Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1.

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 Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. METHODS: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <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. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. RESULTS: 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 drug 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 after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. CONCLUSIONS: Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02858401.

Remdesivir for COVID-19 in Hospitalized Children: A Phase 2/3 Study.

OBJECTIVES: Remdesivir decreases the risk of SARS-CoV-2 infection progressing to severe disease in adults. This study evaluated remdesivir safety and pharmacokinetics in infants and children. METHODS: This was a phase 2/3, open-label trial in children aged 28 days to 17 years hospitalized for polymerase chain reaction-confirmed SARS-CoV-2 infection. Participants received for ≤10 days once-daily intravenous remdesivir doses defined using physiologically based pharmacokinetic modeling (for ≥40 kg, 200 mg day 1, then 100 mg/day; for age ≥28 days and ≥3 to <40 kg, 5 mg/kg day 1, then 2.5 mg/kg/day). Sparse pharmacokinetic samples were analyzed using population-pharmacokinetic approaches for remdesivir and metabolites GS-704277 and GS-441524. RESULTS: Among 53 participants, at enrollment the median (Q1, Q3) number of days of COVID-19 symptoms was 5 (3, 7) and hospitalization was 1 (1, 3). Underlying conditions included obesity in 19 (37%), asthma in 11 (21%), and cardiac disorders in 11 (21%). Median duration of remdesivir treatment was 5 days (range, 1-10). Remdesivir treatment had no new apparent safety trends. Two participants discontinued treatment because of adverse events including elevated transaminases; both had elevated transaminases at baseline. Three deaths occurred during treatment (and 1 after). When compared with phase 3 adult data, estimated mean pediatric parameters (area under the concentration-time curve over 1 dosing interval, AUCτ, Cmax, and Cτ) were largely overlapping but modestly increased (remdesivir, 33%-129%; GS-704277, 37%-124%; GS-441524, 0%-60%). Recovery occurred for 62% of participants on day 10 and 83% at last assessment. CONCLUSIONS: In infants and children with COVID-19, the doses of remdesivir evaluated provided drug exposure similar to adult dosing. In this study with a small sample size, no new safety concerns were observed.

The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy.

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.

Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in Asian participants with human immunodeficiency virus 1 infection: A sub-analysis of phase 3 clinical trials.

Background: The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naive and ART-experienced Asian participants infected with human immunodeficiency virus (HIV)-1 through 96 or 144 weeks.Objective: In Asian population requiring treatment, it is imperative to have data specific to this group, particularly as there is a general concern that Asians with lower body weight have increased risk of tenofovir disoproxil fumarate (TDF)-related renal dysfunction.Methods: Studies -104 and 111 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naive participants, comparing E/C/F/TAF versus E/C/F/TDF. Study 109 was a randomized, open-label, 96-week study conducted in virologically suppressed, ART-experienced participants, who switched to E/C/F/TAF from ritonavir/cobicistat-boosted atazanavir ATV+(RTV or COBI) + F/TDF regimens, from non-nucleoside reverse transcriptase inhibitors (NNRTI) + F/TDF regimens, or from E/C/F/TDF. Study 112 was a single arm, open-label, 144-week study conducted in HIV suppressed, ART-experienced participants with mild-moderate renal impairment, who switched to E/C/F/TAF.Results: Asian participants in these studies had sustained efficacy safety and tolerability. In Study 104/111, Asian participants achieved 93% virologic suppression on TAF vs 88% on TDF at week 144. At baseline, there were numerically more Asians with median CD4 counts < 200 cells/uL and VL > 100,000 c/mL. In Study 109, 95% of Asians on TAF vs 86% on TDF maintained virologic suppression at week 96. Lastly, in Study 112, 91% maintained virologic suppression at week 144. There were no discontinuations due to renal AE, no cases of PRT or Fanconi syndrome in any of the studies.

Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of 26 clinical trials.

OBJECTIVE: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomized trials; however, the comparative incidence of clinically significant renal events remains unclear. DESIGN: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes. METHODS: We pooled clinical renal safety data across 26 treatment-naive and antiretroviral switch studies to compare the incidence of proximal renal tubulopathy and discontinuation due to renal adverse events between participants taking TAF-containing regimens vs. those taking TDF-containing regimens. We performed secondary analyses from seven large randomized studies (two treatment-naive and five switch studies) to compare incidence of renal adverse events, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein-to-creatinine ratios). RESULTS: Our integrated analysis included 9322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12 519 person-years to TAF and 5947 to TDF. There were no cases of proximal renal tubulopathy in participants receiving TAF vs. 10 cases in those receiving TDF (P < 0.001), and fewer individuals on TAF (3/6360) vs. TDF (14/2962) (P < 0.001) discontinued due to a renal adverse event. Participants initiating TAF-based vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy. CONCLUSION: These pooled data from 26 studies, with over 12 500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.

Review of the treatment of trigeminal neuralgia with gamma knife radiosurgery.

