Interruption Strategies Research Articles

Real-life management of dual antiplatelet therapy interruption: the REGINA survey

Concern about procedure-related bleeding is a major reason for premature discontinuation of dual oral antiplatelet therapy (APT); treatment cessation is detrimental in patients with coronary artery disease (CAD), especially after drug-eluting stent (DES) placement. The nationwide REGINA survey was designed to evaluate how the interruption of dual APT is managed in the 'real world'. Physicians (2700/4581) were randomly selected to participate in a computer-assisted telephone interview. Knowledge about DES and APT was appraised by multiple-choice questions. Strategies for temporary interruption of dual APT before an invasive or surgical procedure were evaluated using 21 scenarios, including high-risk (30 days after DES) and low-risk (18 months after DES) periods. Out of 2700 practitioners, 2515 completed the interview. Rates of correct answers to basic knowledge questions ranged from 0% (dentists) to 52% (cardiologists). Unjustified total interruption of dual APT was much more frequent than expected (22.0% vs. 11.8%). A strategy of total interruption was less frequently chosen in the period of high ischemic risk compared to the low-risk period (13.7% vs. 31.1%, p<0.0001). Dual APT interruption in patients who require additional invasive cardiac or surgical procedures depended on type of physician consulted (more frequent in specialists than general practitioners or dentists), and on the physician's age and practice type (rural/private vs. urban/hospital). Correct answers were more frequently given in situations bearing a major risk, either ischemic or bleeding risk, than in those with no risk (49.2% vs. 30.2%, p<0.0001). Low-molecular-weight heparin was the substitution therapy in over two-thirds of scenarios and was associated with longer periods of APT interruption. Adequate management of APT in patients with intracoronary stents who undergo potentially haemorrhagic invasive procedures depends mainly on the type of physician involved and their practice rather than on a carefully weighted assessment of ischemic/bleeding risk. Our findings suggest a lack of scientific evidence, insufficient knowledge of guidelines, and poor communication between physicians managing these patients.

Current practices in the management of lymphatic filariasis

Lymphatic filariasis is a major cause of acute and chronic morbidity in 81 countries. The availability of safe treatment regimens along with rapid diagnostic tools resulted in a global program to eliminate the disease. The two main objectives of the global elimination program are to interrupt transmission of the parasites and to provide care for those with the disease. The strategy for transmission interruption is preventive chemotherapy through mass drug administration. This article reviews the current treatment regimens for lymphatic filariasis and discusses the challenges posed by co-endemicity with other diseases. The role of integrated vector management as a supplementary strategy for mass drug administration and new strategies for treatment and morbidity control through antibiotic targeting of the Wolbachia endosymbionts are also discussed.

Costs of Intermittent Versus Continuous Antiretroviral Therapy in Patients With Controlled HIV Infection: A Substudy of the ANRS 106 Window Trial

Structured treatment interruptions in chronic HIV infection have been explored as a drug-sparing strategy to reduce drug-related adverse events and costs while maintaining CD4 cell counts at a level high enough to prevent the risk of disease progression. To test the hypothesis and put a figure on the reduction in total medical costs, we conducted a cost study analysis in the setting of a randomized open-label study comparing an intermittent to a continuous antiretroviral regimen. Four hundred three HIV-1-infected adults who were tolerating highly active antiretroviral therapy (HAART), with a nadir CD4 count of 100 cells per microliter or more and a CD4 count above 450 cells per microliter at screening, were randomly assigned to switch to a fixed 8-week off, 8-week on intermittent treatment (IT) or to maintain their current treatment (CT) strategy. The proportions of patients who reached a CD4 cell count below 300 cells per microliter through 96 weeks (primary end point) were not significantly different between arms. Costs were estimated from the viewpoint of the payer over the 96-week study period. Unit costs were provided from the national reimbursement schedules for hospital inpatient and outpatient admissions and ambulatory visits and the national selling price for medications. All analyses were performed on an intention-to-treat basis. Complete cost data were available for 391 patients (197 patients in the IT and 194 in the CT arms). The mean cost in euros (Euro) per patient over the 96 weeks of follow-up (excluding protocol-driven costs) was 9738 in the IT arm vs. 16,162 in the CT arm, a 6424 difference almost entirely due to the difference in HAART cost. Mean protocol-driven costs represented Euro290 in the IT vs. Euro280 in the CT arm. The use of IT achieved a 40% reduction in the total cost of HAART. Reducing by 40% the cost ofHAART medications in a treatment interruption strategy did not increase the costs related to adverse events or consultations.

Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen

Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.

Inferior Clinical Outcome of the CD4+ Cell Count–Guided Antiretroviral Treatment Interruption Strategy in the SMART Study: Role of CD4+ Cell Counts and HIV RNA Levels during Follow-up

The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported. During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count <350 cells/microL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count <350 cells/microL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5-3.4]) for periods with the latest CD4+ cell count >or= 350 cells/microL-an increase explained by the higher HIV RNA levels in the DC group. The higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death.

Treatment interruption as a tool to measure changes in immunologic response to HIV-1

Introduction of potent combination antiretroviral therapy has led to the successful treatment of HIV infection, although adverse side effects, toxicities and drug resistance to currently available antiretroviral therapy regimens emerge, resulting in poorer outcomes. Alternative therapeutic interventions are needed to enhance HIV-1-specific immunity. The review will discuss the rationale for use of therapeutic immunization as a method to enhance HIV-1-specific immunity, and support the use of analytical treatment interruption to obtain and define immune correlates. Results of recent studies using structured treatment interruption strategies demonstrate that with proper features to protect against drug resistance and drops in CD4 cell counts, viral endpoints following analytical treatment interruption can be used as a tool for measuring efficacy of immunologic therapeutic interventions. The viral rebound dynamics during and viral set points established following analytical treatment interruptions should be used as study endpoints as they represents the host's anti-HIV immune response to the therapeutic vaccine. The results of recent treatment interruption studies support the use of an analytical treatment interruption as an effective tool to identify and define immune function correlates, and to generate data to support the subsequent conduct of larger, more definitive phase II/III studies.

Immune modulators and treatment interruption

This article reviews the relevance of sudden immune activation in HIV pathogenesis and summarizes the strategies that could prevent the high peaks of viral replication after antiretroviral therapy interruption. Systemic immune activation could have both beneficial and harmful effects in chronic infection. Recent findings suggest that in addition to viral replication other factors could drive immune activation. The changes in natural regulatory T cell number or function and microbial translocation have been hypothesized as potential causes. Immune activation after antiretroviral therapy interruption could play a critical role in the increase in the rates of AIDS-defining and non-AIDS-defining malignancies or cardiovascular events between patients on a CD4 T-cell-guided intermittent antiretroviral therapy strategy in the SMART study. The use of a cytostatic drug would help T lymphocytes to remain quiescent, becoming refractory to productive HIV-1-infection and thus avoiding high peaks of viral replication after antiretroviral interruption without blunting HIV-1 specific immune responses. This has been the rationale for the use of immunomodulators (such as corticosteroids, hydroxyurea, mycophenolate mofetil, thalidomide, and cyclosporin A) as adjuvant to antiretroviral therapy in structured treatment interruption strategies.

Treatment interruption strategies: how great are the risks?

This review brings together the results of recent definitive trials of treatment interruption strategies in order to evaluate the risks and to examine whether there is evidence to support this approach in clinical practice. Recent studies confirm that there is no clear benefit of treatment interruption in the settings of virological failure or acute infection. The most important recent data relate to the use of structured treatment interruption in the setting of chronic HIV disease. The SMART and Trivacan trials found that a CD4 lymphocyte count guided interruption strategy was clearly inferior to continuous therapy, but Staccato (using a higher threshold for treatment re-initiation) did not. The largest fixed-schedule treatment interruption trial also reported inferior clinical outcomes with interruption, although the evidence of harm was less clear in other smaller studies. A broad spectrum of clinical effects of treatment interruption was highlighted by this research. Overall, recent studies indicate that treatment interruption is associated with a variable degree of net harm. Continuous treatment should remain the strongly preferred approach, although, if it is carefully managed, there may be some clinical situations in which the benefits of a short period of interruption may potentially outweigh the risks.

