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Introduction: Vaginalrings are a promising approach to provide a woman-centred, long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV-1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three-month rings with different DPV dosages, compared with the monthly DPV ring. Methods: From December 2017 to October 2018, MTN-036/IPM-047 enrolled 49 HIV-negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three-month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow-up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginalfluid (CVF) and cervicaltissue, at nominaltimepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. Results: There were no differences in the proportion of participants with grade [greater than or equal to]2 genitourinary AEs or grade [greater than or equal to]3AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervicaltissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at alltimes, with no product discontinuations/outages) with no differences between the monthly versus three-month rings. Most participants found the ring acceptable (median = 8 on 10-point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). Conclusions: The extended duration DPV rings were well-tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three-month DPV rings for HIV prevention. Keywords: dapivirine; vaginalring; pharmacokinetics; safety; microbicide; pre-exposure prophylaxis, 1 INTRODUCTION Over half of the 38 million people living with the human immunodeficiency virus (HIV) globally are women [1]. In sub-Saharan Africa, women and girls account for 59% of [...]

Background The Ring Study demonstrated 35.1% human immunodeficiency virus type 1 (HIV-1) infection risk reduction among participants who used the Dapivirine vaginal ring-004 (DVR), whereas the Dapivirine Ring Extended Access and Monitoring (DREAM) trial, approximated a 62% risk reduction. The observed non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs) and effects on viral susceptibility are described here. Methods Population-based genotyping on plasma samples collected longitudinally, and next-generation sequencing (NGS) and phenotypic susceptibility testing were done on plasma collected at seroconversion. Retrospective HIV-1 RNA testing was used to more accurately establish the time of infection. Results In the Ring Study, NNRTI RAMs were not observed in most viruses at seroconversion (population-based genotyping: DVR: 71 of 84, 84.5%; placebo: 50 of 58, 86.2%). However, more E138A was found in the DVR group (E138A DVR: 9 of 84, 10.7%; placebo: 2 of 58, 3.4%; P =.2, Fisher exact test). NGS detected 1 additional mutation in each group (DVR: G190A; placebo: G190A and G190E). Marginal dapivirine susceptibility reduction was found with NNRTI RAMs at seroconversion (geometric mean fold-change, range: DVR, 3.1, 1.3–5.1; placebo, 5.8, 0.9–120). NNRTI RAMs were not emergent between first detectable HIV-1 RNA and seroconversion when these visits differed (paired samples, mean ring use: DVR, n = 52, 35 days; placebo, n = 26, 31 days). After stopping DVR, 2 of 63 viruses had emergent G190G/A or K103K/N with V106V/M at final study visit. Resistance profiles from the DREAM trial were consistent with the Ring Study. Conclusions DVR showed little potential for selection of NNRTI-resistant variants. Clinical Trials Registration NCT01539226 and NCT02862171. [ABSTRACT FROM AUTHOR]

Politicians across parties repeatedly agreed that their visions of social improvement rested as much on the promotion of character virtues as on the efficacy of economic systems. Character posed recurring political dilemmas. Ideological dispute over character, as to whether it is formed best through individual exertion or collective support, lies at the heart of the division of politics between right and left. Further, the limits to the people's character were seen as a constraint upon social progress. Yet, contrary to much historiography, this is not a story of decline from a supposed Victorian heyday of 'moral politics'. British politics proved notably adaptive in forging updated, optimistic visions, in which the forces of modernity which might have seemed to threaten the moral calibre of the body politic, or of society, whether democracy, state expansion, or, later, 'individualism', were recast instead as supportive foundations for the people's moral growth. If the century has seen a steadily 'quieter', less loudly moralizing, more nurturing approach to the encouragement of character, this reflected a growth in the sophistication of the method of advancing character, not a decline in either the political importance accorded to it, or the people's possession of it. [ABSTRACT FROM AUTHOR]