MTN-011

Primary Objectives

• Assess the impact of coitus (and semen) on the pharmacokinetics (PK) of tenofovir 1% gel in female genital and rectal tract secretions and tissue
• Assess the impact of coitus (and semen) on pharmacodynamics (PD) of luminal drug by measuring the anti-HIV-1 activity in CVL samples

Study Summary
MTN-011 was a Phase 1 study that evaluated the effect of coitus on the PK and PD of tenofovir 1% gel following pericoital or daily gel dosing. The study enrolled 24 heterosexual, sexually active monogamous couples, in which both individuals were healthy and HIV-negative. This Phase 1 expanded safety study assessed tenofovir PK in genital tract secretions (CVL), rectal (rectal sponge) and both intracellular and extracellular genital tissue compartments (vaginal and cervical biopsies) in the absence of or following coitus. PD (i.e., antiviral activity) was also assessed in CVL samples. Group 1 examined PK/PD following a single dose of gel applied 1-hour prior, 24 hours prior, or 1-hour before and 1-hour after (BAT) sex. The single or BAT dosing regimens provide PK/PD data in the absence of any tissue reservoir. It was determined that Group 2 which aimed to examine PK/PD following seven daily doses of gel with the last dose applied 1 hour or 72 hours prior to sex would not proceed.

Group 1 completed follow-up on June 9, 2014. Preliminary results were reported at the HIV Research for Prevention (HIV R4P) meeting held on October 28-31, 2014, in Cape Town, South Africa. The primary manuscript, the only paper from this study, was published online in Clinical Infectious Diseases on October 27, 2015.

Primary Results
BAT dosing achieved the highest TFV levels (CVL: 3.5×105 ng/mL; cervical: 129 ng/mg; vaginal: 258 ng/mg) and -24 h + sex the lowest TFV levels (CVL: 2.9×103 ng/mL; cervical: 1.46 ng/mg; vaginal: 5.3 ng/mg). Compared to dosing without sex, mean TFV levels after sex decreased 42% and 78% (1.33x105 ng/mL, p=0.005 and 8.53x103 ng/mL, p<0.001) in CVL and decreased 74% and 55% (13.92 ng/mg, p=0.04 and 2.64 ng/mg, p< 0.001) in cervical tissue with -1 h and -24 h dosing, respectively. Vaginal tissue decreases were even greater. In contrast, mean plasma TFV was 128% higher (1.61 ng/mL, p< 0.01) following sex with -1 h dosing, presumably reflecting greater absorption. Postcoital CVL anti-HIV activity increased significantly from a median [IQR] baseline of 55 (54%) in the absence of gel to 99 (7%), 77 (57%), and 100 (0.4%) with -1, -24, or BAT dosing, respectively. The antiviral activity of CVL correlated significantly with drug level. These data suggest that timing of dosing relative to sex impacts TFV gel PK/PD. Pericoital dosing or sustained delivery may be optimal for PrEP, particularly with poor adherence.