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Ian Mcgowan - One of the best experts on this subject based on the ideXlab platform.
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The development of rectal Microbicides for HIV prevention
Expert opinion on drug delivery, 2013Co-Authors: Ian McgowanAbstract:Introduction: Individuals practicing unprotected receptive anal intercourse are at particularly high risk of HIV infection. Men who have sex with men in the developed and developing world continue to have disproportionate and increasing levels of HIV infection. The last few years have seen important progress in demonstrating the efficacy of oral antiretroviral pre-exposure prophylaxis, vaginal Microbicides, and treatment as prevention, but there has also been significant progress in the development of rectal Microbicides for HIV prevention. Areas covered: The purpose of this review is to summarize the status of rectal microbicide research and to identify opportunities, challenges, and future directions in this important field of HIV prevention research. The design of completed and ongoing Phase I rectal microbicide studies that include the generation of comprehensive pharmacokinetic/pharmacodynamic data may allow for more rational decisions about which rectal Microbicides should be advanced to later stage...
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Rectal microbicide development.
Current topics in microbiology and immunology, 2013Co-Authors: Ian Mcgowan, Charlene S. DezzuttiAbstract:The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal Microbicides, and treatment as prevention as effective strategies for reducing the risk of acquiring or transmitting HIV infection. There has also been significant progress in the development of rectal Microbicides. Preclinical non-human primate studies have demonstrated that antiretroviral Microbicides can provide significant protection from rectal challenge with SIV or SHIV. Recent Phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics (PK), and pharmaco-dynamics (PD) of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal-specific formulations have been developed and evaluated in Phase 1 studies. The PK/PD data generated in these Phase 1 studies may reduce the risk of advancing ineffective candidate rectal Microbicides into late stage development. Tenofovir gel is currently poised to move into Phase 2 evaluation and it is possible that a Phase 2B/3 effectiveness study with this product could be initiated in the next 2–3 years.
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Chapter 4 – Microbicides
HIV Prevention, 2009Co-Authors: Ian McgowanAbstract:Publisher Summary AIDS is becoming a disease of poverty and more particularly of women. There is an urgent need to develop modalities of HIV prevention that can be used by women with or without partner consent. Microbicides are an important prevention technology in a state of rapid evolution. Microbicides are products (formulated as gels, sponges, films or rings) that can be applied to the vaginal or rectal mucosa with the goal of preventing or significantly reducing the acquisition of sexually transmitted infections (STIs), including HIV. The first generation of Microbicides included agents that were primarily detergents or surfactants, such as N-9, which damaged the viral envelope; products that enhanced vaginal defenses through mechanisms such as maintenance of vaginal acidity; or products that blocked the virus from attaching to cellular targets in the genital mucosa. Increasingly, the microbicide pipeline is linked to a growing understanding of the pathogenesis of HIV-1 transmission and the identification of viral and cell receptor targets. A successful microbicide will have to address these challenges. In particular, it will have to outdistance the virus, outlast the virus, and prevent dissemination of infected cells from the local mucosa to the regional lymph nodes. While these challenges may seem insurmountable, they are compensated for, by the fact that HIV-1 infection is a relatively inefficient process and that the female genital tract is a relatively small anatomical area to protect. A fundamental difference between the development of Microbicides for HIV prevention and the development of drugs for treating HIV infection is that in the former case trial participants are healthy HIV-uninfected individuals who are being evaluated, whereas in the latter case participants are HIV-infected individuals who may or may not have HIV-associated disease.
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Microbicides: a new frontier in HIV prevention.
