Rituximab maintenance therapy has been shown to improve the duration of remission or progression-free survival (PFS) in patients with follicular lymphoma. However, the optimal duration of maintenance therapy remains unclear. In a recent trial (SAKK 35/98) in which rituximab was administered by 4 infusions every 2 months, rituximab maintenance was found to prolong median event-free survival (EFS) from 12 to 23 months when compared to patients that did not receive any maintenance treatment (p=0.02). This benefit was maintained with continued follow-up. In this multinational randomized, controlled trial (SAKKK 35/03), 165 patients that received rituximab induction therapy were subsequently randomized to receive either short- or long-term rituximab maintenance therapy to assess the benefit of prolonging rituximab therapy to a maximum of 5 years. Short-term maintenance therapy consisted of 4 rituximab infusions (375 mg/m2) administered intravenously every 2 months, while long-term maintenance therapy was comprised of rituximab infusions every 2 months for a maximum of 5 years or until relapse, progression of disease, or unacceptable toxicity occurred. Because of the low event rate, a final analysis of event-free survival was performed after 95 events had occurred. It should be noted that despite randomization, there were some differences in the treatment groups. Proportionally more women were randomized to the long-term maintenance group (69%) than the short-term group (55%), and more patients in the long-term group presented with extranodal involvement (45%) compared to the short-term arm of the study (22%). Researchers found that at a median follow-up of 6.4 years, the median EFS was 3.4 years (95% CI 2.1to 5.3) in the short-term group, and 5.3 years (95% CI 3.5 to unavailable upper CI limit) in the long-term group, although this difference in EFS was not statistically significant (p=0.14). PFS was significantly longer in the long-term group compared to the short-term group (7.4 vs. 3.5 years, p=0.04),however, there were no significant differences in overall survival (OS) between the groups. Furthermore, 76% of the patients in the long-term arm experienced at least one adverse event compared to 50% in the short-term group (p<0.001). The results of this study therefore show that long-term rituximab maintenance therapy does not improve EFS or OS, and is associated with increased toxicity compared to short-term maintenance therapy.
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants younger than 1 year. Certain infants are at a particularly increased risk of being hospitalized for RSV, including those that are born premature, those affected by chronic lung disease, congenital heart disease or immunodeficiency. Palivizumab, a monoclonal antibody, has been shown to significantly decrease pulmonary viral replication, and when administered on a monthly basis (15mg/kg), may reduce hospitalizations by approximately 55%. Currently, the American Academy of Pediatrics recommends a maximum of 5 palivizumab doses in selected risk groups during the RSV season. It has been suggested, however, that equivalent protection may be achieved with fewer doses, which may reduce cost-related barriersto its use. In this prospective cohort study, 1,180 infants received either 3 or 4 doses of palivizumab during RSV season (November to April) to determine whether an abbreviated palivizumab dosing schedule in high-risk infants decreases the risk of hospitalization due to lower respiratory infections, compared to historical cohorts treated under the currently recommended 5-dose regimen. The receipt of either 3 or 4 doses was based on predetermined criteria, where only infants born between 39 and 35 weeks gestation without bronchopulmonary dysplasia or chronic lung disease received 3 doses. Hospitalizations were assessed up to April 30 of each year of the study. Researchers found that in the 3-dose group, 1 patient (0.2% of the cohort) was hospitalized with RSV after receiving the second dose of palivizumab, and another was hospitalized 58 days after the third dose. In the 4-dose group, 10 infants (1.5%) were hospitalized with RSV after the second dose, and 2 infants (0.3%) were hospitalized 65 days after the fourth dose. These rates were comparable to historical cohorts from a previous study where the 5-dose regimen was used. In assessing serum antibody titers, researchers also found neutralizing antibody titers to be above the protective equivalent in infants that had received the abbreviated dose of palivizumab, which persisted beyond the end of the RSV season. This study therefore shows that adequate protection for infants at high risk of RSV hospitalization can beachieved using an abbreviated palivizumab dosing schedule.
Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection
Chronic hepatitis C virus (HCV) infection causes progressive liver fibrosis, which in turn, leads to cirrhosis, hepatic decompensation and hepatocellular carcinoma. While there are now effective combinations of direct-acting antiviral agents that can be used in most patients, clinicians must be mindful of a patient’s treatment history, HCV genotype and subtype, stage of fibrosis, patterns of antiviral resistance and risk of experiencing adverse events. Sofosbuvir is an HCV NS5B polymerase inhibitor, which has been approved for the treatment of HCV in combination with other agents, such as NS5A inhibitors. One such NS5A inhibitor is velpatasvir, which has antiviral activity against HCV replicons in genotypes 1-6. In recent trials, the combination of 400 mg sofosbuvir and 100 mg velpatasvir resulted in high rates of sustained virologic response in a wide range of patients. In this multinational double-blind randomized controlled trial, 740 patients were randomized in a 5:1 ratio to receive sofosbuvir and velpatasvir once daily, or placebo for 12 weeks to assess efficacy and safety of the combination therapy in previously treated or untreated patients chronically infected with HCV. Patients with compensated cirrhosis were also included in the study. Researchers found that the rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% CI 98% to >99%). With respect to drug safety, of the 624 patients randomized to receive sofosbuvir-velpatasvir, only 1 patient, accounting for less than 1% of the cohort, discontinued treatment due to an adverse event. Of the 116 patients in the placebo group, 2 (2%) discontinued treatment due to an elevated aminotransferase level. While serious adverse events were reported in 15 patients (2%) from the sofosbuvir-velpatasvir group compared to none in the placebo group, there were no significant differences in the rates of any adverse event between the two arms of the study. This study therefore shows that treatment with once-daily sofosbuvir-velpatasvir for 12 weeks provides high rates of virologic response in patients chronically infected with HCV genotypes 1-6, including those with compensated cirrhosis, with a relatively low risk of experiencing adverse events.
Opioid prescribing after nonfatal overdose and association with repeated overdose: A cohort study
Over the last decade, rates of opioid misuse and overdose have increased. Presentation to an emergency department or hospital with a nonfatal opioid overdose represents an opportunity to identify and refer patients who may be misusing opioids. Guidelines indicate that misuse and opioid-related adverse events are indications to discontinue long-term therapy, however, patterns of treatment, including rates of continued prescribing after overdose are unknown. This has important implications, as opioid overdose is associated with substance use disorders. In this retrospective cohort study, 2,848 patients that experienced a nonfatal opioid overdose during long-term opioid therapy for non-cancer pain were assessed using pharmacy claims from a large U.S. health insurer to characterize opioid use after overdose. Patients were followed up for 90 days from the index event. Researchers found that over a median follow-up of 299 days, 91% of patients received 1 or more opioid dispensings, and that up to 36% of patients received high daily opioid dosages 30 days after the initial overdose event. Researchers also found that compared to patients not dispensed opioids after overdose, patients receiving moderate dosages (HR 1.89, 95% CI 1.18 to 3.04) and large dosages (HR 2.57, 95% CI 1.72 to 3.85) were at an increased risk of repeated overdose. Active daily dispensing of benzodiazepines was also associated with an increased risk of repeated overdose (HR 1.74, 95% CI 1.31 to 2.32). This study therefore shows that nearly all patients that experience an opioid overdose continue to receive prescription opioids. At moderate-high doses, these patients may be at an increased risk of having a repeated overdose.
Olanzapine is an atypical antipsychotic. Although it was originally studied for the chronic treatment of schizophrenia and other psychiatric disorders, its use has been expanded to the emergency department (ED) where it is often used in the management of acute agitation. Currently, the U.S. Food and Drug Administration (FDA) has approved olanzapine to be administered by oral or intramuscular (IM) injection only. Droperidol is a typical antipsychotic administered by IM and intravenous (IV) routes for the treatment of acute agitation, headache, pain, nausea and vomiting. Droperidol has a similar pharmacologic profile to olanzapine, and there is little evidence to suggest that olanzapine cannot be safely administered by the IV route. In this retrospective cohort study, 713 patients administered IV olanzapine were assessed to review the safety of IV olanzapine in the ED. Researchers found that 2 patients had signs and symptoms of akathisia “likely related” to olanzapine, and an additional 2 patients had symptoms of akathisia “possibly related” to olanzapine. None of the patients had a dystonic reaction. In addition, 14% of patients experienced respiratory complications. While the majority of these complications were considered minor, 81 (11.4%) patients received supplemental oxygen and of these, 74 (10.4%) were treated for hypoxia (oxygen saturation <92%). Fifteen patients (2.1%) also had more serious airway complications requiring airway stimulation and/or repositioning, and 7 patients required intubation. Of the 7 patients intubated, only 1 was “likely related” to olanzapine, and 4 were considered “unrelated”. In terms of effectiveness, adequate sedation was achieved with a single dose of IV olanzapine in 66.8% of patients, while 35.0% of patients required additional doses of sedative medications, not limited to olanzapine. This study therefore shows that IV olanzapine may be considered as an alternative to droperidol in the ED, however, clinicians should be cautious of the potential increased risk of experiencing respiratory complications.
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