In Vitro Evaluation of Nonnucleoside Reverse Transcriptase Inhibitors UC-781 and TMC120-R147681 as Human Immunodeficiency Virus Microbicides

Herrewege, Yven Van; Michiels, Jo; Roey, Jens Van; Fransen, Katrien; Kestens, Luc; Balzarini, Jan; Lewi, Paul; Vanham, Guido; Janßen, Paul

doi:10.1128/aac.48.1.337-339.2004

Cited by 137 publications

(92 citation statements)

References 21 publications

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“…This will be closely followed by a microbicide containing dapivirine, which belongs to the nonnucleoside reverse transcriptase inhibitor (NNRTI) class of ARVs (6); trial results will be available in 2010. Three other ARV-based microbicides, containing NNRTIs, are in earlier-phase trials (3,5,(7)(8)(9)(10). ARV-based microbicides are anticipated to be highly effective; however, there is concern that, if used by HIV-positive women, class-specific drug resistance may emerge.…”

mentioning

confidence: 99%

The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

Wilson

Coplan

Wainberg

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Vaginal microbicides, designed to prevent HIV infection in women, are one of the most promising biomedical interventions. Clinical trials of second-generation microbicides have begun; if shown to be effective, they could be licensed within 5–10 years. Because these microbicides contain antiretrovirals (ARVs), they could be highly effective. However, there is concern that, if used by HIV-positive women, ARV resistance may evolve. By analyzing a mathematical model, we find that adherence could have both beneficial and detrimental effects on trial outcomes. Most importantly, we show that planned trial designs could mask resistance risks and therefore enable high-risk microbicides to pass clinical testing. We then parameterize a transmission model using epidemiological, clinical, and behavioral data to predict the consequences of wide-scale usage of high-risk microbicides in a heterosexual population. Surprisingly, we show that reducing a participant's risk of resistance during a trial could lead to unexpectedly high rates of resistance afterward when microbicides are used in public health interventions. We also find that, paradoxically, although microbicides will be used by women to protect themselves against infection, they could provide greater benefit to men. More infections in men than in women will be prevented if there is a high probability that ARVs are systemically absorbed, microbicides are less than ∼50% effective, and/or adherence is less than ∼60%. Men will always benefit more than women in terms of infections prevented per resistant case; but this advantage decreases as the relative fitness of drug-resistant strains increases. Interventions that use ARV-based microbicides could have surprising consequences.

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mentioning

confidence: 99%

The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

Wilson

Coplan

Wainberg

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…These are designed to provide a single dose of a microbicidal agent (38)(39)(40)(41)(42). Intravaginal delivery systems for microbicides have been formulated and traditionally include a large variety of pharmaceutical dosage forms such as semi-solids, tablets, capsules, pessaries, liquid preparations, vaginal films, vaginal rings, foams, and tampons.…”

Section: Current Intravaginal Microbicide Delivery Methods For Prevenmentioning

confidence: 99%

A Review of Current Intravaginal Drug Delivery Approaches Employed for the Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Infections

et al. 2008

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Abstract. The objective of this review is to describe the current status of several intravaginal anti-HIV microbicidal delivery systems these delivery systems and microbicidal compounds in the context of their stage within clinical trials and their potential cervicovaginal defence successes. The global Human Immuno-Deficiency Virus (HIV) pandemic continues to spread at a rate of more than 15,000 new infections daily and sexually transmitted infections (STIs) can predispose people to acquiring HIV infection. Male-to-female transmission is eight times more likely to occur than female-to-male transmission due to the anatomical structure of the vagina as well as socio-economic factors and the disempowerment of women that renders them unable to refuse unsafe sexual practices in some communities. The increased incidence of HIV in women has identified the urgent need for efficacious and safe intravaginal delivery of anti-HIV agents that can be used and controlled by women. To meet this challenge, several intravaginal anti-HIV microbicidal delivery systems are in the process of been developed. The outcomes of three main categories are discussed in this review: namely, dual-function polymeric systems, non-polymeric systems and nanotechnology-based systems. These delivery systems include formulations that modify the genital environment (e.g. polyacrylic acid gels and lactobacillus gels), surfactants (e.g. sodium lauryl sulfate), polyanionic therapeutic polymers (e.g. carageenan and carbomer/lactic acid gels), proteins (e.g. cyanovirin-N, monoclonal antibodies and thromspondin-1 peptides), protease inhibitors and other molecules (e.g. dendrimer based-gels and the molecular condom). Intravaginal microbicide delivery systems are providing a new option for preventing the transmission of STIs and HIV.

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“…Dapivirine (formerly TMC 120) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) (Njai et al, 2005;Van Herrewege et al, 2004) that is being developed as a vaginal microbicide to prevent the heterosexual transmission of the human immunodeficiency virus (HIV) (Nuttall et al, 2008;Jespers et al, 2007;Woolfson et al, 2006). Earlier formulation approaches to HIV microbicide candidates have focused largely on conventional aqueous gel systems, reflecting their predominant use in established vaginal products (Di Fabio et al, 2003;Malcolm et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network

Woolfson

Umrethia

Kett

et al. 2010

International Journal of Pharmaceutics

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b s t r a c tDapivirine mucoadhesive gels and freeze-dried tablets were prepared using a 3 × 3 × 2 factorial design. An artificial neural network (ANN) with multi-layer perception was used to investigate the effect of hydroxypropyl-methylcellulose (HPMC): polyvinylpyrrolidone (PVP) ratio (X1), mucoadhesive concentration (X2) and delivery system (gel or freeze-dried mucoadhesive tablet, X3) on response variables; cumulative release of dapivirine at 24 h (Q 24 ), mucoadhesive force (F max ) and zero-rate viscosity. Optimisation was performed by minimising the error between the experimental and predicted values of responses by ANN. The method was validated using check point analysis by preparing six formulations of gels and their corresponding freeze-dried tablets randomly selected from within the design space of contour plots. Experimental and predicted values of response variables were not significantly different (p > 0.05, two-sided paired t-test). For gels, Q 24 values were higher than their corresponding freeze-dried tablets. F max values for freeze-dried tablets were significantly different (2-4 times greater, p > 0.05, twosided paired t-test) compared to equivalent gels. Freeze-dried tablets having lower values for X1 and higher values for X2 components offered the best compromise between effective dapivirine release, mucoadhesion and viscosity such that increased vaginal residence time was likely to be achieved.

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In Vitro Evaluation of Nonnucleoside Reverse Transcriptase Inhibitors UC-781 and TMC120-R147681 as Human Immunodeficiency Virus Microbicides

Cited by 137 publications

References 21 publications

The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

A Review of Current Intravaginal Drug Delivery Approaches Employed for the Prophylaxis of HIV/AIDS and Prevention of Sexually Transmitted Infections

Freeze-dried, mucoadhesive system for vaginal delivery of the HIV microbicide, dapivirine: Optimisation by an artificial neural network

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