Rectal microbicides

McGowan, Iana; Anton, Peterb

doi: 10.1097/COH.0b013e32830891cf
Microbicides: Edited by John Kaldor and Melissa Robbiani

Purpose of review: This review will summarize the rationale for developing rectal microbicides and discuss recent developments in the preclinical and clinical evaluation of these products.

Recent findings: It is clear that heterosexual women often engage in anal intercourse and that men who have sex with men can be found in both the developed and developing world. These observations have catalyzed the need to assess rectal safety of vaginal products and develop rectal specific microbicides. New approaches to the preclinical evaluation of rectal microbicides include the use of transgenic mice, nonhuman primate studies, and human colorectal explant systems. The design of phase I rectal safety studies is becoming increasingly sophisticated, including safety biomarkers to evaluate microbicide-induced immunotoxicity.

Summary: There is growing acceptance that all vaginal microbicide candidates moving towards effectiveness studies should be evaluated for rectal safety. In addition, there is increasing awareness of the need to develop rectal specific microbicide formulations.

aUniversity of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

bDavid Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA

Correspondence to Ian McGowan, MD, PhD, FRCP, University of Pittsburgh School of Medicine, 204 Craft Ave, Room B505, Pittsburgh, PA, 15213, USA Tel: +1 412 641 4710; fax: +1 412 641 6170; e-mail:

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Rectal microbicides are needed for individuals who engage in unprotected anal intercourse (UAI) [1–5]. The rectal compartment is highly vulnerable to HIV transmission with a conservative estimate of a 10–20 fold increased risk of HIV transmission associated with anal [6,7] compared with vaginal intercourse [8,9]; these data do not reflect the increased risk when non-HIV sexually transmitted infections are present. Women in the developed [10,11] and developing world [12–14] engage in anal intercourse at epidemiologically significant levels. It is, therefore, assumed that vaginal microbicides, once available, will also be used rectally and it will be important to know whether a microbicide that is safe in the vagina will also be safe in the rectal compartment. This is a lesson first learned with nonoxynol-9. Men who have sex with men (MSM) continue to engage in UAI [1,2] and this behaviour fuels the HIV epidemic in the developed world. Recently, epidemiological and anthropological studies have suggested that MSM associated UAI also occurs in the developing world [15,16•,17,18,19•] with predictable acquisition of HIV infection [20•].

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Rectal safety of vaginal microbicides and sexual lubricants

As women may well use vaginal microbicides as lubricants to facilitate anal intercourse, often during the same sexual episode, it is important to determine the rectal safety of these products during the microbicide development process and, preferably, before large scale effectiveness studies are undertaken. Commercially available sexual lubricants are widely used by MSM as well as women and may not necessarily have an appropriate safety profile for anal intercourse [21,22••]. Further safety studies are indicated for this group of over-the-counter (OTC) lubricant products.

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Rectal safety of vaginal microbicides

The first rectal safety studies evaluated a vaginal formulation of nonoxynol-9 in MSM. Tabet et al. [23] described mild rectal histological changes seen in participants receiving up to 6 weeks of nonoxynol-9 or placebo gel use. In contrast, marked epithelial exfoliation was seen after a single exposure to nonoxynol-9 in studies conducted by Phillips et al. [24,25] using rectal lavage and histology as endpoints. Epithelial reconstitution can occur within 1–8 h after exposure to nonoxynol-9 [25,26]. In the Tabet study samples were collected up to 12 h after nonoxynol-9 exposure but after only 15 min in the Phillips study. The implication of these studies is that rectal safety should be assessed after acute (within 1 h) and chronic (at least 7 days) product exposure.

There is increasing concern that repeated mucosal exposure to vaginal microbicides or rectal microbicides could induce subtle immunological changes in the vaginal or rectal mucosa, potentially increasing the risk of HIV transmission [27]. As a consequence, it will be necessary to develop more sensitive, immunological safety biomarkers. Over time and with trial experience, these new indices may be reduced to the most predictive ones, but it is increasingly clear that the current panel of endoscopic appearance and histology may be inadequate.

