Abstract
HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT’s preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24–45 years. In the open label period, all participants (n = 7) received single dose of PC-6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials.gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation.
Highlights
HIV continues to be a major global public health issue, ranking as the leading cause of death in women aged 15–44 worldwide
Human ectocervical tissues without gross pathological changes were obtained from routine hysterectomies through the National Disease Research Interchange (NDRI; Philadelphia, P) and transported overnight (ON) in RPMI medium. 5x5mm and 3x3mm explants were prepared as we previously described for macaque and human cervicovaginal tissues [48, 50]
Seven participants were enrolled in the single dose open label (OL) period, all of whom completed the study (October-November 2017)
Summary
HIV continues to be a major global public health issue, ranking as the leading cause of death in women aged 15–44 worldwide. Once daily oral Truvada (tenofovir disoproxil fumarate-emtricitabine [TDF/ FTC]) is the only product for HIV pre-exposure prophylaxis (PrEP) approved by the Food and Drug Administration (FDA) for cisgender women. Approval was based on the results of clinical trials demonstrating significantly reduced risk of HIV acquisition in cisgender men and transgender women who have sex with men (iPrEX) and in serodiscordant couples (Partners PrEP Study) [2, 3]. LA parenteral products (injectables and implants) could offer simpler administration regimens and may be preferred over daily oral regimens for some women. These products require health care provider delivery, have injection site and potential systemic side effects, and, for the case of implants, may not be removable. User-controlled vaginally administered PrEP (gel, fast dissolving vaginal insert (FDI), intravaginal rings (IVR), vaginal film) offers the distinct advantage of increasing local exposure to the active pharmaceutical ingredients (APIs) at the HIV transmission site and low to no systemic side effects
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