It remains unknown whether tenofovir alafenamide (TAF) could replace tenofovir disoproxil fumarate (TDF) in patients with drug-resistant hepatitis B virus (HBV).
In this multicenter randomized ...non-inferiority trial, 174 patients with HBV resistant to multiple drugs (lamivudine, entecavir, and/or adefovir) under TDF monotherapy for ≥96 weeks were randomized 1:1 to switch to TAF (n = 87) or continue TDF (n = 87) for 48 weeks. The primary endpoint was proportion of patients with HBV DNA <60 IU/mL at week 48.
At baseline, 84 and 80 patients had HBV DNA <60 IU/mL in the TAF and TDF groups, respectively. At week 48, the proportion of patients with HBV DNA <60 IU/mL was 98.9% (86/87) in TAF group, showing non-inferiority to TDF group (97.7%, 85/87; difference, 1.1%; 95% confidence interval, -2.7% to 5.0%). Changes in median alanine aminotransferase at week 48 from baseline were statistically different between TAF and TDF groups (-3 IU/L vs +2 IU/L; P = .02). TAF group showed a statistically greater increase in bone mineral density at spine (+1.84% vs +0.08%; P = .01) and numerically higher increase in mean estimated glomerular filtration rate (+8.2% vs +4.5%; P = .06) compared with TDF group. Compared with TDF group, TAF group showed significantly greater increases in mean body weight (0.71 vs -0.37 kg; P = .01) and total, low-density lipoprotein, and high-density lipoprotein cholesterol levels (P < .001 for all) at week 48 from baseline.
TAF could be substituted for TDF in patients with multidrug-resistant HBV for improved bone and renal safety without a loss of efficacy. However, increases in body weight and cholesterol levels with TAF treatment would be a concern. ClinicalTrials.gov no.: NCT03241641.
Summary Background We previously reported rates of pathological complete responses (51% 95% CI 39−62 per independent central review, the primary endpoint) and major pathological responses (13% per ...independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. Methods This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II–IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. Findings Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66–81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6–22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79–94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82–97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83–96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one 6% cardiomyopathy and one 6% hypophysitis). There were no grade 4 adverse events or treatment-related deaths. Interpretation For patients with resectable stage II–IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. Funding Regeneron Pharmaceuticals and Sanofi.
Combination therapy has been recommended for the treatment of patients harboring multiple drug‐resistant hepatitis B virus (HBV). However, we recently demonstrated that monotherapy with tenofovir ...disoproxil fumarate (TDF) for 48 weeks displayed noninferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with HBV resistant to multiple drugs, including ETV and adefovir. Nonetheless, whether prolonged TDF monotherapy would be safe and increase the virologic response rate in these patients was unclear. Among 192 patients with HBV‐resistance mutations to ETV and/or adefovir, who were randomized to receive TDF monotherapy (n = 95) or TDF/ETV combination therapy (n = 97) for 48 weeks, 189 agreed to continue TDF monotherapy (TDF‐TDF group) or to switch to TDF monotherapy (TDF/ETV‐TDF group) and 180 (93.8%) completed the 144‐week study. Serum HBV DNA <15 IU/mL at week 48, the primary efficacy endpoint, was achieved in 66.3% in the TDF‐TDF group and 68.0% in the TDF/ETV‐TDF group (P = 0.80). At week 144, the proportion with HBV DNA <15 IU/mL increased to 74.5%, which was significantly higher compared with that at week 48 (P = 0.03), without a significant difference between groups (P = 0.46). By on‐treatment analysis, a total of 79.4% had HBV DNA <15 IU/mL at week 144. Transient virologic breakthrough occurred in 6 patients, which was due to poor drug adherence. At week 144, 19 patients who had HBV DNA levels >60 IU/mL qualified for genotypic resistance analysis, and 6 retained some of their baseline resistance mutations of HBV. No patients developed additional resistance mutations throughout the study period. Conclusion: TDF monotherapy was efficacious and safe for up to 144 weeks, providing an increasing rate of virologic response in heavily pretreated patients with multidrug‐resistant HBV. (Hepatology 2017;66:772–783).
Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV.
In this multicentre randomised trial, patients who had HBV with ETV ...resistance-associated mutations and serum HBV DNA concentrations >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=45) or TDF and ETV (1 mg/day) combination therapy (n=45) for 48 weeks.
Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log10 IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA <15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs. 73%; p>0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (-3.66 vs. -3.74 log10 IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p>0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups.
TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV.
ClinicalTrials.gov ID NCT01639092.
Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV.
In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV ...DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks.
Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (-3.03 log10 IU/mL vs -3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups.
In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks.
NCT01639066.
To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy for patients diagnosed with exudative age-related macular degeneration (AMD) accompanied by ...submacular hemorrhage.
Retrospective, observational case series.
Ninety-one eyes of 91 patients who initially presented with submacular hemorrhage associated with exudative AMD from October 2009 to September 2012. Patients were followed up for at least 6 months after treatment.
Best-corrected visual acuity (BCVA) was measured at diagnosis and at 1, 3, and 6 months after treatment. The duration of symptoms was estimated. The extent of hemorrhage was estimated using fundus photography, and central foveal thickness was measured using optical coherence tomography. Change in BCVA during 6 months after treatment was estimated. The correlation of BCVA at 6 months with duration of symptoms, extent of hemorrhage, and central foveal thickness was evaluated.
The BCVA, duration of symptoms, extent of hemorrhage, and central foveal thickness.
The mean duration of symptoms was 27.6±39.5 days. The mean extent of hemorrhage was 7.8±5.6 disc areas, and the mean central foveal thickness was 610.1±249.6 μm. All eyes were treated with 3.2±0.8 (range, 1-5) monthly intravitreal anti-VEGF injections during the 6-month follow-up period. The logarithm of the minimum angle of resolution BCVA at diagnosis and at 1, 3, and 6 months after the initial diagnosis was 1.38±0.53 (Snellen equivalent, 20/479), 1.27±0.57, 1.05±0.58, and 0.96±0.65 (Snellen equivalent, 20/182), respectively. The BCVA at 6 months significantly improved from baseline (P < 0.001). Poor BCVA at 6 months correlated with a longer duration of symptoms, greater extent of hemorrhage, and greater central foveal thickness (P = 0.008, P = 0.004, and P = 0.014, respectively).
Anti-VEGF monotherapy was found to be a useful treatment option for exudative AMD accompanied by submacular hemorrhage. However, the limited efficacy in eyes with large hemorrhage may suggest the need for more aggressive treatment in these cases.
Intrinsic resistance to agents targeting phosphoinositide 3-kinase (PI3K)/AKT pathway is one of the major challenges in cancer treatment with such agents. The objective of this study is to identify ...the genes or pathways that can be targeted to overcome the resistance of non-small cell lung carcinoma (NSCLC) to the AKT inhibitor MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide siRNA library screening and biologic characterization, we identified that inhibition of thioredoxin reductase-1 (TXNRD1), one of the key antioxidant enzymes, with siRNAs or its inhibitor, auranofin, sensitized NSCLC cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species production, which was involved in c-jun-NH2-kinase (JNK; MAPK8) activation and cell apoptosis. Furthermore, we found that the synthetic lethality interaction between the TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway. Finally, we found that synthetic lethality induced by TXNRD1 and AKT inhibitors relied on wild-type KEAP1 function. Our study indicates that targeting the interaction between AKT and TXNRD1 antioxidant pathways with MK2206 and auranofin, a U.S. Food and Drug Administration-approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches.
To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or ...metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression.
In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA).
Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA.
Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti–PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology.