A recent study, HPTN-056, investigated the biological variability of potential intestinal safety biomarkers [28•]. To assess stability and intra/inter-subject variability of specified indices, colorectal biopsies were collected at 15 and 30 cm from the anal verge from 16 participants on three occasions over a 4-week period in the absence of any microbicide exposure. Tissue was evaluated for biological variability of a broad range of parameters including histology, mucosal cytokine gene expression, rectal immunoglobulins, and mucosal T-cell phenotype. The study demonstrated that tissue from both sites was essentially equivalent and that the most stable parameters included mucosal cytokine gene expression and T-cell phenotype. The study also demonstrated that histological quantification of specific cell types was far more variable than using a pre-established qualitative score. Importantly, in contrast to the vaginal microbicides field, endoscopic appearance of the rectal mucosa was not a study parameter, given the experience in gastroenterology that the subtle endoscopic changes may have no clinical or histological significance.

The first microbicide product to undergo phase I rectal safety assessment with this broader range of safety biomarkers is the vaginally formulated microbicide, non-nucleoside reverse transcriptase inhibitor UC-781 [29]. In the rectal safety study, following baseline blood and mucosal assessments, the participants received a single rectal dose of UC-781 gel with a flexible sigmoidoscopy 30 min later to assess acute mucosal responses [30]. After a minimum of a 1-week recovery period, seven daily doses of UC-781 were administered followed by a final mucosal assessment. A unique feature of this study was the evaluation of intestinal tissue explants, exposed to UC-781 in vivo, to resist HIV infection in vitro [31]. This design feature allows for preliminary assessment of microbicide efficacy as well as safety, before potentially proceeding to much larger clinical effectiveness studies.

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Rectal safety of sexual lubricants

Sexual lubricants are widely used by MSM [32] and have even been considered as potential rectal microbicides themselves because some products appear to have in-vitro efficacy against HIV [33]. Unfortunately, sexual lubricants may also have the capacity to induce rectal damage. This situation has been well documented for nonoxynol-9 containing lubricants but may also be seen with other commercially available products that do not contain nonoxynol-9 [21]. Studies conducted in 2001–2003 among MSM in San Francisco documented that 26–67% had used nonoxynol-9 containing products, often in the absence of condoms [34,35]. There is a clear need for wider evaluation of the safety profile of sexual lubricants as well as increased health education around this issue.

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Development of rectal specific microbicides

The development of a safe, effective, and acceptable rectal microbicide will require significant formative research in the areas of formulation science, preclinical evaluation, product distribution, compartmental pharmacokinetics, mucosal safety, and acceptability before moving towards effectiveness studies. There seems little doubt that MSM would use such products. MSM commonly use sexual lubricants to facilitate anal intercourse [32], are interested in participating in rectal microbicide trials [36], and would use products if commercially available [35,37].

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Formulation science

Formulation is a pivotal component of rectal microbicide development, especially when one considers the dynamic compartmental differences between the lower intestine/rectum and the vagina. It will be a challenge to identify a single agent that will perform optimally in both compartments. Microbicides could be formulated as gels, suppositories, or douches [38]. To date, the majority of rectal formulation work has focused on a microbicide gel formulation. Carballo-Dieguez et al. [39••] recently conducted a rectal microbicide volume escalation study in which participants were asked to insert increasing volumes of a rectal microbicide surrogate (5–50 ml of Femglide; Trumbull, Connecticut, USA) on three consecutive days. When an unacceptable volume was encountered the participants then evaluated the previously tolerated volume during anal intercourse. Using this approach, the investigators were able to demonstrate volume acceptability of up to 35 ml in couples engaging in anal intercourse [39••]. A practical and likely clinically relevant problem is that the majority of gel formulations are hyper-osmolar. It is known that hyper-osmolar products can induce epithelial damage [22••], probably an undesirable characteristic for rectal microbicides. Rectal douches might be another useful vehicle for microbicide delivery. In one US study 53% of HIV-negative and 96% of HIV-positive men douched prior to rectal sex [40•]. Again, this approach might not be safe if the douche is hyper or hypo-osmolar. If enema results turn out to be similar to published gel results (studies underway), an iso-osmolar enema/douche could be safer and potentially deliver a microbicide product to the left side of the colon.

