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FTC/Tenefovir as a Rectal Gel Microbicide
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Reported by Jules Levin
14th CROI, Feb 2007, Los Angeles
Pre-exposure Prophylaxis in Macaques against Rectal SIV Challenge by Mucosally Applied PMPA: Potential for Complementation of Microbicide and Vaccination Strategies
Martin Cranage*1, S Sharpe2, A Cope1, C Herrera1, M Dennis2, N Berry3, C Ham3, P Anton4, I McGowan4, and R Shattock1
1St George's, Univ of London, UK; 2Hlth Protection Agency, Porton Down, UK; 3Natl Inst for Biological Standards and Control, South Mimms, UK; and 4David Geffen Sch of Med, Univ of California, Los Angeles, US
Rectal transmission is a significant route for the acquisition of HIV. The pre-exposure prophylactic use of anti-retroviral nucleotide analogues has given mixed results in preclinical tests. The study hypothesized that a rectally applied nucleoside reverse transcriptase inhibitor (NRTI) may have enhanced protective efficacy against mucosal virus challenge.
The nucleotide analogue, 9-[(R)-2-(phosphonmethoxy) propyl] adenine monohydrate (PMPA) formulated as tenofovir (TDF) gel was given rectally in a single dose 15 minutes or 2 hours before, or 2 hours after, intrarectal challenge of rhesus macaques with SIVmac.
In 4 of 4 untreated macaques and 3 of 4 macaques given placebo gel, virus was recovered at every time-point tested. In contrast, 6 of 9 animals given TDF prior to challenge were protected from overt infection, and virus detection was intermittent or delayed in 2 other animals. Including historical controls, this indicates a very significant degree of protection (p <0.001; Fisher's exact test). Virus was isolated on every occasion of testing from 2 of 3 animals where gel was administered 2 hours after virus challenge. Polymerase chain reaction (PCR) for proviral DNA in uncultured peripheral blood mononuclear cells (PBMC) confirmed the results of virus isolation and no evidence of viral sequestration was detected in lymphoid tissues tested 20 weeks after virus challenge. Furthermore, plasma vRNA profiles were modified in animals given gel prior to challenge and were not protected from infection. Protection was associated with the concentration of TDF detected in plasma at the time of virus challenge. Interestingly, Gag-specific interferon-γ-secreting T cells were detected by ELISpot in 4 of 7 protected animals, despite absence of seroconversion, with frequencies ranging from 144 spot forming cells (SFC)/106 PBMC to 261 SFC/106 PBMC.
These data indicate that rectal pre-dosing with TDF gel has potential as part of a microbicide strategy and may enable priming of the immune system through mucosal exposure to virus challenge.
Pre-clinical in vitro Evaluation of FTC, TDF, and FTC/TDF Microbicide Gels
Urvi Parikh*, P Guenthner, H Jia, J Garcia-Lerma, S Butera, T Folks, and W Heneine
CDC, Atlanta, GA, US
The topical use of nucleoside or nucleotide reverse transcriptase inhibitors (NRTI) may be a powerful HIV-specific strategy for the prevention of sexually transmitted HIV infection. Ongoing safety studies in women have demonstrated acceptability of a 1% tenofovir (TDF) gel applied vaginally. The availability of other single or combination NRTI in gel formulation would greatly improve the potential for finding a successful microbicide, and may provide more options for preventing the transmission of drug-resistant HIV. The CDC evaluated the activity, stability, cytotoxicity, and drug resistance profile of 3 formulations of microbicide gels containing emtricitabine (FTC), TDF, and the combination FTC/TDF.
FTC and TDF were prepared in a 2% hydroxyethyl cellulose (HEC) -based gel in both a vaginal formulation (pH 4.5) and rectal formulation (pH 6.5) containing (weight/volume) 5% FTC, 1% TDF, or the combination 5% FTC/1% TDF. Using an MT4/MTT phenotypic assay, all gels were tested for activity against wild type HIV-1HXB2, and TDF- and FTC-resistant viruses containing the K65R or M184V mutation, respectively. Stability of antiviral activity was assessed during storage at room temperature. The gels were also tested for cytotoxicity in a cervical explant model system.
FTC and TDF were successfully formulated at a 5% or 1% (weight/volume) concentration, respectively, and the combination 5% FTC/1% TDF into a clear, odorless gel at an acidic pH (4.5) suitable for vaginal use, and pH 6.5 suitable for rectal use. All NRTI (5% FTC, 1% TDF, 5% FTC/1% TDF) retained activity in gel formulation at levels equivalent to NRTI preparation in water. All gels were stable at room temperature for at least 5 months with no loss in activity; and gels retained full activity at both pH 4.5 and pH 6.5. Testing the gels against resistant mutants demonstrated that both NRTIs are active in the combination gel. No significant cytotoxicity was seen in the cervical explant model.
The study demonstrates that FTC and FTC/TDF combination can be formulated into clear and odorless topical gels with pH suitable for vaginal or rectal use, and be stably stored at room temperature for at least 5 months without loss of activity. These data provide promising evidence of the feasibility of using single or combination NRTI in a topical strategy for the prevention of sexually transmitted HIV infection.
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