Hyperosmolar Sexual Lubricant Causes Epithelial Damage in the Distal Colon: Potential Implication for HIV Transmission

Fuchs, Edward J.; Lee, Linda A.; Torbenson, Michael; Parsons, Teresa L.; Bakshi, Rahul P.; Guidos, Anita; Wahl, Richard L.; Hendrix, Craig W.

doi:10.1086/511279

Cited by 131 publications

(132 citation statements)

References 30 publications

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“…Despite these clinical findings as well as publications associating the use of hyperosmolar products rectally with mucosal damage, 20 TFV 1% gel was not associated with any significant index of mucosal damage overall. 35 Using paired t-tests, some rectal-secretion cytokines (IL-1b, TNFa, IL-6, MIP-1a; all often classified as ''pro-inflammatory'' were shown to be reduced in the TFV-treated groups at different study stages.…”

Section: Discussioncontrasting

confidence: 65%

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RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

131

176

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This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs ( p = 0.002). Only 25% of participants liked the TFV gel. Likelihood of use ''if somewhat protective'' was *75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C max 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p = 0.12, analysis of covariance (ANCOVA) p = 0.006; 7-day rectal: p = 0.02, ANCOVA p = 0.005]. Tissue PK-PD was significantly correlated ( p = 0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.

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Section: Discussioncontrasting

confidence: 65%

“…18 Despite this, there were no significant differences in genital tract adverse events (AEs) in clinical trials of this formulation. 14,19 However, given that hyperosmolar products can induce mucosal damage in the colon, 20,21 they require careful phase 1 evaluation if they are to be considered as candidate RMs.…”

mentioning

confidence: 99%

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

131

176

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“…25 Despite the enhanced comfort and pleasure lubricants afford, recent literature has highlighted the enhanced risk they may also confer. 22 Laboratory research has shown that many of these agents compromise the integrity of the epithelial lining of the rectum and colon, which could increases susceptibility to infection, 20,21,24,39 and that several products even amplify HIV replication in vitro. 20 Notably, research to date exploring lubricant as a mechanism of HIV/STI transmission has largely focused on PAI risk as it pertains to the receptive partner, and it is therefore unknown whether lubricants enhance susceptibility of the insertive partner's penis to infection.…”

Section: Calabrese Et Almentioning

confidence: 99%

“…18 Moreover, documentation of condom use often relies on aggregate retrospective self-reports, which have proven vulnerable to distortion, with MSM more commonly underestimating than overestimating unprotected PAI. 19 Additionally, Black MSM's participation in other behavioral practices known or suspected to influence vulnerability to HIV and other STIs, including lubricant use [20][21][22][23][24] and precoital rectal douching or enema use, [25][26][27][28][29][30] has received insufficient attention in the literature.…”

mentioning

confidence: 99%

An Event-Level Comparison of Risk-Related Sexual Practices Between Black and Other-Race Men Who Have Sex with Men: Condoms, Semen, Lubricant, and Rectal Douching

Calabrese

Rosenberger

Schick

et al. 2013

AIDS Patient Care and STDs

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Black men who have sex with men (MSM) living in the U.S. are disproportionately affected by HIV/AIDS. An online survey of sexual behavior was completed by Black, White, Hispanic/Latino, Asian/Pacific Islander, and other-race MSM (n = 11,766) ages 18-87 years. Complete condom use, semen exposure, pre-coital rectal douching (enema use), and lubricant use at last male-partnered sexual event were compared by race, controlling for relevant sociodemographic variables and stratifying by sexual position (receptive, insertive, or both). Across sexual positions, 55-62% of Black MSM reported condom use, 5-8% reported semen exposure, 18-53% reported douching, and 33-43% reported lubricant use. Reported behavioral profiles were not significantly different from other races, except that Black MSM reported greater condom use than White MSM in the insertive position. Although findings argue against disproportionate rates of risk behavior accounting for racial disparities in HIV prevalence, they nonetheless highlight a need for continued behavioral intervention.

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“…14,15 Regarding colon vs. vaginal pharmacology issues, the 1% TFV gel dosed rectally in RMP-02/MTN-006 resulted in higher colon tissue TFV concentrations compared to vaginal tissue TFV concentrations after vaginal dosing in other studies. 13,[16][17][18] This difference is likely due to increased colorectal mucosal absorption of TFV secondary to single columnar histology in the colon compared to the multilayer stratified squamous epithelium in the vagina.…”

mentioning

confidence: 94%

Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates

Leyva

Fuchs

Bakshi

et al. 2015

AIDS Research and Human Retroviruses

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Preexposure prophylaxis (PrEP) of HIV infection with tenofovir-containing regimens is effective, but plagued by poor adherence in some studies. Options for safe, effective, and acceptable PrEP products, especially for men and women at risk of HIV via receptive anal intercourse (RAI), are needed. We performed a randomized, partially blinded, first-in-human evaluation of four candidate rectal microbicide vehicles-aqueous gel, aqueous fluid, lipid gel, and lipid fluid-to select a prototype for further clinical development. Eight seronegative participants received three doses of each product with each dose separated by at least 2 weeks: one dose was given alone without simulated RAI in clinic, another dose was followed by simulated RAI in clinic, and another dose was self-administered at home in the context of RAI with a partner. Assessments included safety, acceptability, colon histology, ex vivo HIV infectivity of colon tissue explants, and colonic luminal distribution of vehicle and HIV surrogates. Adverse events were all mild and mainly sigmoidoscopy associated. There were minor differences in colon distribution of products and little effect of RAI. Vehicle distribution covered 95% (-7% standard deviation) of the distribution of an HIV surrogate in the colonic lumen. The lipid fluid vehicle increased HIV colon tissue infectability 5-fold [log 10 p24 0.68 (95% confidence interval 0.08, 1.28)] and aqueous gel provided 6-fold protection [log 10 p24 0.80 (95% confidence interval 0.20, 1.41)] compared to no product baseline. Colon permeability of lipid vehicles was more than 10-fold greater than aqueous vehicles. All products received similar acceptability ratings, though trends favored the gel products. Intensive simultaneous assessment of safety and toxicity, luminal and tissue distribution, ex vivo HIV infectivity, and product acceptability in relevant sexual contexts provided clear differentiation among candidate gels very early in product development. We selected the aqueous gel for further development as a rectal microbicide vehicle.

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Hyperosmolar Sexual Lubricant Causes Epithelial Damage in the Distal Colon: Potential Implication for HIV Transmission

Cited by 131 publications

References 30 publications

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

An Event-Level Comparison of Risk-Related Sexual Practices Between Black and Other-Race Men Who Have Sex with Men: Condoms, Semen, Lubricant, and Rectal Douching

Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates

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