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Preclinical evaluation

There are limited preclinical data evaluating microbicide safety in the rectal compartment and the majority of data focus on nonoxynol-9. The nonoxynol-9 data have provided important insights concerning the intestinal mucosal response to microbicide-induced injury. With this factor as an agreed concern, the rectal injury model still needs tighter evidence linking epithelia and histological focal injury with actual increased HIV infection. In the future, murine, nonhuman primate and human explant models may provide this needed link.

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Murine models

Phillips et al. [26] demonstrated that rectal application of nonoxynol-9 in mice resulted in rapid exfoliation of intestinal epithelium within 10 min of product exposure. The changes were transient and histological examination of the intestinal biopsy samples collected at 1 h after nonoxynol-9 exposure appeared normal. The study also demonstrated a nonoxynol-9 dose-dependent increase in murine susceptibility to anorectal herpes simplex infection. Increasingly sophisticated humanized mouse models are providing exciting opportunities to screen microbicides for rectal safety and efficacy [41,42].

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Colorectal explants

Preclinical evaluation of candidate microbicides for safety and efficacy has been conducted using human intestinal explants [43,44]. In these models, intestinal tissue explants are collected using endoscopy or harvested from surgical resection specimens. The explants can be exposed to product and evaluated for toxicity using histological techniques and/or the MTT assay (an assay that measures cellular mitochondrial toxicity as an index of product induced damage [43]). One limitation of intestinal explant safety assessment is that explants undergo profound architectural deterioration within 24 h of collection; consequently, any meaningful histological assessment of toxicity can only be conducted within this period.

Intestinal explants have also been used to demonstrate the efficacy of antiretroviral microbicide candidates such as tenofovir, UC-781, and TMC-120, alone and in combination. In these studies, intestinal tissue is exposed to the product in vitro and then virus is added to the model. Explants are then cultured for up to 2 weeks with repeated measurement of HIV-1 p24 in the culture supernatant to indicate the presence or absence of productive HIV infection [44]. Despite the limitations of the system, explants can provide important preliminary safety and efficacy data on a microbicide candidate before moving into more expensive animal models.

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Nonhuman primate studies

Dramatic intestinal epithelial exfoliation has been documented in macaques rectally exposed to nonoxynol-9 [45]. Other candidate microbicides, however, including Buffergel, Savvy, and VivaGel appeared to be safe in the macaque rectal model [46–48].

Despite concerns about the feasibility of developing a safe and effective rectal microbicide, two macaque studies evaluating cyanovirin and tenofovir have demonstrated significant protection from rectal challenge with SIV/SHIV. In 2003, Tsai et al. [49] reported that adult male cynomolgus macaques that received a 2 ml dose of 1 or 2% cyanovirin gel 20 min before rectal exposure to SHIV89.6P were completely protected from infection. In contrast, all the animals receiving placebo or virus alone were infected. In the second study, Cranage et al. [50] exposed Indian rhesus macaques to rectal challenge with SIVmac251/32H. The macaques given tenofovir per rectum up to 2 h prior to virus challenge were protected from infection (n = 6) or had modified virus outcomes (n = 2) while all untreated macaques and three of four macaques given placebo gel were infected.

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Distribution studies

Imaging studies including MRI have been used to define vaginal microbicide product distribution [51]. For rectal microbicides, Hendrix et al. [52••], have used MRI, single photon emission tomography (SPECT), computed tomography, and endoscopic pharmacokinetic sampling to carefully characterize the distribution of a semen simulant and microbicide candidate in participants undergoing simulated anal intercourse with an artificial phallus. The semen simulant was a 1: 1 combination of hydroxy-ethylcellulose gel (K-Y Jelly; Johnson & Johnson, New Brunswick, New Jersey, USA) and saline designed to have the same viscosity of coagulated semen. K-Y Jelly was used as the microbicide surrogate. Over a 4-h period, the semen surrogate introduced into the rectum after simulated anal intercourse showed significant retrograde movement into the descending colon. In 12% of SPECT studies, the semen simulant migrated as far as the splenic flexure, approximately 60 cm from the anal verge. This observation has led to skepticism about the feasibility of delivering an adequate volume of microbicide to protect regions potentially at risk of HIV transmission. Such pessimism is probably premature as gastroenterologists routinely prescribe topical products (gels, enemas, foams, and suppositories) that are able to deliver 5′ aminosalicylic acid (5′ASA) products to the left side of the colon in patients with ulcerative colitis [53,54]. Hopefully, pharmacological experience with the design and delivery of 5′ASA products can be used in the development of rectal microbicides.

