- Microbicide Intravaginal Rings

Keyword(s):  
2020 ◽  
Author(s):  
Lungwani Muungo

Vaginal microbicides for the prevention of HIV transmission maybe an important option for protecting women from infection.Incorporation of dapivirine, a lead candidate nonnucleoside reversetranscriptase inhibitor, into intravaginal rings (IVRs) for sustainedmucosal delivery may increase microbicide product adherence andefficacy compared with conventional vaginal formulations. Twentyfourhealthy HIV-negative women 18–35 years of age were randomlyassigned (1:1:1) to dapivirine matrix IVR, dapivirine reservoir IVR,or placebo IVR. Dapivirine concentrations were measured in plasmaand vaginal fluid samples collected at sequential time points over the33-day study period (28 days of IVR use, 5 days of follow-up). Safetywas assessed by pelvic/colposcopic examinations, clinical laboratorytests, and adverse events. Both IVR types were safe and well toleratedwith similar adverse events observed in the placebo and dapivirinegroups. Dapivirine from both IVR types was successfully distributedthroughout the lower genital tract at concentrations over 4 logs greaterthan the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximumconcentration (Cmax) and area under the concentration–time curve(AUC) values were significantly higher with the matrix than reservoirIVR. Mean plasma concentrations of dapivirine were ,2 ng/mL.These findings suggest that IVR delivery of microbicides is a viableoption meriting further study.Key Words: dapivirine, HIV, intravaginal ring, microbicide,pharmacokinetics, prevention


2015 ◽  
Vol 91 (Suppl 2) ◽  
pp. A53.3-A54
Author(s):  
L Hardy ◽  
V Jespers ◽  
I De Baetselier ◽  
J van de Wijgert ◽  
T Crucitti

2012 ◽  
Vol 56 (11) ◽  
pp. 5952-5960 ◽  
Author(s):  
John A. Moss ◽  
Amanda M. Malone ◽  
Thomas J. Smith ◽  
Irina Butkyavichene ◽  
Cassandra Cortez ◽  
...  

ABSTRACTAntiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel “pod IVR” platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ± 109 μg ml−1(slow releasing) and 1.84 ± 1.97 mg ml−1(fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ± 54.8 μg g−1and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ± 150 fmol/106cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIVSF162p3) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.


2018 ◽  
Vol 549 (1-2) ◽  
pp. 124-132 ◽  
Author(s):  
Yujing Wang ◽  
Peter Boyd ◽  
Alyson Hunter ◽  
R. Karl Malcolm

2014 ◽  
Vol 58 (9) ◽  
pp. 5125-5135 ◽  
Author(s):  
John A. Moss ◽  
Priya Srinivasan ◽  
Thomas J. Smith ◽  
Irina Butkyavichene ◽  
Gilbert Lopez ◽  
...  

ABSTRACTPreexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g−1(tenofovir [TFV],in vivohydrolysis product of TDF) and 500 μg g−1(FTC) and in the TDF-FTC-MVC group were 10 μg g−1(TFV), 150 μg g−1(FTC), and 20 μg g−1(MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation.


2003 ◽  
Vol 91 (3) ◽  
pp. 355-364 ◽  
Author(s):  
Karl Malcolm ◽  
David Woolfson ◽  
Julie Russell ◽  
Chris Andrews

2014 ◽  
pp. 1801 ◽  
Author(s):  
Emmanuel Ho ◽  
Yufei Chen ◽  
Yannick Traore ◽  
Amanda Li ◽  
Keith Fowke

2017 ◽  
Vol 529 (1-2) ◽  
pp. 218-226 ◽  
Author(s):  
G. Verstraete ◽  
L. Vandenbussche ◽  
S. Kasmi ◽  
L. Nuhn ◽  
D. Brouckaert ◽  
...  

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