Biologicals : journal of the International Association of Biological Standardization, 2006Co-Authors: Ian McgowanAbstract:Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections (STIs) including HIV-1. Despite more than two decades of HIV-1 vaccine research, there is still no efficacious HIV-1 vaccine, and the scientific community appears skeptical about the short or long-term feasibility of developing a vaccine that has the ability to induce sterilizing immunity against HIV-1. In this setting, microbicide research has gathered momentum. Currently, 16 candidate Microbicides are in clinical development and five products are being evaluated in large-scale Phase 2B/3 effectiveness studies. Initial data from these trials will be available within the next 2-3 years, and it is feasible that there could be one or more licensed Microbicides by the end of the decade. The first generation of surfactant Microbicides had a non-specific mechanism of action. However, subsequent candidate Microbicides have been developed to target specific steps in the process of viral transmission. The purpose of this article is to provide an overview of microbicide development and an update on the candidate pipeline.
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Microbicides 2006 conference
AIDS research and therapy, 2006Co-Authors: Gita Ramjee, Robin J Shattock, Ian Mcgowan, Sinead Delany, Neetha S. Morar, Megan GottemoellerAbstract:Current HIV/AIDS statistics show that women account for almost 60% of HIV infections in Sub-Saharan Africa. HIV prevention tools such as male and female condoms, abstinence and monogamy are not always feasible options for women due to various socio-economic and cultural factors. Microbicides are products designed to be inserted in the vagina or rectum prior to sex to prevent HIV acquisition. The biannual Microbicides conference took place in Cape Town, South Africa from 23-26 April 2006. The conference was held for the first time on the African continent, the region worst affected by the HIV/AIDS pandemic. The conference brought together a record number of 1,300 scientists, researchers, policy makers, healthcare workers, communities and advocates. The conference provided an opportunity for an update on microbicide research and development as well as discussions around key issues such as ethics, acceptability, access and community involvement. This report discusses the current status of microbicide research and development, encompassing basic and clinical science, social and behavioural science, and community mobilisation and advocacy activities.
Salim S. Abdool Karim - One of the best experts on this subject based on the ideXlab platform.
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No Evidence for Selection of HIV-1 with Enhanced Gag-Protease or Nef Function among Breakthrough Infections in the CAPRISA 004 Tenofovir Microbicide Trial
PloS one, 2013Co-Authors: Denis Chopera, Vivek Naranbhai, Jaclyn K. Mann, Philip Mwimanzi, Saleha Omarjee, Xiaomei T. Kuang, Nonkululeko. Ndabambi, Sarah Goodier, Eric Martin, Salim S. Abdool KarimAbstract:Background Use of antiretroviral-based Microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial.
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Topical Microbicides--what's new?
JAIDS Journal of Acquired Immune Deficiency Syndromes, 2013Co-Authors: Quarraisha Abdool Karim, Cheryl Baxter, Salim S. Abdool KarimAbstract:Topical Microbicides are an important, promising but complex HIV prevention technology under development. After 11 disappointing effectiveness trial outcomes of 6 candidate products (some tested as multiple doses and formulations) over the past 20 years, there is renewed optimism that a safe and effective microbicide will soon be available if the recent success of coitally linked use of the antiretroviral-based microbicide, 1% tenofovir gel, is confirmed. Studies of new antiviral agents, novel delivery mechanisms, and combination/multipurpose products that address challenges of adherence, enhance the effectiveness of tenofovir gel, and address sexual and reproductive health needs of men and women, including preventing HIV infection, are already underway.
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Microbicides for Prevention of HIV Infection: Clinical Efficacy Trials
Current topics in microbiology and immunology, 2013Co-Authors: Salim S. Abdool Karim, Cheryl BaxterAbstract:Microbicides are an important HIV prevention technology under development, but the clinical testing of candidate products for efficacy faces many design and ethical challenges. Nevertheless, several microbicide candidates have been tested or are under development. Eight candidate products have entered late stage microbicide effectiveness trials. Following 11 disappointing effectiveness trial results of six candidate products over the past 20 years, substantial progress is now being made in microbicide development following the release of the CAPRISA 004 tenofovir gel trial results in 2010, which provided proof of concept that topical antiretroviral Microbicides can prevent sexual transmission of HIV and herpes simplex type-2 infection. A trial is currently underway to confirm the effectiveness of tenofovir gel and two others have recently been initiated to assess ring formulations of the antiretroviral drug, dapivirine.
