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

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

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