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Compartmental pharmacokinetics

A critical issue in prevention research is the determination of whether antiretroviral prophylaxis should be given orally, topically, or using both approaches. Varying degrees of protection against rectal viral challenge has been achieved by both routes [50,55,56•] but further studies are needed to document whether compartmental pharmacokinetics vary by route of administration and whether either route alone or both together are needed to achieve tissue and intracellular concentrations of drug that correlate with protection.

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Mucosal safety

The design of phase I rectal safety studies of rectal specific formulations will be similar to the assessment of rectal safety of vaginal microbicides outlined above. Given the differences in the compartments' structure, however, histology, baseline inflammation and constitutive physiology, safety parameters will need to include many of the indices used in vaginal microbicides trials with the addition of assays that may better assess the vulnerable rectal linings. As well, rectal microbicides acceptability may be better characterized in participants who regularly engage in anal intercourse.

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The current generation of rectal safety studies has used vaginal applicators or syringe-like devices to deliver test product to the rectal compartment. Clearly, this approach is suboptimal. Vaginal applicators are not designed for rectal insertion and have not been found to be acceptable in rectal safety studies [57]. Carballo-Dieguez et al. [58] recently conducted a comprehensive interview-based qualitative assessment of the design requirements for a rectal applicator. This assessment has led to the production of a prototype model that will hopefully be evaluated in future rectal safety studies.

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Effectiveness trials

The last decade of vaginal microbicide development has generated significant experience in the logistical challenges associated with conducting microbicide effectiveness studies. Key issues are identifying populations with an adequate background annual rate of HIV seroincidence (usually considered to be about 3%), maintaining high adherence rates to study product, and avoiding interruptions in administration of study product due to events such as unplanned pregnancy. These lessons can be directly transferred to the design of future rectal microbicide effectiveness studies. Identifying suitable populations for these studies will be critical. Fortunately, HIV vaccine and antiretroviral pre-exposure prophylaxis studies have already identified populations of MSM at risk of HIV acquisition secondary to UAI. It is also important to include women who engage in anal intercourse in rectal microbicide development. It would be extremely challenging, however, to identify women with the required seroincidence rates who have a history of UAI.

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Breban et al. have published a mathematical model that explores the impact of introducing rectal microbicides into a high-risk sexual zone for HIV transmission. The setting they chose was a ‘virtual’ bathhouse. Bathhouses are venues commonly found in Europe and North America where MSM congregate and often have sex with multiple partners [59,60]. In this model, the authors varied microbicide effectiveness and frequency of use by the bathhouse clients and assessed the reduction of new, secondary infections. After making appropriate adjustments for condom use, it was possible to demonstrate that if a product that was thought to be only 30% effective but was used by 30–50% of the clients, a rectal microbicide could prevent HIV dissemination within the bathhouse environment [61]. Based on the macaque data, it should be possible to develop products with greater than 30% effectiveness especially those products that incorporate antiretroviral compounds.

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A significant component of the increased interest in rectal microbicide development has been driven by the advocacy community. The International Rectal Microbicides Advocates (IRMA) group has lobbied extensively for increased funding support for rectal microbicide research while producing their own field research on lubricant use and preference as well as holding monthly educational teleconferences. IRMA recently published an overview of the rectal microbicides field, Less Silence, More Science [62], distributed at the 2008 International Microbicide Conference in Delhi, India.

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Future priorities in rectal microbicides research are to optimize the design of phase I safety studies, to develop rectal specific formulations, and to define the operational requirements needed to evaluate rectal specific microbicides in effectiveness studies. These studies may not occur for another 5 years but the preparatory work needs to start now.

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References and recommended reading

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Papers of particular interest, published within the annual period of review, have been highlighted as:

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• of special interest

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•• of outstanding interest

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Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 602).