Role of High Frequency Atrial Pacing for the Termination of Acute Atrial Fibrillation and Atypical Atrial Flutter

The aim of this study was to assess the efficacy of high-frequency (HF) pacing from the right atrial appendage (RAA) or coronary sinus ostium (CS-Os) for the termination of acute atrial fibrillation (AF) and atypical atrial flutter (AAFL) during an electrophysiological (EP) study. 128 episodes of acute fast atrial arrhythmias (FAAs; 93 AF and 35 AAFL) were analyzed in 110 patients. Patients were initially observed for 60s leading to spontaneous termination of 28 FAAs. The remaining 100 FAAs (70 AF) episodes were randomized to the following strategies: (A) pacing at RAA using up to 10 consecutive 20-Hz trains followed by the same stimulation protocol at CS-Os if RAA pacing failed, (B) pacing at CS-Os using the same stimulation protocol followed by HF pacing at RAA, or (C) observation up to 6 minutes ("no pacing"). The 20-Hz pacing at both RAA and CS-Os was associated with higher conversion of AAFL, as compared to strategy C (60% and 77% vs 11%; P < 0.05). Only HF pacing at CS-Os was superior to observation strategy for the conversion of AF (21% vs 4%; P < 0.05). The 20-Hz pacing protocol is superior to observation strategy for interruption of either acute AF or acute AAFL episodes; however, its efficacy is higher in AAFLs. These results can be helpful for the termination of acute atrial tachyarrhythmias during EPstudy and should be further evaluated in patients with implantable devices capable of antitachycardia pacing.

Using mathematical modeling and control to develop structured treatment interruption strategies for HIV infection

The goal of this article is to suggest that mathematical models describing biological processes taking place within a patient over time can be used to design adaptive treatment strategies. We demonstrate using the key example of treatment strategies for human immunodeficiency virus type-1 (HIV) infection. Although there has been considerable progress in management of HIV infection using highly active antiretroviral therapies, continuous treatment with these agents involves significant cost and burden, toxicities, development of drug resistance, and problems with adherence; these latter complications are of particular concern in substance-abusing individuals. This has inspired interest in structured or supervised treatment interruption (STI) strategies, which involve cycles of treatment withdrawal and re-initiation. We argue that the most promising STI strategies are adaptive treatment strategies. We then describe how biological mechanisms governing the interaction over time between HIV and a patient's immune system may be represented by mathematical models and how control methods applied to these models can be used to design adaptive STI strategies seeking to maintain long-term suppression of the virus. We advocate that, when such mathematical representations of processes underlying a disease or disorder are available, they can be an important tool for suggesting adaptive treatment strategies for clinical study.

Pilot Study of a Novel Short-Cycle Antiretroviral Treatment Interruption Strategy: 48-Week Results of the Five-Days-On, Two-Days-Off (FOTO) Study

Purpose: The challenges associated with daily lifelong antiretroviral therapy (ART) have stimulated interest in alternative treatment schedules, including planned, cyclical interruptions of therapy in patients with virologic suppression and sufficient CD4+ T-cell counts. Method: We conducted a 48-week, open-label, single-arm, prospective pilot study of a novel short-cycle treatment interruption strategy. Upon enrollment, 30 HIV+ individuals with a history of durable viral suppression on daily ART changed their weekly treatment schedule to 5 consecutive days on treatment (typically Monday through Friday) followed by 2 days off treatment (five-on, two-off, or FOTO treatment schedule). Results: At 24 and 48 weeks, as-treated analysis revealed that virologic suppression was maintained in 26/29 subjects (89.6%), including 100% of subjects taking efavirenz-based regimens. Participants adhered well to the FOTO treatment schedule and expressed a strong preference for the FOTO treatment schedule compared to daily ART. Conclusion: If validated, the FOTO treatment strategy with efavirenz-based regimens could avoid the viremia witnessed in longer cycle structured treatment interruptions yet still ameliorate a number of problems associated with the current paradigm of daily ART for HIV infection, including the high cost of therapy and the pill fatigue that, in many patients, leads to erratic adherence and ultimately treatment failure

