Vaginal microbicides containing antiretrovirals (ARVs) have shown to prevent vaginally acquired human immunodeficiency virus (HIV), but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs has shown to result in drug exposures in rectal tissues, thus raising the possibility of dual compartment protection. To test this concept, we investigated whether intravaginal dosing with emtricitabine (FTC)/tenofovir (TFV) gel, which fully protected macaques against repeated vaginal exposures to simian human immunodeficiency virus (SHIV), protects against rectal SHIV exposures. Pharmacokinetic studies revealed rapid distribution of FTC and TFV to rectal tissues and luminal fluids, albeit at concentrations 1-2 log10 lower than those in the vaginal compartment. Efficacy measurements against repeated rectal SHIV challenges demonstrated a 4.5-fold reduction in risk of infection in macaques that received intravaginal FTC/TFV compared to placebo gel (P = .047; log-rank test). These data support the concept of dual compartment protection by vaginal dosing and warrants developing ARV-based vaginal products with improved bidirectional dosing.

BACKGROUND:Chlamydia trachomatis and Trichomonas vaginalis, two prevalent sexually transmitted infections, are known to increase HIV risk in women and could potentially diminish preexposure prophylaxis efficacy, particularly for topical interventions that rely on local protection. We investigated in macaques whether coinfection with Chlamydia trachomatis/Trichomonas vaginalis reduces protection by vaginal tenofovir (TFV) gel. METHODS:Vaginal TFV gel dosing previously shown to provide 100 or 74% protection when applied either 30 min or 3 days before simian HIV(SHIV) challenge was assessed in pigtailed macaques coinfected with Chlamydia trachomatis/Trichomonas vaginalis and challenged twice weekly with SHIV162p3 for up to 10 weeks (two menstrual cycles). Three groups of six macaques received either placebo or 1% TFV gel 30 min or 3 days before each SHIV challenge. We additionally assessed TFV and TFV diphosphate concentrations in plasma and vaginal tissues in Chlamydia trachomatis/Trichomonas vaginalis coinfected (n = 4) and uninfected (n = 4) macaques. RESULTS:Chlamydia trachomatis/Trichomonas vaginalis coinfections were maintained during the SHIV challenge period. All macaques that received placebo gel were SHIV infected after a median of seven challenges (one menstrual cycle). In contrast, no infections were observed in macaques treated with TFV gel 30 min before SHIV challenge (P < 0.001). Efficacy was reduced to 60% when TFV gel was applied 3 days before SHIV challenge (P = 0.07). Plasma TFV and TFV diphosphate concentrations in tissues and vaginal lymphocytes were significantly higher in Chlamydia trachomatis/Trichomonas vaginalis coinfected compared with Chlamydia trachomatis/Trichomonas vaginalis uninfected macaques. CONCLUSION:Our findings in this model suggest that Chlamydia trachomatis/Trichomonas vaginalis coinfection may have little or no impact on the efficacy of highly effective topical TFV modalities and highlight a significant modulation of TFV pharmacokinetics.

BACKGROUND:Rectal human immunodeficiency virus (HIV) transmission is an important driver of the HIV epidemic. Optimally formulated gels of antiretroviral drugs are under development for preventing rectally acquired HIV. We investigated in a macaque model the pharmacokinetics and efficacy of 3 rectal gel formulationsMETHODS:Single-dose pharmacokinetics of low-osmolar 1% maraviroc (MVC), 1% tenofovir (TFV), or 1% MVC/1% TFV combination gel were evaluated in blood, rectal fluids, colorectal biopsy specimens, and rectal lymphocytes. Efficacy was evaluated over 10 twice-weekly rectal SHIV162p3 challenges in rhesus macaques that received either placebo (n = 7), MVC (n = 6), TFV (n = 6), or MVC/TFV (n = 6) gel 30 minutes before each challenge.RESULTS:MVC and TFV were detected in plasma 30 minutes after gel application and remained above 95% inhibitory concentrations in rectal fluids at 24 hours. MVC, TFV, and TFV diphosphate (TFV-DP) concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2 hours, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r(2) = 0.82). All 3 gel formulations were highly protective (82% efficacy; P ≤ .02 by the log-rank test).CONCLUSIONS:Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection.

acceptability by women. evaluation of topical integrase inhibitors for HIV prevention and the assessment of after-sex use for improved macaques when applied 30 min before or 3 hours after vaginal challenge with simian HIV. The study supports model to assess efficacy, the authors further showed that a vaginal gel containing an integrase inhibitor protected hours after virus infection, providing a wide window for dosing with integrase inhibitors after sex. Using a macaque application after HIV exposure during sex. They first confirmed that HIV integration into cellular DNA begins about 6 inhibitors, which belong to a different ARV class that blocks later steps in virus infection, may be more suitable for . in their new study reasoned that HIV integrase et al infection and thus require application before sex. Dobard acceptance. However, all ARV-based gels in development contain ARV drugs that block the early steps in virus sex would be more desirable because it will have more user control and less need for sex anticipation and partner after applied by women before sex, which can interfere with sex practices and limit their use. A gel that can be applied Vaginal gels containing antiretroviral (ARV) drugs are important for HIV prevention but are all designed to be An After-Sex Gel to Protect Against HIV

Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P < 0.05, Fisher's exact test). Breakthrough infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.