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Preservation HIV-1-specific IFNγ+ CD4+ T-cell responses in breakthrough infections after exposure to tenofovir gel in the CAPRISA 004 microbicide trial.
Journal of acquired immune deficiency syndromes (1999), 2012Co-Authors: Marianne W. Mureithi, Quarraisha Abdool Karim, Sengeziwe Sibeko, Salim S. Abdool Karim, Lise. Werner, Vivek Naranbhai, Danielle Poole, Shabashini Reddy, Nompumelelo Mkhwanazi, Marianne W. Mureithi, Shabashini Reddy, Nompumelelo Mkhwanazi, Thumbi NdungʼuAbstract:The Centre for the AIDS Program of Research in South Africa 004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a vaginal microbicide containing tenofovir. A better understanding of the consequences of antiretroviral-containing Microbicides for immune responses in individuals with intercurrent HIV-1 infection is needed for future trials combining the use of Microbicides with HIV-1 vaccines. Investigation of immune responses in women who acquired HIV-1 although using tenofovir gel showed significantly higher (P = 0.01) Gag-specific IFNγ+ CD4+ T-cell responses. The use of tenofovir-containing gel around the time of infection can modulate HIV-1 immunity, and these immunological changes need to be considered in future trials combining vaccines and Microbicides.
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Overview of Microbicides for the prevention of human immunodeficiency virus.
Best practice & research. Clinical obstetrics & gynaecology, 2012Co-Authors: Salim S. Abdool Karim, Cheryl BaxterAbstract:Human immunodeficiency virus (HIV) prevention tools that women can use and control are urgently needed. Microbicides are chemical products applied to the vagina or rectum to prevent the sexual transmission of HIV. Four classes of candidate Microbicides have been tested to date: those that (1) enhance the natural defences in the vagina to inactivate HIV; (2) inactivate HIV in the vagina; (3) prevent HIV from attaching to, and fusing with, the host cells; and (4) prevent HIV from replicating in genital tract host cells. Despite numerous disappointing efficacy trial results over the past 20 years, substantial progress is now being made in microbicide development after the release of the CAPRISA 004 trial, which provided proof-of-concept that topical antiretroviral Microbicides can prevent sexual transmission of HIV and herpes simplex type-2 infection. Microbicides, which fill an important gap for women-controlled prevention methods, have the potential to alter the course of the HIV pandemic.
Robin J Shattock - One of the best experts on this subject based on the ideXlab platform.
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Cyanovirin-N produced in rice endosperm offers effective pre-exposure prophylaxis against HIV-1_BaL infection in vitro
Plant Cell Reports, 2016Co-Authors: Evgenia Vamvaka, Lrh Krumpe, Robin J Shattock, B. R. O’keefe, Koreen Ramessar, A Evans, Panagiotis Christou, Teresa CapellAbstract:Key message Cyanovirin-N produced in rice endosperm provides efficient pre-exposure prophylaxis against HIV-1 _ BaL infection in vitro . Abstract Cyanovirin-N (CV-N) is a lectin with potent antiviral activity that has been proposed as a component of Microbicides for the prevention of infection with Human immunodeficiency virus (HIV). The production of protein-based microbicide components requires a platform that is sufficiently economical and scalable to meet the demands of the large at-risk population, particularly in resource poor developing countries. We, therefore, expressed CV-N in rice endosperm, because the dried seed is ideal for storage and transport and crude extracts could be prepared locally and used as a microbicide component without further purification. We found that crude extracts from rice seeds expressing up to 10 µg CV-N per gram dry seed weight showed dose-dependent gp120 binding activity, confirming that the protein was soluble, correctly folded and active. The recombinant lectin (^OSCV-N) reduced the infectivity of HIV-1_BaL (an R5 virus strain representing the majority of transmitted infections) by ~90 % but showed only weak neutralization activity against HIV-1_RF (representative of X4 virus, rarely associated with transmission), suggesting it would be highly effective for pre-exposure prophylaxis against the vast majority of transmitted strains. Crude extracts expressing ^OSCV-N showed no toxicity towards human cells at working dilutions indicating that microbicide components produced in rice endosperm are safe for direct application as topical Microbicides in humans.
