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Tenofovir in Intravaginal Ring Protects 6 of 6 Macaques From SHIV Challenge
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Intravaginal rings loaded with 130 mg of tenofovir disoproxil fumarate (TDF) protected all 6 macaques vaginally challenged with simian HIV (SHIV) weekly for 16 weeks [1]. Eleven of 12 control animals not fitted with rings became infected with SHIV.
Because preexposure prophylaxis (PrEP) with oral tenofovir/emtricitabine depends on steady (near-daily) adherence, researchers are looking for ways to deliver HIV-blocking drugs to target cells without requiring day-to-day pill taking. One approach is to infuse intravaginal rings with drug, a strategy that works in contraception.
CDC researchers and colleagues at other institutions developed an intravaginal polyurethane ring that delivers an average 2.3 mg of tenofovir daily--a level above 500 times more potent against HIV than tenofovir in cell studies. The rings contain 120 mg of TDF plus sodium chloride (NaCl) in an 85:15 ratio as a dry formulation. The NaCl speeds establishment of internally soluble drug to drive drug release. The ring wall is also loaded with TDF to reduce the lag to drug release.
Investigators inserted the rings in 6 normally cycling female macaques and replaced rings every 28 days. These 6 animals, 6 normally cycling real-time controls without rings, and 6 historical controls without rings were challenged with SHIV162p3 at a TCID50 of 50 once weekly for up to 16 weeks. The investigators measured SHIV-specific antibody in blood, and they collected vaginal secretions during ring replacement to measure TDF levels. They monitored the macaques for HIV infection with real-time polymerase chain reaction (PCR) and Western blot.
Eleven of 12 macaques without intravaginal rings became infected with SHIV. Peak median plasma viral load in these animals reached 3.4 million copies/mL. All animals with positive HIV RNA assays became seropositive by Western blotting within 2 weeks of the positive viral load test. These macaques tested positive for SHIV after a median of 4 viral exposures.
The 6 macaques fitted with intravaginal rings tolerated them well for 5 months. None of the 6 ring-wearing macaques became infected with HIV after 16 weekly exposures (P < 0.0004 compared with control animals). Cumulative tenofovir release from two rings removed after 28 days was 70 mg, close to the in vitro release of 77 mg over a 28-day span.
The researchers believe their findings, "coupled with previously demonstrated in vivo safety of the TDF intravaginal ring in nonhuman primates, support its rapid advancement into the clinical pipeline." The investigators expect a phase 1 trial of the TDF ring to begin in the third quarter of 2013.
Dapivirine, a nonnucleoside reverse transcriptase inhibitor, is also being tested in intravaginal rings [2].
The CDC's James Smith, who presented the TDF findings, endorsed development of parallel HIV-prevention strategies, reasoning that, "if you give people enough choices, they'll find something they like."
References
1. Smith J, Rastogi R, Teller R, et al. A tenofovir disoproxil fumarate intravaginal ring completely protects against repeated SHIV vaginal challenge in nonhuman primates. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 25LB.
2. International Partnership for Microbicides. Dapivirine microbicide ring. www.ipmglobal.org/node/532.
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