Risk of selecting resistance mutations during treatment interruption

To describe the evolution of drug-resistant mutations in patients undergoing treatment interruption strategies. We discuss potential predictors for selecting resistant mutations during treatment interruption. Current studies on the evolution of drug-resistant mutations during treatment interruption show a low selection frequency for de-novo and archived mutations. The de-novo selection of resistant mutations increases when lamivudine or non-nucleoside reverse transcriptase inhibitor-containing regimens are withdrawn. Although treatment interruption in the context of failing antiretroviral therapy induces the selection of more drug-susceptible strains, resistant virus remains archived and re-emerges once therapy is re-administered, thus thwarting long-term clinical benefits. Alternatively, partial treatment interruption data support the evaluation of treatment strategies aimed at maintaining the benefit of therapy while reducing drug exposure. The safety and efficiency of treatment interruption strategies remain controversial. The selection of new drug-resistance mutations during treatment interruption is not a key factor in accelerating disease progression when compared with continuous therapy. Conversely, reversion towards more drug-susceptible virus after treatment interruption in heavily treated patients may be accompanied by increased viral pathogenicity, and provides little clinical benefit in subsequent HIV-1 chemotherapy. Partial treatment interruption may be valuable in this context, but larger randomized clinical trials are needed.

Treatment interruption in chronic HIV-1 infection: does it deliver?

This review sets out to overview treatment interruption in chronic HIV-1 infection: what treatment interruption promised, results from recent trials, and what the future holds. Recent studies have produced mixed results; several trials have been prematurely halted, whereas others have reported more positive outcomes. One consistent finding has been the identification of the CD4 T-cell count nadir as a critical parameter in determining the outcome of treatment interruption. The use of treatment interruption is still controversial, but it is becoming clear that certain individuals could benefit, and partial treatment interruption strategies warrant further investigation.

Treatment interruption for convenience, cost cutting and toxicity sparing

Scheduled treatment interruption appears to be an attractive alternative to continuous treatment in reducing side effects and costs and increasing comfort and quality of life by reducing overall drug exposure. The question is whether such an interruption is safe. The development of resistance, treatment failure, and the occurrence of diseases induced by decreasing CD4 cell counts or virological rebound are matters of concern. Fixed-cycle scheduled treatment interruption and CD4 cell-guided treatment interruption have been evaluated in randomized controlled trials. Scheduled treatment interruptions, particularly guided by CD4 cell counts, dramatically reduce drug exposure by approximately 60%. The results regarding toxicity and quality of life are more confusing. Against expectations, most trials show little or no reduction in drug-related toxicity and no increase in quality of life. Antiretroviral treatment interruption strategies reduce costs significantly but have inconclusive effects on toxicity and quality of life. The progression of HIV and development of resistance have been reported; therefore scheduled treatment interruption cannot be recommended over continuous treatment. Interruptions using a lower threshold of at least 350 CD4 cells/microl, lasting less than 3 months, and considering the pharmacological properties of drugs may be safe for most patients.

Treatment interruption in children with HIV infection

To review studies evaluating the role of planned/structured treatment interruptions in the management of HIV-infected children. Randomized controlled treatment interruption trials in adults have reported varying results. Three trials were stopped early by their data safety and monitoring boards because of inferiority of the interruption arm, based on differences in the risk of clinical events between randomized arms. Although the risk in the treatment interruption arms relative to continuous treatment was substantial, the absolute risks of AIDS/death were low in both arms. Little research has been carried out evaluating treatment interruptions in children, even though their role may be more critical as children frequently start antiretroviral therapy at an early age with the expectation that they will need to take it for life. In addition to observational studies, two ongoing randomized paediatric trials in chronic infection are based on CD4-guided treatment interruption strategies, using higher CD4 thresholds for restart/stop of antiretroviral therapy than in adult trials. Three trials are evaluating strategies of interruption following treatment of primary infection in infancy. It is vital that this research continues as antiretroviral therapy is rolled out to increasing numbers of young children in resource-limited settings.