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Potential use of protease inhibitors as vaginal and colorectal Microbicides.
Current HIV research, 2012Co-Authors: Carolina Herrera, Robin J ShattockAbstract:The new generation of microbicide candidates is based on the use of antiretroviral (ARV) drugs. The first compounds tested were selected among ARV classes that block the early stages of viral replication cycle, either entry/fusion or reverse transcription. Recently, an additional class of ARVs acting on a later step of viral replication has entered the microbicide pipeline, the protease inhibitors (PIs). This class of ARVs has shown strong potency in highly active antiretroviral therapy (HAART) against human immunodeficiency-1 virus (HIV-1) and lower levels of induced resistance compared to other ARV classes. As candidate Microbicides, PIs will have to follow the guiding principles of Microbicides being effective, safe, user-friendly and affordable. Hence, aspects including antiviral potency, adverse effects in mucosal tissues, formulation, pharmacology at mucosal sites, emergence of resistance, will have to be considered in the design of a PI-based microbicide. In addition, PIs will have to be tested for their capacity to be used in combination-based Microbicides with other ARV classes and in combination with other preventive strategies, such as HIV-1 vaccines. Microbicides containing HIV PIs could also be potentially used against other pathologies specific to the female and/or male genital tract or colorectum.
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Animal models for microbicide studies.
Current HIV research, 2012Co-Authors: Ronald S. Veazey, Robin J Shattock, Per Johan Klasse, John P. MooreAbstract:There have been encouraging recent successes in the development of safe and effective topical Microbicides to prevent vaginal or rectal HIV-1 transmission, based on the use of anti-retroviral drugs. However, much work remains to be accomplished before a microbicide becomes a standard element of prevention science strategies. Animal models should continue to play an important role in pre-clinical testing, with emphasis on safety, pharmacokinetic and efficacy testing.
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novel approaches to vaginal delivery and safety of Microbicides biopharmaceuticals nanoparticles and vaccines
Antiviral Research, 2010Co-Authors: Kevin J Whaley, Robin J Shattock, Justin Hanes, Richard A Cone, David R FriendAbstract:The HIV-1 epidemic remains unchecked despite existing technology; vaccines and Microbicides in development may help reverse the epidemic. Reverse transcriptase inhibitors (RTIs) formulated in gels tenofovir (TFV) and IVRs (dapivirine) are under clinical development. While TFV or similar products may prove successful for HIV-1, alternatives to RTIs may provide additional benefits, e.g., broader STI prevention. Biopharmaceutical agents under development as Microbicides include cyanovirin, RANTES analogues, commensals, and Mabs. Cost of manufacturing biopharmaceuticals has been reduced and they can be formulated into tablets, films, and IVRs for vaginal delivery. Nanotechnology offers a novel approach to formulate Microbicides potentially leading to uniform epithelial delivery. Delivery through vaginal mucus may be possible by controlling nanoparticle size and surface characteristics. Combining prevention modalities may be the most effective means of preventing STI transmission, importantly, codelivery of Microbicides and vaccines has demonstrated. Finally, the safety of microbicide preparations and excipients commonly used can be assessed using a mouse/HSV-2 susceptibility model. Screening of new microbicide candidates and formulation excipients may avoid past issues of enhancing HIV-1 transmission. This article forms part of a special supplement covering several presentations on novel microbicide formulations from the symposium on “Recent Trends in Microbicide Formulations” held on 25 and 26 January 2010, Arlington, VA.
