Vanessa C. Williams

Prospective, Intensive Study of Metabolic Changes Associated with 48 Weeks of Amprenavir-Based Antiretroviral Therapy

To determine whether a 48-week course of amprenavir-based antiretroviral therapy is associated with metabolic alterations, 14 clinically stable human immunodeficiency virus (HIV)-infected, protease inhibitor-naive adults initiated amprenavir-based triple therapy. Twelve subjects (86%) achieved HIV RNA levels of <400 copies/mL at week 24. Fasting glucose and insulin levels did not change. Insulin sensitivity did not decrease in the first 24 weeks, but a trend toward a decrease appeared at week 48. Six subjects experienced onset or worsening of glucose tolerance by week 24. Levels of fasting triglycerides and low-density lipoprotein, high-density lipoprotein, and total cholesterol increased. Bone mineral content, lean tissue, total fat, trunk fat, limb fat, and the ratio of trunk to limb fat increased at week 48. Amprenavir-based therapy was associated with increases in serum lipid levels but no short-term decrease in insulin sensitivity. A trend toward insulin resistance appeared late in the study following weight gain, particularly of trunk fat, but without loss of limb fat.

Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study

Background: Sumatriptan is an acute treatment for migraine which is often used by women in their child-bearing years, and who become unexpectedly pregnant. Within the context of the post-marketing use of sumatriptan injection for the acute treatment of migraine, and in compliance with approved labeling, we wished to compare perinatal pregnancy outcomes in women who did and did not use the drug after conception. Methods: Open-label, prospective study conducted in 12,339 migraineurs (including 9,861 women) whose demography and consumption pattern of sumatriptan injections were typical, and were predicted to include 150 pregnancies. Outcome of pregnancy was the end-point. Results: There were 168 of 173 pregnancies that were well-documented. Sumatriptan was only used prior to conception in 92 cases. There were 76 first trimester exposures to sumatriptan. There were no differences in pregnancy outcome between the two groups. Conclusions: Perinatal and pregnancy outcome did not differ between patients who had and had not used sumatriptan after conception, at the resolution of these sample sizes. This study design complements the ongoing pregnancy registry, which is now widened to patients exposed to all formulations of sumatriptan.

Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study

BACKGROUND Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia. METHODS This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0-2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00802737. FINDINGS Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the allocated intervention (withdrawal of consent). The median follow-up was 19·1 months (IQR 10·3-28·8). Progression-free survival was improved in patients assigned to the ofatumumab group (29·4 months, 95% CI 26·2-34·2) compared with those assigned to observation (15·2 months, 11·8-18·8; hazard ratio 0·50, 95% CI 0·38-0·66; p<0·0001). The most common grade 3 or higher adverse events up to 60 days after last treatment were neutropenia (56 [24%] of 237 patients in the ofatumumab group vs 23 [10%] of 237 in the observation group) and infections (31 [13%] vs 20 [8%]). 20 (8%) of 237 patients in the ofatumumab group and three (1%) of 237 patients in the observation group had adverse events that led to permanent discontinuation of treatment. Up to 60 days after last treatment, two deaths related to adverse events occurred in the ofatumumab treatment group and five deaths related to adverse events occurred in the observation group; no deaths were attributed to the study drug. INTERPRETATION These data are important for the development of optimum maintenance strategies in patients with relapsed chronic lymphocytic leukaemia, notably in the present era of targeted drugs, many of which are to be used until progression.

Short-term Safety and Tolerability of a Once-Daily Fixed-Dose Abacavir-Lamivudine Combination versus Twice-Daily Dosing of Abacavir and Lamivudine as Separate Components: Findings from the ALOHA Study

Study Objective. To evaluate the short‐term (12 wks) safety and tolerability of a once‐daily, fixed‐dose abacavir‐lamivudine combination versus twice‐daily dosing of the separate components, both with background antiretroviral therapy.

Efficacy and Safety of Abacavir/Lamivudine/Zidovudine Plus Tenofovir in HBV/HIV-1 Coinfected Adults: 48-Week Data

In HBV/HIV-coinfected patients, the risk of end-stage liver disease and death is increased. This open-label, prospective, pilot study evaluated abacavir/lamivudine/zidovudine twice daily plus tenofovir once daily in HBV/HIV-coinfected antiretroviral-naïve subjects. Nine adults (8 males) enrolled, with baseline mean HIV-1 RNA = 4.5 log10 copies/mL, HBV DNA = 9.0 log10 copies/mL, and median CD4 count =158 cells/mm3. No subject had baseline ALT >5x ULN. Six subjects completed the study: 1 withdrew due to non-treatment-related toxoplasmosis and 2 were lost-to-follow-up. At week 48, 100% (6/6) of remaining subjects had ≥2 log10 decrease in HBV DNA, and 100% (6/6) and 83% (5/6) had HIV-1 RNA <400 and <50 copies/mL, respectively. Median change from baseline in CD4 count was 157 cells/mm3. One subject experienced treatment-related grade 3 leukopenia. These results demonstrate that abacavir/lamivudine/zidovudine and tenofovir were well tolerated with sustained HIV-1 and HBV antiviral activity through 48 weeks in HBV/HIV-coinfected, antiretroviral-naïve subjects.

CHOP Chemotherapy Followed by Tositumomab and Iodine-131 Tositumomab for Previously Untreated Diffuse Large B-cell Lymphoma

The efficacy and safety of tositumomab/iodine-131 tositumomab (TST/I-131 TST) were evaluated in diffuse large B-cell lymphoma patients who responded to first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Fifteen patients (median age, 52 years) received dosimetric and therapeutic doses of TST/I-131 TST. The most common Grade 3/4 hematologic adverse events were decreased absolute neutrophil count (47%), white blood cell count (40%), platelet count (27%), and hemoglobin (20%). The complete response (CR) rate increased from 60% post-CHOP to 80% post TST / I-131 TST. With a median follow-up of 120.0 months (range, 14-130 months), median duration of response (95% confidence intervals) was 58.4 months (12.0-not reached [NR]) for patients with confirmed complete response and 58.4 months (20.9-NR) for all confirmed responders. Median progression-free survival and time to treatment failure were 63.0 months (16.1-NR). Median overall survival was not reached; 2 patients died on study. CHOP and TST/I-131 TST demonstrated clinical activity with acceptable toxicity.

Twice-daily Trizivir versus combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: A formulation-switch trial

Study Objective. To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg‐lamivudine 150 mg‐zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg‐zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300‐mg tablet, administered twice/day, in antiretroviral‐experienced, human immunodeficiency virus (HIV)‐1‐infected patients.