Historical development of vaginal microbicides to prevent sexual transmission of HIV in women: from past failures to future hopes

Figures & data

Table 1 Classification of antiretroviral drugs

Mechanism of action	Drugs
Entry inhibitors or FIs	Enfuvirtide, maraviroc
NRTIs	Tenofovir, adefovir, zidovudine, didanosine, stavudine, emtricitabine, abacavir, lamivudine
NNRTIs	Efavirenz, rilpivirine, nevirapine, dapivirine or etravirine
PIs	Ritonavir, darunavir
IIs	Dolutegravir, raltegravir

Abbreviations: FIs, fusion inhibitors; IIs, integrase inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors.

Figure 1 Targeting site of antiretroviral drugs at different stages of the viral cycle.

Figure 2 Diagram of the action sites of different microbicides against HIV.

Figure 3 Chemical structure of tenofovir (A) and tenofovir disoproxil fumarate (B).

Figure 4 Structure of a matrix type (A) and reservoir type (B) vaginal ring.

Figure 5 Mechanism of drug release from sustained release tablets by in situ gelation of the polymer.

Notes: At the time of administration, the tablet is completely solid (A). In contact with the vaginal fluid, the polymer of the outer layers forms a drug-loaded gel (B). The drug reaches the vaginal environment by diffusing through the gel layer or by erosion of the gel (C).

Figure 6 Mechanism of drug release from osmotic release tablets.

Figure 7 Structure of a drug-loaded polymer nanoparticle.

Figure 8 Diagram of the nanofiber manufacturing process by electrospinning.

Table 2 Vaginal formulations for the prevention of sexual transmission of HIV

Mechanism of action	Microbicide	Pharmaceutical form	Animal tests	Clinical trials	Current status	References
Surfactants	Nonoxynol-9	Gel Film	–	Not safe Not effective	Rejected	^Citation20, ^Citation24 ^Citation171, ^Citation172
	Savvy gel^®	Gel	–	Safe Not effective	Rejected	^Citation21, ^Citation23
Acidifier	BufferGel^®	Gel	–	Safe Not effective	Rejected	^Citation32, ^Citation33
Polyanions	Carraguard^®	Gel	–	Safe Not effective	Its use as a carrier is being assessed	^Citation25^–^Citation28, ^Citation30
	PRO 2000^®		Safe Effective	Safe Not effective	Rejected	^Citation32, ^Citation33, ^Citation35^–^Citation37
	VivaGel^®		Safe Effective	Not safe	Rejected	^Citation38^–^Citation46
gp120-neutralizing monoclonal antibody	Vitamin B12	Gel	Safe Dose-dependent effectiveness	–	Large amounts are required and it is very expensive to produce	^Citation50^–^Citation52
	Cyanovirin-N	Gel	Safe Effective	–	Candidate for clinical trials It has been expressed and purified from transgenic plants	^Citation55^–^Citation59
		Probiotics (genetically modified Lactobacillus jensenii strain)	Safe and positive for the vaginal environment Effective	–	In clinical trials	^Citation217^–^Citation219
Entry inhibitors	Maraviroc	Gel (hydroxyethyl cellulose)	Safe Effective	–	Its period of effectiveness must be increased	^Citation69^–^Citation71
		Gel (silicone)	Higher and sustained concentrations	–	Candidate for clinical trials	^Citation72, ^Citation73
		Intravaginal ring	Safe		Controlled release over 28 days	^Citation140
Viral enzyme inhibitors	Tenofovir/tenofovir disoproxil fumarate	Gel	Safe Effective	Safe Effective	The first microbicide that demonstrated efficacy in women	^Citation80^–^Citation89, ^Citation100
		Intravaginal ring	Safe Effective	Safe	In clinical trials It provides lasting protection in animals	^Citation16, ^Citation17, ^Citation132^–^Citation138
		Nanoparticles (into a film)	Safe	–	Controlled release over 24 hours Further evaluation is needed	^Citation204, ^Citation205
	MIV-150	Gel Intravaginal ring	Effective Effective	Safe –	In clinical trials Candidate for clinical trials	^Citation107, ^Citation109^–^Citation111, ^Citation113, ^Citation116 ^Citation141^–^Citation144
	Dapivirine	Gel	Safe Effective	Safe	In clinical trials	^Citation119^–^Citation123
		Intravaginal ring	Safe Effective	Safe Effective	Controlled release over 28 days Has demonstrated efficacy in women	^Citation151^–^Citation156
		Film	Safe Effective	Safe	In clinical trials	^Citation169, ^Citation179

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