BACKGROUND: Trigeminal neuralgia is a debilitating condition caused by compression of the trigeminal nerve, ganglions, or divisions. Gamma knife radiosurgery has been increasingly used in the treatment of trigeminal neuralgia as a non-invasive alternative to microvascular decompression and rhizotomies. METHODS: We reviewed the medical literature regarding outcomes, time course, and prognostic factors for successful pain control in gamma knife radiosurgery. The dosimetry, target, complications of treatment, as well as perceived quality of life in treatment were also reviewed. RESULTS AND CONCLUSION: The growing body of literature suggests that the low rates of complications of gamma knife radiosurgery, coupled with the high success rates and patient satisfaction, allow it to be increasingly used as primary intervention for trigeminal neuralgia for appropriate patients.

Brief Report: Randomized, Double-Blind Comparison of Tenofovir Alafenamide (TAF) vs Tenofovir Disoproxil Fumarate (TDF), Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144 Results.

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.

Clinical and Radiographic Outcomes From Repeat Whole-brain Radiation Therapy for Brain Metastases in the Age of Stereotactic Radiosurgery.

OBJECTIVES: Repeating whole-brain radiation therapy (WBRT) in patients with progressive/recurrent brain metastases is controversial. We retrospectively reviewed our experience of repeat WBRT in an era where stereotactic radiosurgery was also available. METHODS: In our IRB-approved database, 49 patients received repeat WBRT from 1996 to 2011. Median initial dose of WBRT was 30 Gy in 10 fractions (range, 27 to 37.5 Gy); median reirradiation dose was 20 Gy in 10 fractions (range, 14 to 30 Gy). Median Karnofsky performance status (KPS) at reirradiation was 70 (range, 40 to 90). Median number of discrete lesions at reirradiation was 6 (range, 1 to 30). Median interval between initial diagnosis of brain metastases and relapse requiring repeat WBRT was 11.5 months (range, 1.5 to 49.2 mo). Overall survival and relapse-free survival were summarized using the Kaplan-Meier method. The log-rank test was used to compare outcomes between groups. RESULTS: Ninety percent of patients completed repeat WBRT. Median survival after repeat WBRT was 3 months (95% CI, 1.9-4.0). Thirteen patients had improved neurological symptoms (27%), 12 were stable (24%), and 14 had worsening symptoms (29%). On radiographic follow-up of 22 patients, 10 (46%) were improved, 4 (18%) were stable, and 8 (36%) progressed. Improved neurological symptoms after repeat WBRT and higher KPS at first follow-up were associated with improved survival (P=0.05 and 0.02). CONCLUSIONS: Repeat WBRT was well tolerated. Modest survival times are seen. Prognostic factors for survival include improved neurological symptoms after repeat WBRT and higher KPS at first follow-up. Repeat WBRT may be useful to improve neurological symptoms in patients with limited treatment options, especially those who are not appropriate stereotactic radiosurgery candidates.

Solitary dural metastasis at presentation in a patient with untreated human papillomavirus-associated squamous cell carcinoma of the oropharynx.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is associated with high cure rates and distant metastases are rare. METHODS AND RESULTS: We report a case of a 61-year-old man presenting with acute left-sided weakness. An enhancing dural mass was noted and resected. Histology revealed p16-positive SCC. Further workup revealed a p16-positive right tonsillar primary with ipsilateral nodal disease and was classified as T2N2bM1. The patient underwent whole brain irradiation and definitive chemoradiation with curative intent. Complete clinical response was achieved and the patient continues to be disease-free 6 months posttreatment. CONCLUSION: HPV-associated oligometastatic oropharyngeal SCC is a rare entity that may have a unique natural history and behavior. Given the excellent treatment response and prognosis of HPV-positive disease in general, these patients may be appropriate for definitive treatment approaches.

Impact of non-small cell lung cancer histology on survival predicted from the graded prognostic assessment for patients with brain metastases.

INTRODUCTION: The Graded Prognostic Assessment (GPA) provides prognostic classification for patients with brain metastases (BM), based on Radiation Therapy Oncology Group (RTOG) data. Recent evidence suggests differential response and outcomes to chemotherapy for different non-small cell lung cancer (NSCLC) histologies. Using a large BM patient database, we assessed the impact of histologic subtypes on survival stratified by the GPA. METHODS: From an IRB-approved database, we analyzed 780 patients with NSCLC BM treated from 1982 to 2004. GPA classification variables included age, KPS, number of BM, and presence of extracranial disease. Histology was identified for each patient. Median survival time (MST) based on GPA class and histology were calculated using Kaplan-Meier analysis. The log rank test was used to determine statistical differences. RESULTS: MST, in months, by histology were: adenocarcinoma (AC) 6.2 (n=464), large cell (LC) 4.1 (n=98), squamous (SQ) 4.2 (n=108) (p=0.0549). For GPA 3.5-4.0, MSTs did not differ significantly by histology. Differences in MST by histology were noted for GPA 3.0 (p=0.04), GPA 1.5-2.5 (p=0.01), and GPA 0-1.0 (p=0.02). For all patients with brain metastases BM from NSCLC, MSTs by GPA score were: GPA 3.5-4.0, 12.6; GPA 3.0, 10.2; GPA 1.5-2.5, 5.8; and GPA 0-1.0, 2.7. CONCLUSIONS: Adenocarcinoma showed a statistically significant higher MST than other histologies of NSCLC for patients with GPA 0-3.0. Using histology as a prognostic factor for BM from NSCLC warrants further investigation. Our cohort of NSCLC BM patients validates the GPA, with MST comparable to that of published data.

Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience.

BACKGROUND: Patients 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. METHODS: We 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. RESULTS: Of 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. CONCLUSIONS: The 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.

The Role of Functional Imaging in Radiotherapy Planning and Management for Gynecologic Malignancies.

In addition to allowing much greater technical precision, the modern era allows investigation of target physiology and it is the potential incorporation of physiologic information into the treatment-planning rubric that gives modern PET-CT its allure and promise. Although oncologic PET scanning has been clinically available for more than 10 years, it is only recently that sufficient investigative and retrospective data have become available to confidently assert that future radiotherapy treatment planning will include functional imaging as an obligatory dimension of clinical characterization for most gynecologic tumors. This article explores the role of functional imaging in radiotherapy planning and management of gynecologic malignancies.

Assessment of nodal target definition and dosimetry using three different techniques: implications for re-defining the optimal pelvic field in endometrial cancer.

PURPOSES: 1. To determine the optimal pelvic nodal clinical target volume for post-operative treatment of endometrial cancer. 2. To compare the DVH of different treatment planning techniques applied to this new CTV and the surrounding tissues. METHODS AND MATERIALS: Based on the literature, we selected a methodology to delineate nodal target volume to define a NEW-CTV and NEW-PTV. Conventional 2D fields, 3D fields based on anatomic guidelines per RTOG 0418, 3D fields based on our guidelines, and IMRT based on our guidelines were assessed for coverage of NEW-CTV, NEW-PTV, and surrounding structures. CT scans of 10 patients with gynecologic malignancies after TAH/BSO were used. DVHs were compared. RESULTS: For NEW-PTV, mean V45Gy were 50% and 69% for 2D and RTOG 0418-3DCRT vs. 98% and 97% for NEW-3DCRT and NEW-IMRT (p < 0.0009). Mean V45Gy small bowel were 24% and 20% for 2D and RTOG 0418-3DCRT, increased to 32% with NEW-3DCRT, and decreased to 14% with IMRT (p = 0.005, 0.138, 0.002). Mean V45Gy rectum were 26%, 35%, and 52% for 2D, RTOG 0418-3DCRT, and NEW-3DCRT, and decreased to 26% with NEW-IMRT (p < 0.05). Mean V45Gy bladder were 83%, 51%, and 73% for 2D, RTOG 0418-3DCRT, and NEW-3DCRT, and decreased to 30% with NEW-IMRT (p < 0.002). CONCLUSIONS: Conventional 2D and RTOG 0418-based 3DCRT plans cover only a fraction of our comprehensive PTV. A 3DCRT plan covers this PTV with high doses to normal tissues, whereas IMRT covers the PTV while delivering lower normal tissue doses. Re-consideration of what specifically the pelvic target encompasses is warranted.

Aminoglycoside complexation with a DNA.RNA hybrid duplex: the thermodynamics of recognition and inhibition of RNA processing enzymes.

Spectroscopic and calorimetric techniques were employed to characterize and contrast the binding of the aminoglycoside paromomycin to three octamer nucleic acid duplexes of identical sequence but different strand composition (a DNA.RNA hybrid duplex and the corresponding DNA.DNA and RNA.RNA duplexes). In addition, the impact of paromomycin binding on both RNase H- and RNase A-mediated cleavage of the RNA strand in the DNA.RNA duplex was also determined. Our results reveal the following significant features: (i) Paromomycin binding enhances the thermal stabilities of the RNA.RNA and DNA.RNA duplexes to similar extents, with this thermal enhancement being substantially greater in magnitude than that of the DNA.DNA duplex. (ii) Paromomycin binding to the DNA.RNA hybrid duplex induces CD changes consistent with a shift from an A-like to a more canonical A-conformation. (iii) Paromomycin binding to all three octamer duplexes is linked to the uptake of a similar number of protons, with the magnitude of this number being dependent on pH. (iv) The affinity of paromomycin for the three host duplexes follows the hierarchy, RNA.RNA > DNA.RNA >> DNA.DNA. (v) The observed affinity of paromomycin for the RNA.RNA and DNA.RNA duplexes decreases with increasing pH. (vi) The binding of paromomycin to the DNA.RNA hybrid duplex inhibits both RNase H- and RNase A-mediated cleavage of the RNA strand. We discuss the implications of our combined results with regard to the specific targeting of DNA.RNA hybrid duplex domains and potential antiretroviral applications.