1 Koblin BA, Chesney MA, Husnik MJ, et al. High-risk behaviors among men who have sex with men in 6 US cities: baseline data from the EXPLORE Study. Am J Public Health 2003; 93:926–932.
2 Hart GJ, Williamson LM. Increase in HIV sexual risk behaviour in homosexual men in Scotland, 1996–2002: prevention failure? Sex Transm Infect 2005; 81:367–372.
3 Erickson PI, Bastani R, Maxwell AE, et al. Prevalence of anal sex among heterosexuals in California and its relationship to other AIDS risk behaviors. AIDS Educ Prev 1995; 7:477–493.
4 Gross M, Holte SE, Marmor M, et al. Anal sex among HIV-seronegative women at high risk of HIV exposure. The HIVNET Vaccine Preparedness Study 2 Protocol Team. J Acquir Immune Defic Syndr 2000; 24:393–398.
5 Baldwin JI, Baldwin JD. Heterosexual anal intercourse: an understudied, high-risk sexual behavior. Arch Sex Behav 2000; 29:357–373.
6 Vittinghoff E, Douglas J, Judson F, et al. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. Am J Epidemiol 1999; 150:306–311.
7 Leynaert B, Downs AM, De VI. Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. European Study Group on Heterosexual Transmission of HIV. Am J Epidemiol 1998; 148:88–96.
8 Gray RH, Wawer MJ, Brookmeyer R, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357:1149–1153.
9 Padian NS, Shiboski SC, Glass SO, Vittinghoff E. Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results from a ten-year study. Am J Epidemiol 1997; 146:350–357.
10 Mosher WD, Chandra A, Jones J. Sexual behavior and selected health measures: men and women 15–44 years of age, United States, 2002. Adv Data 2005; 362:1–55.
11 Misegades L, Page-Shafer K, Halperin D, McFarland W. Anal intercourse among young low-income women in California: an overlooked risk factor for HIV? AIDS 2001; 15:534–535.
12 Karim SS, Ramjee G. Anal sex and HIV transmission in women. Am J Public Health 1998; 88:1265–1266.
13 Lane T, Pettifor A, Pascoe S, et al. Heterosexual anal intercourse increases risk of HIV infection among young South African men. AIDS 2006; 20:123–125.
14 Schwandt M, Morris C, Ferguson A, et al. Anal and dry sex in commercial sex work, and relation to risk for sexually transmitted infections and HIV in Meru, Kenya. Sex Transm Infect 2006; 82:392–396.
15 Wade AS, Kane CT, Diallo PA, et al. HIV infection and sexually transmitted infections among men who have sex with men in Senegal. AIDS 2005; 19:2133–2140.
16• Sanders EJ, Graham SM, Okuku HS, et al. HIV-1 infection in high risk men who have sex with men in Mombasa, Kenya. AIDS 2007; 21:2513–2520.
17 van Griensven F. Men who have sex with men and their HIV epidemics in Africa. AIDS 2007; 21:1361–1362.
18 Geibel S, van der Elst EM, King'ola N, et al. ‘Are you on the market?’: a capture–recapture enumeration of men who sell sex to men in and around Mombasa, Kenya. AIDS 2007; 21:1349–1354.
19• Grijsen ML, Graham SM, Mwangome M, et al. Screening for genital and anorectal sexually transmitted infections in HIV prevention trials in Africa. Sex Transm Infect 2008; 28 Mar [Epub ahead of print]. A second study from Africa that found a significant level of anal intercourse in both MSM (36%) and women (18%) being screened for inclusion in an HIV-vaccine cohort.
20• Baral S, Sifakis F, Cleghorn F, Beyrer C. Elevated risk for HIV infection among men who have sex with men in low- and middle-income countries 2000–2006: a systematic review. PLoS Med 2007; 4:e339.
21 Sudol KM, Phillips DM. Relative safety of sexual lubricants for rectal intercourse. Sex Transm Dis 2004; 31:346–349.
22•• Fuchs EJ, Lee LA, Torbenson MS, et al. Hyperosmolar sexual lubricant causes epithelial damage in the distal colon: potential implication for HIV transmission. J Infect Dis 2007; 195:703–710.
23 Tabet SR, Surawicz C, Horton S, et al. Safety and toxicity of nonoxynol-9 gel as a rectal microbicide. Sex Transm Infect 1999; 26:564–571.