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hiv 1 infection of human penile explant tissue and protection by candidate Microbicides
AIDS, 2009Co-Authors: Lucia Fischetti, Sheila M Barry, Thomas J Hope, Robin J ShattockAbstract:Lucia Fischetti a , Sheila M. Barry b , Thomas J. Hope b and Objective: Factors governing events between exposure of male genital mucosa surfaces and the establishment of infection are poorly understood. Furthermore, little is known about the safety and efficacy of Microbicides on male genital mucosa. Design: Here we present a novel penile tissue explant model to characterize the mechanisms of HIV-1 infection of male genital tissue and evaluate candidate Microbicides. Methods: Mucosal explant culture conditions were determined for glans, urethra and foreskin obtained from gender reassignment and circumcision. Density and distribution of CD4 + and CD1 a + cells were visualized by microscopy. In vitro HIV-1 infection was determined by measuring p24 release, whereas microbicide biocompatibility and efficacy were assessed by measurement of tissue viability, cytokine expression and p24 production. Results: Cultured glans and foreskin showed comparable epithelial thickness but some differences in CD4 + and CD1a + cell density. All tissue sites examined (foreskin, glans, meatus, urethra) were equally susceptible to R5 HIV-1 infection, which was productively disseminated by migratory cells emigrating from tissue. In contrast, X4 HIV-1 failed to infect mucosal tissue and dissemination by migratory cells was less efficient. The three candidate Microbicides poly(methyl 2-propionamidoacrylate), PRO 2000 and Cyanovirin-N, showed good tissue compatibility and efficient prevention of HIV-1 infection, causing only minor changes in tissue cytokine profile. Conclusion: The described model provides a useful model to study the determinants of HIV-1 infection of male genital tissue and is likely to be an important tool for the future development of microbicide candidates and concepts.
Sally Blower - One of the best experts on this subject based on the ideXlab platform.
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Modeling the potential impact of rectal Microbicides to reduce hiv transmission in bathhouses.
Mathematical Biosciences and Engineering, 2006Co-Authors: Romulus Breban, Chad M. Topaz, Elissa J. Schwartz, Peter A. Anton, Ian Mcgowan, Sally BlowerAbstract:We evaluate the potential impact of rectal Microbicides for reducing HIV transmission in bathhouses. A new mathematical model describing HIV transmission dynamics among men who have sex with men (MSM) in bathhouses is constructed and analyzed. The model incorporates key features affecting transmission, including sexual role behavior (insertive and receptive anal intercourse acts), biological transmissibility of HIV, frequency and efficacy of condom usage, and, most pertinently, frequency and efficacy of rectal microbicide usage. To evaluate the potential impact of rectal microbicide usage, we quantify the effect of rectal Microbicides (ranging in efficacy from 10% to 90%) on reducing the number of HIV infections in the bathhouse. We conduct uncertainty analyses to assess the effect of variability in both biological and behavioral parameters. We find that even moderately effective rectal Microbicides (if used in 10% to 50% of the sex acts) would substantially reduce transmission in bathhouses. For example, a 50% effective rectal microbicide (used in 50% of sex acts) would reduce the number of secondary infections by almost 13% at disease invasion. Our modeling analyses show that even moderately effective rectal Microbicides could be very effective prevention tools for reducing transmission in bathhouses and also potentially limit the spread of HIV in the community.