•Cemiplimab provided clinical benefit among patients with advanced cervical cancer in a phase I study.•Responding patients had squamous histology.•PD-L1 protein expression in commercially available samples and PD-L1 mRNA expression in The Cancer Genome Atlas were analyzed.•Analyses of PD-L1 protein and mRNA expression showed greater PD-L1 expression in squamous versus non-squamous cervical cancer.•Results support the rationale and design of a global randomized phase III cemiplimab study in metastatic cervical cancer.
Mitochondria serve as platforms for innate immunity. The mitochondrial antiviral signalling (MAVS) protein forms aggregates that elicit robust type-I interferon induction on viral infection, but ...persistent MAVS signalling leads to host immunopathology; it remains unknown how these signalling aggregates are resolved. Here we identify the mitochondria-resident E3 ligase, MARCH5, as a negative regulator of MAVS aggregates. March5(+/-) mice and MARCH5-deficient immune cells exhibit low viral replication and elevated type-I interferon responses to RNA viruses. MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. MARCH5, but not its RING mutant (MARCH5(H43W)), reduces the level of MAVS aggregates. MARCH5 transfers ubiquitin to Lys7 and Lys500 of MAVS and promotes its proteasome-mediated degradation. Our results indicate that MARCH5 modulates MAVS-mediated antiviral signalling, preventing excessive immune reactions.
The repeated growth and reduction of the ice sheet have controlled the striking variation of the continental shelf environment in the Ross Sea. Particularly, glaciomarine shelf sedimentation is ...closely related to the ice sheet dynamics and ice shelf development since the Last Glacial Maximum (LGM). Using the four gravity (and box) cores obtained from the northern Drygalski Basin in the western Ross Sea, multi-proxies including sediment properties, geochemical proxies, carbon isotopic values of organic matter, clay mineral compositions of fine-grained sediments, and diatom assemblage were analyzed with AMS 14C dating from bulk organic matters. Based on the core description, X-radiograph observation, and results of grain size distribution, the core sediments were classified into the seven sediment facies: clast-rich muddy diamicton, clast-rich sandy diamicton, massive mud, laminated mud, bioturbated mud, massive sandy mud, and bioturbated sandy mud. The association of these sediment facies defines the four lithologic units in terms of the depositional evolution. Lithologic unit 1 represents diamicton deposited proximal to the grounding line. When the ice sheet and ice shelf retreated since the LGM, the unsorted sediment mass was deposited proximal to the grounding line. Lithologic unit 2 consists of the massive mud deposited under the sub-ice shelf condition. During the ice sheet retreat, the fine-grained particles were transported by the meltwater plume to the sub-ice shelf floor. The biogenic materials were also transported from the seasonal open marine area to the sub-ice shelf by the currents. Lithologic unit 3 was composed of sandy mud and mud with abundant dropstones that might have been deposited at the calving line. As the calving line passed the Drygalski Basin, a large amount of the coarse fractions was deposited due to ice shelf breakup. The terrestrial sediments from the Victoria Land coast were transported from the grounding line of the remained local ice sheet, when the calving line passed the north side of Drygalski Ice Tongue. Lithologic unit 4 comprises the bioturbated mud and sandy mud that were deposited under the seasonal open marine condition. The biological productivity increased significantly during the late Holocene, while the terrestrial sedimentation decreased under seasonal open marine conditions. The diatom assemblage and δ13C values of sediment organic matter indicate the mid-Holocene warm climate with more sea ice melting. Since the LGM, the paleoenvironmental change and glaciomarine depositional evolution on the northern Drygalski Basin were closely linked with the ice sheet dynamics and ice shelf activity, in addition to the climate change during the Holocene.
•Glaciomarine shelf sedimentation related to the movement of the ice sheet and ice shelf•Seven sediment facies of four gravity cores in the northern Drygalski Basin•Four lithologic units by the depositional evolution since the Last Glacial Maximum•The mid-Holocene warm climate with more sea ice melting from the diatom assemblage
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