A randomized, double-blind, placebo-controlled Phase II extended safety study of two Invisible Condom® formulations in Cameroonian women
François‐Xavier Mbopi‐KéouSylvie TrottierRabeea F. OmarNgoh N. NkeleSéraphin FokouaEnow Robinson MbuMarc-Christian DomingoJean‐François GiguèreJocelyne PiretAnthony MwathaBenoı̂t MâsseMichel G. Bergeron
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Vaginal microbicide
Intravaginal administration
Female condom
Intrauterine device
Intravaginal and menstrual practices may potentially influence results of trials of microbicides for HIV prevention through effects on the vaginal environment and on adherence to microbicide and placebo products. As part of the feasibility study for the Microbicides Development Programme Phase 3 trial of a vaginal microbicide in Mwanza, a variety of quantitative and qualitative methods were used to describe these practices, associations with behaviour and underlying social norms among women working in food and recreational facilities. Intravaginal cleansing by inserting fingers and either water alone or soap and water was thought necessary to remove "uchafu" (dirt), referring to vaginal secretions, including menstrual blood and post-coital discharge. Vaginal cleansing was carried out within 2 hours after 45% of sex acts. Sexual enhancement practices were less common. Intravaginal and menstrual practices and associated behaviours and demographic factors should be measured and monitored throughout microbicide trials to enable analyses of their impacts on microbicide effectiveness.
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Intravaginal insertion is often associated with the concept of 'dry' sex. All HIV-prevention microbicides tested to date have been vaginally applied lubricant-based gels. In this paper, we examine whether the use of intravaginal insertions could be in conflict with the introduction of vaginal microbicide gels. The Africa Centre site was part of the Microbicides Development Programme evaluating PRO2000/5 microbicide gel. We conducted in-depth-interviews and focus-group discussions with women enrolled in the trial as well as women and men from the community. The analysis focused on people's knowledge of intravaginal insertion in the community and trial participants' experience of using trial gels. Intravaginal use of a variety of products was widely acknowledged. We found that the experience of using trial gels – which made sex 'hot', 'tight' and 'dry' – matched the desired outcomes of intravaginal insertion. We found that vaginal 'dryness' described the removal of excessive amounts of unusual discharge, rather than the removal of normal vaginal secretions and that intravaginal insertion is not exclusively associated with a desire for 'dry' sex. Study findings provide evidence that vaginal microbicide gels may be more acceptable in communities where intravaginal insertion is practiced than was previously thought.
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We present a simple mathematical model for assessing the effects of introducing a microbicide as an HIV infection protective method. As very little is known about the in vivo efficacy of microbicides, we ran sample scenarios for microbicides of various efficacies. We found that, in general, if existing condom usage in a community is low, introducing a microbicide will most likely have a positive impact on HIV incidence as abandonment of condom use in favor of microbicides will not play a significant role. If condom use in a community is high, though, attrition of condom users could play a role large enough to overwhelm any added risk reduction afforded new microbicide users. Our model illustrates the importance of knowing key behavioral parameters, such as the proportion of the population that uses condoms, before microbicides can be safely introduced. These parameters include the proportion of condom users likely to maintain condom use and the proportion of condom nonusers likely to adopt microbicides, as well as the efficacy of the candidate microbicide.
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Female condom
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Abandoning condoms for microbicides is termed 'condom migration'. This study estimated the reduction in condom use that can be tolerated following the introduction of an HIV- and sexually transmitted disease (STD)-efficacious microbicide without increasing an individual's risk of HIV infection, and explored how microbicide use affects HIV-risk.Development of a static mathematical model to compare how different combinations of condom and microbicide use affect individual risk of HIV and STD infection at a particular point in time.The model is used to identify the 'break-even point' at which any increased risk associated with condom migration is counter-balanced by the protection afforded with microbicides. Data from Benin is used as a case-example.Considering a 50% HIV- and STD-efficacious microbicide, groups that use condoms with 25% consistency or less could cease using condoms without increasing their risk if they use microbicides in 50% or more of sex acts. However, migration may increase risk if the initial condom-consistency is high (> 70%) and microbicide-consistency is low (< 50% of non-condom-protected acts). For the Benin case-example, if condoms are initially used in 70% or less of sex acts, and if consistency of condom use is sustained following microbicide introduction, there will be a 20% or greater reduction in HIV-risk if the microbicide is used in 50% of non-condom-protected sex acts.There are likely to be many situations in which the benefits of microbicide use outweigh the negative impact of condom migration, and where microbicides could substantially reduce HIV-risk.
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Female condom
Vaginal microbicide
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In the absence of an approved and effective vaccine, topical microbicides have become the strategy of choice to provide women with the ability to prevent the sexual transmission of HIV. Topical microbicides are chemical and physical agents specifically developed and formulated for use in either the vaginal or rectal environment to prevent the sexual transmission of infectious organisms. Although a microbicide product will have many of the same properties as other anti-infective therapeutic agents, the microbicide development pathway has significant differences which reflect the complex biological environment in which the products must act. These challenges to the development of an effective microbicide are reflected in the recently released FDA Guidance document which defines the microbicide development algorithm and includes the evaluation of preclinical efficacy and toxicity, and safety and toxicology, and indicates the necessity of testing of the active pharmaceutical product as well as an optimal formulation for delivery of the microbicide product. The microbicide development algorithm requires evaluation of the potential microbicidal agent and final formulated product in assays which mimic the microenvironment of the vagina and rectum during the sexual transmission of HIV, including the evaluation of activity and cytotoxicity in the appropriate biological matrices, toxicity testing against normal vaginal flora and at standard vaginal pH, testing in ectocervical and colorectal explant tissue, and irritation studies to vaginal, rectal and penile tissue. Herein, we discuss currently accepted practices required for the development of a successful microbicide product which will prevent virus transmission in the vaginal and rectal vaults. Keywords: Topical microbicide, HIV-1, Preclinical development, Pharmacodynamics, Pharmacokinetics, Toxicity, Prevention.
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For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.
Maraviroc
CCR5 receptor antagonist
Vaginal microbicide
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Intravaginal administration
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The impact on HIV prevalence in men and women of the introduction of vaginal microbicides, and subsequent changes in condom usage, depends critically on the efficacy of microbicides in both blocking transmission to women and reducing the infectiousness of infected women. Neglecting to consider how differences in microbicide efficacy by direction of transmission can affect HIV prevalence over time will result in underestimation of the effect of condom replacement.
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Vaginal microbicide
Intravaginal administration
Female condom
Intrauterine device
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