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evaluating the potential impact of vaginal Microbicides to reduce the risk of acquiring hiv in female sex workers
AIDS, 2005Co-Authors: Robert J Smith, David Wilson, Erin N Bodine, Sally BlowerAbstract:The following questions were addressed: would the introduction of vaginal Microbicides substantially reduce the risk of female sex workers (FSWs) acquiring HIV? Which factor would it be most important to maximize microbicide efficacy or microbicide use? What level of microbicide efficacy and use would be necessary to counterbalance a possible reduction in condom use? Mathematical modeling with parameter estimations from available literature. Risk equations were developed and Monte Carlo simulations were performed to model a FSW’s daily risk of HIV acquisition currently and after microbicide introduction. Uncertainty and sensitivity analyses were used as well as tornado plots for two ranges of microbicide efficacy (30–50%) and (50–80%). Risk was estimated for FSWs whose clients sometimes (10–50%) use condoms and those whose clients never use condoms. An analytical threshold for which reducing condom use increases risk was estimated. For both groups of FSWs daily risk would decrease by approximately 17% or approximately 28% using 30–50% or 50–80% effective Microbicides respectively. Increasing microbicide use would have greater impact on reducing risk than increasing microbicide efficacy. The microbicide efficacy and usage required to ensure that ‘condom replacement’ does not increase a FSW’s risk of acquiring HIV was calculated. Microbicides could substantially reduce FSWs’ risk of acquiring HIV; absolute decrease in risk would be greatest in high-prevalence regions. The public health impact of Microbicides will depend upon usage and efficacy. Even if the Microbicides that become available are only low-to-moderately effective the probability that risk in FSWs will increase (due to replacing condoms with Microbicides) is low. (authors)
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Microbicides: anti-HIV efficacy and ethics.
Science (New York N.Y.), 2004Co-Authors: David Wilson, Sally BlowerAbstract:In their policy forum “regulatory challenges in microbicide development” (25 June, p. [1911][1]), P. M. Coplan et al. discuss the Food and Drug Administration's (FDA's) concern that use of HIV transmission—inhibiting Microbicides in the future could decrease condom use and result in an
Charlene S. Dezzutti - One of the best experts on this subject based on the ideXlab platform.
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Non-Antiretroviral Microbicides for HIV Prevention.
AIDS reviews, 2016Co-Authors: Yanille Scott, Charlene S. DezzuttiAbstract:Non-antiretroviral microbicide candidates were previously explored as a female-controlled method of preventing sexual transmission of HIV. These products contained non-HIV specific active compounds that were ultimately found to disrupt the vaginal epithelium, cause increased immune activation in the female genital tract, disturb vaginal flora, and/or cause other irritation that precluded their use as vaginal Microbicides. Due to the failure of these first-generation candidates, there was a shift in focus to developing HIV pre-exposure prophylaxis and Microbicides containing small-molecule antiretrovirals. Even with the limited success of the antiretroviral-based Microbicides in clinical evaluations and no commercially available products, there has been significant progress in microbicide research. The lessons learned from previous trials have given rise to more rigorous preclinical evaluation that aims to be better at predicting microbicide efficacy and safety and to novel formulation and delivery technologies. These advances have resulted in renewed interest in developing non-antiretroviral-based Microbicides, such as broadly neutralizing antibodies (for example, VRC01) and anti-viral proteins (for example, Griffithsin), as options for persons not wanting to use antiretroviral drugs, and for their potential to prevent multiple sexually transmitted infections.
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Rectal microbicide development.
Current topics in microbiology and immunology, 2013Co-Authors: Ian Mcgowan, Charlene S. DezzuttiAbstract:The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal Microbicides, and treatment as prevention as effective strategies for reducing the risk of acquiring or transmitting HIV infection. There has also been significant progress in the development of rectal Microbicides. Preclinical non-human primate studies have demonstrated that antiretroviral Microbicides can provide significant protection from rectal challenge with SIV or SHIV. Recent Phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics (PK), and pharmaco-dynamics (PD) of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal-specific formulations have been developed and evaluated in Phase 1 studies. The PK/PD data generated in these Phase 1 studies may reduce the risk of advancing ineffective candidate rectal Microbicides into late stage development. Tenofovir gel is currently poised to move into Phase 2 evaluation and it is possible that a Phase 2B/3 effectiveness study with this product could be initiated in the next 2–3 years.