24 Phillips DM, Taylor CL, Zacharopoulos VR, Maguire RA. Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium. Contraception 2000; 62:149–154.
25 Phillips DM, Sudol KM, Taylor CL, et al. Lubricants containing N-9 may enhance rectal transmission of HIV and other STIs. Contraception 2004; 70:107–110.
26 Phillips DM, Zacharopoulos VR. Nonoxynol-9 enhances rectal infection by herpes simplex virus in mice. Contraception 1998; 57:341–348.
27 van de Wijgert JH, Shattock RJ. Vaginal microbicides: moving ahead after an unexpected setback. AIDS 2007; 21:2369–2376.
28• McGowan I, Elliott J, Cortina G, et al. Characterization of baseline intestinal mucosal indices of injury and inflammation in men for use in rectal microbicide trials (HIV Prevention Trials Network-056). J Acquir Immune Defic Syndr 2007; 46:417–425.
29 Schwartz JL, Kovalevsky G, Lai JJ, et al. A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor. Sex Transm Dis 2008; 35:414–419.
30 Anton PA. A phase 1 safety and acceptability study of the UC-781 microbicide gel applied rectally in HIV seronegative adults: an interim safety report at 50% completion [abstract]. In: Microbicides 2008; 24–27 February 2008; New Delhi. New Delhi: Plan it!; 2008. Abstract B05-290.
31 Elliot J. Ex vivo HIV-1 challenge of colorectal explants may be an important predictor of microbicidal effectiveness in vivo [abstract]. In: Microbicides 2008; 24–27 February 2008; New Delhi. New Delhi: Plan it!; 2008. Abstract B04-241.
32 Carballo-Dieguez A, Stein Z, Saez H, et al. Frequent use of lubricants for anal sex among men who have sex with men: the HIV prevention potential of a microbicidal gel. Am J Public Health 2000; 90:1117–1121.
33 Baron S, Poast J, Nguyen D, Cloyd MW. Practical prevention of vaginal and rectal transmission of HIV by adapting the oral defense: use of commercial lubricants. AIDS Res Hum Retroviruses 2001; 17:997–1002.
34 Mansergh G, Marks G, Rader M, et al. Rectal use of nonoxynol-9 among men who have sex with men. AIDS 2003; 17:905–909.
35 Carballo-Dieguez A, O'Sullivan LF, Lin P, et al. Awareness and attitudes regarding microbicides and nonoxynol-9 use in a probability sample of gay men. AIDS Behav 2007; 11:271–276.
36 Gross M, Buchbinder SP, Celum C, et al. Rectal microbicides for U.S. gay men. Are clinical trials needed? Are they feasible? HIVNET Vaccine Preparedness Study Protocol Team. Sex Transm Dis 1998; 25:296–302.
37 Nodin N, Carballo-Dieguez A, Ventuneac AM, et al. Knowledge and acceptability of alternative HIV prevention bio-medical products among MSM who bareback. AIDS Care 2008; 20:106–115.
38 Garg S, Tambwekar KR, Vermani K, et al. Development pharmaceutics of microbicide formulations. Part II: formulation, evaluation, and challenges. AIDS Patient Care STDS 2003; 17:377–399.
39•• Carballo-Dieguez A, Exner T, Dolezal C, et al. Rectal microbicide acceptability: results of a volume escalation trial. Sex Transm Dis 2007; 34:224–229.
40• Carballo-Dieguez A, Bauermeister JA, Ventuneac A, et al. The use of rectal douches among HIV-uninfected and infected men who have unprotected receptive anal intercourse: implications for rectal microbicides. AIDS Behav 2007; 18 Aug [Epub ahead of print]. This study reported that rectal douching is a common practice among MSM engaging in anal intercourse. This finding has two implications. Firstly, studies are needed to determine whether rectal douching results in damage to the intestinal mucosa and secondly douches may provide a useful platform for the development of microbicides that can deliver active agents to the left side of the colon.
41 Sun Z, Denton PW, Estes JD, et al. Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med 2007; 204:705–714.
42 Berges BK, Akkina SR, Folkvord JM, et al. Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2−/−γc −/− (RAG-hu) mice. Virology 2008; 373:342–351.
