2 Minute Medicine Rewind September 7 – September 14, 2015

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

BRAF V600E has been identified as the genetic lesion responsible for the development of hairy-cell leukemia.  In this study, researchers conducted two phase-2, single-group, multicenter trials looking at the effectiveness and safety of oral vemurafenib (a BRAF inhibitor) in patients with relapsed or refractory hairy-cell leukemia.  One trial was completed in Italy (n=26) and the other in the United States (n=24).  In the Italian study, after a median of 8 weeks, the overall response rate was found to be 96% (25 of 26 patients) and the complete response rate was 35% (9 of 26 patients).  After a median follow-up of 23 months, the median relapse-free survival in the Italian trial was 19 months amongst patients with a complete response, and 6 months amongst those with a partial response.  In the American trial, after a median of 12 weeks, the overall response rate was found to be 100 % (24 of 24 patients) and the complete response rate was 42% (10 of 24 patients).  In the US trial, the progression-free survival rate was found to be 73% and the overall survival rate 91% at 1 year.  This study showed that a short oral course of vemurafenib might be highly effective in patients suffering from hairy-cell leukemia that relapsed after refractory to purine analogues.

Pre-exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection (PROUD): Effectiveness Results From the Pilot Phase of a Pragmatic Open-Label Randomized Trial

Despite the incredible advances and improvements in the medications used to treat HIV, primary prevention remains the gold standard.  Previous research has shown that, when used properly, pre-exposure prophylaxis (PrEP) reduces rates of HIV transmission amongst men who have sex with men (MSM).  In this study, researchers completed an open-label randomized trial at 13 sexual health clinics in England in order to study whether or not men receiving PrEP (tenofovir-emtricitabine) engage in riskier sexual behaviors.  544 participants were randomly assigned to receive PrEP immediately (n=275) or after a deferral period of one year (n=269).  The primary outcomes were time to accrue 500 participants and retention.  The secondary outcomes were incidence of HIV infection during the deferral period, safety, PrEP adherence, and risk compensation.  It was found that only three HIV infections occurred in the immediate group versus 20 in the deferred group (RR 86%, 90% CI 64-96, p=0.0001).  This finding supports previous research documenting the effectiveness or PrEP in the prevention of HIV transmission amongst MSM.  Researchers did not find any difference with respect to the incidence of sexually transmitted infections (including rectal gonorrhea and chlamydia) between the two groups, suggesting that MSM taking PrEP do not engage in risker sexual behaviors.  This study adds to a growing body of literature supporting the addition of PrEP to the standard of HIV prevention for MSM.

Symptom-Onset Dosing of Sertraline for the Treatment of Premenstrual Dysphoric Disorder

Selective serotonin reuptake inhibitors (SSRI’s) can be effective in reducing the severity of premenstrual dysphoric disorder (PMDD) when given daily or during the luteal phase of the menstrual cycle.  In this study, researchers sought to determine whether or not symptom-onset dosing of sertraline (an SSRI) would be effective in treating PMDD.  To study this, researchers conducted a double-blind, multisite, parallel-group, randomized controlled trial in which 252 women with PMDD were randomly assigned to receive either a placebo (n=127) or 50-100 mg of sertraline (n=125).  Women were instructed to start treatment at symptom onset and were asked to continue treatment throughout the first few days of menses for a total of 6 menstrual cycles.  The Premenstrual Tension Scale (PMTS) was used to measure efficacy of placebo/sertraline in each of the groups.  The PMTS scores for the placebo group declined from 21.4 to 12.0, whereas the PMTS scores for the sertraline group declined from 22.3 to 11.7 (group mean difference 1.88; 95% CI 0.01-3.75; p=0.06).  Secondary outcomes measures included the Inventory Depressive Symptomatology-Clinician Rated (IDS-C), Daily Record of Severity of Problems (DRSP), Clinical Global Impression (CGI) scales, and Michelson SSRI Withdrawal Symptoms Scale scores.  Compared to the placebo group, those receiving sertraline showed greater improvement on the DRSP score (estimated mean difference 1.09; 95% CI 0.96-1.25, p=0.02) and on the anger/irritability DRSP subscale score (estimated mean difference 1.22; 95% CI 1.05-1.41, p<0.01).  This study suggests that a shorter duration of treatment with an SSRI may be beneficial in women with PMDD, dependent on the symptoms scale used to evaluate symptomatology.  Future research in this area is needed to ascertain whether or not there is any consistent benefit to this type of SSRI dosing for PMDD.

Screening for Iron Deficiency Anemia and Iron Supplementation in Pregnancy: U.S. Preventative Services Task Force Recommendations

Affecting over 18% of women, iron deficiency is well recognized as a common cause of anemia amongst all women.  Given the increased need for iron for fetal and placental development, asymptomatic pregnant women are often screened for iron deficiency anemia and many healthcare providers recommend routine supplementation with iron during pregnancy.  In this systematic review, the U.S. Preventative Services Task Force (USPSTF) reviewed evidence on whether or not there was any association between iron supplementation in pregnant women and maternal/fetal health outcomes.  Researchers found that there is currently insufficient evidence to recommend screening asymptomatic pregnant women for iron deficiency anemia.  Despite adequate evidence suggesting that iron supplementation during pregnancy does improve maternal serum ferritin and hemoglobin levels, researchers found insufficient evidence to recommend routine iron supplementation during pregnancy.  The USPSTF concluded that the current evidence is largely insufficient and does not allow for a proper assessment of the benefits and harms of routine screening of pregnant women for iron-deficiency. 

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency

Lysosomal acid lipase is an essential lipid-metabolizing enzyme.  Individuals who have lysosomal acid lipase deficiency are unable to properly breakdown lipids, which leads to the accumulation of by-products in the liver and eventually, to liver failure and cirrhosis.  In this randomized controlled trial, 66 patients over the age of 4 years with proven lysosomal acid lipase deficiency were randomized to the placebo (n=30) or treatment group (n=36) in order to ascertain whether or not enzyme replacement therapy has a role in the treatment of lysosomal acid lipase deficiency.  Those in the treatment group received enzyme replacement therapy with sebelipase alfa (1 mg per kg of body weight IV) every other week for 20 weeks.  The primary endpoint was normalization of the aminotransferase level (ALT).  The ALT level was found to be normal in 11 of the 36 patients (31%; mean reduction from baseline -58 U/L) in the sebelipase alfa group compared to only 2 of the 30 patients (7%; mean reduction from baseline -7 U/L) in the placebo group (p=0.03).  Similar results were seen with AST levels (42% of patient with mean reduction from baseline -42 U/L in sebelipase alfa group compared to only 3% of patients with mean reduction from baseline -6 U/L in placebo group; p<0.001).  Researchers also found that those in the sebelipase alfa group had significant improvements in lipid levels, including decreased LDL levels (p<0.001), triglycerides (p=0.04), increased HDL levels (p<0.001), and a reduction in hepatic fat content (p<0.001).  This study suggests that enzyme replacement therapy with sebelipase alfa may reduce many of the disease-related hepatic and lipid abnormalities in individuals with lysosomal acid lipase deficiency.  Future research should focus on any long-term benefits and any long-term side effects of sebelipase alfa in these individuals.

Image: PD

©2015 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.