AIDS Research and Human RetrovirusesVol. 30, No. S1 Animal Model Studies of Microbicides and InjectablesRectal Specific Gels Containing Maraviroc and/or Tenofovir Protect against Rectal SHIV Transmission in a Macaque ModelCharles Dobard, Andrew Taylor, Sunita Sharma, Dinh Chuong, Chou-Pong Pau, Lisa Rohan, Ian McGowan, and Walid HeneineCharles DobardCenters for Disease Control and Prevention, Atlanta, GA, United StatesSearch for more papers by this author, Andrew TaylorCenters for Disease Control and Prevention, Atlanta, GA, United StatesSearch for more papers by this author, Sunita SharmaCenters for Disease Control and Prevention, Atlanta, GA, United StatesSearch for more papers by this author, Dinh ChuongCenters for Disease Control and Prevention, Atlanta, GA, United StatesSearch for more papers by this author, Chou-Pong PauCenters for Disease Control and Prevention, Atlanta, GA, United StatesSearch for more papers by this author, Lisa RohanMagee Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, United StatesSearch for more papers by this author, Ian McGowanMagee Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, United StatesSearch for more papers by this author, and Walid HeneineCenters for Disease Control and Prevention, Atlanta, GA, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5013a.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Rectal Specific Gels Containing Maraviroc and/or Tenofovir Protect against Rectal SHIV Transmission in a Macaque Model." AIDS Research and Human Retroviruses, 30(S1), pp. A13–A14FiguresReferencesRelatedDetailsCited ByEvaluation of the Safety, Acceptability, and Pharmacokinetic Profile of a Gel Formulation of OB-002 in Healthy Volunteers Ian Michael McGowan, Niko Tzakis, Beata Kosak, Bozena Korczak, Jarret Engstrom, Monika Tomaszewska-Kiecana, and Oliver Hartley1 June 2021 | AIDS Research and Human Retroviruses, Vol. 37, No. 6Topical Delivery of Tenofovir Disoproxil Fumarate and Emtricitabine from Pod-Intravaginal Rings Protects Macaques from Multiple SHIV Exposures8 June 2016 | PLOS ONE, Vol. 11, No. 6 Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Charles Dobard, Andrew Taylor, Sunita Sharma, Dinh Chuong, Chou-Pong Pau, Lisa Rohan, Ian McGowan, and Walid Heneine.Rectal Specific Gels Containing Maraviroc and/or Tenofovir Protect against Rectal SHIV Transmission in a Macaque Model.AIDS Research and Human Retroviruses.Oct 2014.A13-A14.http://doi.org/10.1089/aid.2014.5013a.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Taylor. A., Jr., A. Santiago. A. Gonzalez-Cortes and E. J. Gangarosa (CDC. Atlanta. Ga. 30333). Outbreak of typhoid fever in Trinidad in 1971 traced to a commercial ice cream product. Am J Epidemiol 100: 150–157, 1974.—In April 1971, a nationwide outbreak of typhoid fever involving 132 persons occurred in Trinidad; there were no deaths. Eighty per cent of cases occurred in children ages 5–14, and more than 90% of ill persons lived or went to school in the main towns or in smaller communities along their connecting roads. The epidemic curve suggested a common source, and a series of food preference questionnaires implicated a nationally distributed ice cream product. Further investigation indicated that the product was distributed on only one day, March 23. The mean incubation period was 19 days, and the attack rate for those at risk was slightly greater than 1%. Samples of the ice cream product obtained a month after the outbreak were found to contain greater than 1100 Escherichia coli per 100 ml. Inspection of the plant revealed frequent hand contact with the product and an absence of pasteurization facilities. Although rectal swabs and stool cultures obtained after purgation from employees failed to identify the carrier, epidemiologic evidence suggested that an employee in the plant, rather than a contaminated ingredient, was the source of the outbreak. This outbreak emphasizes the need for mandatory pasteurization of milk and ice cream products, especially when strict sanitary procedures cannot be adhered to or enforced.