43 Abner SR, Guenthner PC, Guarner J, et al. A human colorectal explant culture to evaluate topical microbicides for the prevention of HIV infection. J Infect Dis 2005; 192:1545–1556.
44 Fletcher PS, Elliott J, Grivel JC, et al. Ex vivo culture of human colorectal tissue for the evaluation of candidate microbicides. AIDS 2006; 20:1237–1245.
45 Patton DL, Cosgrove Sweeney YT, Rabe LK, Hillier SL. Rectal applications of nonoxynol-9 cause tissue disruption in a monkey model. Sex Transm Dis 2002; 29:581–587.
46 Patton DL, Sweeney YC, Cummings PK, et al. Safety and efficacy evaluations for vaginal and rectal use of BufferGel in the macaque model. Sex Transm Dis 2004; 31:290–296.
47 Patton DL, Sweeney YT, Balkus JE, Hillier SL. Vaginal and rectal topical microbicide development: safety and efficacy of 1.0% Savvy (C31G) in the pigtailed macaque. Sex Transm Dis 2006; 33:691–695.
48 Patton DL, Cosgrove Sweeney YT, McCarthy TD, Hillier SL. Preclinical safety and efficacy assessments of dendrimer-based (SPL7013) microbicide gel formulations in a nonhuman primate model. Antimicrob Agents Chemother 2006; 50:1696–1700.
49 Tsai CC, Emau P, Jiang Y, et al. Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 2003; 19:535–541.
50 Cranage M, Sharpe SA, Cope A, et al. Preexposure prophylaxis in macaques against rectal SIV challenge by mucosally applied PMPA: potential for complementation of microbicide and vaccination strategies [abstract]. In: 14th Conference on Retroviruses and Opportunistic Infections; 25–28 February 2007; Los Angeles. Alexandria: CROI; Abstract 29.
51 Barnhart KT, Pretorius ES, Timbers K, et al. In vivo distribution of a vaginal gel: MRI evaluation of the effects of gel volume, time and simulated intercourse. Contraception 2004; 70:498–505.
52•• Hendrix CW, Fuchs EJ, Macura KJ, et al. Quantitative imaging and sigmoidoscopy to assess distribution of rectal microbicide surrogates. Clin Pharmacol Ther 2008; 83:97–105.
53 Haghighi DB, Lashner BA. Left-sided ulcerative colitis. Gastroenterol Clin North Am 2004; 33:271–284, ix.
54 Arlander E, Cederlund T, Mare K. No volume effect on retrograde colonic spread of rectally-administered ropivacaine gel. Aliment Pharmacol Ther 2003; 18:655–660.
55 Subbarao S, Otten R, Ramos A, et al. Chemoprophylaxis with oral tenofovir disoproxil fumarate (TDF) delays but does not prevent infection in rhesus macaques given repeated rectal challenges of SHIV. In: 12th Conference on Retroviruses and Opportunistic Infections; Boston. Alexandria: CROI; 2005; 22–25 February 2005. Abstract 136LB.
56• Subbarao S, Ramos A, Kim C, et al. Direct stringency comparison of two macaque models (single-high vs. repeat-low) for mucosal HIV transmission using an identical anti-HIV chemoprophylaxis intervention. J Med Primatol 2007; 36:238–243.
57 Gross M, Celum CL, Tabet SR, et al. Acceptability of a bioadhesive nonoxynol-9 gel delivered by an applicator as a rectal microbicide. Sex Transm Dis 1999; 26:572–578.
58 Carballo-Dieguez A, Ventuneac A, Cohen J, Robertson J. Importance of the right microbicide delivery device (MDD) for rectal microbicide acceptability. In: Microbicides 2008; 24–27 February 2008; New Delhi. New Delhi: Plan it!; 2008.
59 Woods WJ, Binson D. Public health policy and gay bathhouses. J Homosex 2003; 44:1–21.
60 Woods WJ, Tracy D, Binson D. Number and distribution of gay bathhouses in the United States and Canada. J Homosex 2003; 44:55–70.
61 Breban R, McGowan I, Topaz C, et al. Modeling the impact of rectal microbicides in reducing HIV transmission in a bathhouse. Math Biosci Eng 2006; 3:459–466.
62 International Rectal Microbicide Advocates. Less Silence, More Science. 2008. [Accessed 5th April 2008].

anal intercourse; lubricants; men who have sex with men; microbicide; mucosa; rectal

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