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 .)

Measurement of inter-particle forces from the osmotic pressure of partially frozen dispersions

When an oil-continuous dispersion is frozen two microdomains are formed: one, the pure oil solvent which is selectively solidified (I), the other, a concentrated 'liquid' dispersion of particles in oil (II). These two domains are intimately mixed within the frozen colloid and exist in a state of equilibrium determined by the system pressure and temperature. The position of equilibrium controls the proportion of the solvent which is solidified, and thereby the concentration of particles within the fluid microdomains (II). Combined with SANS measurements, to determine the inter-particle separation in these microdomains, an analysis based on osmotic pressure provides a measure of the inter-particle repulsion forces presented by the surfactant layers

Effects of solidification of the oil phase on the structure of colloidal dispersions in cyclohexane

The liquid-to-solid transition of the alkane-continuous phase of a dilute surfactant-stabilized particle or droplet dispersion can be induced in a reversible manner without destabilizing the colloid by pressure and/or temperature changes. The structural changes have been studied by small-angle neutron scattering (SANS) over a range of pressure (1-600 bar) and temperatures (3-20-degrees-C). The SANS results indicate that there are different levels of structure in the solidified system in which a solid alkane coexists with fluid cluster domains. The clusters show large-scale structural correlations of order 5-50 mum; within these clusters the particles are in close contact, so that under certain conditions, e.g. high pressure, the stabilizing surfactant layers of adjacent particles are interdigitated. The distance between particle centers, and therefore the degree of surfactant interdigitation, can be readily varied by the application of pressure. An interpretation of the SANS results is given in terms of the effects of temperature and pressure upon the osmotic pressure of the concentrated solution of particles/droplets. The analysis provides an estimate of the interparticle pair potential energy between adjacent particles in a cluster as a function of separation

Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: A randomised, open-label, crossover trial

Background: Half of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women. Methods: MTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16–21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655. Findings: From Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17–19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up. Interpretation: Adherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences

Structure of Cobalt Aerosol-OT Reversed Micelles Studied by Sall-Angle Scattering Methods

The surfactant-cyclohexane-water ternary phase behaviour and reversed micelle and water-in-oil (w/o) micro-emulsion structure of the cobalt (II) derivative of the anionic amphiphile Aerosol-OT (AOT) [Co(water)6](AOT)2 have been studied by polarising microscopy, small-angle neutron and X-ray scattering (SANS, SAXS). The surfactant forms an H2 reversed hexagonal phase on swelling with up to 25 wt.% cyclohexane. At higher concentrations of oil the fluid L2 reversed micellar phase is present, and a w/o phase forms up to w = 25.0 (w = [water]/[AOT-]). For w > 25.0 at 25-degrees-C a Winsor II system separates cleanly i.e. a w/o droplet system at the 'natural' radius of the monolayer, co-existing with an essentially surfactant-free water phase. The SAXS I(Q) profiles show that major changes in aggregate shape occur as a function of w at constant surfactant concentration. At low surfactant concentrations, [AOT-] = 0.075 mol dm-3, the w = 0 reversed micelles, formed from diluting the H2 phase, are small near-spherical aggregates. The scattering is consistent with cylindrical micelles at low w, 5-10, and spherical w/o droplets at the Winsor II boundary w = 25.0. The results are explained in terms of the influence of parent H2 and co-existing water phases on the aggregate shapes in the L2 phase. We have used the SANS contrast variation method to investigate the internal cross-section structure of the cylindrical, w = 5.0, reversed micelles. The results show that the radius of the polar core, r, is only slightly larger than the hydrated radius of the [Co(water)6]2+ counterion and that the surfactant shell thickness, delta, is essentially equal to the length of the AOT hydrocarbon chains. This suggests an open staggered 'string of beads' structure for the micelles, rather than a polar core that can be significantly swollen with water. This model gives us some insight into structure of the lyotropic H2 phase

Characterization of viruses in Phase 3 and Phase 3b trials (the Ring Study and the Dapivirine Ring Extended Access and Monitoring Trial) of the Dapivirine vaginal ring for human immunodeficiency virus type 1 infection risk reduction

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 presentation, treatment response, and virology outcomes of women who seroconverted in the Dapivirine Vaginal Ring Trials—The Ring Study and DREAM

Background: Participants with human immunodeficiency virus (HIV) seroconversion in The Ring Study, a phase 3 trial of dapivirine vaginal ring (DVR), or in the open-label extension trial dapivirine ring extended access and monitoring (DREAM) were offered enrollment in an observational cohort study (IPM 007) to assess clinical presentation and response to antiretroviral therapy (ART). Methods: Participants\u27 HIV infection was managed at local treatment clinics according to national treatment guidelines. IPM 007 study visits occurred 3 and 6 months after enrollment and every 6 months thereafter. Assessments included plasma HIV-1 RNA, CD4+ T-cell counts, and recording of HIV/AIDS-associated events and antiretroviral use. Post hoc virology analyses were performed for participants identified with virologic failure. Results: One hundred fifty-one of 179 eligible participants (84.4%) enrolled into IPM 007; 103 had previously received the DVR in the Ring or DREAM studies, and 48 had received placebo in The Ring Study. HIV-1 RNA and CD4+ T-cell counts after 12 months\u27 follow-up were similar for participants who used the DVR in The Ring Study and DREAM, compared to those who received placebo. Of the 78 participants with a study visit approximately 6 months after ART initiation, 59 (75.6%) had HIV-1 RNAConclusions: Seroconversion during DVR use did not negatively affect clinical presentation or treatment outcome. Mutation patterns at virologic failure were in line with individuals failing an NNRTI-based regimen. Clinical Trials Registration: NCT01618058

Structural and dynamic studies of water in mesoporous silicas using neutron scattering and nuclear magnetic resonance

Experimental techniques for studying the behaviour of water in confined geometry using neutron scattering and NMR methods are reviewed. A brief survey is given of earlier work on sol-gel silicas and these findings are updated by reference to current work on MCM- and SBA-type silicas. Particular attention is focused on the phase transitions and the relation between supercooled water and ice phases in the confined geometry of the mesopores. The characteristics are found to behave in a systematic manner although the nucleation phenomenon for partially filled pores reveals some unexpected complexity for the SBA silicas