Rectal microbicides

Current Opinion in HIV and AIDS

Volumn 3, Issue 5, 2008, Pages 593-598

  McGowan, Ian ^a   Anton, Peter ^b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Anal intercourse; Lubricants; Men who have sex with men; Microbicide; Mucosa; Rectal

Indexed keywords

AMINOSALICYLIC ACID; ANTIVIRUS AGENT; CARBOPOL 974P; CYANOVIRIN N; CYTOKINE; DAPIVIRINE; FEMGLIDE; HYDROXYETHYLCELLULOSE; LUBRICATING AGENT; MESALAZINE; MICROBICIDE; N [4 CHLORO 3 (3 METHYL 2 BUTENYLOXY)PHENYL] 2 METHYL 3 FURANCARBOTHIOAMIDE; NONOXINOL 9; PLACEBO; SAVVY; TENOFOVIR; UNCLASSIFIED DRUG; VIVAGEL;

ANUS INTERCOURSE; CLINICAL EFFECTIVENESS; CLINICAL TRIAL; COMPUTER ASSISTED TOMOGRAPHY; CONDOM; CREAM; CYTOKINE PRODUCTION; DEVELOPING COUNTRY; DRUG DISTRIBUTION; DRUG DOSAGE FORM; DRUG EFFECT; DRUG EFFICACY; DRUG FORMULATION; DRUG MONITORING; DRUG SAFETY; DRUG SCREENING; ENDOSCOPY; EXPLANT; FEASIBILITY STUDY; FOAM; GEL; GENE EXPRESSION; HETEROSEXUAL FEMALE; HETEROSEXUAL MALE; HISTOLOGY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IN VITRO STUDY; IN VIVO STUDY; INTESTINE BIOPSY; INTESTINE EPITHELIUM; INTESTINE MUCOSA; MACACA; NITROBLUE TETRAZOLIUM TEST; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PATIENT COMPLIANCE; PHENOTYPE; PRIMATE; PRIORITY JOURNAL; RECTUM MUCOSA; REVIEW; SIGMOIDOSCOPY; SIMIAN IMMUNODEFICIENCY VIRUS; SINGLE DRUG DOSE; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SKIN EXFOLIATION; SUPPOSITORY; T LYMPHOCYTE; TRANSGENIC MOUSE; ULCERATIVE COLITIS; VIRUS INFECTION; VIRUS TRANSMISSION;

EID: 66149101134     PISSN: 1746630X     EISSN: 17466318     Source Type: Journal    
DOI: 10.1097/COH.0b013e32830891cf     Document Type: Review

References (62)

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. An important study clearly demonstrated that MSM are found in sub-Saharan Africa and that they have a high prevalence of HIV infection.
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. A systematic review of the literature shows that MSM from low- and middle-income countries in the Americas, Asia, and Africa have a higher prevalence of HIV infection than the general population in their respective countries.
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. An extremely important paper shows that commercially available sexual lubricants that are hyper-osmolar can induce greater epithelial denudation than iso-osmolar gels. Because epithelial damage may increase the risk of HIV transmission, hyperosmolar gels would make poor rectal microbicide formulations.
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. This paper defines the biological variability of mucosal safety biomarkers that might be used in phase I rectal safety studies. Important conclusions are that mucosal cytokine gene expression and T-cell phenotype appear stable and may have utility in assessing microbicide rectal safety.
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. This study defined the volume acceptability of a microbicide used in the rectal compartment. The authors demonstrate that over 35 ml of microbicide was found to be unacceptable by the majority of study participants. This critical information helps define the formulation profile for future products.
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. This landmark study has begun to define the performance characteristics that would be needed to develop an effective rectal microbicide. Using a combination of imaging techniques and luminal sampling, the authors are able to provide preliminary data about the extent of semen surrogate and candidate microbicide transit within the colon following rectal delivery. This type of study may well become an essential component for evaluating future rectal microbicide formulations.
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. Nonhuman primate studies provide a mechanism to evaluate the effectiveness of both topical and systemic administration of antiretroviral agents. Investigators at the US CDC have shown that a repetitive rectal low-dose viral challenge model might have enhanced stringency in evaluating protection against rectal challenge compared to the more traditional high dose challenge model.
57. Gross M, Celum CL, Tabet SR, et al. Acceptability of a bioadhesive non-oxynol-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. http://www.aidschicago.org/rectalmicrobicides. [Accessed 5th April 2008].