacific guideline for discontinuation. Observing virological relapse (VR) rates during 1 year of NAs discontinuation and analyzing the relationship between EOT pgRNA, HBcrAg, and VR.ResultsA total of 64 patients were enrolled in this study and 33 (51.5%) patients experienced VR in 1 year. EOT pgRNA positivity (OR = 14.59, p = 0.026) and EOT higher HBcrAg levels (OR = 14.14, p = 0.001) were independent risk factors for VR. The area under the receiver-operating characteristic (AUROC) value of EOT HBcrAg for VR was 0.817 (p < 0.001), optimal cut-off value was 3.3 log10 U/mL. Patients with EOT pgRNA positivity and EOT HBcrAg >3.3 log10 U/mL were more likely to experience VR after discontinuation of NAs (88.9 vs. 45.5%, p = 0.027).ConclusionAccording to current guidelines, a higher VR rate occurs after cessation of NAs. EOT pgRNA positivity and higher HBcrAg level carries a higher risk of VR. Combining these novel markers can better help us assess whether patients can safely cease NAs treatment.

Assessment of Strategies for Safe Drug Discontinuation and Transition of Denosumab Treatment in PMO-Insights From a Mechanistic PK/PD Model of Bone Turnover.

Denosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures. However, concerns have been recently raised regarding safety when drug treatment is discontinued. Mechanistic pharmacokinetic-pharmacodynamic (PK-PD) models are the most sophisticated tools to develop patient specific drug treatments of PMO to restore bone mass. However, only a few PK-PD models have addressed the effect of Dmab drug holidays on changes in BMD. We showed that using a standard bone cell population model (BCPM) of bone remodelling it is not possible to account for the spike in osteoclast numbers observed after Dmab discontinuation. We show that inclusion of a variable osteoclast precursor pool in BCPMs is essential to predict the experimentally observed rapid rise in osteoclast numbers and the associated increases in bone resorption. This new model also showed that Dmab withdrawal leads to a rapid increase of damage in the bone matrix, which in turn decreases the local safety factor for fatigue failure. Our simulation results show that changes in BMD strongly depend on Dmab concentration in the central compartment. Consequently, bone weight (BW) might play an important factor in calculating effective Dmab doses. The currently clinically prescribed constant Dmab dose of 60 mg injected every 6 months is less effective in increasing BMD for patients with high BW (2.5% for 80 kg in contrast to 8% for 60 kg after 6 years of treatment). However, bone loss observed 24 months after Dmab withdrawal is less pronounced in patients with high BW (3.5% for 80kg and 8.5% for 60 kg). Finally, we studied how to safely discontinue Dmab treatment by exploring several transitional and combined drug treatment strategies. Our simulation results indicate that using transitional reduced Dmab doses are not effective in reducing rapid bone loss. However, we identify that use of a bisphosphonate (BP) is highly effective in avoiding rapid bone loss and increase in bone tissue damage compared to abrupt withdrawal of Dmab. Furthermore, the final values of BMD and damage were not sensitive to the time of administration of the BP.