Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .)

Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial

Objective: VIOLIN (TMC125IFD3002; NCT01422330) evaluated the safety, tolerability, and pharmacokinetics of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected patients. Methods: In a 48-week, phase IV, single-arm, multicenter study, patients on prior antiretroviral therapy (⩾8 weeks) who needed to change regimen for virologic failure (viral load ⩾ 500 copies/mL) or simplification/adverse events (viral load < 50 copies/mL) received etravirine 200 mg bid with ⩾1 other active antiretroviral, excluding darunavir/ritonavir or only nucleoside/tide reverse transcriptase inhibitors. Results: Of 211 treated patients, 73% (n = 155) had baseline viral load ⩾ 50 copies/mL and 27% (n = 56) had baseline viral load < 50 copies/mL. Protease inhibitors were the most common background antiretrovirals (83%). Diarrhea was the most frequent adverse event (17%). Serious adverse events (no rash) occurred in 5% of patients; none were etravirine related. Overall, median etravirine AUC 12h was 5390 ng h/mL and C 0h was 353 ng/mL (N = 199). Week 48 virologic response rates (viral load < 50 copies/mL; Food and Drug Administration Snapshot algorithm) were 48% (74/155) (baseline viral load ⩾ 50 copies/mL) and 75% (42/56) (baseline viral load < 50 copies/mL). Virologic failure rates were 42% and 13%, respectively. The most frequently emerging etravirine resistance-associated mutations in virologic failures were Y181C, E138A, and M230L. Virologic response rates for patients with baseline viral load ⩾ 50 copies/mL were 38% (30/79) (non-adherent) versus 64% (44/69) (adherent subset). Conclusion: Etravirine 200 mg bid in combination with antiretrovirals other than darunavir/ritonavir was well tolerated in the studied treatment-experienced HIV-1-infected population. The overall etravirine safety and tolerability profile and pharmacokinetics (specifically in those patients who were adherent) were similar to those previously observed for etravirine in HIV-1-infected adults. The relatively high level of non-adherence, also observed in the pharmacokinetic assessments, negatively impacted virologic response, especially in patients with ⩾50 copies/mL at baseline

Uptake and distribution of technetium in several marine algae

The uptake or chemical form of technetium in different marine algae (Acetabularia, Cystoseira, Fucus) has been examined and a simple model to explain the uptake of technetium in the unicellular alga, Acetabularia, has been conceptualized. At low concentrations in the external medium, Acetabularia can rapidly concentrate technetium. Concentration factors in excess of 400 can be attained after a time of about 3 weeks. At higher mass concentrations in the medium, uptake of technetium by Acetabularia becomes saturated resulting in a decreased concentration factor (approximately 10 after 4 weeks). Approximately 69% of the total radioactivity present in /sup 95m/Tc labelled Acetabularia is found in the cell cytosol. In Fucus vesiculosus, labelled with /sup 95m/Tc, a high percentage of technetium is present in soluble ionic forms while approximately 40% is bound, in this brown alga, in proteins and polysaccharides associated with cell walls. In the algal cytosol of Fucus vesiculosus, about 45% of the /sup 95m/Tc appears to be present as anionic TcO/sup -//sub 4/ and the remainder is bound to small molecules. 8 references, 5 figures, 1 table

Altered configuration of Gc on the plasma membrane of transformed and malignant human B lymphocytes

Normal human peripheral blood B cells exhibit strong membrane fluorescence for Gc (vitamin D-binding protein), and this protein can form a close spatial relationship with integral membrane immunoglobulin (mIg) with evidence of codistribution in the lipid bilayer. In contrast, fluorescence for both Gc and mIg has been found in this study to be weak or absent in several B lymphoblastoid cell lines and in chronic lymphocytic leukemia B cells. Moreover, the comobility of these components, where detectable, was also impaired. In abnormal B cells, the intensity of membrane fluorescence for Gc was substantially increased after crosslinking of mIg with antibody, and the latter was also associated with increased specific radioiodination of Gc by lactoperioxidase. These results indicate that Gc can apparently become displaced under certain circumstances within or through the lipid bilayer. The altered content or membrane topography of Gc in such abnormal B cells might be associated with impaired expression and mobility of mIg

Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM) : an open-label, extension study

BACKGROUND : The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS : The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS : Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03–0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1–2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION : Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice.The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government’s Foreign, Commonwealth and Development Office, and the US President’s Emergency Plan for AIDS Relief through the US Agency for International Development.https://www.thelancet.com/journals/lanhiv/homeam2022Family Medicin

