Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women - Fig 2

<p><b>(A) TFV in CV aspirate</b>. Blue Bars: TFV IVR, Red Bars: TFV/LNG IVR, Visit 4, pooled across sampling times of 1, 2, 4 and 8 hours post insertion [n = 18 for each IVR group], Visit 5: 24 hours post insertion [n = 20 for TFV and n = 19 for TFVLNG IVRs], Visit 6: LH surge or Menstrual Cycle day 17 [n = 20 for each IVR group], Visit 7: Prior to IVR Removal [n = 19 for each IVR group], Visit 8: 24 hours post removal [n = 15 for TFV and n = 20 for TFVLNG IVRs]. Reference line indicates 1,000 ng/mL, aspirate level associated with 75% reduction in HIV acquisition in CAPRISA 004 study subset [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref041" target="_blank">41</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref042" target="_blank">42</a>] <b>(B) TFV [ng/mg] in vaginal tissue</b>. Blue Bars: TFV IVR, Red Bars: TFV/LNG IVR, Proximal indicates biopsy was obtained close to the IVR, in the posterior vaginal fornix, Distal indicates biopsy was obtained farther from the IVR, in the lower 1/3 of the vagina closer to the introitus. Visit 5: 24 hours post insertion [for proximal biopsies n = 15 for TFV and n = 16 for TFVLNG IVR. For distal biopsies, n = 19 for TFV and n = 20 for TFVLNG IVR]. Visit 7: Prior to IVR Removal [for proximal biopsies n = 15 for TFV and n = 17 for TFVLNG IVR] and [for distal biopsies, n = 19 for TFV and n = 20 for TFVLNG IVR]. Visit 8: 24 hours post removal [n = 9 for TFV and n = 8 for TFVLNG IVR], Visit 9 72 hours post removal [n = 5 for TFV and n = 9 for TFVLNG IVR]. Dashed line indicates TFV level [10 ng/mg] associated with high TFV-DP concentrations of approximately 1,000 fmol/mg [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref024" target="_blank">24</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref041" target="_blank">41</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref042" target="_blank">42</a>]. <b>(C) TFV-DP [fmol/mg] in vaginal tissue</b>. Blue Bars: TFV IVR, Red Bars: TFV/LNG IVR. Proximal indicates biopsy was obtained close to the IVR, in the posterior vaginal fornix. Distal indicates biopsy was obtained farther from the IVR, in the lower 1/3 of the vagina closer to the introitus. Visit 5: 24 hours post insertion [for proximal biopsies, n = 14 for TFV and n = 16 for TFVLNG IVR. For distal biopsies, [n = 19 for TFV and n = 20 for TFVLNG IVR], Visit 7: Prior to IVR Removal [for proximal biopsies, n = 14 for TFV and n = 17 for TFVLNG IVR]. For distal biopsies, n = 19 for both IVRs], Visit 8: 24 hours post removal [n = 8 for TFV and n = 7 for TFVLNG IVR], Visit 9 72 hours post removal [n = 5 for TFV and n = 9 for TFVLNG IVR]. Dashed line indicates levels found to be protective against SHIV transmission in non-human primates [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref043" target="_blank">43</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199778#pone.0199778.ref044" target="_blank">44</a>] <b>(D) TFV in CV fluid [ng/mg] obtained from lower genital tract swabs</b>. Blue Bars: TFV IVR, Red Bars: TFV/LNG IVR, Visit 4: 1–8 hours post IVR insertion vaginal swab taken near IVR [n = 20 combined observations for TFV IVR and TFVLNG IVR], Visit 5: 24 hours post insertion taken near IVR [n = 20 for both IVRs], ectocervix [n = 20 for both IVRs] and introitus [n = 20 for both IVRs], Visit 7: Prior to IVR removal, taken near IVR [n = 20 for both IVRs], ectocervix [n = 20 for both IVRs] and introitus [n = 20 for TFV and n = 18 for TFV/LNG IVR], Visit 8: 24 hours post removal [n = 19 for TFV and n = 20 for TFVLNG IVR]. Cx = Ectocervix, Int = Introitus, IVR = vaginal near IVR.</p

Study overview.

<p>Study overview.</p

Comparison of viral replication [P24 antigen production] in ectocervical biopsy tissue obtained from participants at baseline [visit 3] and post-treatment [visit 7] after use of placebo, TFV and TFV/LNG rings.

<p>Comparison of viral replication [P24 antigen production] in ectocervical biopsy tissue obtained from participants at baseline [visit 3] and post-treatment [visit 7] after use of placebo, TFV and TFV/LNG rings.</p

Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women - Fig 3

<p>(A) HIV inhibition by cervico-vaginal fluids in vitro among placebo IVR users at baseline [visit 4] versus end of treatment [visit 7]. (B) HIV inhibition by cervico-vaginal fluids in vitro among TFV and TFV/LNG IVR users at baseline [visit 4] versus end of treatment [visit 7].</p

Surrogates of contraceptive efficacy in completer population.

<p>Surrogates of contraceptive efficacy in completer population.</p

Immune cells in ectocervical tissues at IVR removal [visit 7], based on treatment assignment.

<p>Completer population.</p

CONSORT figure CONRAD A13-128 study population.

<p>CONSORT figure CONRAD A13-128 study population.</p