Correlation between Compartmental Tenofovir Concentrations and an <i>Ex Vivo</i> Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study

<div><p>Objectives</p><p>This study was designed to assess the dose-response relationship between tissue, blood, vaginal and rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and <i>ex vivo</i> rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and rectal administration of TFV 1% vaginally-formulated gel.</p><p>Design</p><p>Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females.</p><p>Methods</p><p>Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 2∶1 to receive a single then seven-daily rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and <i>ex vivo</i> HIV-1 challenge.</p><p>Results</p><p>There was a significant fit for the TFVdp dose-response model for rectal tissue (<i>p</i> = 0.0004), CD4⁺_MMC (<i>p</i><0.0001), CD4⁻_MMC (<i>p</i><0.0001), and Total_MMC (<i>p</i><0.0001) compartments with <i>r²</i> ranging 0.36–0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC₅₀ of rectal tissue TFVdp predicted to be necessary to suppress HIV in rectal tissue. The EC₅₀ for CD4⁺_MMC was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided <i>in-vivo</i> doses predicted to provide for 50% efficacy in the <i>ex vivo</i> assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC₉₀ biopsy efficacy for CD4⁻_MMC, CD4⁺_MMC and Total_MMC compartments.</p><p>Conclusion</p><p>The TFVdp MMC compartment (CD4+, CD4− and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression.</p><p></p><p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00984971" target="_blank">NCT00984971.</a></p>