Development and External Validation of Nomograms To Predict Adverse Pathological Characteristics After Robotic Prostatectomy: Results of a Prospective, Multi-institutional, Nationwide series

BACKGROUND: The possibility of predicting pathologic features before surgery can support clinicians in selecting the best treatment strategy for their patients. We sought to develop and externally validate pretreatment nomograms for the prediction of pathological features from a prospective multicentre series of robotic-assisted laparoscopic prostatectomy (RALP) procedures. DESIGN, SETTING, AND PARTICIPANTS: Between 2009 and 2016, data from 6823 patients undergoing RALP in 25 academic and community hospitals were prospectively collected by the Belgian Cancer Registry. Logistic regression models were applied to predict extraprostatic extension (EPE; pT3a,b-4), seminal vesicle invasion (SVI; pT3b), and high-grade locally advanced disease (HGLA; pT3b-4 and Gleason score [GS] 8-10) using the following preoperative covariates: prostate-specific antigen, clinical T stage, biopsy GS, and percentage of positive biopsy cores. Internal and external validation was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The stability of the model was assessed via tenfold cross-validation using 80% of the cohort. The nomograms were independently externally validated using the test cohort. The discriminative accuracy of the nomograms was quantified as the area under the receiver operating characteristic curve and graphically represented using calibration plots. RESULTS AND LIMITATION: The nomograms predicting EPE, SVI, HGLA showed discriminative accuracy of 77%, 82%, and 88%, respectively. Following external validation, the accuracy remained stable. The prediction models showed excellent calibration properties. CONCLUSIONS: We developed and externally validated multi-institutional nomograms to predict pathologic features after RALP. These nomograms can be implemented in the clinical setting or patient selection in clinical trials. PATIENT SUMMARY: We developed novel nomograms using nationwide data to predict postoperative pathologic features and lethal prostate cancer.status: publishe

Development and external validation of nomograms to predict adverse pathological characteristics after robotic prostatectomy : results of a prospective, multi-institutional, nationwide series

Background: The possibility of predicting pathologic features before surgery can support clinicians in selecting the best treatment strategy for their patients. We sought to develop and externally validate pretreatment nomograms for the prediction of pathological features from a prospective multicentre series of robotic-assisted laparoscopic prostatectomy (RALP) procedures. Design, setting, and participants: Between 2009 and 2016, data from 6823 patients undergoing RALP in 25 academic and community hospitals were prospectively collected by the Belgian Cancer Registry. Logistic regression models were applied to predict extraprostatic extension (EPE; pT3a,b-4), seminal vesicle invasion (SVI; pT3b), and high-grade locally advanced disease (HGLA; pT3b-4 and Gleason score [GS] 8-10) using the following preoperative covariates: prostate-specific antigen, clinical T stage, biopsy GS, and percentage of positive biopsy cores. Internal and external validation was performed. Outcome measurements and statistical analysis: The stability of the model was assessed via tenfold cross-validation using 80% of the cohort. The nomograms were independently externally validated using the test cohort. The discriminative accuracy of the nomograms was quantified as the area under the receiver operating characteristic curve and graphically represented using calibration plots. Result and limitation: The nomograms predicting EPE, SVI, HGLA showed discriminative accuracy of 77%, 82%, and 88%, respectively. Following external validation, the accuracy remained stable. The prediction models showed excellent calibration properties. Conclusion:We developed and externally validated multi-institutional nomograms to predict pathologic features after RALP. These nomograms can be implemented in the clinical setting or patient selection in clinical trials. Patient summary: We developed novel nomograms using nationwide data to predict postoperative pathologic features and lethal prostate cancer. (C) 2018 Published by Elsevier B.V. on behalf of European Association of Urology

Nationwide quality assurance of high-throughput diagnostic molecular testing during the SARS-CoV-2 pandemic : role of the Belgian National Reference Centre

Abstract: Since the onset of the coronavirus disease (COVID-19) pandemic in Belgium, UZ/KU Leuven has played a crucial role as the National Reference Centre (NRC) for respiratory pathogens, to be the first Belgian laboratory to develop and implement laboratory developed diagnostic assays for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and later to assess the quality of commercial kits. To meet the growing demand for decentralised testing, both clinical laboratories and government-supported high-throughput platforms were gradually deployed across Belgium. Consequently, the role of the NRC transitioned from a specialised testing laboratory to strengthening capacity and coordinating quality assurance. Here, we outline the measures taken by the NRC, the national public health institute Sciensano and the executing clinical laboratories to ensure effective quality management of molecular testing throughout the initial two years of the pandemic (March 2020 to March 2022)