RESUMEN
Rectally applied antiretroviral microbicides for preexposure prophylaxis (PrEP) of HIV infection are currently in development. Since enemas (rectal douches) are commonly used by men who have sex with men prior to receptive anal intercourse, a microbicide enema could enhance PrEP adherence by fitting seamlessly within the usual sexual practices. We assessed the distribution, safety, and acceptability of three enema types-hyperosmolar (Fleet), hypoosmolar (distilled water), and isoosmolar (Normosol-R)-in a crossover design. Nine men received each enema type in random order. Enemas were radiolabeled [(99m)Tc-diethylene triamine pentaacetic acid (DTPA)] to assess enema distribution in the colon using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Plasma (99m)Tc-DTPA indicated mucosal permeability. Sigmoidoscopic colon tissue biopsies were taken to assess injury as well as tissue penetration of the (99m)Tc-DTPA. Acceptability was assessed after each product use and at the end of the study. SPECT/CT imaging showed that the isoosmolar enema had greater proximal colonic distribution (up to the splenic flexure) and greater luminal and colon tissue concentrations of (99m)Tc-DTPA when compared to the other enemas (p<0.01). Colon biopsies also showed that only the hyperosmolar enema caused sloughing of the colonic epithelium (p<0.05). In permeability testing, the hypoosmolar enema had higher plasma (99m)Tc-DTPA 24-h area under the concentration-time curve and peak concentration compared to the hyperosmolar and isoosmolar enemas, respectively. Acceptability was generally good with no clear preferences among the three enema types. The isoosmolar enema was superior or similar to the other enemas in all categories and is a good candidate for further development as a rectal microbicide vehicle.
Asunto(s)
Antiinfecciosos/administración & dosificación , Enema/efectos adversos , Enema/métodos , Infecciones por VIH/prevención & control , Aceptación de la Atención de Salud , Soluciones/administración & dosificación , Soluciones/química , Biopsia , Colon Sigmoide/efectos de los fármacos , Colon Sigmoide/patología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Soluciones/farmacocinética , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
BACKGROUND: Rational development of drugs to prevent human immunodeficiency virus (HIV) transmission benefits from an understanding HIV distribution in the female genital tract after intercourse. This study describes HIV distribution using surrogates of cell-free and cell-associated HIV and semen. METHODS: Apheresis-derived, autologous, lymphocyte-rich cells radiolabeled with 3.7-MBq (100-µCi) indium 111 ((111)In)-oxine (cell-associated HIV surrogate) and 18.5-MBq (500-µCi) technetium 99m ((99m)Tc)-sulfur colloid (HIV-sized 100-nm particle, cell-free HIV surrogate) were resuspended in 3 mL of hydroxyethylcellulose gel (semen simulant) with gadoteridol and dosed via artificial phallus after simulated intercourse. Postdosing dual-isotope single photon emission computed tomography with computed tomography (SPECT/CT) and magnetic resonance (MR) images were acquired to determine the surrogates' distribution. Seven hours after dosing, vaginal biopsy and luminal samples were collected at discrete locations in 8 subjects. RESULTS: SPECT/CT and MR analysis showed HIV and semen surrogate distribution with highest signal intensity in the vaginal pericervical area, without detectable signal in the uterus. One-third of the administered dose was retained in the female genital tract after 4 hours. Cell-free and cell-associated surrogate distribution coincided. CONCLUSIONS: We demonstrate the feasibility of dual-isotope SPECT/CT and MR imaging to determine the distribution of HIV and semen surrogates after simulated intercourse without disrupting vaginal contents. Surrogate distribution suggests topical microbicides do not need to reach the uterus for efficacy.