An intravaginal ring loaded with tenofovir disoproxil fumarate (TDF, Viread) provided mucosal tenofovir concentrations high enough to protect against ex vivo HIV challenge in a 14-day placebo-controlled trial that enrolled healthy women. Product-related adverse events were all grade 1.
TDF with or without emtricitabine has proved effective as oral pre-exposure prophylaxis (PrEP) in women and men. The high tissue and cell penetration of TDF and its long intracellular half-life make it a good candidate for intravaginal ring administration, which could promote better adherence than daily or as-needed oral or gel TDF. Also, TDF retains anti-HIV activity in the presence of seminal plasma. A TDF intravaginal ring completely protected macaques from 16 weeks of intravaginal simian SIV challenge.
U.S. academic researchers recruited 30 healthy, sexually abstinent women 18 to 45 years old and randomized them after cessation of menses in a 1:1 ratio to insert a polyurethane reservoir intravaginal ring bearing TDF or to insert a placebo ring. Participants gave blood and vaginal swab samples on study days one, three, seven and 14, and they removed rings on day 14. They provided additional samples two to four and seven days after ring removal. Researchers also collected an ectocervical biopsy on day 14 for pharmacokinetic analysis and rectal swabs on days seven and 14.
Age averaged about 29 years in study participants and body mass index about 25 kg/m2. One woman withdrew from the study. Rings remained in place for 14 days in all other women, all of whom reported it was very easy or somewhat easy to wear.
Researchers recorded 29 adverse events in 12 women randomized to the TDF ring and 14 adverse events in seven women randomized to placebo. Eight events judged to be product related occurred in six women randomized to TDF and in one randomized to placebo. All product-related events involved cervical or vaginal discharge and were grade 1. There were two nonproduct-related grade 2 adverse events and no grade 3 or 4 or serious adverse events.
The TDF ring provided high tenofovir disoproxil (TFV-DP) and tenofovir concentrations in cervicovaginal fluid (CVF) from the vagina, ectocervix and introitus within one day of insertion, and concentrations remained high through day 14. After ring removal, median initial tenofovir half-life in CVF from the vagina, ectocervix and introitus stood respectively at 14, 12 and 11 hours. Median tenofovir concentrations remained above 1000 ng/mL two to four days after ring removal, a finding suggesting that the ring could protect women who remove the device before sex.
Median tenofovir and TFV-DP concentrations in ectocervical biopsies collected on day 14 were respectively 5.4 ng/mg and 120 fmol/mg. Rectal tenofovir could be measured in five of five participants who agreed to anoscopy on day seven and in four of five on day 14. Median CVF vaginal-to-rectal fluid ratio was 104 on day seven and 240 on day 14.
An ex vivo model using T cells challenged with HIV-1 in the presence of CVF collected from the cervix indicated 29% median inhibitory activity at enrollment, 96% inhibitory activity on day seven and 94% inhibitory activity on day 14.
The researchers conclude that the TDF ring "is safe, well tolerated, and results in mucosal tenofovir concentrations that exceed those associated with HIV protection." On the basis of their results, the authors "anticipate that the ring will continue to deliver ~5-6 mg/day of TDF for 30-45 days and will result in very rapid steady state tissue TFV-DP concentrations that exceed those achieved following oral TDF PrEP in adherent women, but with significantly lower systemic concentrations, thus avoiding potential toxicities."