Supplemental Digital Content is available in the text

In 2 double-blind phase 3 trials, 1733 antiretroviral-naive adults were randomized to tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 144 weeks, TAF was superior to TDF in virologic efficacy, with 84.2% vs 80.0% having HIV-1 RNA <50 copies/mL (difference 4.2%; 95% confidence interval: 0.6% to 7.8%). TAF had less impact than TDF on bone mineral density and renal biomarkers. No participants on TAF had renal-related discontinuations vs 12 on TDF (P < 0.001), with no cases of proximal tubulopathy for TAF vs 4 for TDF. There were greater increases in lipids with TAF vs TDF, with no difference in the total cholesterol to high-density lipoprotein ratio. For initial HIV therapy, E/C/F/TAF is superior to E/C/F/TDF in efficacy and bone and renal safety.

Background Treatment with vesatolimod, an investigational oral toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a phase 1 study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with HIV-1. Methods In this double-blind, multicentre, placebo-controlled trial (ClinicalTrials.gov NCT02858401), participants on antiretroviral therapy with screening plasma HIV-1 RNA levels &lt;50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose escalation cohorts. Primary study objectives included safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. Findings A total of 48 individuals were randomly assigned to vesatolimod (n=36) or placebo (n=12). Vesatolimod was generally well tolerated with no study drug-related serious adverse events or adverse events leading to study discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups compared to placebo. Vesatolimod plasma exposures increased dose-proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours post 6 mg dose were &gt;3·9-fold for IP-10, IL-1Ra, and ITAC when compared to baseline values. Interpretation Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation observed at doses above 4 mg, providing rationale for future combination trials in people with HIV.

Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1–infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection.

BackgroundPatients with locally advanced or recurrent rectal cancer often require multimodality treatment. Intraoperative radiation therapy (IORT) is a focal approach which aims to improve local control.MethodsWe retrospectively reviewed 42 patients treated with IORT following definitive resection of a locally advanced or recurrent rectal cancer from 2000–2009. All patients were treated with the Intrabeam® Photon Radiosurgery System (PRS). A dose of 5 Gy was prescribed to a depth of 1 cm (surface dose range: 13.4-23.1, median: 14.4 Gy). Median survival times were calculated using Kaplan-Meier analysis.ResultsOf 42 patients, 32 had recurrent disease (76%) while 10 had locally advanced disease (24%). Eighteen patients (43%) had tumors fixed to the sidewall. Margins were positive in 19 patients (45%). Median follow-up after IORT was 22 months (range 0.2-101). Median survival time after IORT was 34 months. The 3-year overall survival rate was 49% (43% for recurrent and 65% for locally advanced patients). Local recurrence was evaluable in 34 patients, of whom 32% failed. The 1-year local recurrence rate was 16%. Distant metastasis was evaluable in 30 patients, of whom 60% failed. The 1-year distant metastasis rate was 32%. No intraoperative complications were attributed to IORT. Median duration of IORT was 35 minutes (range: 14–39). Median discharge time after surgery was 7 days (range: 2–59). Hydronephrosis after IORT occurred in 10 patients (24%), 7 of whom had documented concomitant disease recurrence.ConclusionsThe Intrabeam® PRS appears to be a safe technique for delivering IORT in rectal cancer patients. IORT with PRS marginally increased operative time, and did not appear to prolong hospitalization. Our rates of long-term toxicity, local recurrence, and survival rates compare favorably with published reports of IORT delivery with other methods.