*11.1.1.2. TMC120 and UC781*

*11.1.1.1. Tenofovir*

**Specific microbicide agents**

Reverse transcriptase inhibitors (NRTIs and

Entry inhibitors: CCR5

**Non-specific microbicide agents**

Vaginal milieu protectors/ acidifying agents

Entry inhibitors: anionic

polymers

NNRTIs)

blockers

Tenofovir is active as a diphosphate, rather than a triphosphate, which does not act via HIV DNA chain termination, coupled with the limited phosporylation ability of macrophages. This explains why the drug might be effective in macrophages and other non-dividing cells [197, 198]. Based on the animal studies and with an appreciation for tenofovir's relatively high barrier to resistance compared with other reverse transcriptase inhibitors [196], the compound became the first antiretroviral drug to be assessed as a VM in a clinical trial. In a phase I study (HPTN 050), 0 3% and 1% vaginal tenofovir gel, formulated as a diphosphate, was used once or twice daily for 14 days by HIV-1 infected and uninfected women. The gel was found to be

safe, well tolerated, and acceptable to participants [199].

150 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

Tenofovir (NRTI); (PMPA; nucleotide analogue)

Naphthalene sulfonate

Carrageenan (Carraguard®) Phase III trial

(PRO2000®)

Cellulose sulfate (Ushercell®)

**Drug Clinical trial\***

(NCT00705679)

PSC-RANTES Protected macaques from SHIV (SF162)

TMC120 (NNRTI) Phase III trial efficacy study and phase I/II safety UC781 (NNRTI) Phase I trial, Phase I(NCT00441909, NCT00132444,

study ongoing(NCT00385554)

CPMD167 Full protection of macaques from SHIV (162P4) not

BMS-378806and C52-L

Acidform (Amphora®) Phase III trial: preventionof *N. gonorrhoeae* and *C. trachomatis*

Carbopol 974P (BufferGel®) Phase II/IIb trial (HPTN 035) (NCT00074425)

Phase III trial

Phase I trial, Phase II (NCT00561496, NCT00540605, NCT00594373), Phase II (NCT00111943), Phase IIb (CAPRISA 004; NCT00441298), and Phase II/IIb

NCT00385554), and Phase I (NCT00408538). Male tolerance

achieved alone, but only with addition two peptides

Phase II/IIb trial (NCT00074425), Phase III (NCT00262106)

Two other compounds of class NNRTIs being studied as topical microbicides to prevent HIV-1 infection, are the TMC120 and UC781. Preclinical or clinical testing as potential topical microbicides showed that they possess several features in common, and both compounds show minimal systemic absorption, having revealed goodsafety profiles in animal studies [200, 201]. *In vitro,* TMC120 and UC781 prevent cell-free and cell-associated virus from infecting cocultures of monocyte-derived dendritic cells and T cells [202-204]. TMC120 (4-[{4-[(2,4,6 trimethylphenyl)amino]pyrimidin-2-yl} amino]benzenecarbonitrile), a diarylpyrimidine, was the first topical microbicide the NNRTIs class, in gel form, with activity and effectiveness proven *in vivo* [201, 203]. The thiocarbanilide UC781 (N-[4-chloro-3-(3-methyl-2-butenyloxy) phyenyl]-2-methyl-furan-3-carbothioamide), presents a good capacity to block cell-free and cell-associated HIV-1 transmission in human cervical tissue-based culture organ [205, 206], and have shown effectiveness as a VM safety studies in rabbits [200]. Additional phase I trials are underway [205, 207] (Table 6).

#### *11.1.2. Entry inhibitors: CCR5 blockers*

CCR5 blockers, also known as CC chemokine receptor 5 [CCR5] antagonists, entered the market in 2007 as antiretroviral drugs, such as drugs capable of effectively blocking the fusion of HIV-1 to CCR5 receptors (Selzentry, Maraviroc®) of the target cell. Its effectiveness at blocking HIV-1 fusion raised its possible ability to act as topical microbicide for the prevention of HIV-1 infection [208, 209]. CCR5 is the most important co-receptor for macrophage-tropic viral strains, which can predominate in the early stages of viral transmission (126). Two CCR5 receptor antagonist have been studied as topical microbicides, the PSC-RANTES [208] and CMPD167 [209].