Structured treatment interruption strategy effective for HIV infection

Structured treatment interruption strategy effective for HIV infection

Interruptible Electricity Contracts from an Electricity Retailer's Point of View: Valuation and Optimal Interruption

We consider interruptible electricity contracts issued by an electricity retailer that allow for interruptions to electric service in exchange for either an overall reduction in the price of electricity delivered or for financial compensation at the time of interruption. We provide a structural model to determine electricity prices based on stochastic models of supply and demand. We use stochastic dynamic programming to value interruptible contracts from the point of view of an electricity retailer, and describe the optimal interruption strategy. We also demonstrate that structural models can be used to value contracts in competitive markets. Our numerical results indicate that, in a deregulated market, interruptible contracts can help alleviate supply problems associated with spikes of price and demand and that competition between retailers results in lower value and less frequent interruption.

Continuous HAART beats interruption strategy in west Africa

Continuous HAART beats interruption strategy in west Africa

CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial

Structured treatment interruptions of highly-active antiretroviral therapy (HAART) might be particularly relevant for sub-Saharan Africa, where cost-saving strategies could help to increase the number of patients on HAART. We did a randomised trial of structured treatment interruption in Abidjan, Côte d'Ivoire. HIV-infected adults were randomised to receive continuous HAART (CT), CD4-guided HAART (CD4GT) with interruption and reintroduction thresholds at 350 and 250 cells per mm3, respectively, or 2-months-off, 4-months-on HAART. Primary endpoints were death and severe morbidity (any WHO stage 3 or 4 events and any events leading to death) at month 24. We report data from the CT and CD4GT groups until Oct 31, 2005, when the data safety monitoring board recommended to prematurely stop the CD4GT arm. Analyses were intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00158405. 326 adults (median CD4 count nadir 272 per mm3) were randomised to the CT or CD4GT groups and followed up for median of 20 months. Incidence of mortality (per 100 person-years) was not different between groups (CT 0.6, CD4GT 1.2; p=0.57). Incidence of severe morbidity (per 100 person-years) was higher in the CDG4T group (17.6) than in the CT group (6.7; p=0.001). The most frequent severe events were invasive bacterial diseases. 79% of severe morbidity episodes occurred in patients with CD4 count 200-500 per mm3. Patients on CD4GT had severe morbidity rates 2.5-fold higher than those on CT. This difference was mainly due to high rates of common diseases in patients with CD4 count 200-500 per mm3. This CD4-guided structured treatment interruption strategy should not be recommended in Abidjan.

Can treatment interruption strategies improve the management of HIV infection ?

Despite clear success, there is growing appreciation that there are significant limitations with continuous administration of antiretroviral therapy. Currently available treatments are suppressive and cannot eradicate HIV infection. Long-term toxicity may negatively impact quality of life and long-term adherence to anti-HIV therapy and favors emergence of resistant variants. New strategies based on scheduled treatment interruption have been evaluated in various distinct clinical situations with different aims. For patient successfully treated, two major strategies have been proposed : stimulate anti-HIV immune response and reduce drug exposure consisting in off and on treatment periods. For patients with virological failure, stopping antiretroviral therapy during a short period in order to modify the HIV-resistance profile from multidrug resistance to a more sensitive pattern might improve the chances of obtaining durable virological suppression and immunological benefit after resumption of therapy. This review covers the main findings of these investigations and examines the main limitations of scheduled treatment interruptions in terms of clinical progression, emergence of resistance, virus reservoir and risk of viral transmission.